Imprinted Polymeric Membranes 9783110652222, 9783110654691, 9783110652314

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Laura Donato Imprinted Polymeric Membranes

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Laura Donato

Imprinted Polymeric Membranes

Author Dr. Laura Donato National Research Council Institute on Membrane Technology Via P. Bucci 17/C 87036 Rende Italy [email protected]

ISBN 978-3-11-065222-2 e-ISBN (PDF) 978-3-11-065469-1 e-ISBN (EPUB) 978-3-11-065231-4 Library of Congress Control Number: 2023932883 Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the internet at http://dnb.dnb.de. © 2023 Walter de Gruyter GmbH, Berlin/Boston Cover image: Science Photo Library/Eward, Kenneth Typesetting: Integra Software Services Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com

To my lovely daughter Gaia, the sun of my life

Contents Introduction

1

Chapter 1 Molecular imprinting 4 1.1 Introduction 4 1.2 The concept of molecular recognition 4 1.3 Imprinting technology 6 1.4 Molecularly imprinted polymers 7 1.5 A look to the basic components of MIP synthesis 1.6 MIP polymerization methods and applications References 23

9 13

Chapter 2 Molecularly imprinted membranes: general aspects 30 2.1 Introduction 30 2.2 Membrane-based separations 31 2.3 Molecularly imprinted membranes 33 2.4 Separation mechanism and performance evaluation of MIMs 2.5 Green imprinted membranes 45 References 48

36

Chapter 3 Preparation strategies of molecularly imprinted membranes 54 3.1 Introduction 54 3.2 About the production of molecularly imprinted membranes 54 3.3 In situ cross-linking polymerization 57 3.4 Alternative molecular imprinting 59 3.5 Surface imprinting 66 3.6 Nanofibers and other composite imprinted membranes 71 References 74 Chapter 4 Imprinted membranes in affinity separation 81 4.1 Introduction 81 4.2 Affinity-imprinted membranes: general considerations 82 4.3 Affinity IMs in water treatment 84 4.3.1 Selective recovery of drugs and pharmaceutical ingredients 84 4.3.2 Removal of pesticides and other toxic compounds 87 4.4 Food, herbal medicine, and pharmaceutical applications 90 4.4.1 Affinity IMs in the solid-phase extraction of bioactive compounds

90

VIII

4.4.2 4.4.3

Contents

Removal of additives and contaminants Drug separation and clinical uses 96 References 99

Chapter 5 Imprinting of proteins 105 5.1 Introduction 105 5.2 About proteins 105 5.3 Protein imprinting: general overview 5.4 Protein-imprinted polymers 109 5.5 Protein-imprinted membranes 115 References 122

95

107

Chapter 6 Molecularly imprinted membranes in enantiomeric separation 6.1 Introduction 127 6.2 Chirality 128 6.3 Enantioselective MIMs 130 6.4 Enantiomeric separation of drugs 132 6.5 Chiral separation of amino acids and their derivatives References 142

127

136

Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors 147 7.1 Introduction 147 7.2 The concept of chemical and biological sensors 148 7.3 Toward imprinted materials as biomimetic receptors 153 7.4 Detection of drugs and biomolecules through MIM-based sensors 156 7.5 MIM-based sensors for detecting additives and pollutants in food and water 161 References 167 Chapter 8 Ion-imprinted membranes 174 8.1 Introduction 174 8.2 General aspects of ion-imprinted membranes 174 8.3 Selective recognition of metal ions with IIMs 177 8.4 IIMs for rare earth elements recognition 187 8.5 IIMs toward inorganic anions 192 References 194

Contents

Chapter 9 Molecular imprinting and controlled drug delivery 201 9.1 Introduction 201 9.2 A small look at controlled drug administration 202 9.3 Molecular imprinting technology in drug delivery purposes 9.4 MIMs in controlled drug delivery 211 References 216 Chapter 10 Cyclodextrins as recognition tools 223 10.1 Introduction 223 10.2 Cyclodextrins as recognition elements 10.3 Cyclodextrin-based membranes 227 10.4 Cyclodextrins and imprinting technology References 238 Index

245

223 232

208

IX

Introduction Nowadays, highly efficient detection and selective separation tools are continuously required in many fields such as analytical chemistry, clinical diagnostics, chiral separation, food science, pharmaceutical formulations and drug delivery, and water treatment. In all these applications, particular relevance assumes the possibility of realizing separations at molecular and ionic levels mimicking the molecular recognition mechanism of living systems, which is a strategic approach adopted by a biological molecule (host) for selectively recognize another molecule (guest) on the basis of their complementarity and interact with it for regulating the cellular activity. The interactions occur between inherent receptors of the biological molecule and specific chemical groups of the guest molecule. The concept of molecular recognition was introduced by Hermann Emil Fischer in 1894, for which he received the Nobel Prize in Chemistry. Today, this is regarded as an efficient method for identifying and separating specific compounds of multicomponent mixtures. In fact, starting from the specific interactions occurring in living systems, the idea of introducing specific synthetic receptors into the matrix or on the surface of polymeric materials attracted more and more attention of the scientific community. In this scenario, the advent of membrane science and of the imprinting technology (IT) opened a new way in the field of detection and separation, allowing the production of the so-called imprinted polymers and membranes, which are smart systems endowing synthetic receptors (recognition sites) ad hoc created for the selective recognition of target molecules or ions of particular interest (templates) from similar compounds. These materials are prepared in a short time and have high sensitivity, stability, and specificity, which allow them to be suitable for working in a wide range of pH, ionic strength, temperature, as well as in aqueous and organic environment. All these features render them advantageous with respect to the biological receptors (antibodies, affinity ligands, etc.) and highly selective with respect to their corresponding nonimprinted materials such as traditional polymers and membranes. Furthermore, imprinted materials led to overcome the problem of high product purification/separation costs of traditional separation techniques (such as solvent extraction and chromatographic separation). They are also promising for designing drug delivery systems and reducing waste streams, with beneficial impact on the environmental and human health. The birth of the imprinted polymers preceded that of the imprinted membranes. Usually, the synthesis of an imprinted polymer occurs in the presence of the template molecule, which coordinates the spatial arrangement of a polymerizable functional monomer around it with the aid of a cross-linker. After the synthesis, the extraction of the template molecules from the newborn polymer leads to the formation of recognition sites that are complementary with the template in chemical function, size, and shape and exhibit high substrate recognition capacity and specificity. Despite their high specificity and properties, imprinted polymers have a restricted processability, owing to the presence of a high cross-linking degree and low capacity of https://doi.org/10.1515/9783110654691-001

2

Introduction

working in continuous mode. From this standpoint, the integration of IT with the membrane science allowed overcoming these drawbacks through the development of imprinted membranes, which represent a special format of imprinted polymers combining their specific recognition properties with the typical advantages of membrane separations. Imprinted membranes exhibit superior selectivity and separation efficiency with respect to the imprinted polymers. In general, a membrane is defined as a selective barrier that arises between two adjacent phases which regulates the transport of chemical species between them. The separation occurs owing to the different permeabilities of the involved substances, and the transport takes place by convection, diffusion, or electrostatic interactions. Membrane technology had started a long time before the birth of the imprinting technique, and membrane operations find application in numerous fields. High permeability and selectivity; mild operating conditions in water and organic environment; wide range of pH, pressure, and temperature; low energy intake; no phase change; absence or minimal presence of additives; and the possibility of working in continuous mode are typical characteristics of membrane-based operations. Nowadays, membrane-based separations are increasingly replacing traditional separation techniques or integrated with them for successful application in various areas such as chemical, pharmaceutical, food, biotechnology, and water treatment, for better utilization of raw materials, and for greater separation efficiency at lower costs. From this viewpoint, the fabrication of membranes with specific molecular or ionic recognition properties was permitted to achieve high separation efficiency of a single tailored ion or molecule in order to overcome the problem concerning the separation of structural homologues and ions having similar radius. The employment of these intelligent membranes as such or in combination with traditional membranes resulted in promising development of sustainable separation processes. Up to now, imprinted membranes with different configurations (flat sheet, hollow fiber, nanofiber, and nanowire) have been developed via either the covalent imprinting, the noncovalent imprinting, and the semicovalent imprinting for the selective recognition of a wide range of compounds (from cations and anions to small molecules, from macromolecules to viruses, bacteria, cells, and plant tissues) by exploiting different materials and strategies. The synthetic routes include surface imprinting, phase inversion, electrospinning, and substructural imprinting. In the last years, green strategies have also been applied. Aiming to give a contribution in promoting the knowledge on the current research trend about the development of imprinted polymeric membranes, this monography explains the different preparation methods and applications. The theory characterizing their different separation mechanisms is also presented. Starting from the concept of molecular recognition and concluding with the presentation of cyclodextrins as intelligent recognition tools used for membrane preparation, this book is organized into 10 chapters. More in detail, Chapter 1 introduces the reader to the fascinating world of molecular IT and to the general aspects characterizing the synthesis of molecularly imprinted polymers. Chapter 2 gives the introduction of membrane-based

Introduction

3

separation processes and molecularly imprinted membranes (MIMs). The separation mechanism and the methods used for characterizing them and for evaluating their performance in terms of permeation and binding properties as well as selectivity are also discussed. Chapters 3 is devoted to the different preparation methods of MIMs, including green synthetic approaches, while Chapters 4 and 5 deal with their application in affinity separation for the selective recognition of drugs, active pharmaceutical ingredients, pesticides, and other toxic compounds and proteins. The employment of MIMs in enantiomeric separation and sensor technology is discussed in Chapters 6 and 7, respectively. Chapter 8 deals with the development of ion-imprinted membranes for the selective recognition of metal ions, rare earth elements, and anions. Finally, Chapters 9 and 10 are dedicated to the application of IT and cyclodextrins in the production of imprinted polymers and membranes used in controlled drug delivery and selective separations. The content of this monography clearly demonstrates the application of imprinted membranes in a wide variety of fields as they are competitive with other systems employed for realizing excellent purification level of targeted ions and molecules, thus giving an important contribution in answering the growing demand of highly selective materials. However, it must be considered that in spite of the advantages from their applications in many sectors, the employment of imprinted membranes at the industrial scale is still in infancy, and more efforts are necessary for promoting their wider diffusion at this level.

Chapter 1 Molecular imprinting 1.1 Introduction The molecular recognition is a strategy adopted by living systems for promoting interactions at the molecular level and supporting their physiological functions. Simply, it is based on the ability exhibited by a molecule (host) to selectively recognize another molecule (guest) and interact with it by means of weak chemical bonds. These kinds of specific interactions, which play an essential role in biology and molecular engineering, have been attracted more and more the attention of scientists in developing selective tools for obtaining products with high-purity degree to meet the needs of society. A contribution in pursuing this objective was coming from the introduction of biological molecular recognition elements (i.e., affinity ligands and antibodies) in different materials for producing advanced molecularly recognition devices [1–4]. However, the production of these biological receptor-based systems is expensive, tedious, and time-consuming. In addition, they present low density of recognition sites, limited application, and low stability. From this standpoint, for producing synthetic more stable and robust recognition systems that imitate the natural ones, the scientific community did a hard work. These efforts led to the development of the imprinting technology, which is an approach allowing to synthesize polymeric materials (polymers and membranes) awarded with specific and selective recognition properties. Up to now, different imprinted polymers and membranes with high specificity versus compounds of particular interest in many fields, such as chemical trade diagnostics, foods, pharmaceuticals, and sensing platforms, have been successfully developed [5, 6]. The target compounds range from ions and small molecules to macromolecules and microorganisms such as viruses, bacteria, cells, and plant tissues. Different routes produce imprinted materials exploiting the formation of either covalent or noncovalent bonding between the analyte and the newborn-imprinted matrix. This chapter discusses the concept of molecular recognition by introducing the readers to the fascinating world of the molecular imprinting technology (MIT) in the perspective of miming biological systems. In addition, it presents an overview of the interactions characterizing imprinted polymers as well as about the synthesis and characterization of imprinted polymers, whose birth preceded that of the imprinted membranes (IMs). A look to their potential applications is also given.

1.2 The concept of molecular recognition Molecular recognition is a key process of biological systems comprising specific interactions at the molecular level, allowing the formation of supramolecular structures. These https://doi.org/10.1515/9783110654691-002

1.2 The concept of molecular recognition

5

kinds of interactions permit the processes that support life and evolution. The basis of the molecular recognition phenomenon comes from the strategic ability of biological molecules to distinguish other compounds (on the basis of their chemical complementarity), interact with them, and regulate the functions of their cells consequently. Noncovalent bonds (coordination forces, electrostatic forces, hydrogen bonds, van der Waals interactions, hydrophobic forces, π–π interactions, etc.) govern these specific interactions. Some examples of molecular recognition are the interaction between DNA and proteins, RNA and ribosomes, enzyme and substrate, and antigen and antibody [1–3]. Hermann Emil Fisher, who received the Nobel Prize in Chemistry, pioneered the concept of molecular recognition at the end of the nineteenth century (in 1894). The scientist hypothesized the “lock-and-key” model for explaining the method used by an enzyme (lock) for the recognition of its substrate (key). This theory postulated that only in the case of an exact geometric complementarity between the enzyme and the substrate, the functional groups of the latter could perfectly interact with the active site of the enzyme [1–3, 7]. However, this model did not explain all the aspects of the enzyme catalysis, for example, owing to the fact that certain enzymes are highly specific near their substrate while others might house some structurally different substrates. Over 60 years ago, Daniel Koshland proposed the induced fit recognition mechanism, which is supposed to show certain flexibility of the interacting molecules during the binding process. In particular, the binding of the substrate leads to a change in the three-dimensional relationship of the active site of the enzyme. The induced fit model is also stated as the “hand in glove model.” This definition reflects the fact that during the binding process, the enzyme and its substrate mutually adjust to each other, similar to that which occurs when a hand tucks into a glove [8–10]. Today, the molecular recognition is regarded as an efficient method for identifying and separating specific compounds of multicomponent mixtures. In fact, studies on the recognition process of living systems, as well those concerning the molecular and supramolecular interactions, have stimulated the scientists to build up synthetic strategies for producing biomimetic materials exhibiting high recognition specificity. It is possible to distinguish two different kinds of molecular recognition: static molecular recognition and dynamic molecular recognition. Figure 1.1 reports a schematic representation of the two different strategies. The static molecular recognition, based on the lock-and-key model, entails the binding of a single molecule (guest) to a specific receptor (host). The dynamic molecular recognition occurs when at least two guest molecules are involved in the process. In this case, the binding of the first guest molecule with the first receptor site determines conformational changes in the host molecule, thus promoting the interaction of its second receptor site with the second guest molecule. The dynamic molecular recognition reflects the induced fit model [1, 10–13]. One of the first approaches used for the production of materials having specific recognition ability toward a given molecule was the synthesis of three-dimensional

6

Chapter 1 Molecular imprinting

Fig. 1.1: Static (a) and dynamic (b) molecular recognition.

“host” structures and natural macromolecular recognition systems, such as crown ethers and cyclodextrins, respectively. Today, one of the most usefully employed methods is the imprinting technology, which produces imprinted materials for applications in different fields, like sensors, selective extraction, drug delivery and enantiomeric separation, enzyme activity like catalysis, and antibody mimic [1, 5, 6, 11–19].

1.3 Imprinting technology The development of man-made materials that are able to recognize selectively molecules or ions of particular interest, by mimicking the molecular recognition mechanism typical of living systems, is an object pursued by the entire scientific community. As already mentioned, an advanced strategy suitable for producing materials having these characteristics is the imprinting technology. It is an approach that permits to create artificial specific recognition sites in polymeric matrices for producing imprinted materials (polymers or membranes) that are able to establish specific interactions with target compounds via either covalent or noncovalent binding. The production strategy of entails the employment of different routes for creating the molecular (or ionic) memory of the target compound (atom, ion, molecule, complex, microorganisms, etc.) into these artifical smart materials during their synthesis. The compound of interest is called template (or target/print molecule as well as target/print ion) and the material endowed with its specific memory named “imprinted polymer” or “imprinted membrane,” depending on its format. Imprinted materials possess high sensitivity, stability, and specificity, which permit them to work in water or organic phase and under a wide range of pH, ionic strength, and temperature. In addition, they are prepared in a short time. They can also be simply regenerated and stored at room temperature, without losing their efficiency [14–19]. Today, different imprinted materials are prepared using a wide range of compounds and they have a great potential in sensing and separating efficiently target ions or molecules of specific interest from a mixture containing similar compounds, like structural homologues, or other ingredients. Furthermore, they are

1.4 Molecularly imprinted polymers

7

good candidates for designing new biomimetic smart catalytic materials and drug delivery devices. Owing to their features, imprinted materials led to overcome the problem of high product purification/separation costs of traditional separation techniques (such as solvent extraction and chromatographic separation). Finally, they are promising tools for reducing waste streams and consequently the environmental impact with benefit for human health [6, 18–23]. An essential aspect is that an imprinted material is prepared in the presence of the template. During the process, the template coordinates the spatial arrangement of the nascent material around it. After the synthesis, the extraction of the template molecules from the nascent imprinted system leads to the formation of recognition sites that are complementary with it in chemical function, size, and shape, and exhibit high substrate specificity [21–24]. The interactions between the imprinted sites and the template are similar to the antibody–antigen interaction typical of biological systems and are based on the “lock-and-key” model, proposed by Fischer for describing the specific enzyme–substrate interaction [2, 7, 26].

1.4 Molecularly imprinted polymers Molecularly imprinted polymers (MIPs) are artificial tailor-made recognition materials with high recognition capacity and specificity produced via MIT. Easy preparation, low cost, good storage, and mechanical stability and applicability in harsh environment conditions are several advantages exhibited by MIPs over their biological counterparts. They can be applied as sorbents or sensing tools in different fields, such as environmental, biomedical, water and food safety, and drug delivery [6, 27–30]. Typically, MIP production entails the polymerization of a functional monomer and a cross-linker around the template, thus obtaining an organic three-dimensional polymer network. Wulff and Sarhan [31, 32] as well as Takagishi and Klots [33] reported the first examples of molecularly imprinted cross-linked polymeric networks. In the first case, authors investigated the possibility of synthesizing an enzyme-analogue polymer for resolution of racemates. Using a mixture containing divinylbenzene (DVB) isomers and ethylvinylbenzene, they polymerized the two vinyl derivatives of functional monomers in the presence of D-glyceric acid and D-mannitol, thus attaining two different polymers: (1) D-glyceric acid-(p-vinylanilide)-2,3-O-(p-vinyl-phenylboranate) and (2) Dmannitol-1,2;3,4;5,6-tri-O-(p-vinylphenylboranate) [31, 32]. In recognition studies with racemates, both polymers were able to selectively bound the template molecules with respect to their isomeric counterparts, which remained free in the tested solutions. In particular, D-glyceric acid interacted with the first polymer via the boronic acid diester (BAD) linkage and the electrostatic interaction with the amino group, while BAD linkages of the corresponding synthesized polymers are bound to D-mannitol [31, 32]. In parallel, Takagishi and Klots produced a cross-linked thiolated-poly(ethyleneimine) (thiol groups were from thiolation with thiobutyrolactone) in the presence of dye methyl orange as the template molecule. Recognition tests showed that the MIP exhibited more

8

Chapter 1 Molecular imprinting

recognition sites and more strong binding toward methyl orange with respect to the corresponding nonimprinted polymer (NIP) synthesized under the same operating conditions but in the absence of the template. This work demonstrated as it is possible to mold a polymeric material for providing a lodging to specific host molecules [33]. As already mentioned, usually two main kinds of interactions are engaged in the preparation of an imprinted polymer: covalent and noncovalent binding. In the covalent imprinting, firstly proposed by Wulff and Sarhan [18, 31, 34, 35], the template and the functional monomer are covalently linked to form a complex, and chemical reactions are necessary to bind the template inside the nascent polymer. The removal of the template from the synthesized polymeric matrix and its rebinding arise through the same covalent interactions occurring in the synthetic process. This approach often exploits reversible condensation reactions employing boronate esters, ketals/acetals, and Schiff’s base [18, 31, 34, 35]. The noncovalent imprinting, firstly proposed by Mosbach and Sellergren [36, 37], entails the formation of noncovalent chemical bonds such as ionic bond, hydrogen bond, hydrophobic interactions, van der Waals forces, and metal coordination. Although the covalent imprinting permits to obtain more homogeneous and stable recognition sites than the noncovalent ones, the latter type of interaction is the most applied. This is because MIPs obtained via covalent imprinting possess low flexibility and a limited number of functional groups for interacting with the template. Furthermore, they show slow binding kinetics because high energy is required for the formation of the covalent bonds. Finally, the covalent bonds render more difficult template removal from the synthesized polymer and after the rebinding process. Therefore, the covalent binding is not useful for a rapid detection and determination of compounds and has a limited application. On the opposite, the weak interactions typical of the noncovalent imprinting lead to an easy recovery of the template under mild conditions. In addition, being the strategy that occurs at a molecular level in living systems, the noncovalent binding is appropriate for the selective recognition of a wide number of target compounds. However, according to Le Châtelier’s principle, an equilibrium process governs the noncovalent approach; therefore, during the synthesis an excess of the functional monomer is necessary with respect to the template for promoting the template–monomer interactions. This can result in the presence of unreacted monomers randomly dispersed in the MIP matrix and in the production of heterogeneous and/or nonselective imprinted sites. The presence of heterogeneous recognition sites is also due to the formation of complexes having different monomer/ template ratios [38–42]. In the logic of overcoming the disadvantages of the two imprinting strategies, sometimes imprinted polymers are prepared via the semicovalent imprinting method. It combines the possibility of hardly controlling the orientation and distribution of the functional groups typical of the covalent imprinting and the low kinetic limitation that characterizes the noncovalent one. More in detail, the polymerization takes place via covalent binding, and the template is washed out via hydrolytic reactions, while

1.5 A look to the basic components of MIP synthesis

9

the rebinding process occurs via the noncovalent binding [24, 29]. Usually, to perform the semicovalent imprinting, two different ways are followed: in the first case, the template and the functional monomer directly interact through an ester or an amide linkage. In the second case, a spacer between them is introduced [43–46].

1.5 A look to the basic components of MIP synthesis Nowadays, different methods allow producing MIPs. Anyway, any synthetic route requires the following elements: the template, a functional monomer complementary to the template, a cross-linker, and a solvent (porogen). Usually the process starts in the presence of a polymerization initiator. Figure 1.2 shows a general scheme of the synthetic process. The first step is characterized by the formation of the donor–receptor prepolymerization complexes between the template and the functional monomer (either via covalent or noncovalent interactions) after their solubilization in an appropriate solvent. The next step entails the addition of the cross-linker and of the initiator to the solution. Afterward, the copolymerization of the preformed complexes with the cross-linker into a rigid polymer occurs. The subsequent removal of the template from the polymeric network leads to the formation of an MIP with recognition sites containing the memory of the template and capable of recognizing it with respect to other compounds, including similar, structural analogues and opposite enantiomers. Covalent Molecular Imprinting Synthesis of Polymerizable Print Molecule

Polymerization

Removal by Chemical Cleavage

Molecular Recognition

Non-covalent Molecular Imprinting Self-assembly

Polymerization

Removal by Solvent Extraction

Molecular Recognition

functional monomer

methacrylic acid, etc.

cross-linkable monomer

divinylbenzene, etc.

print molecule

target molecule (or its analogue)

Fig. 1.2: Scheme of the imprinting process (reprinted from ref. [47]. Copyright 2016, with the permission of the American Chemical Society).

10

Chapter 1 Molecular imprinting

The center of the process is the template. Not all the existing chemical compounds are suitable of imprinting. First, the template must be stable and inert under the polymerization conditions. Furthermore, it must contain functional groups capable of forming complexes with the functional monomer and that do not prevent polymerization. Other parameters that influence the selectivity and the binding capacity of an MIP are the type and the amount of functional monomer, cross-linker, initiator, and solvent [6, 48–51]. The functional monomer must present chemical groups able to interact with the template. In addition, it must be able to interact also with the crosslinker (or other monomers) [51–56]. Different functional monomers having acid or basic moieties in MIP synthesis are used. Owing to its donor and acceptor properties, the most widely used acidic functional monomer is methacrylic acid (MA), which interacts via ionic bonds with amines and via hydrogen bonds with amides, carbamates, and carboxyl groups. Owing to their strong force with respect to the hydrogen bond, the ionic interactions allow obtaining better performance of the MIP materials. MA has the ability of dimerizing, thereby improving the imprinting effect. Furthermore, when used in high molar fractions, it leads to the formation of polymers having large pore size and therefore high binding capacity [18]. The most common basic functional monomer is the vinyl monomer 4-vinylpyridine (4-VPY). It is able to interact with the carboxyl function of template molecules. Other used functional monomers are methyl methacrylate, 4-ethylstyrene, itaconic acid (IA), acrylic acid, 1-vinylimidazole, 2-VPY, and so on [51–56]. In some cases, for improving the interaction with the target compound and obtaining more stable complexes, modified as well as two or more functional monomers are used, as it is the case of imprinting of macromolecules, which present different functional groups [57–59]. For example, 2-trifluoromethyl acrylic acid developed for preparing MIPs versus nicotine exhibited high recognition performance than the one showed by the most used MA [57]. In another case, both MA and 2-dimethylamino ethyl-methacrylate have been used as functional monomers for fabricating a lysozyme (LYS)-imprinted polymer [21]. The obtained MIP showed higher LYS binding with respect to the MIP obtained by polymerization carried with the only MA [21]. Photoresponsive porphyrin-imprinted polymers were also prepared using both diaminopyridine and azobenzene groups [58]. Table 1.1 lists some traditional and new functional monomers used in MIP synthesis. β-Cyclodextrins (β-CDs) and their derivatives as functional recognition tools have also been investigated [59–61]. Their structure entails a hydrophilic part surrounding a hydrophobic cavity. The ability of complexing templates via hydrogen bonds, electrostatic and host–guest interactions rendered β-CDs attractive as functional monomers. In addition, they can act as terminals of polymerization via their hydroxyl groups [18, 25]. The employment of the cross-linker ensures the synthesized polymer the necessary rigidity for the formation and stabilization of the recognition sites and, together with the solvent, leads to control the polymer morphology: gel-type, macroporous, or microgel powder [38]. Furthermore, the recognition efficiency is strongly dependent

1.5 A look to the basic components of MIP synthesis

11

Tab. 1.1: Some traditional and new functional monomers employed in MIP synthesis. Covalent imprinting

Noncovalent imprinting

New functional monomers

-Vinyl benzene boric acid

Acrylic acid

Benzo--crown--acrylamide

-Vinyl benzaldehyde

Methacrylic acid

-Hydroxy--(prop-enyl)-,-anthraquinone

-Vinyl aniline

Trifluoromethyl acrylic acid

-Hydroxy--(prop--enyloxy)-,anthraquinone

Tert-butyl pvinylphenylcarbonate

Methyl methacrylate

-Vinyl--hydroxyquinoline

p-Vinylbenzoic acid

-[(E)--(-methyl-,-bipyridin--yl)vinyl] phenyl methacrylate

Itaconic acid

-Vinylphenylazo--naphthol

-Ethylstyrene

N-Ethyl--(N-[-vinylphenyl] hydrazinecarboxamidyl)-,-naphthalimide

Styrene

-Vinylbenzo--crown-

-Vinylpyridine -Vinylpyridine -Vinylimidazole Acrylamide Methacrylamide Acrylamido--methyl-propane sulfonic acid; -Hydroxyethyl methacrylate Trans--(-pyridyl)-acrylic acid -Aminopropyltriethoxysilane Methylvinyldiethoxysilane -Methylacryloxyprolyl trimethoxysilane

on the cross-linker/functional monomer molar ratio. In general, an excess of 80% crosslinker with respect to the functional monomer permits to obtain MIPs with good mechanical stability and recognition performance [62]. The higher cross-linker molar ratio allows to obtain polymers with exacerbate rigidity, which negatively affects the interactions with the template. On the other hand, a low cross-linker content causes the formation of polymers with low stability (owing to the reduced cross-linking of the polymer matrix), too close site proximity, and nearby molecular interferences that hinder the

12

Chapter 1 Molecular imprinting

template rebinding [63–66]. The most commonly used cross-linkers in covalent imprinting are triallyl isocyanurate, bis(1-(tert-butylperoxy)-1-methylethyl)-benzene, dicumyl peroxide. In the noncovalent imprinting, a large number of cross-linkers is used. Up to date, the most employed diester is the ethylene glycol dimethacrylate (EGDMA) that holds two vinyl groups. Other examples of cross-linkers are tetramethylene dimethacrylate, trimethylolpropane trimethacrylate, glycidyl methacrylate, DVB, 1,3-diisopropenyl benzene, N,N-methylenebisacrylamide (MBAAM), 3,5-bis(acryloylamido) benzoic acid, N,O-bismethacryloyl ethanolamine, 1-butyl-3-methylimidazoliumtetrafluoroborate (BMIM), and glutaraldehyde [6, 18, 25, 38, 67]. The choice of the solvent is also important because its polarity can affect the strength of the interactions between the template, the functional monomer, and the cross-linker. In fact, the solvent may establish interactions with the target molecules and change its structure, thus negatively affecting the formation of template–functional monomer complexes. For reducing solvent–template interactions in noncovalent imprinting, nonpolar and low polar organic solvents (i.e., acetonitrile, chloroform, and toluene) with respect to water are mostly used. On the other hand, in case of protein imprinting and of metal–ligand complexation synthesis, the water environment promotes the formation of highly stable and efficient complexes. Another aspect to consider is the presence of high solvent volume leads to obtain smaller polymer powder/ particles, with high surface area and accessibility to the imprinted sites. This is because the nascent polymer is not able to live in the completely available reaction volume [49, 68]. Finally, in the binding process, the solvent can affect the swelling degree of polymer and alter the spatial arrangement of the functional groups of the recognition sites. Therefore, the template-binding efficiency will be intensely reduced [49, 68]. Another parameter that influences the synthetic process of MIPs as well as their structure, swelling, and performance is the polymerization temperature. Some authors demonstrated that at lower polymerization temperature (from 0 to 60 °C), MIPs exhibited better recognition performance with respect to processes carried out at high temperature, even if low temperature requires longer time for achieving the synthesis [69–72]. The type of initiator employed when using radical polymerization can influence the choice of the temperature. For example, the use of thermal iniferters, peroxides, or azo compounds requires high polymerization temperature for ensuring their rapid decomposition, thus avoiding the formation of toxic side products [6]. Some commonly used initiators are azobisisobutyronitrile, azobisdimethylvaleronitrile, 4,4-azo(4-cyanovaleric acid), benzoylperoxide, potassium persulfate [6, 18, 25]. Owing to its suitability of working at low temperature without production of any toxic compound and reducing the polymerization time, the Fenton reagent as redox initiator was also proposed [6, 73]. The removal of the template after an MIP synthesis and the rebinding step is an aspect that we cannot overlook. This is because, in some cases, it is hard to remove some template traces from the imprinted matrix, also after an extensive washing procedure. Consequently, during the rebinding step, the polymer matrix can release the residual template and the analytical investigations result altered. In addition, the

1.6 MIP polymerization methods and applications

13

presence of residual template into the polymer matrix determines a reduction of the number of recognition sites available for the template rebinding. As was discussed by Lorenzo et al. [74] for obtaining complete template removal, different strategies (also including green approaches) have been exploited. Some examples are the ultrasoundand microwave-assisted extraction [75], the pressurized hot water extraction, and the supercritical carbon dioxide [75, 76] extraction. Sometimes for preventing the leaching problem or when the template is highly toxic is not imprintable or insoluble and unstable in the used solvent, a template analogue (dummy template) is used instead of the template itself [77, 78]. Two types of template molecules are also used simultaneously [79]. As mentioned earlier, it is well assessed that the intrinsic features and the recognition properties of an MIP are strongly affected by the choice of the appropriate reagents and of the polymerization conditions with respect to the template of interest. Important ones are the intermolecular interactions and aggregation in the prepolymerization step. In this context, molecular dynamic studies [80–83], quantum mechanic calculations [84– 87], and combinatorial chemistry [88–93] help to select optimal reagents and polymerization conditions for producing highly selective MIPs toward specific compounds of interest. These approaches also allow to reduce labor time and the amount of reagents and solvents used (and therefore the waste), in the logic of a rational design of MIP synthesis. Prasad and Rai applied the second-order Moller Plesset theory (MP2) and the density functional theory (DFT) to select best functional monomers for different templates [86, 87]. Combining different monomers and cross-linkers, Cederfur et al. developed a library of imprinted polymers using penicillin G as the template molecule [90]. Polymer precursors for the synthesis of benzo[α]pyrene-imprinted polymers were selected by a combinatorial screening method [91]. In another case, the effect of four different solvents (acetone, acetonitrile, chloroform, and methanol) on the template–monomer binding energy was investigated, and for the calculation of structural and vibrational frequencies, the DFT was applied [18]. More recently, for design and developing MIPs for the selective recovery of deltamethrin from olive oil, an integrated computational-assisted approach was strategically exploited [93]. These are only some examples of different theoretical studies applied for obtaining the best operating conditions in the synthesis of highly efficient MIPs. The number of these studies is increasing, and the integration of different subjects will promote a flourishing development in this field for more and more understanding of the mechanism governing the synthetic processes and the molecular interactions.

1.6 MIP polymerization methods and applications Different strategies exist for MIP production. Even if their deep explanation is beyond the scope of this book, a brief discussion on these methods follows. Traditional MIP synthetic strategies are carried out via the free-radical mechanism, which includes

14

Chapter 1 Molecular imprinting

different polymerization methods. The general rule of any synthetic route is to obtain a high conversion degree as well as the formation of stable recognition sites into the polymeric matrix. Therefore, it is important to adopt case-by-case operative conditions that favor the interaction between the polymerizable monomers and the template molecules. The most applied free-radical synthetic process is the bulk polymerization. This is due to the operative mild conditions of the method and to the possibility of using a wide range of functional monomers and cross-linkers. This approach requires the presence of an initiator system, which is the source of free radicals for initiating the polymerization via its thermal or ultraviolet decomposition. It is fast, easy to realize, and does not require sophisticated or expensive instrumentation. A weak point of the bulk polymerization strategy is the requirement of large template amount and the time-consuming of grinding and sieving. Other drawbacks are that the polymer particles are highly irregular in size and shape, and some of them are lost during the grinding and sieving procedure, resulting in reduction of the recovered material upon synthesis. In addition, it is difficult to control the kinetics of the process and the obtained MIPs present heterogeneous pore size distribution, have low template accessibility, and consequently, low binding capacity. These drawbacks are overcome by the employment of other synthetic routes, such as emulsion polymerization, precipitation polymerization, seed polymerization, suspension polymerization, and other methods. All of them allow obtaining different MIP format (i.e., powder, particles, monolithic forms, etc.) [18, 25, 53, 94–96]. The suspension polymerization entails the use of two different phases: the water continuous phase (dispersing medium) and the organic phase consisting of template, functional monomer, cross-linker, and initiator. Initially, the dispersion of organic droplets into the water phase in the presence of a stabilizer or surfactant takes place. During polymerization, gradual transformation of the droplets into solid spherical particles occurs. Some advantages of this method are the absence of mechanical grinding, the high reproducibility, and the large-scale application. A weak point is the wide size range of the synthesized polymer particles (from 50 nm to 500 µm in size) even if sufficiently diluted systems lead to obtain uniformly sized microspheres. Another problem is the poor recognition, probably owing to the interference of water in the template-monomer interactions. The surfactant (or the stabilizer) can also exert this negative action. For solving these problems, perfluorocarbons as dispersing phase can be used together with appropriate fluorinated stabilizers instead of water. Yet, the use of mineral oil as a dispersing medium avoids the employment of stabilizers/surfactants. However, perfluorocarbons are expensive, and the employment of mineral oil limits the choice of the solvent [18, 53, 94–96]. Emulsion polymerization leads to produce high yield of monodispersed polymer particles in water-in-oil or oil-in-water system. The method entails the dispersion of water-insoluble monomers and water-soluble initiator in a water-continuous phase and the presence of a surfactant having both hydrophobic and hydrophilic moieties

1.6 MIP polymerization methods and applications

15

for stabilizing the emulsion monomer–water phase. Initially, the surfactant molecules form micelles and after the migration of the initiator and of the monomer in these micelles, the polymerization starts. During the process, uniform polymeric particles having size in the range of 50–700 nm in dependence of operating conditions are produced. Surfactant residual and low imprinting effect represent the problems of this process [18, 53, 94–96]. The seed polymerization, also named multistep swelling polymerization, is suitable for producing MIP particles used in the preparation of column-imprinted stationary phases. However, also in this case, the water can negatively affect the formation of the template–monomer complexes. Furthermore, the process is difficult and time-consuming [18, 53, 94–96]. The precipitation polymerization is a method that allows obtaining uniform polymeric particles in high-diluted solutions. All reagents are soluble in the solvent, while the nascent polymer gradually grows enveloping monomers and already formed oligomers until it becomes insoluble and precipitates from the reaction environment. It is a one-step process carried out without the presence of any stabilizer or surfactant. Some negative aspects are the necessity of using high solvent volume and the hard control of the operating conditions. Moreover, the high dilution rate may determine the formation of weak template–monomer interactions. In situ prepared polymeric imprinted monoliths are produced by means of the in situ polymerization method, which entails a onestep free-radical polymerization in a stainless chromatographic column. The process is easy to realize, is highly reproducible, and requires low template amount [18, 25, 94–96]. The separation properties and the monolithic structure are determined by the polymerization temperature and the composition of the reaction mixture. For obtaining higher binding capacity as well as higher binding kinetics, faster mass transfer, and easy recovery of template molecules, the surface imprinting polymerization was developed. In the case of this method the polymerization process occurs on a suitable surface which at the end of the process will result covered by a thin imprinted layer. In this case, the recognition sites are located only on the surface of the obtained imprinted system. For achieving this object, different materials such as porous silica particles, chitosan, Fe3O4 magnetic nanoparticles, activated beads, quantum dots, and membranes are used [18, 25, 94–96]. Table 1.2 reports the advantages and the drawbacks of all the aforementioned traditional polymerization methods. In the perspective of overcoming their disadvantages, these traditional synthetic routes have been continuously improved and in parallel new approaches have been developed. Among the other polymerization strategies, the controlled radical polymerization (CRP) is an efficient and interesting method that permits a better control of the process (e.g., polymer chain propagation and termination), thus promoting the formation of MIPs with much uniform structure and improved recognition performance. The most useful CRP techniques are the atom transfer radical polymerization (ATRP), the reversible addition-fragmentation chain transfer (RAFT) polymerization, and the iniferter polymerization (IFP) [18, 25, 94–97]. For promoting the growth of polymeric chains, ATRP uses transition metal complexes as reversible halogen-atom

16

Chapter 1 Molecular imprinting

Tab. 1.2: Advantages and drawbacks of the traditional synthetic methods for MIP production. Synthetic methods

Advantages

Drawbacks

Bulk polymerization

Rapid, simple, and cheap Nor employment of expensive and sophisticated instrumentation High purity of produced MIPs

Needing of large template amount Boring and time-consuming procedure of grinding and sieving Not uniform shape and particle size Low binding capacity Limited application in chromatography

Emulsion polymerization

High productivity Monodispersed polymer particles

Surfactant residues Low imprinting capacity

In situ polymerization

One-step procedure In situ synthesis Low template amount High reproducibility

Requirement of optimization for each template system

Precipitation polymerization

One-step process High yields Uniform microspheres and nanospheres Absence of stabilizers and of surfactants

Requirement of large amount of template High solvent volume Strict control of operating conditions

Seed polymerization

Controlled spherical particles or beads Monodisperse beads in size and shape Low viscosity

Multistep and difficult procedure and reaction conditions Time-consuming Water interference

Surface imprinting polymerization

Thin imprinted layers and monodisperse product

Time consuming and tedious procedure

Suspension polymerization

One-step process with high reproducibility Large-scale application Production of spherical particles

Water interference High costs of perfluorocarbons as alternative continuous phase Requirement of special surfactants Large particles size Poor recognition

transfer reagents. The RAFT deals with the introduction of a proper chain transfer agent into the free radical system (emulsion, suspension, and precipitation). The IFP entails the addition to the solution of a chemical compound (called iniferter) that acts as an initiator, a chain propagator, and a teminator agent [18, 25, 94, 97]. Another interesting synthetic mechanism is the sol–gel process that comprises the formation of a colloidal solution together with a metal oxide precursor (i.e., tetraethyl orthosilicate and 3-(propylmethacrylate) trimethoxysilane) and the subsequent polycondensation for producing highly crosslinked gels [18, 25, 94, 98]. From the experimental point of view, the process consists in the dissolution of the precursor in a low-molecular-weight solvent (by means of a catalyst) and the subsequent hydrolysis in water and polycondensation. Some advantages of

1.6 MIP polymerization methods and applications

17

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IPs

IP M ale Sc no Na

Mul

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mpla

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IPs

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mp

Co M s IP

W ate r

D

Co M mp IP ati s ble

yM umm

r ome Mon l a n nctio ti-fu MIPs Mul

Molecular Imprinting Technology Restricted Access Materials Combined with MIPs

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Monolithic MIPs

ng nti pri s Im IP ce M rfa ed Su bas

Holl

s

the sol–gel process are the ease of implementation, the room temperature, and the use of eco-friendly solvents. Furthermore, it permits to modify polymeric surfaces and to produce different types of nanomaterials (i.e., nanocomposite-IMs). Finally, owing to the employment of silica-based materials, the recognition sites possess a stable strong structure, and the template removal from the polymer network is easy to realize [18, 25, 95, 99]. Other polymerization strategies such as electrosynthesis, new surface imprinting approaches, chemical oxidation, microwave-assisted heating, and the core–shell technology [18, 25, 99, 100] have also been developed. In the last years, all these methods have been deeply reviewed [18, 25, 100, 101] and recently Arabi et al. [101] discussed about the different novel synthetic strategies of MIPs for solid-phase extraction (SPE), which dates back to the 1940s and is the most prominent application field. Figure 1.3 shows these new synthetic routes.

Hydrophilic Surface

Macromolecule

Fig. 1.3: Novel strategies for molecular imprinting-based SPE (reprinted from ref. [101] . Copyright 2020, with the permission of Elsevier).

18

Chapter 1 Molecular imprinting

Single or combined strategies have proven effective in the synthesis of MIPs to use in SPE or in a different way. In the last years, the combination of molecular imprinting approach with the nanotechnology allowed to produce nanostructure-imprinted polymers (N-MIPs). This new format of MIPs presents many advantageous properties with respect to the traditional MIPs. First, they have higher surface area/volume ratio, which enhances the accessibility of the template to the recognition sites and therefore the binding kinetics and the binding capacity [18]. Another interesting aspect is the ease removal of the template. Nowadays, many types of N-MIPs (i.e., nanoparticles, nanotubes, and nanowires) by means of different nanotechnologies and materials are synthesized [102–104]. For example, by combining graphene nanomaterials with imprinting techniques, graphene-based MIP sensors were developed [104]. Graphene is a carbonaceous nanomaterial having some interesting characteristic such as chemical inertness, thermal stability, cost-effectiveness, high mechanical resistance, good conductivity, and high resistance to oxidation, which render it the most used nanomaterial in a wide range of applications, as occurs in molecular imprinting [104]. Table 1.3 lists the different properties of traditional bulk MIPs and of N-MIPs. Tab. 1.3: Comparison of properties of the bulk MIPs and nanostructured MIPs. Bulk MIPs

N-MIPs

Low surface-to-volume ratio, difficult to elute

High surface-to-volume ratio, greater total active surface area per weight unit of polymer

Broad distribution of binding sites with varying affinity, high level of nonspecific binding sites

Similar affinity for all binding sites and high level of specific binding sites

Insoluble material, difficult to process, bulk, batch-to-batch variability

Soluble nanoparticles well dispersing in solution, better control of manufacturing process

Difficult to access the empty cavities encased within the rigid matrix

Imprinted cavities being more easily accessible to the templates, improving binding kinetics, and facilitating the template removal process

High possibility of template leaking from the polymer

Traces of template being easily removed

Limited prospects for in vivo applications

Biological activity showing infinite prospects for in vivo applications

Reprinted from ref. [18]. Copyright 2017, with the permission of the Royal Society of Chemistry.

In the context of developing new and more efficient imprinting strategies, stimuliresponsive MIPs became also attractive. They are capable of responding to external stimuli, modulating their affinity for the template of interest. Chen et al. [18, 105] accurately highlighted the preparation and application of stimuli-responsive MIPs (i.e., pH-responsive MIPs, magnetic responsive MIPs, temperature-responsive MIPs, etc.). In the last years, green imprinted strategies, which are based on the employment of

1.6 MIP polymerization methods and applications

19

environmentally friendly reagents (i.e., as ionic liquid and deep eutectic solvents), have been used singly or in combination with traditional reagents [18, 67, 74, 94, 106]. For example, Li and coworkers developed an isoquercitrin green imprinted polymer using a mixture of BMIMBFA (ionic liquid)/N′N-dimethylformamide/dimethyl sulfoxide as a porogenic solvent, and 4-VPY and EGDMA as a functional monomer and cross-linker, respectively [106]. Nowadays, MIPs are used not only in SPE but also in many other areas, such as drug delivery, water treatment, sensors, enantiomeric separation, and food analysis [18, 25, 92, 94, 107–114]. For example, different functional monomers for producing carbamazepine-N-MIPs, able of removing carbamazepine (a typical pharmaceutical residue) from drinking water, were investigated. In agreement with molecular simulation, recognition experiments revealed that the binding capacity was in the order of 4-vinylbenzoic acid (4-VBZA) > IA > MA. In the case of 4-VBZA, the maximum binding capacity was 28.40 mg · g−1 [115]. In another wok, the use of magnetic carbon nanospheres as carrier and acrylamide as functional monomer led to developing quinolone-magnetic surface MIPs [116]. These novel imprinted materials exhibited high binding capacity toward quinoline in real cooking water, thus permitting its recovery and recycle. Quinoline is an intermediate in many fields, like medicine, pesticides, and electricity production; therefore, its recovery moves in the direction of the recycle policy. Previously, multiwalled carbon nanotube surface imprinted with poly(methacrylic acid) led to selectively extract the bioactive compound emodin from kiwifruit root with a recovery range from 89.2% to 93.8% [117]. Core–shell surface-imprinted nanospheres, prepared by copolymerizing a nanothin layer of asparaginase and 3-aminophenylboronic acid monohydrate (3-APBAM) around the core of nanospheres, were applied in the recovery of asparaginase from real pharmaceutical preparations. Asparaginase is an important enzyme extracted from Escherichia coli and catalyzing the hydrolysis of the amino acid L-asparagine into L-aspartic acid and ammonia. L-Asparagine is essential for the life cycle of leukemia cells, and its hydrolysis leads to an interruption of the growth of neoplastic cells. Asparaginase is also interesting in the food industry because the hydrolysis of asparagine hinders the formation of acrylamide, as in the case of fried some foods [118]. Figure 1.4 shows the scanning electron microscopic images of the functionalized silica nanospheres (FSS1), the imprinted-functionalized nanospheres, and their corresponding nonimprinted ones. In 2017, Pijush and coauthors [119] demonstrated the possibility of using insulinimprinted polymer nanoparticles as carriers for drug delivery. In in-vivo experiments, insulin-loaded MIP administered via oral route to diabetic rats determined a more gradual reduction of the blood glucose level (with the maximum at 4 h) with respect to the subcutaneous insulin administration, which determined a severe decrease of glucose level within 2–3 h and after the return to the basal level. Furthermore, the glucose level was low up to 12 h. In the case of NIP, control polymer placebo, and oral insulin administration, the hypoglycemic effect was absent. Figure 1.5 shows a schematic representation

20

Chapter 1 Molecular imprinting

Fig. 1.4: Scanning electron microscopic images of nanospheres functionalized with 3-aminophenylboronic acid monohydrate (FSS1) (a), imprinted FSS1 (b) and nonimprinted FSS1 (c) (reprinted from ref. [118]. Copyright 2019, with the permission of the Royal Chemistry of Society).

of the synthetic process, carried out via the free radical aqueous precipitation polymerization at room temperature. The polymeric nanoparticles were prepared using MAA and N-hydroxyethyl acrylamide as functional monomers and MBAAM as the cross-linker [119]. Other examples are the application in forensic science [120], the imprinting of microorganisms for biosensing [121], the production of imprinted intelligent scaffolds for tissue engineering [122], and the detection of pesticides [123]. The last case is the production of chiral MIPs as separation agents for high-performance liquid chromatography (HPLC) analysis, as for example, the production of imprinted polymers for the chiral recognition of racemic 1,1′-binaphthalene-2,2′-diamine by HPLC [124]. These few cases represent only a very small part of the numerous applications of imprinted polymers, and additional information can be found in the reported literature [5, 18, 25, 54, 94–100, 108–115, 125]. About the SPE, starting from 190, more and more imprinted polymers were developed, and some companies produced SPE-based packing of MIP materials (i.e., chromatographic columns and cartridges) for sample preparation and analysis in biomedical,

21

1.6 MIP polymerization methods and applications

O

H

O

OH

O

O

(Crosslinking MBAA Monomer)

CH2

2

N H

O

OH

HEAA Monomers)

OH

NH

O

2

O

O

MAA (Functional

NH

H 2C

N H H H N N

OH

OH

Free radical initiator (AIBN) PBS pH 7.4

2

OH

O

Protein rebinding OH

HO

H N

2

O

NH

O

NH

OH

H N

O

OH

N H

HHO

O

O

O

O

HO

Protein removal

OH

O

N H

Nanoparticles formation

Precipitation polymerization Room temperature OH

O

OH

OH O

O

O

N H

Insulin (Template)

O

Fig. 1.5: Illustration of synthetic process of the insulin-imprinted polymer nanoparticles (reprinted from ref. [119]. Open Access).

food, and environmental fields [5, 94–96, 126–128]. Some companies, which are leaders in MIP technologies, are Biotage, Polyntell, Toximet, and so on [5, 94]. Some examples of commercial production of SPE-based MIP systems, which are advertised by Affinisep (Petit-Couronne, France), Biotage (Lund, Sweden), and Sigma-Aldrich (St. Louis, USA) are listed in Tab. 1.4 [94]. Other examples present in the market are an MIP-based sensor for detecting explosives produced by the American company Raptor and an MIP-based system for detecting and removing toxic compounds from biological fluids produced by Semorex, an Israeli-American company. However, up to now, the most commercialized application is separation than the sensor technology [5, 9]. Besides their high specificity, MIPs have restricted processability owing to high cross-linking degree and low capacity of working in the continuous mode. Therefore, the integration of imprinting technology and membrane science allowed producing a special format of imprinted polymers: the IMs, which combines the advantages of both imprinted polymers and membrane separation features, overcoming the drawbacks of MIPs. The next chapters of this book deal with the preparation strategies and

22

Chapter 1 Molecular imprinting

Tab. 1.4: Some commercially available molecularly imprinted polymer (MIP)-based solid-phase extraction (SPE) products in the market. Company SPE products

Applications

AFFINISEP AFFININIMIP SPE FumoZON

SPE of fumonisins and zearalenone from food samples

Biotage

AFFININIMIP SPE Deoxyvalenol

SPE of deoxyvalenol from food samples

AFFININIMIP SPE Multimyco

SPE of fumonisins, ochratoxin A, zearalenone aflatoxins, and deoxyvalenol from cereals

AFFININIMIP SPE Metanephrines

SPE of metanephrines from biological matrices

AFFININIMIP SPE Glyphosate – AMPA

SPE of glyphosate and aminomethylphosphonic acid (AMPA) from water

AFFININIMIP SPE Picolinic herbicides

SPE of picloram, clopyralid, and aminopyralid from environmental matrices

AFFINILUTE MIP – Clenbuterol

SPE of clenbuterol from biological matrices

AFFINILUTE MIP – β-Agonist SPE of β-agonist from biological matrices AFFINILUTE MIP – Triazine

SPE of triazines from environmental matrices

AFFINILUTE MIP – β-Blocker SPE of β-blocker from biological matrices

Sigma Aldrich

AFFINILUTE MIP – Amphetamine

SPE of amphetamine from biological matrices

AFFINILUTE MIP – PAH

SPE of polyaromatic hydrocarbons from organic matrices

SupelMIP SPE – Patulin

SPE of patulin from fruit and fruit products

SupelMIP SPE – Aminoglycosides

SPE of aminoglycoside antibiotics from tissue samples and cell culture

SupelMIP SPE – Bisphenol A (BPA)

SPE of bisphenol A from environmental food samples

SupelMIP SPE – Riboflavin (vitamin B)

SPE of riboflavin from milk and other aqueous samples

Reprinted from ref. [94]. Copyright 2020, with the permission of Elsevier.

the applications of imprinted polymeric membranes for the specific recognition of targeted compounds at both the molecular and ionic levels.

References

23

References [1] [2] [3] [4] [5] [6] [7] [8]

[9] [10]

[11]

[12] [13] [14]

[15] [16] [17] [18] [19] [20]

[21]

Donato L. Molecular recognition. In: Drioli E, Giorno L, eds. Encyclopedia of membranes. SpringerVerlag, Berlin Heidelberg, 2015, https://doi.org/10.1007/978-3-642-40872-4_1613-1. Persch E, Dumele O, Diederich F. Molecular recognition in chemical and biological systems. Angew Chem Int Ed 2015, 54, 3290–3327. Chen W, Tian X, He W, Li J, Feng Y, Pan G. Emerging functional materials based on chemically designed molecular recognition. BMC Mat 2020, 2, https://doi.org/10.1186/s42833-019-0007-1. Subrahmanyam S, Piletsky SA, Turner APF. Application of natural receptors in sensors and assays. Anal Chem 2002, 74, 3942–3951. BelBruno JJ. Molecularly imprinted polymers. Chem Rev 2019, 119, 94–119. Algieri C, Drioli E, Guzzo L, Donato L. Bio-mimetic sensors based on molecularly imprinted membranes. Sensors 2014, 14, 13863–13912. Fischer E. Influence of configuration on the action of enzymes. J Chem Amer Soc 1894, 3, 2985–2993. Holyoak T. Molecular recognition: Lock-and-key, induced fit, and conformational selection. In: Gordon CKR, ed. Encyclopedia of biophysics. Springer, Berlin, Heidelberg, 2013, https://doi.org/ 10.1007/978-3-642-16712-6_468. Bosshard HR. Molecular recognition by induced fit: How fit is the concept? News Physiol Sci 2001, 16, 171–173. Wang Q, Zhang P, Hoffman L, Tripathi S, Homouz D, Liu Y, Waxham MN, Cheung MS. Protein recognition and selection through conformational and mutually induced fit. PNAS 2013, 110, 20545–20550. Balle Th, Liljefors T. Molecular recognition. In: Stromgaard K, Krogsgaard-Larsen P, Madsen U, eds. Textbook of drug design and discovery. 5th ed. CRC Press, Taylor & Francis Group, Boca Raton, NW, USA, 2017, 15–16. Liang R, Wang T, Zhang H, Yao R, Wei W. Soluble molecularly imprinted nanorods for homogeneous molecular recognition. Front Chem 2018, 6, article 81, https://doi.org/10.3389/fchem.2018.00081. Ehrlich P. Static and dynamic molecular recognition. In: Chatterji D, ed. Basic of molecular recognition. CRC Press, Taylor & Francis Group, Boca Raton, NW, USA, 2016, 31–32. Say R, Rüstem Keçili R, Denizli A, Ersöz A. Biomimetic imprinted polymers: Theory, design methods, and catalytic applications. In: Li S, Cao S, Piletsky SA, Turner APF, eds. Molecularly imprinted catalysts. Principles, syntheses, and applications. Elsevier, 2016, 103–120. Vasapollo G, Del Sole R, Mergola L, Lazzoi MR, Scardino A. Molecularly imprinted polymers: Present and future prospective. Int J Mol Sci 2011, 12, 5908–5945. Martín-Esteban A. Molecularly imprinted polymers: New molecular recognition materials for selective solid-phase extraction of organic compounds. Fresenius J Anal Chem 2001, 370, 795–798. Jia M, Zhang Z, Li J, Ma X, Chen L, Yang X. Molecular imprinting technology for microorganism analysis. TrAC 2018, 106, 190–201. Chen L, Wang X, Lu W, Wu X, Li J. Molecular imprinting: Perspectives and applications. Chem Soc Reviews 2016, 45, 2137–2211. Whitcombe MC, Kirsch N, Nicholls IA. Molecular imprinting science and technology: A survey of the literature for the years 2004−2011. J Mol Recognit 2014, 27, 297–401. Alexander C, Andersson HS, Andersson LI, Ansell RJ, Kirsch N, Nicholls IA, O’Mahony J, Whitcombe MJ. Molecular imprinting science and technology: A survey of the literature for the years up to and including 2003. J Mol Recognit 2006, 19, 106–180. Ylmaz E, Schmidt RH, Mosbach K. Molecularly imprinted materials: Science and technology. 1st ed. CRC Press, Taylor & Francis Group, Boca Raton, NW, USA, 2005, 25–57.

24

[22]

[23] [24] [25] [26] [27] [28]

[29] [30] [31] [32] [33] [34] [35] [36] [37]

[38] [39] [40] [41]

[42] [43]

Chapter 1 Molecular imprinting

Komiyama M, Takeuchi T, Mukawa T, Asanuma H. Fundamentals of molecular imprinting. In: Komiyama M, Takeuchi T, Mukawa T, Asanuma H, eds. Molecular imprinting: From fundamentals to applications. Wiley-VCH, Weinheim, 2016, 9–19. Shea KJ, Sakaki DY. On the control of microenvironment shape of functionalized network polymers prepared by template polymerization. J Am Chem Soc 1989, 111, 3442–3444. Wulff G. The role of binding-site interaction in the molecular imprinting of polymers. Trends Biotechnol 1993, 11, 85–87. Chen L, Xu S, Li J. Recent advances in molecular imprinting technology: Current status, challenges and highlighted applications. Chem Soc Rev 2011, 40, 2922–2942. Fisher E. Einfluss der configuration auf die wirkung der enzymes. Ber Dt Chem Ges 1894, 27, 2985–2993. Haupt K. Molecularly imprinted polymers: The next generation. Anal Chem 2003, 75, 376–383. Andaç M, Baydemir G, Denizli A. Molecularly imprinted polymers as a tool for biomolecule separation. In: Grumezescu AM, ed. Nanoscale fabrication, optimization, scale-up and biological aspects of pharmaceutical nanotechnology. Elsevier, 2018, 511–545. Tiwari A, Uzun L. Advanced molecularly imprinting materials. Co-published by John Wiley & Sons, Inc. Hoboken, New Jersey, and Scrivener Publishing LLC, Beverly, Massachusetts, 2017. Zaidi SA. Molecular imprinting polymers and their composites: A promising material for diverse applications. Biomater Sci 2017, 5, 388–402. Wulff G, Sarhan A. Ǚber die Anwendung von enzymanalog gebauten polymeren zur racemattrennung. Angew Chem 1972, 84, 364–364. Wulff G, Sarhan A, Zabrocki K. Enzyme-analogue built polymers and their use for the resolution of racemates. Tetrahedron Lett 1973, 8, 4329–4332. Takagishi T, Klotz I. Macromolecule-small molecule interactions; introduction of additional binding sites in polyethyleneimine by disulfide cross-linkages. Biopolymers 1972, 11, 483–491. Martin-Esteban A. Molecularly-imprinted polymers as a versatile, highly selective tool in sample preparation. TrAC 2013, 45, 169–181. Wulff G. Molecular imprinting in cross-linked materials with the aid of molecular templates – A way towards artificial antibodies. Angew Chem Int Ed Engl 1995, 34, 1812–1832. Mosbach K, Ramström O. The emerging technique of molecular imprinting and its future impact on biotechnology. Nat Biotechnol 1996, 14, 163–170. Sellergren B, Lepisto M, Mosbach K. Highly enantioselective and substrate selective polymers obtained by molecular imprinting utilizing non-covalent interactions. NMR and chromatographic studies on the nature of recognition. J Am Chem Soc 1988, 110, 5853–5860. Cormack PAG, Elorza AZ. Molecularly imprinted polymers: Synthesis and characterization. J. Chromatogr B 2005, 804, 173–182. Piletska EV, Guerriero AR, Whitcombe MJ, Piletsky SA. Influence of the polymerization conditions on the performance of molecularly imprinted polymers. Macromolecules 2009, 42, 4921–4928. Andersson L, Sellergren B, Mosbach K. Imprinting of amino acid derivatives in macroporous polymers. Tetrahedron Lett 1984, 25, 5211–5214. Garcia R, Cabrita MJ, Costa Freitas AM. Application of molecularly imprinted polymers for the analysis of pesticide residues in food. A highly selective and innovative approach. Am J Anal Chem 2011, 2, 16–25. Wang CC, Lee WC. Chromatographic characteristics of cholesterol-imprinted polymers prepared by covalent and non-covalent imprinting methods. J Chromatogr A 2002, 962, 69–78. Peipei Q, Wang G, Wang L, Li Y, Jin J, Su F, Tian Y, Chen J. Molecularly imprinted polymers synthesized via semi-covalent imprinting with sacrificial spacer for imprinting phenols. Polymer 2021, 51, 5417–5423.

References

25

[44] Nilsson C, Nilsson S. Nanoparticle-based pseudostationary phases in capillary electrochromatography. Electrophoresis 2006, 27, 76–83. [45] Rosengren AM, Karlsson JG, Andersson PO, Nicholls IA. Chemometric models of template–molecularly imprinted polymer binding. Anal Chem 2005, 77, 5700–5705. [46] Crapnell RD, Hudson A, Foster CW, Eersels K, Grinsven BV, Cleij TJ, Banks CE, Peeters M. Molecularly imprinted polymer sensing platforms for bioanalyte detection. Sensors 2019, 19, 1204, https://doi. org/10.3390/s19051204. [47] Yoshikawa M, Tharpa K, Dima SO. Molecularly imprinted membranes: Past, present, and future. Chem Rev 2016, 116, 11500–11528. [48] Schich ZL, Zhang Y, Feith M, Beyer S, Sternbaek L, Ohlsson L, et al. Molecularly imprinted polymers in biological applications. Biotechniques 2020, 69, https://doi.org/10.2144/btn-2020-0091. [49] Kotrotsiou O, Kiparissides C. Water treatment by molecularly imprinted materials. In: Sabu T, Pasquini D, Leu SY, Gopakumar DA, eds. Micro and nanotechnologies. Nanoscale materials in water purification. Elsevier, AE Amsterdam, The Netherlands, 2019, 179–230. [50] Yan H, Row KH. Characteristics and synthetic approach of molecularly imprinted polymers. Int J Mol Sci 2006, 7, 155–178. [51] Sundaresan V, Frances HA. Molecular imprinting: Materials for separations, sensor and catalysis. Curr Opin Biotech 1995, 6, 218–224. [52] Olsson GD, Karlsson BCG, Shoravi S, Wiklander JG, Nicholls IA. Mechanisms underlying molecularly imprinted polymer molecular memory and the role of crosslinker: Resolving debate on the nature of template recognition in phenylalanine anilide imprinted polymers. J Mol Recognit 2012, 25, 69–73. [53] O’Mahony J, Nolan K, Smyth MR, Mizaikoff B. Molecularly imprinted polymers-potential and challenges in analytical chemistry. Anal Chim Acta 2005, 534, 31–39. [54] Li J, Zhang L, Fu C. The recognizing mechanism and selectivity of the molecularly imprinting membrane. In: Li S, Cao S, Piletsky SA, Turner APF, eds. Molecularly imprinted catalysts. Principles, syntheses, and applications. Elsevier Inc., 2016, 159–182. [55] Wulff G. The role of binding-site interaction in the molecular imprinting of polymers. Trends Biotechnol 1993, 11, 85–87. [56] Yano K, Nakagiri T, Takeuchi T, Matsui J, Ikebukuro K, Karube I. Stereoselective recognition of dipeptide derivatives in molecularly imprinted polymers which incorporate an L-valine derivative as a novel functional monomer. Anal Chim Acta 1997, 357, 91–98. [57] Matsui J, Doblhoff-Dier O, Takeuchi T. 2-(Trifluoromethyl) acrylic acid: A novel functional monomer in non-covalent molecular imprinting. Anal Chim Acta 1997, 343, 1–4. [58] Takeuchi T, Akeda K, Murakami S, Shinmori H, Inoue S, Lee WS, Hishiya T. Photoresponsive porphyrin-imprinted polymers prepared using a novel functional monomer having diaminopyridine and azobenzene moieties. Org Biomol Chem 2007, 5, 2368–2374. [59] Hishiya T, Asanuma H, Komiyama M. Spectroscopic anatomy of molecular-imprinting of CD. Evidence for preferential formation of ordered CD assemblies. J Am Chem Soc 2002, 124, 570–575. [60] Asanuma H, Akiyama T, Kajiya K, Hishiya T, Komiyama M. Molecular imprinting of CD in water for the recognition of nanometer-scaled guests. Anal Chim Acta 2001, 435, 25–33. [61] Zhang W, Qin L, He XW, Li WY, Zhang YK. Novel surface modified molecularly imprinted polymer using acryloyl-β-CD and acrylamide as monomers for selective recognition of lysozyme in aqueous solution. J Chromatogr A 2009, 1216, 4560–4567. [62] Li J, Wei G, Zhang Y. Molecularly imprinted polymers as recognition elements in sensors. In: Li S, Ge Y, Piletsky SAA, Lunec J, eds. Molecularly imprinted sensors: Overview and applications. Elsevier, AE, Amsterdam, The Netherlands, 2012, 35–55. [63] Cormack PAG, Mosbach K. Molecular imprinting recent developments and the road ahead. React Funct Polym 1999, 41, 115–124.

26

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[64] Yungerman I, Srebnik S. Factors contributing to binding-site imperfections in imprinted polymers. Chem Mater 2006, 18, 657–663. [65] Hilal N, Kochkodan V, Busca G, Kochkodan O, Atkin BP. Thin layer composite molecularly imprinted membranes for selective separation of cAMP. Sep Purif Technol 2003, 31, 281–289. [66] Sellergren B, Lepisto M, Mosbach K. Highly enantioselective and substrate selective polymers obtained by molecular imprinting utilizing non-covalent interactions. NMR and chromatographic studies on the nature of recognition. J Am Chem Soc 1988, 110, 5853–5860. [67] Madikizela LM, Ncube S, Chimuka L. Green chemistry features in molecularly imprinted polymers preparation process. In: Marć M, ed. Comprehensive analytical chemistry. Elsevier BV, 2019, 337–364. [68] Kobaiasi MA, Tate M, Rix C, Jakubov TS, Mainwaring DE. The effect of molecular imprinting on the pore size distribution of polymers. Adsorption 2007, 13, 315–321. [69] Lu Y, Li C, Wang X, Sun P, Xing X. Influence of polymerization temperature on the molecular recognition of imprinted polymers. J Chromatogr B 2004, 804, 53–59. [70] Nicholls IA, Adbo K, Andersson HS, Andersson PO, Ankarloo J, Hedin-Dahlstrom J, et al. Can we rationally design molecularly imprinted polymers?. Anal Chim Acta 2001, 435, 9–18. [71] Lin JM, Nakagama T, Uchiyama K, Hobo T. Temperature effect on chiral recognition of some amino acids with molecularly imprinted polymer filled capillary electro-chromatography. Biomed Chromatogr 1997, 11, 298–302. [72] O’Shannessy DJ, Ekberg B, Mosbach K. Molecular imprinting of amino acid derivatives at low temperature (0 °C) using photolytic homolysis of azobisnitriles. Anal Biochem 1989, 177, 144–149. [73] Cirillo G, Puoci F, Curcio M, Parisi OI, Iemma F, Spizzirri UG, Picci N. Molecular imprinting polymerization by Fenton reaction. Colloid Polym Sci 2010, 288, 698–693. [74] Lorenzo RA, Carro AM, Alvarez-Lorenzo C, Concheiro A. To remove or not to remove? The challenge of extracting the template to make the cavities available in molecularly imprinted polymers (MIPs). Int J Mol Sci 2011, 12, 4327–4347. [75] Batlokwa BS, Mokgadi J, Nyokong T, Torto N. Optimal template removal from molecularly imprinted polymers by pressurized hot water extraction. Chromatographia 2011, 73, 589–593. [76] Wu X, Du J, Li M, Wu L, Hana C, Su F. Recent advance in green reagents for molecularly imprinted polymers. RSC Adv 2018, 8, 311–327. [77] Chen J, Huang X, Wang L, Ma C, Wu S, Wang H. Dummy template surface molecularly imprinted polymers based on silica gel for removing imidacloprid and acetamiprid in tea polyphenols. J Sep Sci 2020, 43, 2467–2476. [78] Liu Y, Wang D, Du F, Zheng W, Liu Z, Xu Z, et al. Dummy-template molecularly imprinted micro-solidphase extraction coupled with high-performance liquid chromatography for bisphenol A determination in environmental water samples. Microchem J 2019, 145, 337–344. [79] Tiwari MP, Madhuri R, Kumar D. Double imprinting in a single molecularly imprinted polymer format for the determination of ascorbic acid and dopamine. Adv Mat Lett 2011, 2, 276–280. [80] Wey S, Jakusch M, Mizaikoff B. Investigating the mechanisms of 17β-estradiol imprinting by computational prediction and spectroscopic analysis. Anal Bioanal Chem 2007, 389, 423–431. [81] Yañez F, Chianella I, Piletsky SA, Concheiro A, Alvarez-Lorenzo C. Computational modelling and molecular imprinting for the development of acrylic polymers with high affinity for bile salts. Anal Chim Acta 2010, 659, 178–185. [82] Pavel D, Lagowski J. Computationally designed monomers and polymers for molecular imprinting of theophylline-part II. Polymer 2005, 46, 7543–7556. [83] Shoravi S, Olsson GD, Karlsson BCG, Nicholls IA. On the influence of crosslinker on template complexation in molecularly imprinted polymers: A computational study of prepolymerization mixture events with correlations to template-polymer recognition behavior and NMR spectroscopic studies. Int J Mol Sci 2014, 15, 10622–10634.

References

27

[84] Lattach Y, Archirel P, Remita S. Influence of the chemical functionalities of a molecularly imprinted conducting polymer on its sensing properties: Electrochemical measurements and semiempirical DFT calculations. J Phys Chem B 2012, 116, 1467–1481. [85] Azimi A, Javanbakht M. Computational prediction and experimental selectivity coefficients for hydroxyzine and cetirizine molecularly imprinted polymer based potentiometric sensors. Anal Chim Acta 2014, 812, 184–190. [86] Prasad BB, Rai G. Molecular structure, vibrational spectra and quantum chemical MP2/DFT studies toward the rational design of hydroxyurea-imprinted polymer. Spectrochim Acta Part A. Mol Biomol Spectros 2013, 105, 400–411. [87] Prasad BB, Rai G. Study on monomer suitability toward the template in molecularly imprinted polymer. An ab initio approach. Spectrochim Acta Part A – Mol Biomol Spectros 2012, 88, 82–89. [88] Martin-Esteban A, Tadeo JL. Selective molecularly imprinted polymer obtained from a combinatorial library for the extraction of bisphenol A. Comb Chem High Throughput Screen 2006, 9, 747–751. [89] Dirion B, Cobb Z, Schillinger E, Andersson LI, Sellergren B. Water-compatible molecularly imprinted polymers obtained via high-throughput synthesis and experimental design. J Am Chem Soc 2003, 125, 15101–15109. [90] Cederfur J, Pei Y, Zihui M, Kempe M. Synthesis and screening of a molecularly imprinted polymer library targeted for penicillin G. J Comb Chem 2003, 5, 67–72. [91] Khan MS, Wate PS, Krupadam RJ. Combinatorial screening of polymer precursors for preparation of benzo[α] pyrene imprinted polymer: An ab initio computational approach. J Mol Model 2012, 18, 1969–1981. [92] Nicholls IA, Andersson HS, Golker K, Henschel H, Karlsson BCG, Olsson GD, et al. Rational design of biomimetic molecularly imprinted materials: Theoretical and computational strategies for guiding nanoscale structured polymer envelopment. Anal Bioanal Chem 2011, 400, 1771–1786. [93] Martins N, Carreiro EP, Locati A, Ramalho JPP, Cabrita MJ, Burke AJ, et al. Design and development of molecularly imprinted polymers for the selective extraction of deltamethrin in olive oil: An integrated computational-assisted approach. J Chromatogr A 2015, 1409, 1–10. [94] Keçili R, Yılmaz E, Ersöz A, Say R. Imprinted materials: From green chemistry to sustainable engineering. In: Szekely G, Livingston A, eds. Sustainable nanoscale engineering. Elsevier, 2020, 317–350. [95] Lu H, Tian H, Wang C, Xu S. Designing and controlling the morphology of spherical molecularly imprinted polymers. Mater Adv 2020, 1, 2182–2201. [96] Yan H, Row H. Characteristic and synthetic approach of molecularly imprinted polymers. Int J Mol Sci 2006, 7, 155–178. [97] Zhang H. Recent advances in macromolecularly imprinted polymers by controlled radical polymerization techniques. Mol Impr 2015, 2, 63–74. [98] Moein MM, Abdel-Rehim A, Abdel-Rehim M. Recent applications of molecularly imprinted sol-gel methodology in sample preparation. Molecules 2019, 24, https://doi.org/10.3390/ molecules24162889. [99] Crapnell RD, Hudson A, Foster CW, Eersels K, van Grinsven B, Cleij JC, et al. Recent advances in electrosynthesized molecularly imprinted polymer-sensing platforms for bioanalyte detection. Sensors 2019, 19, 1204, https://doi.org/10.3390/s19051204. [100] Gui R, Jin H. Recent advances in synthetic methods and applications of photo-luminescent molecularly imprinted polymers. J Photochem Photobiol C: Photochem Rev 2019, 41, 100315, https:// doi.org/10.1016/j.jphotochemrev.2019.08.002. [101] Arabi M, Ostovan A, Bagheri AR, Guo X, Wang L, Li J, et al. Strategies of molecular imprinting-based solid-phase extraction prior to chromatographic analysis. TrAC 2020, 128, https://doi.org/10.1016/j. trac.2020.115923.

28

Chapter 1 Molecular imprinting

[102] Irshad JM, Iqbal N, Mujahid A, Afzal A, Hussain T, Sharif A, et al. E. Molecularly imprinted nanomaterials for sensor applications. Nanomaterials 2013, 3, 615–637. [103] Li Y, Tan T, Svec F. Molecular imprinting of proteins in polymers attached to the surface of nanomaterials for selective recognition of biomacromolecules. Biotechnol Adv 2013, 31, 1172–1186. [104] Roy E, Patra S, Tiwari A, Madhuri R, Sharma PK. Introduction of selectivity and specificity to graphene using an inimitable combination of molecular imprinting and nanotechnology. Biosens Bioelectron 2017, 89, 234–248. [105] Chen W, Ma Y, Pan J, Meng Z, Pan G, Sellergren B. Molecularly imprinted polymers with stimuliresponsive affinity: Progress and perspectives. Polymers 2015, 7, 1689–1715. [106] Li XJ, Chen XX, Sun GY, Zhao YX, Aisa HA. Green synthesis and evaluation of isoquercitrin imprinted polymers for class-selective separation and purification of flavonol glycosides. Anal Methods 2015, 7, 4717–4724. [107] Azizi A, Bottaro CS. A critical review of molecularly imprinted polymers for the analysis of organic pollutants in environmental water sample. J Chromatogr A 2020, 1614, https://doi.org/10.1016/j. chroma.2019.460603. [108] Dong C, Shi H, Han Y, Yang Y, Wang R, Men J. Molecularly imprinted polymers by the surface imprinting technique. Eur Polym J 2021, 145, https://doi.org/10.1016/j.eurpolymj.2020.110231. [109] Malik MI, Shaikh H, Mustafa G, Bhanger MI. Recent applications of molecularly imprinted polymers in analytical chemistry. Sep Pur Rev 2019, 48, 179–219. [110] He S, Zhang L, Bai S, Yang H, Zheng C, Zhang X, et al. Advances of molecularly imprinted polymers (MIP) and the application in drug delivery. Eur Polym J 2021, 143, https://doi.org/10.1016/j. eurpolymj.2020.110179. [111] Tuwahatua CA, Yeung CC, Lam YW, Arul V, Roy L. The molecularly imprinted polymer essentials: Curation of anticancer, ophthalmic, and projected gene therapy drug delivery systems. J Control Release 2018, 287, 24–34. [112] Mohsenzadeh MS, Mohammadinejad A, Mohajeri SA. Simple and selective analysis of different antibiotics in milk using molecularly imprinted polymers: A review. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2018, 35, 1959–1974. [113] Maier NM, Lindner W. Chiral recognition applications of molecularly imprinted polymers: A critical review. Anal Bioanal Chem 2007, 389, 377–397. [114] Song X, Xu S, Chen L, Wei Y, Xiong H. Recent advances in molecularly imprinted polymers in food analysis. Appl Polym Sci 2014, 131, https://doi.org/10.1002/app.40766. [115] He Q, Liang JJ, Chen LX, Chen SL, Zheng HL, Liu HX, et al. Removal of the environmental pollutant carbamazepine using molecular imprinted adsorbents: Molecular simulation, adsorption properties, and mechanisms. Water Res 2020, 168, https://doi.org/10.1016/j.watres.2019.115164. [116] Cui Y, Kang W, Qin L, Ma J, Liu X, Yang Y. Magnetic surface molecularly imprinted polymer for selective adsorption of quinoline from coking wastewater. Chem Eng J 2020, 397, https://doi.org/ 10.1016/j.cej.2020.125480. [117] Yang X, Zhang Z, Li J, Chen X, Zhang M, Luo L, Yao S. Novel molecularly imprinted polymers with carbon nanotube as matrix for selective solid-phase extraction of emodin from kiwi fruit root. Food Chem 2014, 145, 687–693. [118] Wagdy HA, Dinc M, Mizaikoff B. Synthesis of surface imprinted core-shell nanospheres for the selective determination of asparaginase. Anal Methods 2019, 11, 4034–4043. [119] Pijush KP, Alongkot T, Roongnapa S. Biomimetic insulin-imprinted polymer nanoparticles as a potential oral drug delivery system. Acta Pharm 2017, 67, 149–168. [120] Yılmaz E, Garipcan B, Patra HK, Uzun L. Molecular imprinting applications in forensic science. Sensors 2017, 17, 691, https://doi.org/10.3390/s17040691. [121] Idil N, Mattiasson B. Imprinting of microorganisms for biosensor applications. Sensors 2018, 17, 708, https://doi.org/10.3390/s17040708.

References

29

[122] Neves M, Wechsler ME, Gomes ME, Reis RL, Granja PL, Peppas NA. Molecularly imprinted intelligent scaffolds for tissue engineering applications. Tissue Eng Part B Rev 2017, 23, 27–43. [123] Farooq S, Nie J, Cheng Y, Yan Z, Li J, Bacha SAS, et al. Molecularly imprinted polymers' application in pesticide residue detection. Analyst 2018, 143, 3971–3989. [124] Dong H, Wang Y, Ou Y, She J, Shen X, Li J, et al. L. Preparation of molecularly imprinted polymer for chiral recognition of racemic 1,1’-binaphthalene-2,2’-diamine by hplc. Acta Chromatogr 2014, 26, 683–693. [125] Xu S, Wang L, Liu Z. Molecularly imprinted polymer nanoparticles: An emerging versatile platform for cancer therapy. Angew Chem Int 2021, 60, 3858–3869. [126] Alvarez-Lorenzo C, Concheiro A. Handbook of molecularly imprinted polymers. Smithers Rapra Technology. Shawbury, Shersbury, Shrophire, SY4 4NR, United Kingdom, 2013. [127] London JW, Diliën H, Singla P, Peteers M, Cleij TJ, van Grinsven B, et al. MIPs for commercial application in low-cost sensors and assays – an overview of the current status quo. Sens Actuators B Chem 2020, 325, 128973, https://doi.org/10.1016/j.snb.2020.128973. [128] Wackerlig J, Schirhagl R. Applications of molecularly imprinted polymer nanoparticles and their advances toward industrial use: A review. Anal Chem 2016, 88, 250–261.

Chapter 2 Molecularly imprinted membranes: general aspects 2.1 Introduction The employment of innovative strategies for achieving high purification level is a necessity of the modern society. In this perspective, membrane-based technology gave a strategic impulse to the development of highly selective and efficient separation processes in different areas. In this scenario, membrane operations are increasingly replacing the traditional techniques (or integrated with them) in the separation of many classes of compounds from raw sources as well as in recycling wastes in the logic of eco-sustainability and process intensification [1–3]. In an attempt of miming the molecular recognition that occurs in biological systems, the interest of the scientific community was devoted to the combination of membrane science with the molecular imprinting technology for producing “smart membranes” that are capable of realizing separations and purifications at the molecular level. In this context, the so-called molecularly imprinted membranes (MIMs) were obtained. Membrane science was developed long time before the advent of imprinting technology, and the strategy of introducing specific recognition sites on the surface or into the matrix of a membrane sign up new frontiers in the fields of separations. In fact, in comparison with traditional membranes, MIMs display improved specific selectivity preserving in the meantime the separation efficiency. They give the possibility to solve the problem of obtaining high separation and purification efficiency of a specific compound from a complex mixture or a microenvironment containing also other substances or its structural homologues. Simple static membrane adsorptions or solution permeation through the membrane allow achieving this object. Nowadays, MIMs are prepared exploiting different strategies. The presence of print molecule during the production process ensures the formation of its complementary recognition sites into the membrane. Up to now, MIMs have been synthesized for the specific recognition of a wide number of templates like pesticides, vitamins, drug, and dyes [4–6]. They find their applications in various areas such as solid-phase extraction of bioactive compounds from raw matrices, enantiomeric separation, controlled drug delivery, enzymatic catalysis, sensor development, and water treatment [4–6]. In the last years, we are witnessing a continuous growth in the production of MIMs that are increasingly innovative as well as their combination with other traditional operations or membranes for the realization of integrated and continuous processes. This is an important and encouraging factor to the world’s population, considering that the efforts done by the research community in this field will have a real positive impact on health care, environmental protection, energy saving, as well as in industrial development.

https://doi.org/10.1515/9783110654691-003

2.2 Membrane-based separations

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This chapter gives an introduction to the membrane-based separation processes and to the general aspects of MIMs. In addition, the separation mechanisms of MIMs and the evaluation of their performance are given. Eventually, strategic approaches for developing them via green routes are also highlighted.

2.2 Membrane-based separations A membrane is definite as a selective barrier interposed between two neighboring phases, which has the ability to control the transport of chemical species among the two phases. The separation is achieved, owing to the different permeabilities of the involved substances, and the transport occurs by convection or diffusion due to the presence of an appropriate driving force (i.e., pressure gradient, concentration gradient, temperature gradient, and electrical field) across the membrane [7–10]. The convective transport of a solute is typical of porous membranes working in liquid phase by employing a pressure gradient as a driving force. In this case, solutes flow together with the solvent, thanks to the pressure difference existing between the two sides of the membrane, which acts as a molecular sieve. The permeate stream contains only solutes having a size smaller than the pore’s diameter of the membrane. The Darcy’s law, which relates flux and pressure, governs the transport through the membrane: J = −Lp · ΔP=Δx

(2:1)

where J is the solvent flow (in L · m−2 · h−1), Lp is the hydraulic permeability of the membrane (in L · m−2 · h−1 · bar−1), ΔP is the pressure gradient existing between the two faces of the membrane, and Δx is the thickness of the membrane. Since the solvent flow, the pressure gradient, and the thickness are experimentally measurable, from equation (2.1), it is possible to calculate the hydraulic permeability of a membrane: Lp = J=ðΔP · ΔxÞ

(2:2)

The diffusive transport is typical of dense membranes or membranes with extremely small pores. In this case, the solutes and the solvent move due to a concentration or a chemical potential gradient and pass through the membrane matrix, thanks to a “solubility-diffusion” process. In particular, the solvent and the solutes dissolve into the membrane phase from the side where the pressure is applied (the pressurized face) and then spreads, finding themselves on the other side of the membrane, which acts as a diffusive barrier. The separation is obtained, owing to the fact that each solute, due to its chemical–physical properties, exhibits a specific solubility (or affinity) and diffusivity in the material forming the membrane. The higher the solubility and diffusivity of a molecule toward a membrane, the more easily it can pass through the membrane. This

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Chapter 2 Molecularly imprinted membranes: general aspects

type of transport also affects the separation of gases and vapors. The following relationship permits to determine the permeability of a component through a membrane: P=S·D

(2:3)

where P is permeability, S is solubility, and D is diffusivity. The solubility represents the amount of penetrant absorbed by the membrane, while the diffusivity indicates how quickly the penetrant through the membrane. In addition to the above-cited transport models, in the presence of charged species, the separation is governed by electrostatic interactions between fixed charges on the membrane and the species to be treated. The separation is due to the membrane capacity to let through by the ions of opposite charge (counterions) with respect to its surface charges and retain ions having the same charge. These interactions allow for other types of transport such as transport facilitated by carriers. The latter can be the fixed charges of a solid membrane or chemical compounds dissolved in a liquid membrane. Finally, the transport of a charged species can also be carried out by coupling it with a charge of opposite sign that moves in its same direction (coupled transport in cocurrent) or with a charge of the same sign that moves in the opposite direction (coupled transport in countercurrent). The advent of membrane separation processes gave a great contribution in different fields for achieving high recovery and purification level of valuable compounds from raw sources or waste streams on both small and large scale. The processes that use membranes as separation tools are named membrane operations; they differ on the basis of the physiochemical properties and size of the substances to be managed. Membrane operations are more efficient with respect to the traditional separation techniques for many reasons: operation in mild conditions in both water and organic medium, low energy intake, and any phase change (or low). In addition, membranes can operate in continuous mode and in integrated systems [11, 12]. The most common membrane separation processes that exploit also the imprinting technique are microfiltration (MF), ultrafiltration, nanofiltration (NF), reverse osmosis (RO), membrane distillation (MD), electrodialysis, and pervaporation (PV) [3, 7, 8, 13–15]. Proceeding from MF to RO, the driving force is a pressure gradient, and the pore size of the membranes and the dimension of the substances that need separation become smaller and smaller. The reduction of membrane’s pores causes an increase in the mass transport (solvent and solutes) resistance exerted by the membrane itself. Therefore, in the RO, the applied pressure is higher than the one applied in the other cases. MD allows separating volatile solutes from nonvolatile solutes such as macromolecules, salts, and colloids by means of a temperature gradient. In PV, both a pressure gradient and a temperature gradient are employed as driving forces, and the process leads to the movement of volatile organic compounds from the liquid phase to the vapor phase by means of the solubilitydiffusion mechanism. The first example of membrane separation at the industrial level

2.3 Molecularly imprinted membranes

33

deals with the water desalination by means of RO. Since then, the membrane-based separation processes have found their applications in various areas: in heterogeneous catalysis [16], drug delivery [17], water treatment [18–20], food processing [21], pharmaceutical purifications and solvent recovery [22, 23], gas separations [24], and so on [5, 24–28]. The growing demand for highly selective materials has stimulated the scientists to take advantage of the combination of molecular imprinting technique and membrane science. Thus, the idea of introducing specific recognition sites into the matrix or on the surface of membranes, conferring them specific recognition properties at both molecular and ionic levels, was born.

2.3 Molecularly imprinted membranes MIMs are a special format of imprinted polymers exhibiting specific recognition properties. The advent of MIMs gave a relevant contribution in developing novel recognition tools in membrane-based advanced processes for the selective separation of targeted biological and chemical substances. In particular, the high specificity, mechanical resistance, easy preparation, and reusability rendered MIMs suitable for operations based on molecular recognition and competitive with respect to MIPs and the traditional separation techniques, which do not have the membrane ability of working in the continuous operation mode. Furthermore, in comparison with traditional membranes, MIMs present highly selective recognition and separation properties. This is because they contain the memory of the targeted molecules and are capable of separating them from the mixture containing other compounds, including also their analogues (see Fig. 2.1). Similar to imprinted polymers, MIMs also interact with targeted compounds via both covalent and noncovalent binding or their combination [29–31]. In the last decades, all these aspects lead to the continuous preparation of MIMs in many configurations (such as flat sheet, hollow fiber, nanofiber, and nanowire) by exploiting different materials and strategies. The arguments treated in this book are devoted to polymeric imprinted membranes. Some of the most synthetic polymers used as membrane-forming materials are acrylic copolymers [32, 33], polyamide (PA) [34, 35], polyvinylidene fluoride (PVDF), polyethersulfone, polycarbonate [36], polystyrene [37], polysulfone [38], chitosan (CS) [39], cellulose acetate (CA)/sulfonated polysulfone blends [40], sodium alginate (SA) [41], and so on. Figure 2.2 shows an example of a flat-sheet MIM retaining the target molecules, thanks to specific interactions occurring between chemical moieties of the template and the complementary recognition sites of the membrane. The other substances present in the initial solution (feed side) are not capable of interacting with the recognition sites of the membrane and are therefore collected into the permeate stream.

34

Chapter 2 Molecularly imprinted membranes: general aspects

Fig. 2.1: General features of imprinted membranes.

Fig. 2.2: Flat-sheet molecularly imprinted membrane that selectively binds the template molecules.

After the separation, the target molecules are recovered from the membrane by means of filtration with appropriate solvents or other processes (i.e., ultrasound or microwave-assisted extraction, etc.). MIMs have attracted great attention for applications in different sectors, such as environmental, pharmaceutical, and agricultural fields. In this context, they are used for detecting food additives and water contaminants, for recovering a specific compound from enzymatic reactions, fermentation broths, natural matrices, or water, and for enantiomeric resolutions. Figure 2.3 shows some classes of target templates in developing MIMs.

2.3 Molecularly imprinted membranes

35

Fig. 2.3: Some types of templates used in developing molecularly imprinted membranes.

Each class includes different substances. For example, some pharmaceuticals are propranolol, tetracycline, theophylline, naproxen, ibuprofen, and so on. Some pesticides are atrazine and trichlorfon, while bisphenol A and estradiol are examples of endocrine disruptors. Phenylalanine, riboflavin, and tobacco mosaic virus are examples of targeted amino acids, vitamins, and viruses, respectively. Yet, naringin and quercetin are examples of bioactive compounds. In the logic of process intensification, MIMs are viewed as smart membranes that can be integrated with traditional or other membrane-based separation procedures by combining different units in a single system. In this context, the integration of MIMs with NF, distillation, or crystallization units gives the possibility of improving the utilization of raw materials and the separation efficiency, always considering the economic and environmental aspects, which are relevant for industrial applications of these separation tools. Some problems that can affect the performance of MIMs can be the restricted approachability of recognition sites, owing to their random distribution on the membrane surface as well as in its bulk structure. Furthermore, it is necessary to reduce the solvent volume and replace toxic reagents used sometimes for their preparation.

36

Chapter 2 Molecularly imprinted membranes: general aspects

From this point of view, innovative and green synthetic strategies are under development. Some of these aspects will be discussed later.

2.4 Separation mechanism and performance evaluation of MIMs The separation of template molecules with MIMs occurs mainly via two different transport mechanisms: facilitated permeation and retarded permeation [5, 29–31, 42]. In the first case, typical of microporous membranes, binding and desorption to the nearby recognition sites create a preferential pathway, promoting a more rapid transport of the template. On the other hand, the nonspecific diffusion of competing solutes is delayed by the membrane matrix. Furthermore, for these membranes, the template binding to the recognition sites may cause a membrane shrinking or swelling, thus reducing or increasing the membrane permeability, respectively [31, 42]. In the presence of a retarded permeation, the binding or binding/desorption to the recognition sites avoids or retards the transport of template molecules through the membrane with respect to the other solutes that move via nonspecific convection or diffusion. This behavior is due to the binding affinity between the template and the complementary recognition sites of the membrane. This type of separation mechanism occurs generally with macroporous membranes, which are regarded as “adsorber systems” [29–31, 42]. Sometimes, the separation relies on the selective adsorption mechanism. It entails the adsorption of template molecules, owing to the interaction with the recognition sites on the membrane’s surface and on the surface of its pores, while other competing compounds accumulate in the treated solution. Table 2.1 reports some selected examples of developed MIMs, their relative templates, functional monomers, and separation mechanisms. For example, Zhao et al. developed MIMs with high adsorption capacity and selective properties toward the bioactive compound acetoside [44]. It is a bioactive compound present in Cistanche tubulosa plant and has many therapeutic properties such as antioxidation, antitumor, antiaging, kidney-replenishing, and improving memory. This study demonstrated the efficiency of acetoside-imprinted membranes in retarding the permeation of the template during permeation experiments. The selectivity factor (α) acetoside versus its structural analogue echinacoside was up to 2.74 [44]. Another application is the removal of pesticides, drugs, and antibiotics from water. Kashani et al. [48] prepared 2,4-dichlorophenoxyacetic acid-imprinted membranes able to selectively remove this herbicide from water via facilitated permeation [48]. Enantiomeric separation of naproxen was also done by Donato et al. [67], who successfully developed poly(propiylene-co-4-vinylpiridine) membranes imprinted with the anti-inflammatory drug S-naproxen. Filtration experiments carried out with racemic naproxen evidenced a selective permeation of the template enantiomer with respect to the opposite enantiomer R-naproxen [67]. Silvestri and coworkers [69] produced MIMs

Acetoside (bioactive compound)

Norfloxacin (antibiotic)

Cholesterol (lipid)

-Vinylpiridine Acrylamide

Acrylamide

Acrylic acid

Methacrylic acid

Acrylamide

Methacrylic acid

Dopamine

N-Methacrylolyl-Ltryptophan methyl ester

Polyvinylidene fluoride/poly (-vinylpiridine)

Polyvinylidene fluoride/polyacrylamide

Polyacrylamide

Polyvinylidene/poly(acrylic acid)

Polysulfone

Polyvinylidene fluoride/polyacrylamide

Polyether ether ketone

Regenerated cellulose/polydopamine

Poly(-hydroxyethylmethacrylatemethacryloylamidotryptofan)

Separation of bioactive compounds

Purification of active pharmaceutical ingredients

Removal from water

Application

Theophylline (anti-asthmatic drug)

Blood detoxification

Selective adsorption

Retarded permeation

Retarded permeation

Solid-phase extraction

Recovery from water

Selective adsorption

Facilitated permeation

Retarded permeation

Facilitated permeation

Selective adsorption

Retarded permeation

Retarded permeation

Transport mechanism

Sensing in biological samples

Decontamination of water

,-Dichlorophenoxyacetic acid (herbicide) Teicoplanin (antibiotic)

Removal of trace analytes in pharmaceutical synthesis

p-Hydroxybenzoic acid (antimicrobic)

Ebracteolata(antitubercle and Extraction from natural plant anti-cancer drug)

Quercetin (bioactive compound)

Bisphenol A (endocrine disrupter)

Methacrylic acid

Polyvinylidene fluoride/poly (methacrylic acid)

Template

Functional monomer

Polymeric membrane matrix

Tab. 2.1: Some examples of molecularly imprinted membranes and their separation mechanisms.

(continued)

[]

[]

[]

[]

[]

[]

[]

[]

[]

[]

Reference

2.4 Separation mechanism and performance evaluation of MIMs

37

Artemisinin (antimalarial agent) Lysozyme (protein)

Methacrylic acid

Acrylamide -Vinyl--ethyl acetate imidazolium chloride Methacrylic acid

Methacrylic acid

Methacrylic acid

Acrylic acid

Acrylic acid

Chloromethylated polysulfone/poly (methacrylic acid)

Polyvinylidenefluoride/polydopamine/ polyacrylamide

Regenerated cellulose

Polyvinylidene fluoride/poly (methacrylic acid)

Poly(acrylonitrile-co-methacrylic acid)

Polysulfone

Poly(acrylonitrile-co-acrylic acid)

Polysulfone/poly(acrylic acid)

Enantiomeric separation

Purification of proteins in biosamples

Selective extraction from plants

Separation of alkaloids

Sensing in serum

Removal from milk

Application

Removal from water

Removal from organic solvent

,-Methylendianiline (genotoxin) Erythromycin (antibiotic)

Purification of antibiotics

Roxithromycin (antibiotic)

(–)-Cinchonidine (antimalaria) Selective extraction

Levodropropizine (antitussive)

Matrine (biological fertilizer)

Taurine (β-amino acid)

verificare

L-Methionine

Poly(L-methionine)

Template Melamine (triazine)

Functional monomer

Cellulose acetate/poly(methacrylic acid) Methacrylic acid

Polymeric membrane matrix

Tab. 2.1 (continued)

Facilitated permeation

Retarded permeation

Facilitated permeation

Selective adsorption

Facilitated permeation

Facilitated permeation

Facilitated permeation

Facilitated permeation

Selective adsorption

Retarded permeation

Transport mechanism

[]

[]

[]

[]

[]

[]

[]

[]

[]

[]

Reference

38 Chapter 2 Molecularly imprinted membranes: general aspects

S-Naproxen (antiinflammatory)

-Vinylpyridine Acrylic acid

Polypropylene/poly(-vinylpyridine)

Poly(acrylonitrile-co-acrylic acid)

Naringin (bioactive compound)

Creatinine (metabolic waste product)

Vinyl alcohol

Poly(ethylene-co-vinyl-alcohol)

Luteolin (bioactive compound) Vanillin (aroma)

Vinyltriethoxysilane

Polysulfone

Diosgenin (hypocholesterolemic)

Cellulose acetate/poly(methacrylic acid) Methacrylic acid

Acrylic acid

Poly(acrylonitrile-co-acrylic acid)

Removal from fruit juices

Enantiomeric separation

Sensing kidney dysfunction

Isomeric separation

Separation of bioactive compounds

Selective extraction from natural source

Retarded permeation

Facilitated permeation

Facilitated permeation

Facilitated permeation

Retarded permeation

[]

[]

[]

[]

[]

[]

2.4 Separation mechanism and performance evaluation of MIMs

39

40

Chapter 2 Molecularly imprinted membranes: general aspects

for clinical applications using poly(ethylene-co-vinyl alcohol) (P(E-co-VA) as membrane forming base polymer and amylase and phosphatidylcholine as templates. The following chapters will discuss more closely about MIMs specific for some of these applications. The attention will also be devoted to the different methods used for preparing MIMs. The performance of MIMs is evaluated by realizing static adsorption or permeation experiments. When membranes are tested only in static rebinding experiments, the mechanism controlling the process is the selective adsorption. For assessing the specific recognition properties and the separation efficiency of MIMs, some important parameters are determined. They are the binding capacity (Q), the imprinting factor (IF), and the selectivity factor (α). The binding capacity and the imprinting factor allow evaluating the specific recognition properties of an MIM, while the selectivity factor permits to evaluate the membrane ability in separating template molecules from other competing similar compounds present in the same test solution. The binding capacity represents the amount of template bound to the membrane. It is calculated by means of the following equation: Q = ðC0 − Ct ÞV=Wm

(2:4)

where C0 is the initial concentration of the template in the test solution, Ct is the concentration of the template measured at interval time, V is the volume of the tested solution, and Wm is the membrane weight. The difference between the binding capacity of an imprinted membrane and that one of corresponding nonimprinted membrane (NIM) gives the specific binding capacity, which represents the amount of the template retained, owing to the imprinted effect. On the contrary, in the case of NIM, only nonspecific interactions occur. The NIM is prepared under the same operating condition of an MIM but in the absence of the template. As it is evident by the following equation, the ratio between the binding capacity of an MIM and one of its corresponding NIM permits to calculate the imprinting factor: IF = QMIM =QNIM

(2:5)

where QMIM is the binding capacity of the imprinted membrane and QNIM is the binding capacity of the nonimprinted one. The separation factor can be determined according to the following equation:
(2:6) α = Ct, p =Cc, p =ðCt, r =Cc, r Þ where Ct,p and Ct,r are the concentrations of the template in the permeate and retentate streams, respectively, while Cc,p and Cc,r are the concentrations of the competing analyte in the same streams.

2.4 Separation mechanism and performance evaluation of MIMs

41

In binding studies, for determining the maximum adsorption/binding capacity of an MIM and evaluate the binding characteristics at equilibrium, adsorption/binding isotherms reporting the concentration of the bounded template versus the concentration of the free template are constructed. These data can be fitted with Langmuir and Freundlich isotherm models for investigating the binding from an energy point of vision. For determining the binding affinity between the template and the recognition sites as well as the type of recognition sites, the Scatchard analysis is also used [44, 46, 47, 70–72]. Equations (2.7) and (2.8) express the Langmuir and Freundlich isotherm models, respectively: ð1=Qe Þ = ð1=ðKa Qm Ce Þ + ð1=Qm Þ

(2:7)

logðQe Þ = logðKF Þ + 1=n · logðCe Þ

(2:8)

where Qe is the amount of the template adsorbed on the membrane at equilibrium, Ce is the equilibrium concentration in the bulk solution, Qm is the maximum monolayer adsorption capacity, n is the adsorption intensity, Ka and Kf are the Langmuir and the Freundlich constants, respectively, which measures the free energy adsorption. The Langmuir isotherm model describes a monolayer adsorption on a membrane containing homogeneous recognition sites. From the slope and the intercept of a linear plot 1/Qe versus 1/Ce, it is possible to determine the isotherm parameters (Ka and Qmax). Yet, the correlation coefficient can be determined. The Freundlich isotherm model suggests an adsorption on a heterogeneous surface with interactions between the adsorbed molecules. From the linear plot of log (Qe) versus log(Ce), it is possible to determine the Freundlich constant, the adsorption intensity, and the correlation factor [44, 46, 47, 70–72]. From understanding the binding control mechanism, the pseudo-first-order and the pseudo-second-order kinetic models are usually applied. They are expressed by the following mathematical equations, respectively: lnðQe − Qt Þ = lnðQe1 − K1 tÞ 1=Qt = ð1=K2 Qe2 Þ + t=Qe

(2:9) (2:10)

where Qe and Qt are the amount of adsorbate at the equilibrium and at time t, respectively. Qe1 and Qe2 are the theoretical adsorption capacities of the first-order and the second-order models, respectively. K1 and K2 are the equilibrium rate constants of first- and second-order sorption. Their values can be determined from the plot of ln(Qe – Qt) versus t and 1/Qt versus t, respectively [44, 46, 47, 70–72]. The Scatchard equation is Qe =Ce = Qmax Ka − Qe Ka + Qmax − Ce =Ka

(2:11)

where Qe and Ce are the amount of the analyte bounded to the membrane and its concentration at equilibrium, respectively. Ka is the association constant and Qmax is the apparent maximum binding capacity. From the plot of Qe/Ce versus Qe, it is possible to

42

Chapter 2 Molecularly imprinted membranes: general aspects

calculate the binding affinity constant. If a membrane has homogeneous binding sites, the Scatchard plot will have a straight line. As a whole, during filtration studies, the transport fluxes exhibited by template molecules and their competing compound allow determining the separation mechanism case by case. Sometimes, the operating conditions such as pH, temperature, and other factors may affect the separation mechanism, as occurs in stimuli-responsive MIMs. For example, Cheng and coworkers [73] demonstrated that podophyllotoxin-imprinted membranes facilitated either retarded permeation of template molecules as a function of the pH of sample solution. In particular, at pH higher than 8.4, the separation was achieved via the retarded permeation of podophyllotoxin with respect to the analogue 4ʹ-demethylpodophyllotoxin. On the other hand, for pH values below 8.4, a facilitated permeation of the template occurred. The keto-enol tautomerization of the β-diketone 1-phenyl-3-methyl-4-methacryloyl-5-pyrazolone (used as the functional monomer) when changing the pH value of the test solution this behaviour was due to the ketoenol [73]. Figure 2.4 shows the effect of pH on the transport of podophyllotoxin and its analogue through the imprinted membranes during permeation experiments.

Fig. 2.4: Transport of podophyllotoxin (PPT) and its analogue 4ʹ-demethylpodophyllotoxin (DMEP) through a pH-responsive podophyllotoxin-imprinted membrane. The initial solution is 60 mL PPT/DMEP CH3OH mixture (200 µg · mL−1) (reprinted from ref. [73]. Copyright 2013, with the permission of Wiley).

Novel multifunctional nanocomposite membranes imprinted with ovalbumin represent an example of thermoresponsive smart membranes able to control their separation performance and reversible cell adhesion/detachment in cell culture in dependence of the temperature variation [74]. In more detail, adsorption and permeation experiments carried out with solutions containing ovalbumin as well as LYS and bovine hemoglobin evidenced high binding capacity and excellent membrane selectivity at 37 °C, while at 20 °C no specific recognition capacity, lower adsorption, and permeation rate were observed. This was because when the operation temperature decreased from 37 to 20 °C, the imprinted sites became expanded conformational transitions losing their complementarity

2.4 Separation mechanism and performance evaluation of MIMs

43

toward template molecules. Furthermore, in Fig. 2.5, it is evident that in cell adhesion/ detachment experiments performed with the template-bound MIM lowering of culture temperature from 37 to 20 °C (after cell adhesion step), more than 80% of the adhered cells was released from the membrane surface together with ovalbumin [74].

Fig. 2.5: Reversible adhesion and detachment of cells on ovalbumin-molecularly imprinted nanocomposite membrane (reprinted from ref. [74]. Copyright 2021, with the permission of Elsevier).

This means that at 20 °C, the template desorption from the membrane surface induced cell detachment. In another case [75], bulk liquid membranes containing nano-sized atenolol-imprinted polymer particles exhibited better selectivity and a facilitated permeation of the template than the corresponding membranes containing micro-sized imprinted particles, which showed a retarded permeation mechanism. This result was because of decreasing particle diameter, and more portions of the recognition sites were drawn near to the surface, thus facilitating their interaction with template molecules [75]. Various analytical techniques for chemical and morphological characterizations of MIMs (and their corresponding NIMs) such as nuclear magnetic resonance, X-ray photoelectron spectroscopy, elemental microanalysis, and Fourier-transform infrared spectroscopy were used for determining the qualitative and quantitative chemical composition of the membrane, thus assessing the presence of the functional moieties in the membrane [45, 51, 53, 59, 61, 64]. In order to support computational studies about the template-monomer interactions for determinign the best functional monomer for a given template, the UV visible spectroscopy is also used [65]. Raman spectroscopy allows performing direct observation of the interaction between the template and the

44

Chapter 2 Molecularly imprinted membranes: general aspects

recognition sites of the membrane [59]. Brunauer–Emmett–Teller analysis determines the membrane-specific surface area [54, 76]. Morphological characterization of membrane surface and microstructure, surface roughness, and pores is done by scanning electron microscopy and atomic force microscopy (AFM) [76, 51]. Figure 2.6 shows AFM images of the original regenerated cellulose membrane and norfloxacin-imprinted regenerated cellulose membranes/polydopamine nanocomposite membrane [51]. For preparing these membranes, dopamine was used as a functional monomer, and a norfloxacinimprinted polydopamine layer was constructed on the surface of TiO2 nanospheres that were subsequently immobilized on the regenerated cellulose support membrane by vacuum-assisted filtration process [51].

Fig. 2.6: AFM images of original regenerated cellulose membrane (h) and norfloxacin-imprinted regenerated cellulose membranes/polydopamine membranes (i) (reprinted from ref. [51]. Copyright 2021, with the permission of Elsevier).

It is evident that the roughness of the imprinted membrane is higher than that of the original one, thus indicating an increase of the surface area. In addition, owing to the presence of the imprinted nanocomposites, the MIM exhibited more hydrophilic characters, as confirmed by the contact angle measurements [51]. The determination of the contact angle of a membrane is a technique that permits to evaluate its wettability. When using water, materials exhibiting a contact angle lower than 90° are defined hydrophilic, while those having a contact angle greater than 90° are hydrophobic [45]. Other characterizing parameters are swelling and water (or solvent) permeability, which can affect the recognition and separation performance [45, 51, 52, 59]. A deep discussion of all characterization methods is beyond the scope of this chapter, and more information can be found in the cited literature.

2.5 Green imprinted membranes

45

2.5 Green imprinted membranes The chemical and mechanical stabilities as well as the possibility of their reuse make imprinted membranes coherent with the green chemistry conception, even if sometimes during their preparation reagents not properly green are used. From this viewpoint, rational synthetic strategies aimed at using renewable and sustainable materials in order to reduce the environmental impact are pursued in the last years. For example, the use of natural polymers and environmentally friendly functional monomers, cross-linkers, and initiators is meaningfully emerging, also with the aid of computational approaches [77–81]. For example, ionic liquids as functional monomers or green solvents are under investigation as a new class of reagents alternative to the organic ones. Ionic liquids possess different features in agreement with the green imprinting concept. They are miscible with a large number of organic solvents, and present high stability, viscosity, and high ionic conductivity. Other properties are low vapor pressure, nonvolatility, nonflammability, and good extractability for a wide variety of materials [78, 79, 82]. Some ionic liquids used as functional monomers are 1-vinyl-3-butylimidazolium chloride [79], SA [41, 83], 1-vinyl-3-ethyl acetate imidazolium chloride, 3-(3-aminopropyl)-1-vinylimidazolium tetrafluoroborate, and so on [78, 84]. For example, Zhou and coworkers [41] synthesized a self-supported membrane for D-tryptophan using the natural polymer SA as the functional polymer, water as the solvent, and calcium chloride as the cross-linker. Membranes, prepared via the phase inversion technique, promoted the selective permeation of the template enantiomer [41]. In another case, authors prepared the compositeimprinted membranes using the same reagents and template molecule via surface imprinting of a commercial PVDF membrane [83]. Results of this study showed as the green synthesis of MIMs reduced not only the operating costs and the environmental impact but also increased the membrane performance with respect to the other traditional synthetic methods. In this case, membranes exhibited a facilitated permeation of the target analyte [83]. Previously, Wang et al. [85] produced surface-initiated atom transfer radical polymerization composite membranes using the ionic liquid 1-vinyl-3ethyl acetate imidazolium chloride (self-synthesized) and regenerated cellulose membrane as a support. The obtained MIMs were applied in solid-phase extraction of the immunostimulant thymopentin from crude samples. Molecular modeling studies for assessing the molecular interaction of thymopentin–functional monomer were also carried out [85]. Another way for realizing the molecular imprinting of toxic, expensive, or precious target substances is the template analogue imprinting strategy with green dummy templates structurally related to the target compounds. For the first time, Lee and coworkers used the nontoxic 1-naphthol for producing hybrid imprinted membranes capable of recognizing the mycotoxin citrinin in rice [86]. This is a very interesting case, demonstrating the green consistency of template analogue strategy in avoiding the use of toxic templates, thus preserving human and environmental health. Figure 2.7 shows the synthetic process.

46

Chapter 2 Molecularly imprinted membranes: general aspects

Fig. 2.7: Schematic representation of the dummy imprinted process using 1-naphthol as a dummy template for the selective recognition of citrinin in rice samples with 1-naphthol–hybrid imprinted membrane (reprinted from ref. [86] Open Access).

Recently, an MIM-based sensor able to detect zearalenone (which is another mycotoxin) in liquid extracts from cereal samples (wheat, rye, and maize flour) was produced using cyclododecyl 2,4-dihydroxybenzoate as a dummy template [87]. Membranes were used as the basis for producing a digital smartphone sensor for the mycotoxin detection via fluorescence measurements in aqueous extracts. Upon binding with the membrane, the fluorescence of the analyte was recorded with a digital smartphone camera. Subsequently, a mobile application processed the recorded signal. The increase of zearalenone concentration (within the range of 1–25 µg · mL−1) in the tested samples allowed a proportional increase in intensity of fluorescence of the cyclododecyl 2,4dihydroxybenzoate-imprinted membrane. Furthermore, during analysis of complex multicomponent samples, the selective fluorescent sensor was able to discriminate the zearalenone from resorcinol, bisphenol A, and other mycotoxins that can contaminate food (aflatoxin B1, aflatoxin G2, and ochratoxin A). Wang and coworkers produced composite MIMs using lovastatin acid as a target similar to the lactone form statin [88]. The structure of these two forms is very similar, and if one of them is used as a template molecule, a cross-reaction of the imprinting effect may result. Interestingly, the multitemplate imprinting approach also fulfills the concept of the green-based MIM synthesis. It entails the imprinting of different target compounds simultaneously, thus reducing the quantity of consumed reagents and permitting the detection and separation of series of similar compounds in complex matrices. Wei and coauthors prepared composite MIMs by photocopolymerization of α-methacrylic acid with a polyvinylidene fluoride commercial membrane using cinnamic acid and ferulic acid as mixed templates [89]. Recently, a new synthetic strategy for producing green

2.5 Green imprinted membranes

47

imprinted membranes was developed [90]. In particular, according to the biomassbased approach, biomass-activated carbon nanoparticles as the porous filler were integrated into hybrid CA/CS membranes for obtaining biodegradable nanocomposite MIMs. Tetracycline was used as the template molecule. It is a broad-spectrum antibiotic largely used in human and animal medications and therefore responsible for environmental pollution. These new membranes exhibited desired degradability and better performance in tetracycline-specific recognition with respect to MIMs prepared with the traditional methods. Furthermore, in comparison with other carbon-based materials (carbon nanotubes and graphene), the production of biomass-activated carbon is a sustainable simple synthetic method and attracted interest for the capacity to enhance membrane hydrophilicity and permeate flux [90]. The used solvents represent also an important factor to consider in green MIM production. According to the green chemistry principles [78, 79, 91–93], in the last years, the attention is devoted to the eco-friendly acetone, ethanol, ionic liquids, isopropanol, ScCO2, deep eutectic solvents, and water. The advantages of ScCO2 are low cost, nontoxicity, nonflammability, and inertia. Furthermore, it can be easily recovered and recycled. It is a fluid that combines the best properties of a gas (high diffusivity and low viscosity) and a liquid (density) and exhibits high mass transport capacity and diffusion coefficient with respect to the liquids. Owing to its low dielectric constant and nonpolar nature, CO2 is a proper solvent for both nonpolar molecules having low-molecular-weight as well as small polar molecules. It is also a good porogen capable of stabilizing template–monomer complexes, leading to the formation of membranes with high affinity for the template. In addition, thanks to its nearzero surface tension, ScCO2 is an optimum extracting medium, and a small change in pressure and temperature allows modulating its properties. In particular, at high pressure, its solvent power is similar to one of liquid solvents, while at low pressure, it acts like a gas by releasing the molecules it had previously solubilized [91, 92]. In 2008, Kobayashi and coworkers [94] firstly employed the supercritical CO2 for preparing uracil-poly(styrene-co-maleic acid) MIMs via the phase inversion technique. During the process, ScCO2 was used as an antisolvent-inducing membrane formation. Membranes were prepared at 35 and 50 °C. Binding experiments showed that membranes prepared at higher temperature exhibited better binding affinity (12.6 µmol · g−1 vs 9.2 µmol · g−1). Furthermore, in selectivity studies, they exhibited good selectivities with respect to the structural analogues cytosine, dimethyluracil, and thymine. The separation factor (α) of uracil/dimethyluracil and uracil/thymine was 17, while the selectivity factor of uracil/cytosine was 13 [93]. Zhang et al. adopted the same strategy for preparing oleanolic acid-composite MIMs using PA-6 as a polymer-forming base membrane, poly(styrene-co-maleic acid) as a functional polymer, and different amounts of the template [95, 96]. Membranes prepared with a mass ratio of functional polymer/template of 6:1, temperature and pressure of ScCO2 of 40 °C and 15 MPa, respectively, exhibited the best adsorption properties. Bisphenol A-hybrid imprinted membranes’ have been also prepared by incorporating highly cross-linked poly

48

Chapter 2 Molecularly imprinted membranes: general aspects

(methacrylic acid)-imprinted polymeric particles synthesized in ScCO2 via the noncovalent approach into a poly(methacrylic acid)-scaffold membrane [97]. Results of adsorption tests in aqueous solutions fitted with Langmuir equation showed that the binding occurred at homogeneous affinity recognition sites within the imprinted membrane surface. Furthermore, in filtration experiments, hybrid MIMs displayed high binding capacity toward the target molecules and an increase in permeability with respect to the original poly(methacrylic acid)-based membrane. In another case, the efficacy of combining semicovalent molecular imprinting and supercriticalassisted phase inversion for producing hybrid membranes imprinted with the same endocrine disruptor was also demonstrated [92]. The removal of the template from an MIM both after membrane preparation and the rebinding step is another important aspect that must be highlighted. In this view, green approaches for template recovery are represented by ultrasonic treatment, ScCO2, pressurized hot water extraction, and deep eutectic solvents [4, 78, 79]. An example of green template extraction is given by the employment of ScCO2 as a fluid extraction system in preparation of the isocoumarin bergenin-imprinted membranes [98]. It is clear that the coming of MIMs sign up a new way for the detection, transport, or retention of targeted biological and chemical substances. All this made them optimal applicants for the development of advanced membrane processes. The significant increase of the scientific literature in this area and the advent of green synthetic strategies confirm the continuous efforts of the research activity on MIM development. Many types of imprinted membranes have been already prepared, and it is expected that in the near future, the green synthetic strategies will replace more and more traditional production routes. This is a very important objective in the logic of realizing sustainable separation processes and process intensification, also for fortifying their applications at industrial level, which is yet in the early stage.

References [1] [2] [3]

[4]

[5]

Rajesha K, Arun MI. Handbook of membrane separations: Chemical, pharmaceutical, food, and biotechnological applications. 2nd ed. CRC Press, London, 2015, 465–481. Drioli E, Stankiewicz A I, Macedonio F. Membrane engineering in process intensification: An overview. J Membr Sci 2011, 380, 1–8. Piacentini E, Mazzei R, Drioli E, Giorno L. From biological membranes to artificial biomimetic membranes and systems. In: Drioli E, Giorno L, Fontananova, E, eds. Comprehensive membrane science and engineering. 2nd ed. Elsevier B.V., Kidlington, 2017, 1–16. Donato L, Mazzei R, Algieri C, Piacentini E, Poerio T, Giorno L. Molecular recognition-driven membrane processes. In: Gugliuzza A, ed. Smart membranes and sensors: Synthesis, characterization, and applications. 1st ed. Wiley-Scrivener, Beverly, 2014, 269–300. Yoshikawa M. Separation with molecularly imprinted membranes, Kobunshi Ronbunshu 2014, 71, 223–241.

References

[6] [7] [8] [9] [10] [11] [12] [13]

[14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

[24] [25] [26]

[27] [28] [29] [30]

49

Ulbricht M. Advanced functional polymer membranes. Polym 2006, 47, 2217–2262. Donato L. A spasso con le membrane. Un mondo tutto da scoprire. CNR Edizioni, Roma, 2021, https://doi.org/10.48263/ASM2021. Strathmann H, Giorno L, Drioli E. An introduction to membrane science and technology, CNR Edizioni, Roma, 2006. Drioli, E, Nakagaki M. Membranes and membrane processes, 1st ed. Springer, US, 1986. Pabby AK, Rizvi SSH, Sastri AM. Handbook of membrane separations: Chemical, pharmaceutical, food, and biotechnological applications. 2nd ed. CRC Press, Taylor & Francis Group, London, 2015. Cassano A, Conidi C, Ruby-Figueroa R. Recovery of flavonoids from orange press liquor by an integrated membrane process. Membranes 2014, 4, 509–524. Drioli E. Romano M. Progress and new perspectives on integrated membrane operations for sustainable industrial growth. Ind Eng Chem Rev 2001, 40, 1277–1300. Kubota N, Hashimoto T, Mori Y. Microfiltration and ultrafiltration. In: Li NN, Fane AG, Ho WSW, Matsuura T, eds. Advanced membrane technology and applications. Wiley, Hoboken, N.J, 2008, 101–129. Cheryan M. Ultrafiltration and microfiltration handbook. Technomic Publishing Company, Lancaster, Basel, 1998. Mulder M. Basic principles of membrane technology. 2nd ed. Kluwer Academic Publishers, Dordrecht, 1991. Donato L, Algieri C, Rizzi A, Giorno L. Kinetic study of tyrosinase immobilized on polymeric membrane. J Membr Sci 2014, 454, 346–350. Algieri C, Drioli E. Donato L. Development of mixed matrix membranes for controlled release of ibuprofen. J Appl Polym Sci 2013, 754–760. Nascimento TA, Fdz-Polanco F, Peña M. Membrane-based technologies for the up-concentration of municipal wastewater: A review of pre-treatment intensification. Sep Purif Rev 2020, 49, 1–19. Macedonio F, Drioli E. Membrane engineering for green process engineering. Engineering 2017, 290–298. Hou DY, Wang J, Qu D, Luan ZK, Zhao CW, Ren XJ. Desalination of brackish groundwater by direct contact membrane distillation. Water Sci Tech 2010, 61, 2010–2013. Girard B, Fukumoto L R. Membrane processing of fruit juices and beverages: A review. Crit Rev Biotechnol 2000, 20, 109–179. Schaepertoens M, Didaskalou C, Kim J F, Livingston A G, Szekely G. Solvent recycle with imperfect membranes: A semi-continuous workaround for diafiltration. J Membr Sci 2016, 514, 646–658. Kim JF, Székely G, Valtcheva I B, Livingston A G. Increasing the sustainability of membrane processes through cascade approach and solvent recovery – Pharmaceutical purification case study. Green Chem 2014, 16, 133–145. Kim JH, Koros WJ, Paul DR. Effects of CO2 exposure and physical aging on the gas permeability of thin 6FDA-based polyimide membranes: Part 2 with crosslinking. J Membr Sci 2006, 282, 32–43. Koltuniewicz AB, Drioli E. Membranes in clean technologies. Theory and practice. 1st ed. Wiley-VCH, Berlin, 2008. Simone S, Figoli A, Santoro S, Galiano F, Alfadul S, Al-Harbi OA, Drioli E. Preparation and characterization of ECTFE solvent resistant membranes and their application in pervaporation of water/toluene mixtures. Sep Purif Technol 2012, 90, 147–161. Galiano F, Briceño K, Marino T, Molino A, Christensen K V, Figoli A. Advances in biopolymer-based membrane preparation and applications. J Membr Sci 2018, 564, 562–586. Charcosset C. Membrane processes in biotechnology: An overview. Biotech Adv, 2006, 24, 482–492. Yoshikawa M. Molecularly imprinted polymeric membranes. Bioseparations 2002, 10, 277–286. Trotta F, Biasizzo M, Caldera F. Molecularly imprinted membranes. Membranes 2012, 2, 440–477.

50

[31] [32] [33] [34] [35] [36]

[37]

[38]

[39] [40] [41]

[42] [43]

[44]

[45] [46]

[47]

[48]

[49]

Chapter 2 Molecularly imprinted membranes: general aspects

Ulbricht M. Membrane separations using molecularly imprinted polymers. Rev J Chromatogr B 2004, 804, 113–125. Garcia Del Blanco S, Donato L, Drioli E. Development of molecularly imprinted membranes for selective recognition of primary amines in organic medium. Sep Purif Technol 2012, 87, 40–46. Tasselli F, Donato L, Drioli E. Evaluation of molecularly imprinted membranes based on different acrylic copolymers. J Membr Sci 2008, 320, 167–172. Reddy PS, Kobayashi T, Abe M, Fujii N. Molecular imprinted Nylon-6 as a recognition material of amino acids. Eur Polym J 2002, 38, 521–529. Faizal CKM, Kobayashi T. Tocopherol-targeted membrane adsorbents prepared by hybrid molecular imprinting. Polym Eng Sci 2008, 6, 1085–1093. Kochkodan V, Hilal N, Melnik V, Kochkodan O, Vasilenko O. Selective recognition of organic pollutants in aqueous solutions with composite imprinted membranes. Adv Colloid Interface Sci 2010, 159, 180–188. Liu Y, Meng M J, Yao J T, Da ZL, Feng YH, Yan Y S, Li CX. Selective separation of phenol from salicylic acid effluent over molecularly imprinted polystyrene nanospheres composite alumina membranes. Chem Eng J 2016, 286, 622–631. Kobayashi T, Reddy PS, Ohta M, Abe M, Fujii N. Molecularly imprinted polysulfone membranes having acceptor sites for donor dibenzofuran as novel membrane adsorbents: Charge transfer interaction as recognition origin. Chem Mat 2002, 14, 2499–2505. Ma X, Chen R, Zheng X, Youn H, Chen Z. Preparation of molecularly imprinted CS membrane for recognizing naringin in aqueous media. Polym Bull 2011, 66, 853–863. Ramamoorthy M, Ulbricht M. Molecular imprinting of cellulose acetate-sulfonated polysulfone blend membranes for rhodamine B by phase inversion technique. J Membr Sci 2003, 217, 207–214. Zhou Z, Cui K, Mao Y, Chai W, Wang N, Ren Z. Green preparation of d-tryptophan imprinted selfsupported membrane for ultrahigh enantioseparation of racemic tryptophan. RCS Adv 2016, 6, 109992–110000. Piletsky SA, Panasyuk TL, Piletskaya EV, Nicholls IA, Ulbricht M. Receptor and transport properties of imprinted polymer membranes ‐ A review. J Membr Sci 1999, 157, 263–278. Lu J, Qin Y, Li C, Wu Y, Meng M, Dong Z, Sun C, Chen M, Yan Y. Irregular dot array nanocomposite molecularly imprinted membranes with enhanced antibacterial property: Synergistic promotion of selectivity, rebinding capacity and flux. Chem Eng J 2021, 405, 126716, https://doi.org/10.1016/j. cej.2020.126716 Zhao X, Cheng Y, Xu H, Hao Y, Lv Y, Li X. Design and preparation of molecularly imprinted membranes for selective separation of acetoside, Front Chem 2020, 8, 775, https://doi.org/10.3389/ fchem.2020.00775. Kamarudin SF, Ahmad MN, Dzahir IHM, Ishak N, Halim NFA. Development of quercetin imprinted membranes‑based PVDF substrate. Polym Bull 2019, 76, 4313–4334. Ma Y, Wang H, Guo M. Stainless steel wire mesh supported molecularly imprinted composite membranes for selective separation of Ebracteolata compound from Euphorbia fischeriana. Molecules 2019, 24, 565, https://doi.org/10.3390/molecules24030565. Dong Y, Ping Y, Qilong S, Yang Lu, Zhenjiang T, Xiaopeng Y. Grafting of MIPs from PVDF membranes via reversible addition-fragmentation chain transfer polymerization for selective removal of phydroxybenzoic acid. Chem Res Chin Univ 2018, 34, 1051–1057. Kashani T, Jahanshahi M, Rahimpour A, Peyravi M. Nanopore molecularly imprinted polymer membranes for environmental usage: Selective separation of 2,4-dichlorophenoxyacetic acid as a toxic herbicide from water. Polym Plast Technol Eng 2016, 55, 1700–1712. Yao R, Yu Z, Wu M, Yu H. Preparation and evaluation of molecularly imprinted membrane of teicoplanin. Anal Methods 2018, 10, 5416–5422.

References

51

[50] Algieri C, Parisi OI, Gullo MF, Puoci F, Drioli E, Donato L. Development of novel hybrid imprinted membranes for selective recovery of theophylline C. Sep Purif Technol 2018, 192, 513–519. [51] Zhao J, Wu Y, Wang C, Huang H, Lu J, Wu X, et al. Insights into high-efficiency molecularly imprinted nanocomposite membranes by channel modification for selective enrichment and separation of norfloxacin. J Taiwan Inst Chem Eng 2018, 89, 198–207. [52] Odabaş M, Uzun L, Baydemir G, Aksoy NH, Acet Ö, Erdönmez D. Cholesterol imprinted composite membranes for selective cholesterol recognition from intestinal mimicking solution. Colloids Surf B 2018, 163, 266–274. [53] Akbari-adergani B, Sadeghian GH, Alimohammadi A, Esfandiari Z. Integrated photografted molecularly imprinted polymers with a cellulose acetate membrane for the extraction of melamine from dry milk before HPLC analysis. J Sep Sci 2017, 40, 1361–1368. [54] Singh AK, Sinngh M. Journal of molecular recognition Electrochemical and piezoelectric monitoring of taurine via electroplymerized molecularly imprinted films. J Mol Recognit 2017, 30, e2652, https:// doi.org/10.1002/jmr.2652. [55] Gao B, Zhang L, Li Y. Designing and preparation of novel alkaloid-imprinted membrane with grafting type and its molecular recognition characteristic and permselectivity. Mater Sci Eng C Mater Biol Appl 2016, 6, 259–267. [56] Cui J, Wu W, Meng M, Lu J, Wan C, Zhao J et al. Bio-inspired synthesis of molecularly imprinted nanocomposite membrane for selective recognition and separation of artemisinin. J Appl Polym Sci 2016, 133, 1–9. [57] Wang CL, Hu XL, Guan P, Wu DF, Yang LF, Du CB. Preparation of molecularly imprinted regenerated cellulose composite membranes by surface-initiated atom transfer radical polymerization method for selective recognition of lysozyme. Adsorpt Sci Technol 2015, 33, 411–425. [58] Xu SP, Liu Y, Sun LQ, Luo AQ. Preparation and recognition properties of levodropopizine molecularly imprinted composite membranes. Adv Mater Res 2012, 399–401, 355–358. [59] Büttiker R, Ebert J, Hinderling C, Adlhart C. Membranes for specific adsorption: Immobilizing molecularly imprinted polymer microspheres using electrospun nanofibers. Chimia 2011, 65, 182–186. [60] Yu JY, Hu XL, Jiao CC, Zhao YM, Yang WW. Synthesis and properties of molecularly imprinted composite membranes of roxithromycin. Adv Mat Res 2010, 87–88, 80–85. [61] De Luca G, Donato L, García Del Blanco S, Tasselli F, Drioli E. On the cause of controlling affinity to small molecules of imprinted polymeric membranes prepared by noncovalent approach: A computational and experimental investigation. J Phys Chem B 2011, 115, 9345–9351. [62] Yu J, Hu X, Li, D, Jiao C. Thin layer molecularly imprinted composite membranes for selective separation of erythromycin from water. Front Earth Sci China 2009, 3, 480–489. [63] Dima SO, Sarbu A, Dobre T, Bradu C, Antohe N, Radu AL, et al. Molecularly imprinted membranes for selective separations. Mater Plast 2009, 46, 372–378. [64] Zhang Y, Gao XQ, Wang YL, Zhang YH, Lu GQ. Study on the build of channels in accurate separation membrane and its selective mechanism. J Membr Sci 2009, 339, 100–108. [65] Zhang C, Zhong S, Yang Z. Cellulose acetate-based molecularly imprinted polymeric membrane for separation of vanillin and o-vanillin. Braz J Chem Eng 2008, 25, 365–373. [66] Lee MH, Tsai TC, Thomas JL, Lin HY. Recognition of creatinine by poly(ethylene-co-vinylalcohol) molecular imprinting membrane. Desalination 2008, 234, 126–133. [67] Donato L, Figoli A, Drioli E. Novel composite poly(4-vinylpyridine)/polypropylene membranes with recognition properties for (S)-naproxen. J Pharm Biomed Anal 2005, 37, 1003–1008. [68] Trotta F, Drioli E, Baggiani C, Lacopo D. Molecular imprinted polymeric membrane for naringin recognition. J Membr Sci 2002, 201, 77–84.

52

Chapter 2 Molecularly imprinted membranes: general aspects

[69] Silvestri D, Barbani N, Coluccio ML, Pegoraro C, Giusti P, Cristallini C, Ciardelli G. Poly(ethylene-covinyl alcohol) membranes with specific adsorption properties for potential clinical application. Sep Sci Technol 2007, 42, 2829–2847. [70] Chou CY, Chang S, Huang WT. Effects of mono‑dentate and bi‑dentate ligands on adsorption characteristics of Cu‑ion‑imprinted hybrids. Res Chem Intermed 2019, 45, 6043–6059. [71] Liu QS, Zheng T, Wang P, Jiang JP, Li N. Adsorption isotherm, kinetic and mechanism studies of some substituted phenols on activated carbon fibers. Chem Eng J 2010, 157, 348–356. [72] Foo KF, Hamee BH. Insights into the modeling of adsorption isotherm systems. Chem Eng J 2010, 156, 2–10. [73] Cheng H, Zhu X, Yang S, Wu Y, Cao Q, Ding Z. A pH-controllable imprinted composite membrane for selective separation of podophyllotoxin and its analog. J Appl Polym Sci 2013, 363–370. [74] Yan M, Wu Y, Zhang K, Lin R, Jia S, Lu J, et al. Multifunctional-imprinted nanocomposite membranes with thermo-responsive biocompatibility for selective/controllable recognition and separation application. J Colloid Interface Sci 2021, 582, 991–1002. [75] Alizadeh T, Memarbashi N. Evaluation of the facilitated transport capabilities of nano- and microsized molecularly imprinted polymers (MIPs) in a bulk liquid membrane system. Sep Purif Technol 2012, 90, 83–91. [76] Hillberg AL, Brain KR, Allender CJ. Design and evaluation of thin and flexible theophylline imprinted polymer membrane materials. J Mol Recognit 2009, 22, 223–231. [77] Su C, Li Z, Zhang D. Wang Z, Zhou X, et al. A highly sensitive sensor based on a computer-designed magnetic molecularly imprinted membrane for the determination of acetaminophen. Biosens Bioelectron 2020, 148, 111819, https://doi.org/10.1016/j.bios.2019.111819. [78] Viveiros R, Rebocho S, Casimiro T. Green strategies for molecularly imprinted polymer development. Polymers 2018, 10, 306, https://doi.org/10.3390/polym10030306. [79] Madikizela LM, Tavengwa NT, Tutu H, Chimuka L. Green aspects in molecular imprinting technology: From design to environmental applications. Trends Environ Anal Chem 2018, 17, 14–22. [80] Cowen T, Karim K, Piletsky S. Computational approaches in the design of synthetic receptors. Anal Chim Acta 2016, 936, 62–74. [81] Gholivand MB, Torkashvand M, Malekzadeh G. Fabrication of an electrochemical sensor based on computationally designed molecularly imprinted polymers for determination of cyanazine in food samples. Anal Chim Acta 2012, 713, 36–44. [82] Liu H, Jin P, Zhu F, Nie L, Qiu H. A review on the use of ionic liquids in preparation of molecularly imprinted polymers for applications in solid-phase extraction. TrAC 2021, 134, 116132, https://doi. org/10.1016/j.trac.2020.116132. [83] Zhou Z, He L, Mao Y, Chai W, Ren Z. Green preparation and selective permeation of d-tryptophan imprinted composite membrane for racemic tryptophan. Chem Eng J 2017, 310, 63–71. [84] He Z, Meng M, Yan Li, Zhu W, Sun F, Yan Y, Liu Y, Liu S. Fabrication of new cellulose acetate blend imprinted membrane assisted with ionic liquid ([BMIM]Cl) for selective adsorption of salicylic acid from industrial wastewater. Sep Purif Technol 2015, 145, 63–74. [85] Wang C, Hu, X, Guan P, Wu D, Qian L, Li J et al. Separation and purification of thymopentin with molecular imprinting membrane by solid phase extraction disks. J Pharm Biomed Anal 2015, 102, 137–143. [86] Lee TP, Saad B, Nakajima L, Kobayashi T. Preparation and characterization of hybrid molecularly imprinted polymer membranes for the determination of citrinin in rice. Sains Malays 2019, 48, 1661–1670. [87] Sergeyeva T, Yarynka D, Dubey L, Dubey I, Piletska E, Linnik R, et al. Sensor based on molecularly imprinted polymer membranes and smartphone for detection of Fusarium contamination in cereals. Sensors 2020, 20, 4304, https://doi.org/10.3390/s20154304.

References

53

[88] Wang XJ, Xu ZL, Feng JL, Bing NC, Yang ZG. Molecularly imprinted membranes for the recognition of lovastatin acid in aqueous medium by a template analogue imprinting strategy. J Membr Sci 2008, 313, 97–105. [89] Wei M, Wang S, Jiang W, Chen H, Wang Y, Meng T. Preparation and characterization of dualtemplate molecularly imprinted membrane with high flux based on blending the inorganic nanoparticles. J Inorg Organomet Polym 2018, 28, 295–307. [90] Xing W, Wu Y, Lu J, Lin X, Yu C. Biomass-based synthesis of green and biodegradable molecularly imprinted membranes for selective recognition and separation of tetracycline. Nano 2020, 15, 2050004, https://doi.org/10.1142/S179329202050004. [91] Anastas PT, Warner JC. Green chemistry: Theory and practice. Oxford University Press Inc, New York, USA, 2000. [92] Da Silva MS, Viveiros R, Aguiar-Ricardo A, Bonifácio VDB. Casimiro T. Supercritical fluid technology as a new strategy for the development of semi-covalent molecularly imprinted materials. RSC Adv 2012, 2, 5075–5079. [93] Donato L, Nasser II, Majdoub M, Drioli E. Green chemistry and molecularly imprinted membranes. Membranes 2022, 12, 472, https://doi.org/10.3390/membranes12050472. [94] Kobayashi T, Leong SS, Zhang, Q. Using polystyrene-co-maleic acid for molecularly imprinted membranes prepared in supercritical carbon dioxide. J Appl Polym Sci 2008, 108, 757–768. [95] Zhang Q, Zhang X, Zhang W, Pan J, Liu L, Zhang H et al. Preparation and adsorption properties of PA6/PSMA-OA molecularly imprinted composite membranes in supercritical CO2. Bull Korean Chem Soc 2011, 32, 3348–3354. [96] Zhang W, Zhang Q, Zhang X, Wu Z, Li Bing, Dong X, et al. Preparation and evaluation of molecularly imprinted composite membranes for inducing crystallization of oleanolic acid in supercritical CO2. Anal Methods 2016, 8, 5651–5657. [97] Da Silva SM, Viveiros R, Coelho MB, Aguiar-Ricardo A. Casimiro T. Supercritical CO2-assisted preparation of a PMMA composite membrane for bisphenol A recognition in aqueous environment. Chem Eng Sci 2012, 68, 94–100. [98] Zhang W, Zhang Q, Wang R, Cui Y, Zhang X, Hong L. Preparation of molecularly imprinted composite membranes for inducing bergenin crystallization in supercritical CO2 and adsorption properties. Bull Korean Chem Soc, 2012, 33(2): 703–706.

Chapter 3 Preparation strategies of molecularly imprinted membranes 3.1 Introduction Together with the technological progress and the increasing development of membrane science, the production of more and more efficient polymeric molecularly imprinted membranes (MIMs) characterized the advancement of the research in the field of separations. In fact, the capacity of MIMs to promote the selective retention or transport of the targeted compounds has rendered them good candidates for the development of highly innovative selective membrane-based tools. The optimization of membrane transport properties and recognition performance is the main objective in preparing imprinted membranes. Therefore, in the last decades, the combination of different materials and preparation methods allowed obtaining efficient MIMs for application in numerous sectors [1–6]. Generally, it is not easy to prepare MIMs exhibiting contemporary high number of recognition sites and a suitable membrane pore structure for achieving high permeability and separation degree. Anyway, the meticulous work of the scientists and the application of modern strategies led to obtain highly efficient and cost-effective imprinted membranes also at the nanoscale level [1–8]. MIMs are prepared with inorganic and organic materials. However, this book is mainly devoted to polymeric imprinted membranes, and this chapter presents an overview of the different synthetic procedures to prepare MIMs exhibiting diverse physical–chemical properties, separation mechanism, selectivity, and potential of application. Among different preparation methods, the alternative molecular imprinting, the surface imprinting, the electrospinning, and the sol–gel process are useful for obtaining flat-sheet films, hollow fibers, and nanofibers, in dependence of the characteristics requested by the template of interest and of the application field.

3.2 About the production of molecularly imprinted membranes The first example of the preparation of an imprinted membrane dates back to 1962, when Michaels et al. prepared imprinted membranes made of polyethylene using p-xylene as the template [9]. During pervaporation experiments, these membranes permeated favorably p-xylene with respect to its isomers. Since then, and in parallel to the development of membrane science and imprinting technology (and thanks to their combination), a wide variety of increasingly efficient MIMs have been prepared, trying to find a balance between their molecular recognition ability, thickness, transport properties, selectivity, flexibility, and mechanical stability. Traditional MIMs have been prepared mainly as thin https://doi.org/10.1515/9783110654691-004

3.2 About the production of molecularly imprinted membranes

55

films (flat sheets) having a dense or a porous structure, and as hollow fibers having a spaghetti-like tubular configuration with a porous structure that supports a dense selective layer. The advent of the nanoimprinting technology allowed developing also polymeric nanometer thin films and nanofiber membranes. The latter have higher porosity and specific surface area with respect to other configurations and therefore a higher availability of recognition sites and diffusivity of compounds of interest [8–11]. The recognition sites play an important role in the transport or retention of targeted compounds. In fact, the membrane structure and the separation performance are in strict relation with the size, shape, distribution, spatial orientation, homogeneity, and accessibility of the created recognition sites. They can be present in the whole membrane matrix or only located on the membrane surface, depending on the synthetic procedure [6]. The first case is typical of the so-called threedimensional (3D) imprinting method, while the second one occurs in two-dimensional (2D) imprinting approach (i.e., surface imprinting strategy), which entails a planar distribution of the recognition sites in the form of a thin monolayer. Figure 3.1 illustrates the different distribution of the recognition sites in the 3D and 2D imprinting.

Fig. 3.1: Distribution of template molecules and recognition sites in bulk-imprinted membrane and surface-imprinted membrane.

In particular, the 3D imprinting promotes the formation of a high number of recognition sites randomly distributed both on the surface and into the membrane bulk. The binding and the recovery of the template are dependent on the intramatrix mass transfer process and binding kinetics. Unfortunately, the accessibility of some recognition sites is poor, owing to their deep embedding into the polymeric network (as in the case of a membrane containing imprinted microparticles or monoliths). This condition leads to an incomplete template removal and therefore to the reduction of the membrane efficiency. On the other hand, the surface location of the sites in the 2D imprinting facilitates their access and the subsequent template removal, leading in the meantime to faster binding kinetics [6]. Nowadays, low-mass target analytes are imprinted successfully by means of 3D approaches exploiting different routes, while the 2D methods are particularly advantageous for imprinting macromolecules, as it is the case of proteins,

56

Chapter 3 Preparation strategies of molecularly imprinted membranes

in the logic of preserving their native structure during the imprinting process and ensure their complete removal. Later, a more deep discussion of this aspect will be done. In the framework of 3D and 2D imprinting strategies, efficient MIMs have been prepared with different methods. Table 3.1 summarizes some reviews devoted to the production of MIMs and to their application in different areas. Tab. 3.1: Some published reviews about the production of molecularly imprinted membranes. Title

Year Reference

Imprinted membranes for sustainable separation processes



[]

Synthesis, performance, and application of molecularly imprinted membranes: a review



[]

Molecular imprinted membrane biosensor for pesticide detection: perspectives and challenges



[]

Recent advances in molecularly imprinted membranes for sample treatment and separation



[]

Imprinted composite membranes



[]

Molecularly imprinted polymer membranes and thin films for the separation and sensing of biomacromolecules



[]

Molecularly imprinted membranes: past, present, and future



[]

The recognizing mechanism and selectivity of the molecularly imprinting membrane, molecularly imprinted catalysts



[]

Approaches for the assembly of molecularly imprinted electrospun nanofibre membranes and consequent use in selected target recognition



[]

Recent developments in molecularly imprinted polymer nanofibers and their applications



[]

Bio-mimetic sensors based on molecularly imprinted membranes



[]

Emerging tools for recognition and/or removal of dyes from polluted sites: molecularly  imprinted membranes

[]

Separation with molecularly imprinted membranes



[]

Molecularly imprinted membranes



[]

Molecularly imprinted nanofiber membranes



[]

Usually, for preparing MIMs, three main synthetic strategies are applied: 1) The synchronized formation of membrane structure and recognition sites of a self-supported membrane 2) The hybrid molecular imprinting (HMI) 3) The surface imprinting of a preexisting membrane

3.3 In situ cross-linking polymerization

57

The synchronized formation of membrane structure and recognition sites is accomplished via two different routes: the in situ cross-linking polymerization and the socalled alternative molecular imprinting. The first method entails the formation of a cross-linked polymeric network film from a solution containing the template, the functional monomer, and the cross-linker, via bulk polymerization or other routes. The alternative molecular imprinting is one of the most used approaches. It involves the preparation of a membrane via the phase inversion technique in the presence of the template using a tailored previously synthesized polymer having functional groups complementary to the template. According to HMIs, the phase inversion technique is useful for preparing MIMs with polymers forming membrane hybridized with a cross-linked imprinted polymer previously synthesized. The surface imprinting deals with the surface functionalization of a membrane with a selective thin layer of a molecularly imprinted polymer. This objective is mainly achieved via the free radical polymerization and controlled radical polymerization. Figure 3.2 shows a schematic representation of the surface imprinting (a), alternative molecular imprinting (b) and of the HMI strategies (c) [1]. All the cited polymerization methods lead to produce simple or composite membranes. In addition, their combination is a fruitful way for developing advanced MIMs. They are more deeply discussed in the following sections.

3.3 In situ cross-linking polymerization The in situ cross-linking polymerization is one of the firstly used synthetic routes. The addition of linear flexible monomers, oligomers, and high-molecular-weight polymer to the dope solution leads to obtain good membrane flexibility, mechanical stability, and permeability. Some examples are oligo urethane acrylate (OUA), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyurethane (PU), polymethylmethacrylate (PMMA), and so on. Another important factor is the membrane thickness. This strategy was pioneered by Piletsky and coauthors who prepared flat-sheet adenosine monophosphate-imprinted membranes using this nucleotide as the template, (N,N-diethyl) aminoethyl methacrylate as the functional monomer, and ethylene glycol dimethacrylate (EGDMA) as the cross-linking agent [18]. In diffusion tests performed under an application of a potential difference, these membranes exhibited a preferential transport of adenosine monophosphate with respect to the similar nucleotide guanosine monophosphate [19]. However, owing to their fragility, other studies for preparing membranes exhibiting more flexibility were carried out [19, 20]. In this perspective, the preparation of flexible membranes from the tetrapeptide derivative H–Asp (OcHex)–Ile–Asp (OcHex)–Glu(OBzl)–CH2– together with a copolymer of acrylonitrile and styrene demonstrated the possibility of separating enantiomers of amino acid derivatives [20]. Later, free-standing and efficient MIMs were synthesized via in situ polymerization by applying the principle of the interpenetrating polymer network. Membranes were produced by copolymerizing methacrylic

58

Chapter 3 Preparation strategies of molecularly imprinted membranes

Fig. 3.2: Scheme of the preparation of an imprinted membrane via the surface imprinting method (a), the alternative molecular imprinting (b), and the hybrid molecular imprinting (c) (reprinted from ref. [1]. Copyright 2021, with the permission of Springer Nature).

acid, tri(ethylene glycol) dimethacrylate, and OUA in the presence of the herbicide atrazine as the template [21, 22]. A linear polymer such as PEG or PU was also added to the prepolymerization mixture. The presence of oligourethane promoted the formation of flexible membranes having thickness of 60 µm. Furthermore, the extraction of the linear polymer from the just formed membranes ensured the formation of a porous membrane structure exhibiting high flux values (from 3,057 to 15,305 L · m−2 · h−1 at 40.7 MPa), while the extraction of the template led to the formation of the recognition sites. Scanning electron microscopic (SEM) analysis confirmed the presence of a porous structure. In filtration tests, MIMs showed high adsorption capacity of atrazine in comparison to the similar herbicides desmetryn, metribuzin, prometryn, and simazine. On the contrary, nonimprinted membranes showed low atrazine binding. Authors also demonstrated that the solvent and the type of the pore-forming polymer affected the number, the shape, and the average diameter of the membrane pores [21, 22].

3.4 Alternative molecular imprinting

59

In a recent paper, 2,4-dichlorophenoxyacetic acid (2,4-DP)-imprinted membranes were prepared via in situ synthesis by γ-initiated polymerization using N-vinyl imidazole and EGDMA as the functional monomer and the cross-linker, respectively, in methanol/ water (1:4 v/v) [23]. The binding properties of the membranes were investigated using real water samples such as tap water and spring water containing also the structurally similar herbicides (R)-2(2,4-dichlorophenoxy)propanoic acid and 4-chlorophenoxyacetic acid. 2,4-DP is a herbicide largely employed in agriculture, and owing to the dangerous effect that it has on humans and animals, the World Health Organization fixed 70 μg · L−1 as its maximum acceptable content in drinking water. Starting from this point, different studies for reducing its presence in the polluted water are continuing. 2,4-DP-imprinted membranes prepared via in situ polymerization in this work resulted more effectively than membranes prepared with other synthetic routes [23]. Recognition specificity to the top surface or in-pore surface of a preexisting membrane was also conferred by exploiting the in situ polymerization method.

3.4 Alternative molecular imprinting The alternative molecular imprinting is the most widely used 3D approach for preparing MIMs. According to this strategy, hollow fibers and flat-sheet membranes are prepared in the presence of the template exploiting the phase inversion technique, the most important technique used for preparing polymeric membranes. Succinctly, the process consists in the transformation of a solution of polymer having functional moieties complementary to the template into a solid state via the “dry” or the “wet” method or their combination. During the process, the polymer chains of the nascent membrane arrange around the template molecules. After the membrane formation, the template removal leaves its molecular memory into the polymeric matrix. As an example, Fig. 3.3 shows the formation process of a naringin-imprinted membrane prepared using chitosan as a functional polymer [24]. According to the “dry” method (also called solvent evaporation-induced phase inversion), the polymer solution is casted on a plate, and the solidification occurs owing to the solvent evaporation under controlled conditions. Because of the progressive increase of polymeric concentration during the solvent evaporation, the membrane exhibits a dense structure. Sometimes, for improving membrane porosity, pore-forming agents are added to the dope solution. In the “wet” method (also called immersion precipitation or nonsolvent-induced phase separation), the plate supporting the dope solution is immersed in a bath containing a nonsolvent for the polymeric material. The polymer solidification is due to precipitation induced by the contact nonsolvent–polymer. Membranes prepared via this method have a porous structure. This is because of the quick liquid–liquid demixing characterizing the nonsolvent-induced phase separation [1, 2, 7]. The schematic representation of the two different preparation methods is shown in Fig. 3.4.

60

Chapter 3 Preparation strategies of molecularly imprinted membranes

Fig. 3.3: Formation process of a naringin–chitosan–MIM via the dry-phase inversion method (reprinted from ref. [24]. Copyright 2011, with the permission of Springer Nature).

Fig. 3.4: Illustration of the “dry” and “wet” phase inversion (reprinted from ref. [7]. Open Access).

3.4 Alternative molecular imprinting

61

Yoshikawa and coauthors pioneered the “dry” phase inversion. In the preparation of enantioselective imprinted membranes, they had used polystyrene having oligopeptide derivatives as functional recognition features [25–28]. Instead, Kobayashi and coworkers introduced the “wet” phase inversion for the preparation of porous asymmetric theophylline-imprinted membranes with acrylate copolymers as membrane-forming materials [29–32]. Experimental studies on the effect of the coagulation temperature showed that a decrease of coagulation temperature from 40 to 10 °C lead to an increase of the template binding. NMR analysis of the membranes before and after the template removal supported these results. In fact, they proved that the template amount in the membrane coagulated at 10 °C was higher than the value measured in the case of membranes coagulated at 40 °C. In addition, infrared analysis evidenced the formation of hydrogen bonds between the carboxylic groups of the membrane and the aminic function of the template [31, 32]. Starting from these first studies, different membranes have been prepared with lone polymers of either polymeric blends using other templates. For example, in combination of the in situ polymerization and phase inversion, linear acrylic copolymers have been synthesized in the presence of the same template theophylline and have been used directly for preparing porous imprinted membranes via the wet method [33]. In a modified approach, Trotta et al. [34] used poly(acrylonitrile-co-acrylic acid) (P(AN-co-AA)) for preparing MIMs imprinted with the antibiotic tetracycline hydrochloride, adding the template to the dope solution during the membrane preparation step instead of during polymer synthesis. MIMs exhibited an asymmetric porous structure and were capable of distinguishing between the template and its similar compound chloramphenicol [34]. The interactions of template with the recognition sites were due to the formation of hydrogen bonds between the hydroxyl groups of tetracycline and the carboxylic groups of the copolymer. Adopting the same strategy, Silvestri and coauthors [35] employed P(E-co-VA) for preparing MIMs having adsorption properties toward the phospholipid phosphatidylcholine. DMSO and DMSO/water (50/50, v/v) had been used as the solvent and as the nonsolvent, respectively. In permeation experiments, membranes exhibited very high binding capacity towards the template with respect to its analogues phosphatidylserine and phosphatidylinositol, which passed almost completely through the tested membranes. Table 3.2 reports some selected examples of MIMs prepared via the phase inversion technique. The wet method was used for preparing imprinted membranes using polysulfone as a polymer-forming membrane and the anticancer drug paclitaxel as the template [37]. After optimization in terms of polymer/template ratio, of feed concentration, and of the template extractor, MIMs have been used for enrichment of paclitaxel from crude yew tree extract. The imprinting factor was 2.28, while the enrichment factor was up to 48%. These results are encouraging for the application of membranes at the industrial level in alternative to the more expensive and complex traditional extraction methods [37]. For the first time, Székely and coworkers [40] employed polybenzimidazole (having excellent chemical and solvent stabilities) as a functional polymer in the preparation (via the “wet” method) of molecularly imprinted-organic solvent

Preparation method

Wet PI

Wet PI

Wet PI

Hybrid imprinting

Wet PI

Dry–wet PI

Hybrid imprinting

Wet PI

Hybrid imprinting

Membrane-forming materials

Poly(acrylonitrile-comethacrylic acid)

Polysulfone

Poly(ethylene-co-vinyl alcohol)

Polysulfone

Polybenzimidazole

Poly(acrylonitrile-co-acrylic acid)

Poly-methylmethacrylate

Poly(acrylonitrile-co-acrylic acid)

Polyvinylchloride

N,N-Dimethylformamide

N,N-Dimethylformamide

Solvent

N,N-Dimethylformamide

,-methylendianiline

Trimethoprim

Puerarin

Tetrahydrofuran

Dimethyl sulfoxide

Acetone

N,N-Dimethylacetamide

-aminopyrimidine

Riboflavin

N,N-Dimethylacetamide

Phenol

Maltose and -keto-- Dimethyl sulfoxide deoxyD-manno-octulosonate

Paclitaxel

Ephedrine

Template

Aquaculture water

Aqueous

Beer

Isopropanol

Acetonitrile

Water

Aqueous

Ethanol/water / v/v

Aqueous

Recognition medium

Tab. 3.2: Some examples of molecularly imprinted polymeric membranes prepared via the phase inversion (PI) technique.

Environmental

Herbal medicine

Food processing

Pharmaceutical Environmental

Pharmaceutical Environmental

Environmental

Pharmaceutical

Pharmaceutical

Food safety

Application field

[]

[]

[]

[]

[]

[]

[]

[]

[]

Reference

62 Chapter 3 Preparation strategies of molecularly imprinted membranes

Wet PI

Wet PI

Wet PI

Wet PI

Poly(acrylonitrile-co-acrylic acid)

Poly(ethylene-co-vinyl alcohol)

Poly(acrylonitrile-co-acrylic acid)

Polysulfone

Dibenzofuran

Uric acid

Phosphatidylcholine

Tetracycline hydrochloride

N,N-Dimethylacetamide

Dimethyl sulfoxide

Dimethyl sulfoxide

Dimethyl sulfoxide

Water

Aqueous

Aqueous

Aqueous

Water and wastewater treatment

Clinical

Clinical

Food safety

[]

[]

[]

[]

3.4 Alternative molecular imprinting

63

64

Chapter 3 Preparation strategies of molecularly imprinted membranes

nanofiltration membranes (MI-OSNFMs) capable of specifically recognizing the genotoxin 2-aminopyrimidine (2-AP) and remove it from active pharmaceutical ingredients [40]. In particular, membranes were able to adsorb the template molecules separating them from both the solvent (acetonitrile) and the catalyst 4-dimethylaminopyridine, which permeated the membranes and were recycled. In addition, the membranes rejected the antibiotic roxithromycin, which accumulated in the retentate stream, while 2AP was recovered from the membrane by a subsequent elution step. Studies on the effect of the transmembrane pressure on the separation performance evidenced an irreversible loss of the imprinting effect when increasing the applied pressure. On the other hand, the permeate flux and the rejection properties typical of nanofiltration were maintained. This is a clear example of how the combination of the imprinting technology with the organic solvent nanofiltration leads to obtain higher efficient membranes with respect to the traditional ones. This is because they act both as size exclusion tools and shape-specific adsorbing membranes [40]. Other MI-OSNFMs have been previously prepared via the “dry–wet” process using the acrylic copolymers: poly(acrylonitrile) (PAN), P(AN-co-AA), poly(acrylonitrile-co-itaconic acid), P(AN-co-IA)) and poly(acrylonitrile-co-methacrylic acid) [41]. 4,4-Methylenedianiline was used as the template. It is a member of the family of primary amines, and is used as an intermediate reagent in many synthetic processes. Among different functional polymers, the P(ANco-AA)-based MIM exhibited the better performance. Increasing the initial feed concentration also increased the number of template molecules available for interacting with the recognition sites of the membrane, and therefore, its binding capacity toward the template. At 10 mg · L−1 of initial template concentration, the binding capacity of MIM was 5.0 µmol · g−1, while the value determined for the corresponding nonimprinted one was 2.4 µmol · g−1. The specific binding capacity of MIM was 2.6 µmol · g−1 [41]. In a different way, MIMs with specific recognition properties for diosgenin were also prepared via the phase inversion using P(AN-co-AA) [47]. Diosgenin has an anticholesterolemic activity and it is extracted from the plant Dioscorea. Membranes exhibited high binding capacity toward the template and were capable of separating it from the similar compound stigmasterol [47]. The exploitation of the phase inversion technique leads to produce also HIMs. They are composite membranes exhibiting high recognition ability, owing to a combination of the specific recognition properties of the MIP with the mechanical and structural properties of the scaffold polymeric membrane. Up to date, many MIMs have been prepared by using this method with the commonly used membrane polymerforming materials. Ashrafian et al. [39] embedded polymeric particles imprinted with phenol into a polysulfone matrix for producing HIMs via the wet phase inversion method. The presence of MIP into a polysulfone matrix determined a substantial increase of the membrane surface roughness and porosity as well as of the permeate flux. Membranes containing 10 wt% of MIP showed the highest binding capacity (65.18 ± 1 mg · g.−1) and a selectivity factor of 2.19 for phenol/catechol. At MIP content above 10 wt%, the polysulfone was not able to uniformly wrap the polymer imprinted

3.4 Alternative molecular imprinting

65

particles and the recognition performance decreased [39]. The incorporation of MIP into the PMMA matrix led to produce hybrid membranes capable of recognizing selectively riboflavin [42]. These membranes permitted to deplete about 80% of this substance from beer real samples and were selective toward the competing compounds lumichrome and uridine [43]. Other HIMs have also been prepared for clinical uses, chiral separations, and much more [48–51]. The random distribution of recognition sites in the polymeric bulk and on the surface is a problem characterizing the phase inversion. In addition, it is not easy to combine the pore structure and separation efficiency. Among different studies performed for solving this problem, MIMs with ordered pore structure are obtained by evaporating the polymer solution in a suitable volatile solvent under controlled humidity. Widawski and coworkers, for producing polystyrene-based films, pioneered this approach called water-assisted method [52]. Then, Lu et al. applied it for the first time for the preparation of MIMs using (S)-5-benzylhydantoin and poly(styrene-stat-acrylonitrile) (SANs) as the template and the functional polymer, respectively [53]. Morphological analysis evidenced a spongy-like membrane structure having highly ordered pores both into the membrane bulk and on the surface (see Fig. 3.5). (a)

(b)

20μm

20μm

(c)

(d)

20μm

20μm

Fig. 3.5: SEM images of membranes prepared by means of the water-assisted method: top surface (a), cross section (b), and bottom surface (c) of the (S)-5-benzylhydantoin-imprinted membrane. Cross section of the corresponding blank membrane (d) (reprinted from ref. [53]. Copyright 2011, with the permission of Elsevier).

On the other hand, the spongy-like structure was not present in blank membranes, indicating the interaction of template–functional polymer that affected the membrane

66

Chapter 3 Preparation strategies of molecularly imprinted membranes

structure. Permeation studies evidenced a facilitated permeation of the template with respect to its opposite enantiomer. Another synthetic strategy is the surface imprinting, the 2D approach leading to the production of composite membranes by ad hoc surface functionalization of a preexisting polymeric membrane. The following section discusses this technique.

3.5 Surface imprinting The great merit of this technique derives from the possibility that offers us to introduce recognition sites on the surface of a membrane (through the formation of an MIP layer) without changing its pore structure. The resultant composite membrane presents the advantage of combining the mechanical strength of the support membrane with the selective properties of the imprinted polymer film, which acts as a selective barrier or transport phase, as well as adsorption layer. All this determines a better control of the binding kinetics with respect to the in situ cross-linking polymerization and to the alternative molecular imprinting. The most used methods for generating surface-imprinted membranes are grafting, coating, and electropolymerization [1–6, 13, 14]. Table 3.3 summarizes the advantages and disadvantages of these techniques. Tab. 3.3: Some advantages and disadvantages of the most used surface imprinting techniques. Imprinting method

Advantages

Disadvantages

Grafting

Good control of the MIP layer structure Long-term stability of modified membrane surface High membrane flux

Requirement of an initiator Limited grafting density on the surface Requirement of special labor for coupling reactions between the membrane surface and the nascent MIP layer

Coating

Simple and versatile Cheap

Low membrane flux Low stability of modified membrane surface

Electropolymerization Nor use of cross linker and of free radicals generating agent Simple and very fast High control of morphology and thickness of the MIP layer High reproducibility

Limitation of the number of electroactive monomers and of the membrane substrate material

The grafting deals with the activation of the membrane surface by the introduction of functional groups or an initiator having functional moieties promoting the formation of radicals and the subsequent surface-initiated polymerization when radicals enter into contact with the polymerizable monomers. The formation of bonds between the

3.5 Surface imprinting

67

MIP layer and the membrane surface ensures the stability of the nascent imprinted composite membrane. The grafting process can be accomplished by exploiting different approaches. They are distinguished in chemical grafting, photochemical grafting, plasma grafting, and radiation grafting. According to the chemical initiated grafting, the membrane surface is activated by means of the formation of free radical sites using redox initiators. The photochemical grafting (“grafting from” strategy) requires the employment of a photosensitive initiator that under UV excitation generates free radicals subtracting hydrogen atoms from the membrane surface, thus producing the radical sites necessary for grafting. The radiation-induced graph polymerization uses very high-frequency ionizing radiation (γ-radiations) to irradiate the membrane surface and generate the radicals that initiate the polymerization process. The plasma-induced grafting combines the plasma treatment with the grafting method. Radicals (or peroxides) are generated, owing to the membrane surface exposition to a plasma in a high-temperature reactor. The coating method entails the simple formation of the thin MIP layer on a surface of a preexisting membrane via physical adhesion, deposition, interpenetration, or crossflow filtration. The method is simple but the membrane presents low stability, owing to a possible loss of MIP layer not firmly anchored to the surface of the membrane support. The electropolymerization uses electrochemical methods for polymerizing electroactive functional monomers. Contrary to the in situ polymerization, the process is carried out without cross-linker and any type of initiator. Different surface-imprinted composite membranes are prepared exploiting these strategies, also via their combination or modifications. One of the first examples of surface imprinting is the UV-initiated graft copolymerization of acrylic acid and N,Nmethylenebisacrylamide in the presence of theophylline as the template on the surface of PAN membrane containing a photosensitive dithiocarbamate group [54]. Later, flat-sheet commercial porous polypropylene membranes were surface functionalized with a thin layer of desmetryn-imprinted layer via photograft copolymerization. Benzophenone was used as a photoinitiator, while 2-acrylamido-2-methylpropanesulfonic acid and N,N′-methylenebis(acrylamide) were used as the functional monomer and the cross-linker, respectively [55]. Yin and Ulbricht [56] combined the surface imprinting with the scaffold imprinting for creating lysozyme-selective recognition sites on the surface of a polyethylene terephthalate (PET)-based membrane via two-step grafting. The first step was devoted to the grafting of the membrane surface with a scaffold poly(methacrylic acid) by means of the surface-initiated atom transfer radical polymerization and to the formation of scaffold polymer/template complexes. The second step entailed the synthesis of polyacrylamide hydrogel around the complexes by UV-initiated grafting/cross-linking copolymerization. In static adsorption experiments, these membranes showed selective recognition properties toward cytochrome C, which has similar size and isoelectric point of lysozyme. Furthermore, the binding capacity and the selectivity were inversely dependent on the polymer scaffold length, the UV irradiation time, and grafting degree: shorter scaffold

68

Chapter 3 Preparation strategies of molecularly imprinted membranes

polymer chains (of the first step) and longer UV irradiation time (in the second step) lead to low binding capacity and higher membrane selectivity [56]. In the framework of nanostructured materials, an imprinted membrane was produced by electropolymerizing the functional monomer o-aminophenol in the presence of metolcarb as the template on the surface of a glass carbon electrode [57]. Electropolymerization was also used for preparing a thin film with pyrrole as a functional monomer and dual templates methcathinone and cathinone for developing an electrochemical sensor used in immunoassay. The detection limit of methcathinone was 3.3 pg · mL−1, while one of cathinone was 8.9 pg · mL−1 [58]. Yet, a polypyrrole-based thin film produced via electropolymerization was applied for sensing clofibric acid in wastewater treatment plants. Clofibric acid is a metabolite of the clofibrate, a lipid-lowering agent present in wastewaters, ground water, surface waters, and tap water [59]. Altintas et al. [60] prepared MIMs imprinted with different templates by means of plasma-induced grafting polymerization. Briefly, authors introduced carboxylic functional groups on the surface of a polyvinylidene difluoride (PVDF) membrane by plasma treatment prior to adding a layer of polymeric-imprinted nanoparticles (by covalent immobilization) synthesized previously. The pharmaceuticals diclofenac, metoprolol, or vancomycin are used as

Glass dielectric

Stainless stell electrodes

chemical injection + HV carrier gas HV

3. Functionalization of nanostructured polymeric membranes with MIPNPs

4. Water purification of pharmaceuticals using target specific membranes

~ 2. Plasma treatment on the membranes

addition of carboxylic groups

5. Filtrate analysis with HPLC 1. PVDF membranes

Fig. 3.6: Scheme of the preparation of nanostructure MIMs and their application in removing pharmaceuticals from water (reprinted from ref. [60]. Copyright 2016, with the permission of Elsevier).

3.5 Surface imprinting

69

templates. Membranes are used in water sample treatment for the removal of the target pharmaceuticals from water. Figure 3.6 illustrates the entire process. It entailed the PVDF surface modification via plasma treatment, the subsequent immobilization of the imprinted nanoparticles, the water purification test, and the HPLC analysis of the recovered permeate. The removal of metoprolol and diclofenac was about 100% and 94%, respectively, while that of vancomycin was 50% of the initial content [60]. A very recent work demonstrated for the first time the reliability of producing composite MIM surface imprinted with cypermethrin by cold plasma-induced grafting polymerization for the recognition of this insecticide in fish samples. Cypermethrin, an insecticide largely used in agriculture, represents an aquatic contaminant and can accumulate in fishes acting as an endocrine disruptor. As the support, functional monomer, and cross-linker, dense polypropylene membrane, MA, and EGDMA were used, respectively [61]. The process started by washing the membrane sequentially with ethanol, acetone, and ultrapure water. After the plasma treatment, the copolymerization of the functional monomer with the membrane surface at 40 °C for 24 h was carried out. AFM analysis and contact angle measurements evidenced a high surface roughness and a reduction of the contact angle in MIMs with respect to the corresponding NIMs and the original hydrophobic polypropylene, thus confirming the success of the modification process. Sometimes, before carrying out the surface imprinting, the membrane surface is modified by the introduction of chemical functional groups capable of interacting with the nascent MIP layer and the subsequent deposition of active molecules. In this context, the Dong’s group developed an efficient strategy for preparing lincomycin surfaceimprinted membranes aiming to remove this veterinary drug from contaminated milk and at the same time to improve hydrophilicity of a PVDF support membrane [62]. Authors investigated the synergistic effect of polyethylenimine (PEI) and dopamine. The first is an amine-rich polymer easily fixable to the membrane surface, while dopamine is an excellent surface-adherent material (i.e., for cell adhesion), which polymerizes on the membrane surface producing a polydopamine (PDA) layer that stabilizes the interaction between the membrane surface and the nascent imprinted sites. The covalent bond that occurred between the PEI and the PDA improved the stability of the hydrophilic PEI layer on the native PVDF membrane and promoted the polymerization of the functional monomer–template complexes. In adsorption experiments, the higher binding capacity (151.62 mg · g−1) was observed at an initial lincomycin concentration of 200 mg · L−1. The permselectivity lincomycin/clindamycin was 4.43 [62]. Polypropylenebased microfiltration membrane as a support for preparing a composite imprinted membrane by the deposition of a thin imprinted layer via emulsion polymerization was also used [63]. Another approach is the production of multilayered MIMs, as it is the case of the production of a multilayered MIM entailing the fabrication of the imprinted layer through an in situ activator generated by electron transfer-radical polymerization method using chitosan-based membrane as support [64]. The anchoration of the ATRP initiator on the membrane surface in advance allowed realizing the polymerization

70

Chapter 3 Preparation strategies of molecularly imprinted membranes

strictly on the surface, evading embedding the target molecules into the membrane matrix. Furthermore, after grafting polymerization, the initiator was still active enabling another polymerization. Very recently, for the selective adsorption of phenol, multilayered molecularly imprinted composite membranes based on porous carbon nanospheres/polydopamine (pDA) cooperative structure were developed [65]. Also, a new strategic approach has been proposed by Bai et al. in 2021 [66] for preparing upper surface-imprinted membranes via the phase inversion method by virtue of the magnetic field force for the selective separation of artemisinin (AM). Briefly, authors firstly synthesized Fe3O4 nanoparticlebased imprinted polymer particles via precipitation polymerization, and then the membranes were prepared by means of the wet phase inversion directing the location of the magnetic molecularly imprinted particles on the membrane surface via the guidance of a magnetic force (see Fig. 3.7). Artesunate has been used as a dummy template of AM [66].

Fig. 3.7: Preparation process of surface magnetically induced PVDF-based MIM (reprinted from ref. [66] Copyright 2021, with the permission of Elsevier).

The above strategies deal with the preparation of both flat-sheet and hollow-fiber membranes. However, the development of hollow fibers leads to exploit a higher surface area, thus improving the imprinting effect and the separation efficiency with respect to the flat-sheet configuration. For example, hollow-fiber surface-imprinted membranes were produced by coating the external surface of PVDF native fibers with a thin layer of levofloxacin-imprinted polymer via thermal polymerization [67]. The repetition of polymerization cycles allowed obtaining composite membranes at different modification degrees and controlling membrane permeability. The selective separation of template molecules was achieved by means of multisite binding with the membrane recognition sites via hydrogen bonds as well as hydrophobic and ionic interactions [67].

71

3.6 Nanofibers and other composite imprinted membranes

3.6 Nanofibers and other composite imprinted membranes Molecularly imprinted nanofiber membranes (MINFMs) are useful for enhancing the specific surface area and therefore the imprinting effect. In general, nanofibers are prepared via electrospinning, which is a method that deals with the application of a high voltage to a polymer solution for producing a polymer jet. Nanofibers originate due to the fast solvent evaporation, which leads to an increase in the charge density of the polymer jet. This technique permits to use a wide variety of materials and to prepare nanofibers with diameter ranging from few nanometers to few micrometers [8, 11, 13, 14, 68, 69]. In developing MINFMs, the simultaneous application of electrospray deposition, electrospinning, and alternative molecular imprinting during the membrane process leads to obtain MINFMs bearing a high concentration of specific recognition sites toward template molecules and exhibit both an increase of membrane flux and permselectivity with respect to other membrane configurations [11]. Electrospraying (also named electrohydrodynamic atomization) is a drying technique based on the electrohydrodynamic processing of polymer melts, solutions, or dispersions by an electric field, and it is useful in nanoencapsulation processes during the preparation of nanostructured materials. It produces fine liquid droplets, which upon evaporation and disruption are collected on the substrate. The surface area of an imprinted nanofiber membrane is 200 times greater than a typical flat-sheet porous membrane prepared with the same polymer having the same volumetric mass density [11]. Table 3.4 lists some examples of developed MINFMs. Tab. 3.4: Examples of molecularly imprinted nanofiber membranes. Template

Membrane-forming materials

Mean fiber diameter

Tetracycline

Polyvinylidenefluoride/ . μm polydopamine

Rosmarinic acid

Polycaprolactone

Nilotinib

Application

Reference

Extraction from water

[]

 ±  nm

Controlled drug release

[]

Polyacrylonitrile

 nm

Removal from human serum

[]

Putrescine

Polyvinyl alcohol

 nm

Sensing in food

[]

N-α-Acetyl-D-phenylalanine N-α-Acetyl-L-phenylalanine

Chitin Chitin

– nm Chiral separation – nm Chiral separation

[]

Atrazine

Polystyrene



[]

Composite polyvinylidene fluoride/sodium Water alginate-imprinted membrane

Calcium chloride

>

[]

[]

Reprinted part of table 2 from ref. [70]. Copyright 2016, with the permission of the Royal Society of Chemistry.

The data of Tab. 6.3 confirm the higher performance of the green self-supported MIM [70] and the green composite MIM [71].

142

Chapter 6 Molecularly imprinted membranes in enantiomeric separation

Few other papers deal with the development of ES-MIMs for chiral resolution of amino acids [25, 31, 35, 63, 81–86], and some of which focused their attention on arginine [31, 63], glutamic acid [25, 82], and serine [69]. The studies concerning the chiral separation with ES-MIMs argued in this chapter confirm the real potential of these intelligent membranes for application at large scale, also at industrial level and in developing sustainable enantiomeric separation processes.

References [1] [2] [3] [4]

[5] [6]

[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

[21]

Devínsky F. Chirality and the origin of life. Symmetry 2021, 13, 2277, https://doi.org/10.3390/ sym13122277. Pal AK, Bahadur B. Chirality in nature and biomolecules: An overview. Int J Life Sci 2020, 9, 72–84. Barron LD. Chirality and life. Space Sci Rev 2008, 135, 187–201. Gogoi A, Mazumder N, Konwer S, Ranawat H, Chen TZ, Zhuo GY. Enantiomeric recognition and separation by chiral nanoparticles. Molecules 2019, 24, 1007, https://doi.org/10.3390/ molecules24061007. Wu D, Pan F, Tan W, Gao LX, Tao Y, Kong Y. Recent progress of enantioseparation under scale production (2014–2019). J Sep Sci 2020, 43, 337–347. Fernandes C, Tiritan ME, Pinto MMM. Chiral separation in preparative scale: A brief overview of membranes as tools for enantiomeric separation. Symmetry 2017, 9, 206, https://doi.org/10.3390/ sym910020. Xie R, Chu LY, Deng JG. Membranes and membrane processes for chiral resolution. Chem Soc Rev 2008, 37, 1243–1263. Zheng H, Yoshikawa M. Molecularly imprinted cellulose membranes for pervaporation separation of xylene isomers. J Membr Sci 2015, 478, 148–154. Wulff G, Sarhan A. The use of polymers with enzyme-analogous structures for the resolution of racemates. Angew Chem Internat 1972, 11, 341–344. Brandt JR, Salerno F, Fuchter MJ. The added-value of small-molecule chirality in technological applications. Nat Rev Chem 2017, 0045, https://doi.org/10.1038/s41570-017-0045. Berthod A. Chiral recognition mechanisms. Anal Chem 2006, 78, 2093–2099. Ward TJ, Ward KD. Chiral separations: Fundamental review 2010. Anal Chem 2010, 82, 4712–4722. Burke D, Henderson DJ. Chirality: A blueprint for the future. Br J Anaesth 2002, 88, 563–5776. Maestri E, Maltoni S, Foroso G, Marata AM, Magrini N. Racemic drugs and enantiomers, identifying really useful innovations. Inf Pack Drugs 2006, 3, 1–4. Choi HJ, Ahn YH, Koh DY. Enantioselective mixed matrix membranes for chiral resolution. Membranes 2021, 11, 279, https://doi.org/10.3390/membranes11040279. Subramanian G. Chiral separation techniques. A practical approach. Wiley-VCH Verlag GmbH, 2001. Giorno L. Enantiospecific membrane processes. Korean Membr J 1999, 1, 38–42. Santos R, Pontes KV, Nogueir IBR. Enantiomers and their resolution. Encyclopaedia 2022, 2, 151–188. Scriba GKE. Chiral recognition in separation science. An update. J Chromatogr A 2016, 1467, 56–78. Zhao Y, Zhu X, Jiang W, Liu H, Sun B. Chiral recognition for chromatography and membrane-based separations: Recent developments and future prospects. Molecules 2021, 26, 1145, https://doi.org/ 10.3390/molecules26041145. Ingole PG, Ingole NP. Methods for separation of organic and pharmaceutical compounds by different polymer materials. Korean J Chem Eng 2014, 31, 2109–2123.

References

143

[22] Yoshikawa M, Higuchi A. Enantioselective membranes. In Hoek EMV, Tarabara VV, eds. Encyclopedia of membrane science and technology. John Wiley & Sons, Inc, online library, 2013, https://doi.org/ 10.1002/9781118522318.emst131. [23] Yoshikawa M, Izumi J, Kitao T, Koya S, Sakamoto S. Molecularly imprinted polymeric membranes for optical resolution. J Membr Sci 1995, 108, 171–175. [24] Dzgoev A, Haupt K. Enantioselective molecularly imprinted polymer membranes. Chirality 1999, 11, 465–469. [25] Gao B, Cui K, Li Y. Preparation of molecule imprinted membrane of single enantiomer of amino acid with an innovative strategy and study on its chiral recognition and resolution properties. J Chem Technol Biotechnol 2017, 92, 1566–1576. [26] Vedovello P, Paranhos CM, Fernandes C, Tiritan ME. Chiral polymeric membranes: Recent applications and trends. Sep Purif Technol 2022, 280, 119800, https://doi.org/10.1016/j. seppur.2021.119800. [27] Huang Y, Zang Y, Xu L, Lei T, Cui J, Xie Y, et al. Synthesis of chiral conjugated microporous polymer composite membrane and improvements in permeability and selectivity during enantioselective permeation. Sep Purif Technol 2021, 266, 118529, https://doi.org/10.1016/j.seppur.2021.118529. [28] Li H, Huang Q, Li D, Li S, Wu X, Wen L, et al. Generation of a molecular imprinted membrane by coating cellulose acetate onto a ZrO2-modified alumina membrane for the chiral separation of mandelic acid enantiomers. Org Process Res Dev 2018, 22, 278–285. [29] Moein MM. Advancements of chiral molecularly imprinted polymers in separation and sensor fields: A review of the last decade. Talanta 2021, 224, 121794, https://doi.org/10.1016/j.talanta.2020.121794. [30] Ying X, Zhu X, Kang A, Li X. Molecular imprinted electrospun chromogenic membrane for L-tyrosine specific recognition and visualized detection. Talanta 2019, 204, 647–654. [31] Ingole PG, Bajaj HC, Singh K. Enantiomeric separation of α-amino acids by imprinted terpolymer membrane. Arab J Chem 2016, 9, 960–965. [32] Qiu X, Xu XY, Liang Y, Hua Y, Guo H. Fabrication of a molecularly imprinted polymer immobilized membrane with nanopores and its application in determination of β2-agonists in pork samples. J Chromatogr A 2016, 1429, 79–85. [33] Kawasaki T, Yoshikawa M. Nanofiber membranes from cellulose triacetate for chiral separation. Desalin Water Treat 2013, 51, 5080–5088. [34] Shiomi K, Yoshikawa M. Multi-stage chiral separation with electrospun chitin nanofiber membranes. Sep Purif Technol 2013, 118, 300–304. [35] Sueyoshi Y, Utsunomiya A, Yoshikawa M, Robertson GP, Guiver MD. Chiral separation with molecularly imprinted polysulfone-aldehyde derivatized nanofiber membranes. J Membr Sci 2012, 401–402, 89–96. [36] Mizushima H, Yoshikawa M, Li N, Robertson GP, Guiver MD. Electrospun nanofiber membranes from polysulfones with chiral selector aimed for optical resolution. Eur Polym J 2012, 48, 1717–1725. [37] Sueyoshi Y, Fukushima C, Yoshikawa M. Molecularly imprinted nanofiber membranes from cellulose acetate aimed for chiral separation. J Membr Sci 2010, 357, 90–97. [38] Chhabra N, Aseri ML, Padmanabhan D. A review of drug isomerism and its significance. Int J App Basic Med Res 2013, 3, 16–18. [39] Nguyen LA, He H, Pham-Huy C. Chiral drugs: An overview. Int J Biomed Sci 2006, 2, 85–100. [40] Mannschreck A, Kiesswetter R, von Angerer E. Unequal activities of enantiomers via biological receptors: Examples of chiral drug, pesticide, and fragrance molecules. J Chem Educ 2007, 84, 2012, https://doi.org/10.1021/ed084p2012. [41] Bhupinder SS. Enantioseparation of chiral drugs – An overview. Int J Pharm Tech Res 2010, 2, 1584–1594. [42] Takumi I, Hideki A, Hiroshi H. Teratogenic effects of thalidomide: Molecular mechanisms. Cell Mol Life Sci 2006, 68, 1569–1579.

144

Chapter 6 Molecularly imprinted membranes in enantiomeric separation

[43] Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004, 4, 314–322. [44] Pu J, Wang H, Huang C, Bo C, Gong B, Ou J. Progress of molecular imprinting technique for enantioseparation of chiral drugs in recent ten years. J Chromatogr A 2022, 462914, https://doi.org/ 10.1016/j.chroma.2022.462914. [45] Bukhari A, Monier M, Elsayed N. Surface molecular imprinting of nylon fibers for chiral recognition of D-phenyl lactic acid. Polym Int 2019, 68, 1460–1467. [46] Huang Q, Li H, Guo T, Li S, Shen G, Ban C, Liu J. Chiral separation of (D,L)-lactic acid through molecularly imprinted cellulose acetate composite membrane. Cellulose 2018, 25, 3435–3448. [47] Lai S, Tang S, Xie J, Cai C, Chen X, Chen C. Highly efficient chiral separation of amlodipine enantiomers via triple recognition hollow fiber membrane extraction. J Chromatogr A 2017, 1490, 63–73. [48] Donato L, Figoli A, Drioli E. Novel composite poly (4-vinylpyridine)/polypropylene membranes with recognition properties for (S)-naproxen. J Pharm Biomed Anal 2005, 37, 1003–1008. [49] Wang JY, Xu ZL, Wu P, Yin SJ. Binding constant and transport property of S-Naproxen molecularly imprinted composite membrane. J Membr Sci 2009, 331, 84–90. [50] Bing NC, Tian Z, Jin HY, Wang LJ, Zhu LP, Xu ZL. Separation of naproxen enantiomers using hollow fiber molecularly imprinted membrane chromatography. Chem Lett 2011, 40, 266–267. [51] Zhao X, Qin P. Preparation and evaluation of molecular imprinted composite membranes for chiral resolution of ibuprofen. J Beijing Univ Chem Technol 2013, 40, 5–9. [52] Liu L, Xu Z, Zhang Y. Preparation and chiral resolution performance of S-ibuprofen molecularly imprinted membranes. Polymer Material Sci Eng 2012, 12, 159–163. [53] Yuan X, Tan Y, Wei X, Li J. Chiral determination of cinchonine using an electrochemiluminescent sensor with molecularly imprinted membrane on the surfaces of magnetic particles. Luminescence 2017, 32, 1116–1122. [54] Brisbane C, McCluskey A, Bowyer M, Holdsworth CI. Molecularly imprinted films of acrylonitrile/ methyl methacrylate/acrylic acid terpolymers: Influence of methyl methacrylate in the binding performance of L-ephedrine imprinted films. Org Biomol Chem 2013, 11, 2872–2884. [55] Zhu J, Li B, Nie Y. Application of molecularly imprinted composite membranes in splitting tetrahydropalmatine enantiomers. Chin Tradit Pat Med 2017, 39, 1838–1840. [56] Gutiérrez-Climente R, Gómez-Caballero A, Unceta N, Aránzazu Goicolea M, Barrio RJ. A new potentiometric sensor based on chiral imprinted nanoparticles for the discrimination of the enantiomers of the antidepressant citalopram. Electrochim Acta 2016, 196, 496–504. [57] Zarándi M, Szolomájer J. Amino acids: Chemistry, diversity and physical properties. In Ryadnov M, Hudecz F, eds. Amino acids, peptides and proteins. Royal Society of Chemistry, Cambridge, UK, 2018, 1–84. [58] Kiriyama Y, Nochi H. D-amino acids in the nervous and endocrine systems. Scientifica 2016, 2016, 6494621, https://doi.org/10.1155/2016/6494621. [59] Boibessot T, Benimelis D, Meffre P, Benfodda Z. Advances in the synthesis of α-quaternary α-ethynyl α-amino acids. Amino Acids 2016, 48, 2081–2101. [60] Liu T, Li Z, Wang J, Chen J, Guan M, Qiu H. Solid membranes for chiral separation: A review. Chem Eng J 2021, 410, 128247, https://doi.org/10.1016/j.cej.2020.128247. [61] Nechifor AC, Pîrt A, Albu PC, Grosu AR, Dumitru F, Dimulescu IA, et al. Recuperative amino acids separation through cellulose derivative membranes with microporous polypropylene fiber matrix. Membranes 2021, 11, 429, https://doi.org/10.3390/membranes11060429. [62] Shiomi K, Yoshikawa M. Molecularly imprinted chitin nanofiber membranes: Multi-stage cascade membrane separation within the membrane. J Memb Separ Technol 2016, 5, 103–114. [63] Ingole PG, Singh K, Bajaj HC. Enantioselective polymeric composite membrane for optical resolution of racemic mixtures of α-amino acids. Sep Sci Technol 2011, 46, 1898–1907.

References

145

[64] Gao B, Li Y, Cui K. Molecularly imprinted membrane with innovative structure and high performance for chiral separation of amino acids. Int J Polym Mater Polym Biomater 2018, 67, 517–527. [65] Liao H, Zhang Z, Nie L, Yao S. Electrosynthesis of imprinted polyacrylamide membranes for the stereospecific L-histidine sensor and its characterization by AC impedance spectroscopy and piezoelectric quartz crystal technique. J Biochem Biophys Methods 2004, 59(1), 75–87. [66] Shah N, Rehan T, Park JK. Adsorptive molecularly imprinted composite membranes for chiral separation of L-phenylalanine. Pol J Chem Technol 2016, 18, 22–29. [67] Ul-Haq N, Park JK. Chiral resolution of phenylalanine D-phe imprinted membrane considering rejection property. Bioprocess Biosyst Eng 2010, 33, 79–86. [68] Ul-Haq N, Khan T, Park JK. Enantioseparation with D-phe- and L-phe-imprinted PAN-based membranes by ultrafiltration. J Chem Technol Biotechnol 2008, 83, 524–533. [69] Son SH, Jegal J. Chiral separation of D,L-serine racemate using a molecularly imprinted polymer composite membrane. J Appl Polym Sci 2007, 104, 1866–1872. [70] Zhou Z, Cui K, Mao Y, Chai W, Wang N, Ren Z. Green preparation of D-tryptophan imprinted selfsupported membrane for ultrahigh enantioseparation of racemic tryptophan. RSC Adv 2016, 6, 109992–110000. [71] Zhou Z, He L, Mao Y, Chai W, Ren Z. Green preparation and selective permeation of D-tryptophan imprinted composite membrane for racemic tryptophan. Chem Eng J 2017, 310, 63–71. [72] Yoshikawa M, Koso K, Yonetani K, Kitamura S, Kimura S. Optical resolution of racemic amino acid derivatives with molecularly imprinted membranes bearing oligopeptide tweezers. J Polym Sci Part A: Polym Chem 2005, 43, 385–396. [73] Li H, Wang J, Fang H, Xu H, Yu H, Zhou T, et al. Hydrophilic modification of PVDF-based sers imprinted membrane for the selective detection of L-tyrosine. J Environ Manage 2022, 15, 114260, https://doi.org/10.1016/j.jenvman.2021.114260. [74] Zheng FX, Lian Q, Yang H. Synthesis of chitosan–gelatin molecularly imprinted membranes for extraction of L-tyrosine. RCS Adv 2014, 480, https://doi.org.10.1039/c4ra90051k. [75] Noaman UH, Park JK. Optical resolution of phenylalanine using D-Phe-imprinted poly(acrylic acid-coacrylonitrile) membrane: Racemate solution concentration effect. Polym Composite 2008, 9, 1006–1013. [76] Ul-Haq N, Park JK. Optical resolution of phenylalanine using D-Phe-imprinted poly(acrylic acid-coacrylonitrile) membrane – pH effect on performance. J Chemic Soc Pak 2014, 36, 561–567. [77] Singh K, Ingole P, Bajaj HC, Gupta H. Preparation, characterization and application of β-cyclodextringlutaraldehyde crosslinked membrane for the enantiomeric separation of amino acids. Desalination 2012, 298, 13–21. [78] Zhou Z, Cheng JH, Chung TS, Hatton TA. The exploration of the reversed enantioselectivity of a chitosan functionalized cellulose acetate membranes in an electric field driven process. J Membr Sci 2012, 389, 372–379. [79] Kim JH, Jegal J, Kim JH, Lee KH, Lee Y. Enantioselective permeation of α-amino acid optical isomers through crosslinked sodium alginate membranes. J Appl Polym Sci 2003, 89, 3046–3051. [80] Singh K, Bajaj HC, Ingole P, Bhattacharya A. Comparative study of enantioseparation of racemic tryptophan by ultrafiltration using BSA-immobilized and BSA-interpenetrating network polysulfone membranes. Sep Sci Technol 2010, 45, 346–354. [81] Akgönüllü S, Yavuz H, Denizli A. Preparation of imprinted cryogel cartridge for chiral separation of lphenylalanine. Artif Cells Nanomed Biotechnol 2017, 45, 800–807. [82] Yoshikawa M, Nakai K, Matsumoto H, Tanioka A, Guiver MD, Robertson GP. Molecularly imprinted nanofiber membranes from carboxylated polysulfone by electrospray deposition. Macromol Rapid Commun 2007, 28, 2100–2105.

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Chapter 6 Molecularly imprinted membranes in enantiomeric separation

[83] Shah N, Ha JH, Ul-Islam M, Park JK. Chiral separation of phenylalanine using D-phenylalanine imprinted membrane containing L-phenylalanine imprinted submicron/nanoscale beads. J Pharm Res 2012, 5, 4425–4433. [84] Itou Y, Nakano M, Yoshikawa M. Optical resolution of racemic amino acid derivatives with molecularly imprinted membranes from tetrapeptide consisting of glycinyl residues. J Membr Sci 2008, 325, 371–375. [85] Conesa A, Palet C. Molecularly imprinted membranes (MIM) for the enantioseparation of selenoaminoacid compound. Desalination 2006, 200, 110–111. [86] Yoshikawa M, Izumi JI. Chiral recognition sites converted from tetrapeptide derivatives adopting racemates as print molecules. Macromol Biosci 2003, 3, 487–498.

Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors 7.1 Introduction The continuous industrial development and the agricultural and human activities have determined the production and the persistence of many types of contaminants. Some of the main polluting agents are pesticides, drugs, microorganisms, volatile organic compounds, and inorganic and radioactive compounds. They now represent a serious ecological and human-health problem that need to be addressed in the best way for ensuring a good quality of life and that of the environment for future generations. For example, the widespread use of antibiotics is responsible for their presence in environmental waters and of the onset of resistant antibiotic bacterial strains. In addition, it must be to consider that the abuse of drugs is dangerous for our health owing to their excessive accumulation in blood, while the large use of pesticides in agriculture led to their presence in waters, soil, and unfortunately in food chain [1–4]. From everything, a continuous monitoring of contaminants has become necessary to keep them below the toxic level and render human life considerably more accessible and better worldwide. In this context, sensor technology takes up a vital role in the modern society for achieving the protection of people and environment toward different factors such as the action of bacteria, viruses, and toxic compounds in the air, waters and soil, drugs abuser, war arms, and much more. Extremely important is also their employment in clinical diagnosis and monitoring as well as in drug discovery [3, 4]. Over time more and more innovative sensors have been developed. They are able to detect and quantify specific characteristics of monitored entity and convert them into a measurable electrical signal (e.g., current, charge, or voltage) by a transducer. Agreeing with the detected properties different types of sensors such are chemical sensors, electric sensors, magnetic sensors, and thermal sensors exist [5–9]. In the field of the analytical chemistry and biological research, the attention has been focalized on the development of new chemical and biological analytical materials and methodologies for fabricate innovative chemical sensors and biosensors [10, 11]. The first type mostly employs conductive materials as sensing element or as a part of composites containing functionalities able of interacting with specific analytes, while in the biological sensors the sensing element is represented by a biological receptor (like enzymes and antibodies) exhibiting high specific recognition ability toward targeted analytes. Unfortunately, despite their high specificity biosensors have the disadvantage of the low stability and rapid degradation of the biological components. Furthermore, the purification costs of the biological receptors are very high [11, 12]. Therefore, the research and the industrial trend deal with the exploration of novel materials alternative to them, even if it is not easy the competition with consolidated technologies. https://doi.org/10.1515/9783110654691-008

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In this framework find new application conducting polymers and biomimetic artificial recognition systems such as aptamers, synthetic peptides, and molecularly imprinted materials. In particular, the employment of imprinted membranes as biomimetic recognition elements permits to achieve high stability, sensitivity, and specificity [12, 13]. This chapter deals with the concept of chemical and biological sensors as well as with the production and application of artificial biomimetic sensors based on imprinted materials. Particularly, the useful application of MIM-based biomimetic sensors, which can represent valid substitutes of biological receptors (and overpass their basic drawbacks) to detect drugs and biomolecules in biomedical field as well as food and water contaminants, will be discussed.

7.2 The concept of chemical and biological sensors Sensing science plays a vital role on different aspects of modern society such as safety, security, and surveillance. It is constantly evolving along with industrial advancement and the increase in human activities especially due to the need for environmental, chemical, clinical, food, and beverage monitoring. All these aspects allowed the development of more and more innovative sensors, which are devices able to detect and quantify specific characteristics of monitored entity and convert them into a measurable electrical signal (e.g., current, charge, or voltage) by a transducer. When a variation of the measured characteristic occurs after the interaction between the detected compound and the sensing element, the output signal of the sensor also displays change of its intensity. Sensors are self-regulating systems built into normal articles or machines for intelligent use. According to the detection properties (e.g., chemical, electrical, magnetic, and physical) different types of sensors such are chemical sensors, electric sensors, magnetic sensors, sensors, pressure sensors, rain/moisture sensors, thermal sensors, speed sensors, tilt sensors, and vibration sensors exist [5–9, 12]. Some examples of measured entities are concentration, humidity, light, magnetic flux, pH, pressure, temperature, etc. [5, 14]. Since the last millennium, sensor technology has experienced rapid growth and sensors are present in different forms. Today intelligent sensors are essential components of cars, computing and navigation systems, smart watches, advanced automated systems such as health care instruments as well as environmental and clinical detection systems and artificial intelligent devices [5, 14–17]. In recent years, there is also a growing interest in manufacturing high-sensitive wearable sensors in order to overcome the disadvantage of the limited detection range and nonportability of traditional devices, which are also more expensive [18–20]. Amongst the different existing sensors, in the field of the analytical chemistry and biological research, studies aimed at the development of new chemical and biological analytical materials and methodologies have given a significant boost particularly to the production and application of chemical sensors and biosensors [10, 11].

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Chemical sensors are able to detect and transform an input chemical or biochemical signal of a target compound (composition, concentration, pH, reaction rate, redox potential, specific ions, etc.) into an analytically useful signal. The input information originated from selective interactions between the sensing element and the analyte or reactions (chemical, enzymatic, etc.) involving them. Owing to these specific interactions, they are able of qualitatively and quantitatively determine the target analyte from complex samples. Usually, a chemical sensor is a component of a chemical sensing device consisting of a chemically (artificial) recognition element (the actual sensor) and of a physicochemical transducer connected in series (see Fig. 7.1). The first interacts with the analyte at the input interface and transfers the acquired information to the transducer that converts it into a measurable signal proportional to the measured quantity. The latter signal is amplified and sent to the outside [21–24].

Fig. 7.1: Block diagram of a chemical sensing device.

According to the various transduction methods applied for producing the final signal, different types of chemical sensors exist (e.g., electrochemical, thermal, optical, and magnetic). Among them, the most widely used are the electrochemical sensors. They exploit mainly electrochemical reactions, which reduce or oxidize the analyte of interest, thus producing an electron flow proportional to its concentration. Electrochemical sensors are distinguished in amperometric, conductometric, impedometric, and potentiometric in virtue of the measured entity: current, conductivity, impedance, and potential, respectively. They employ conductive materials as sensing element or as a part of composites containing functionalities able of interacting with specific analytes. However, nonconductive new materials in potentiometric sensing are also used [22–27]. Optical chemical sensors for the detection of the optical properties (e.g., absorbance, luminescence, and florescence) of chemical compounds have gained also popularity owing to their low cost, compactness, and possibility to display analytes in a noninvasive and continuous manner including biomedical application and their integration in miniaturized-scale bioreactors [27, 28]. A typical and well-known application of chemical sensors is the monitoring of blood glucose level in people with diabetes. In this context, blood glucose meters have been in use for a long time and more and more innovative detection devices are in continuous development including wearable electrochemical sensors and subcutaneous implantable [29–32]. For example, Zhang et al. [32] developed an advanced optical nanosensor based on poly(amido amine) functionalized microgels for continuous in vivo glucose monitoring. In particular, the fluorescent poly(amido amine) was introduced into glucose sensitive poly(N-isopropylacrylamide-(2-dimethylamino)ethyl

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methacrylate-3-acrylamidephenylboronic acid) copolymer microgels and used as optical code. Microgels were injected into the skin; after the subsequent recognition of glucose molecules, the optical code emitted a blue fluorescent signal, which was proportional to the concentration of the detected analyte. Figure 7.2 shows the schematic illustration of the process [32].

Fig. 7.2: Schematic illustration of fluorescent poly(amido amine)-functionalized microgels that recognize glucose and emit blue fluorescence after injection (reprinted from ref. [32]. Copyright 2014, with the permission of the American Chemical Society).

Electrochemical and fluorescence-based sensors have been also developed via other routes exploiting quenching, resonance energy transfer, photoinduced electron transfer, electrostatic assembly, and carbon nanotubes [33–35]. Another example is a miniaturized and disposable electrochemical sensor applied for the detection of phenolic compounds [36]. It was prepared casting the modifier carbon black (having excellent conductive and electrocatalytic properties) on the surface of a working electrode. Experimental results showed that the modified electrode was able to detect phenolic compounds at lower potential with higher sensitivity with respect to the nonmodified one. Interestingly, the novel electrode was also able to distinguish the mono-phenols and the ortho-diphenols with a rapid and easy measurement [36]. More recently, a carbon back-based sensor was also applied for detecting low levels of ascorbic acid in fresh-cut fruit [37] and bisphenol A in diary analysis [38]. Grafene and ionic liquids gel past electrodes were also useful for the detection of the antioxidant caffeic acid [39]. In the framework of chemical sensors assumed relevant importance the biosensors. They are particular sensors employing biological receptors immobilized on the surface of a recognition element integrated with a transducer for converting the biological

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response generated by the interaction bioreceptor-analyte into an optical or electrical output signal. The response is in the form of charge, pH, light, mass variation, etc., and the output signal is proportional to the amount of the analyte–bioreceptor interactions [12, 30, 40]. The detection and the quantification occur in one step [11, 12]. Figure 7.3 shows the schematic representation of a biosensor [12].

Fig. 7.3: Scheme of a biosensor (reprinted from ref. [12]. Open access).

A typical feature characterizing the biosensors is their high selectivity, which permits them to detect a specific analyte present in a complex sample. The most representative example of this specificity is the antibody–antigen interaction. According to the different receptors used, the biosensors are distinguished in enzyme biosensors and affinity biosensors. In the first type, the receptors are pure enzymes catalyzing highly specific substrate–analyte reactions [10, 12, 41]. A disadvantage of these biosensors is the high enzyme purification cost, the enzyme stability, and the shelf life. Often, for avoiding the enzyme purification step, animal and plant tissues, cells, bacteria, fungi, and their organelles containing the desired enzyme are employed as recognition elements. In these cases, the enzyme stability increases with respect to the pure form [41–44]. Affinity biosensors promote selective interactions between the investigated sample and a specific ligand of the recognition element to achieve the formation of a thermodynamically stable complex. In this case, antibodies, antigens, DNA fragments, etc. are used as biological receptors [10, 12, 45]. In addition to the selectivity, important aspects to consider in developing biosensors are their accuracy and precision. In this context, the immobilization of the biological receptor on the surface of the recognition element plays a significant role in order to avoid the degradation of the receptor and preserve its specificity. In general, the nature of the receptor, the type of the transducer, and the operating conditions determine the choice of the immobilization method. The foremost immobilization methods are the covalent binding, the physical sorption, and the immobilization by means of affinity reagents. Among these, the physical entrapment (the oldest) has several weak points and first of all the loss of the specificity of the receptor as the pH changes. Chemical bonds occur between the functional groups of the surface of the recognition element and those of the biological receptor.

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Since the production of the first biosensor by Updike and Hicks [46] in 1967, many biosensors for application in different areas such as drug discovery, biomedical diagnosis and research, environmental and food control, clinical monitoring, forensic science, and much more have been studied and developed. In this context, the detection of biomolecules as a disease markers or drug targets (as in the case of cancer and specific antigens) is one of the most important applications [12, 40, 47, 48]. Useful is also the employment of biosensors in artificial implantable devices as pacemakers as well as platforms for detecting pesticides, metals, and pharmaceuticals in food, beverages, and water in order to nursing their quality, nutritional value, and pollution degree [12, 40, 49–51]. Their application also entails the detection of viruses and bacteria [12, 40, 52]. An example of the application of enzymatic biosensors is the detection of serum creatinine, a very important biomarker for the diagnosis of renal and muscle dysfunction. Yadav and coworkers [53] developed a biosensor specific for creatinine by coimmobilizing commercial creatininase, creatinase, and sarcosine oxidase enzymes onto iron oxide nanoparticles/chitosan-graft-polyaniline composite film electrodeposited on the surface of platinum electrode with the aid of glutaraldehyde. The biosensors gave a rapid response and showed high sensitivity, reproducibility, and long-term stability [53]. Recently, Dasgupta et al. [54] developed an innovative creatinine-biosensor entailing the conversion of creatinine by a mono-enzymatic pathway to 1-methylhydantoin. The quantification of the latter via the transmittance measurement at 290 nm of wavelength allowed to indirectly obtain the creatinine concentration. The estimated value was in the range 0.2–4.0 mg · dL−1 in a sample volume of 300 μL [54]. It cannot be denied that chemical and biological sensors have the potential to produce innovative future systems that can help us prevent serious health risks, optimize agricultural production, and manage supply chains. However, it is necessary to point out that despite their high specificity, the disadvantages of low stability and rapid degradation of their biological components during storage and use, which render difficult calibration and stability, limit the application of biosensors. In addition, these sensing systems are too expensive and hard to obtain for every molecule of interest in environmental and clinical detection [10, 12, 55, 56]. In this context, today there are numerous emerging actions in chemical and biological sensors production. In fact, the rapid advancement of materials science and technology has encouraged to explore novel materials as sensing elements for achieving high sensor’s stability and selectivity in the detection of specific analytes. For example, the attention of the research in this field is devoted to the development of new generation of sensors based on nanostructured materials, new conducting polymers, and biomimetic artificial recognition systems like aptamers, synthetic peptides, and molecularly imprinted materials as alternative to the natural sensible biological receptors [10, 12, 55–57].

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7.3 Toward imprinted materials as biomimetic receptors The development of imprinted polymers and membranes as artificial biomimetic recognition systems for overpowering the problems characterizing the biological receptors is becoming more and more widespread. In fact, the direct interaction, the rapid determination of the template, and the preservation of sensitiveness represent boosting factors for employing such systems as substitute to the traditional methods of bioassay. In sensors using imprinted materials, the latter represent the biomimetic recognition elements that interact with the target analytes without the necessity of adding secondary reagents [12, 58, 59]. The detection is based on the determination of tailored features of the template (e.g. absorbance and IR spectrum/fluorescence/electrochemical activity) or modification of the physicochemical parameters of the system in response to the binding with it. More in detail, these sensors are cheaper than those employing natural receptors and at the same time exhibit similar affinity and sensitivity in recognizing the target analytes. Furthermore, they resist to the autoclave treatment and can work in acid and basic solutions, high temperature, and pressure as well as in organic environment without undergoing denaturation as happens for biological receptors [12, 58, 59]. First applications of artificial imprinted biomimetic sensors involved the use of imprinted polymers [59, 60]. For example, MIPs can successfully replace antibodies and enzymes when a specific recognition of tailored bioanalytes is required [13, 60, 61]. Figure 7.4 shows how an MIP-based chemosensor can mimic the recognition ability of antibodies in an immunosensor [59].

Fig. 7.4: Example of an MIP-based sensor that mimics an immunosensor (reprinted from ref. [59]. Copyright 2016, with the permission of Elsevier).

Briefly, instead of antibodies immobilized on the transducer surface, the MIP-based chemosensor is provided by an additional thin selective imprinted polymer layer having specific recognition sites able of interact and subsequently let it free. Other examples are MIP-based ELISA-like test with the template, MIP-DNA chemosensors, electrode coated with catalytic MIP, etc. [13, 59]. Their application entails those typical of chemical and biological traditional sensors [13, 59, 62–66].

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In developing MIP-based biosensors, the MIP is synthesized on a suitable solid surface (e.g., glass electrode, graphene/carbon nanotube electrode, qutum dots, gold, and silver nanoelectrodes) often via eletropolymerization from solutions containing electroactive functional monomers (e.g., aniline, dopamine, o-phenylenediamine, pyrrole, and thiophene), template, and cross-linker. However, this method also involves the use of nonconductive monomers such as phenol and phenylenediamine. In general, after the MIP synthesis, the template is removed from the polymer layer and when it is reintroduced into the system it is bounded by the recognition sites of the MIP producing a measurable change in electrochemical or thermal properties. Sensors based on electropolymerized MIPs resulted useful in the detection of neurotransmitters dopamine and serotonine [66, 67]. Moreover, this method was applied for fabricating MIP-based sensors for the detection of cancer antigens [68, 69]. A recent paper reports the development of electrically conducting poly(toluidine blue) as a recognition element on a gold electrode for the detection of the prostatic specific antigen (PSA) [70]. For stabilizing the recognition sites, the electrode was conjugated with glutaraldehyde–cysteamine mixture before starting the polymerization. The MIP resulted useful for the protein antigen detection via voltammetric measurements in the range 1.0–60 μg · L−1 of sample with 1.0 μg · L−1 as the detection limit. This MIP-based sensor resulted useful as alternative to the anti-PSA antibody immunosensor. In a different work Pacheco et al. [68] developed a 2-aminophenol-based MIP for detecting the breast cancer biomarkers CA 15-3 and HER2-ECD [71]. Other highly efficient applications include the detection of the mycotoxin deoxynivalenol in food [72] and the antidepressant tradozone in human serum and water samples [73]. Raziq et al. [74] reported for the first time the fabrication of a portable sensor based on an antibodylike MIP as recognition element for the detection of the SARS-CoV-2 nucleoprotein in nasopharyngeal swab samples of COVID-19 positive patients. The sensor exhibited a linear response to the antigen in the concentration range of 0.7–2.2 pg · L−1 and was able to differentiate from interfering proteins [74]. Other production methods are the precipitation polymerization, the surface grafting, and the sol–gel polymerization. A patulin-imprinted polymer was copolymerized via thermal polymerization at 60 ºC with graphene oxide nanosheets modified with magnetic nanoparticles on the surface of a glassy carbon electrode. The obtained sensor was applied on real apple juice samples for determining this toxin. The excellent conductivity of graphene oxide increased the sensitivity of the sensor, while the presence of MIP allowed an increase of the selectivity [75]. A magnetic-supported polymer was synthesized via coprecipitation polymerization of acrylamide as the functional monomer and trimethylolpropane trimethacrylate as the cross-linking with magnetic nanoparticles in the presence of reduced gluthatione as the target analyte [76]. The nanocomposite was applied with success in the determination of the template in mice’s liver tissues through electrochemical and spectrophotometric techniques. A high correlation between the used methods and a low relative error of 1.06% was obtained, signifying the virtuous functionality of the fabricated sensor [76].

7.3 Toward imprinted materials as biomimetic receptors

155

As it is evident from the cited papers and the existing literature, the applications of MIP-based biomimetic sensors entail successfully those typical of chemical and biological traditional sensors [62–66]. However, it is necessary to consider that despite the great success at research level, these innovative sensors have not yet received the proper consideration they deserve on an industrial level. Probably this is due to the dominant use of antibodies and with the fact that it is hard to compete with the consolidated technologies for which large investments were done [62–66]. Another useful strategy of employing the molecular imprinting technology is the fabrication of biomimetic sensors based on imprinted membranes, which overcome the excessive response time, the slow mass transfer, and the possible low adhesion between polymer particles and transducer surface, resulting therefore more efficient with respect MIPs. Furthermore, they exploit their features of working in continuous and long-term operation mode under conditions not abided by biomolecules without dropping sensitiveness [12]. In MIM-based sensors, similar to MIPs, the imprinted membrane is the recognition element of a system directly integrated with the transducer. Hedborg et al. [77], who produced an L-phenylalanine anilide-imprinted membrane in combination with a field-effect capacitance device, did one of the first studies on this focus. The system was prepared via in situ polymerization of methacrylic acid on an activated silicon surface. In ethanol solution, the selective binding of the template with the recognition sites of the membrane determined a small change in capacitance of the system. During the same period, Piletsky et al. [78] developed a sensor device that allowed the selective permeation of the template L-phenylalanine and its separation from the opposite enantiomer. In other sensors, a reverse response between covalent and noncovalent bonding-based systems occurred. More in detail, in covalent-imprinted device an increase of the template concentration caused a decrease of the conductivity signal, while for the noncovalent-imprinted sensor, an increase in the signal was registered. This different trend was attributed to the presence of more numerous and homogeneous recognition sites in the covalent-imprinted sensor, which upon template binding shrank transmitting a lower electroconductivity signal [79]. So far, various biomimetic sensors based on imprinted membranes have been developed. Today, most prominent areas of their application are the detection of pollutants in water and food as well as the sensing of bioactive molecules, drugs, and metal ions. The following paragraphs will discuss about some of these applications, except for ions detection, which will be discussed in the next chapter dealing with ion-imprinted membranes production and application.

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7.4 Detection of drugs and biomolecules through MIM-based sensors The detection of drugs and biomolecules plays an important role in clinical diagnosis for monitoring human health in real time. For example, it gives the possibility of controlling drug abuser and revealing the presence of toxic exogenic compounds in biological fluids as well an excessive level of endogenic compounds as it is the case of cholesterol, creatinine, glucose, bacterial endotoxins, etc. In this context, the control of cholesterol level is increasingly important for avoiding the development of atherosclerosis and cardiovascular diseases, which represent the leading cause of death in Europe [80, 81]. In the framework of the different methods used for determining this compound, biosensors based on imprinted membranes resulted promising for realizing a direct, rapid, and high selective analytical determination. The Piletsky’s group developed one of the first MIM-based amperometric sensors useful for detecting cholesterol [82]. Its fabrication entailed the self-assembly of the monomer hexadecyl mercaptan as a thin film of a gold electrode surface in the presence of cholesterol. The removal of the latter through a proper washing let free the recognition sites, which were able to rebind it during the application of sensor in 50% aqueous ethanol. The rebinding of cholesterol to the recognition sites of the membrane determined a reduction of the mass transport of the electroactive electrode surface and consequently of the current signal. This decrease was proportional to the concentration of bounded cholesterol [82]. More recently, Ji et al. [83] have developed an electrochemical innovative sensor based on the synthesis of a membrane film on the surface of a glassy carbon electrode modified with multiwall carbon nanotubes and AU nanoparticles. The proposed device was promising for cholesterol sensing in high-speed real time with low sample consumption and high sensitivity. The low detection limit was 3.3 × 10−14 mol · L−1. Composite MIMs are also good candidates as sensing elements for detect cholesterol. For example, Ciardelli et al. [84] produced MIMs as recognition elements for the extracorporeal blood detection of cholesterol. Membranes were prepared by the deposition of cholesterol-poly(methacrylic acid) imprinted nanospheres on the surface of methylmethacrylate-co-acrylic acid-based membranes obtained via the phase inversion technique. Composite MIMs also resulted as useful sensing elements for recognizing the anesthetic propofol in blood [85]. Membranes were fabricated by polymerizing a thin propofol-imprinted polymer film on the surface of polytetrafluoroethylene, cellulose, and nylon membranes. Detection test performed on real samples for 3 min evidenced good linearity and specificity at clinically significant concentrations of 1.0–10 µg · mL−1. In a different work composite MIMs, prepared polymerizing the functional monomer 9-vinyladenine on the surface of cellulose membrane (via UV irradiation) using the plant hormone H-indole-3acetic acid [86] as the template, were applied for detecting it in plant samples. More recently the imprinting technology was applied for producing 9-aminoacridine sensors based on hybrid MIMs for static and hydrodynamic quality (an antimicrobial agent) control of this drug in pharmaceutical and biological formulations [87]. The sensing

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7.4 Detection of drugs and biomolecules through MIM-based sensors

membranes were prepared via the phase inversion, dispersing a presynthesized aminoacridine-based MIP into a dope solution of poly(vinyl chloride). Afterward, they were used in conjunction with a potentiometric transduction system for detecting low template level in the investigated samples. MIM-based biomimetic sensors exhibiting good linearity range and low detection limit resulted useful for the selective recognition of many other drugs and biomolecules. Table 7.1 summarizes some few examples. Tab. 7.1: Some examples of MIM-based sensors for the selective detection of drugs and biomolecules. Analyte

Imprinted sensing membrane

Linearity range (mol · L−)

Acetaminophen

Magnetic FeO-SiO-poly(vinylpyridine/methacrylic acid) on a surface of a magnetic a carbon paste electrode

From  × − to  × − and from  × − to  × −

Catechol

Detection limit (mol · L−)

Reference

. × −

[]

Chitosan film electrodeposited on From . × − to a boron-doped diamond electrode . × −

. × −

[]

Ketamine

Poly(methacrylic acid)-imprinted From . × − to membrane on a metal-organic . × − framework/graphene nanocomposite (MOFs@G) modified screen-printed electrode.

. × −

[]

Salbutamol

Poly(methacrylic acid) on a quartz crystal microbalance sensor

From . × − to . × −

. × −

[]

Mebeverine hydrochloride

Poly(-vinylimidazole) in a polyvinylchloride membrane matrix coupled with a liquid electrode

From  × − to · −

 × −

[]

Lamotrigine

Polysiloxane-imprinted membrane From . × − to on the surface of a carbon . × − and from electrode modified with graphene . × − to . × −

. × −

[]

Azithromycin

Poly(acrylic acid) in polyvinyl chloride membrane matrix coated on a graphite electrode

. × −

[]

Doxycycline

Poly-pyrogallol polymeric film on a From . × − to gold electrode . × −

. × −

[]

From  × − to  × −

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Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

Tab. 7.1 (continued) Analyte

Imprinted sensing membrane

Linearity range (mol · L−)

Glutathione

FeO-polyaniline/reduced graphene oxide layer on the surface of magnetic carbon electrode

From . × − to . × −

. × −

[]

Dextromethorphan Poly(-vinylpyridine) in hydrobromide polyvinylchloride membrane matrix coupled with a liquid electrode

From  × − to  × −

. × −

[]

Dopamine

Poly(methacrylic acid) on the surface of graphene oxide

From . × − to . × −

. × −

[]

Creatinine

Poly(acrylamide--methyl-propanesulfonic acid) on polyvinylidene fluoride support

From . × − to . × −

. × −

[]

Urea

Electrochemical sensor based on chitosan films

From  × − to . × −

. × −

[]

Detection limit (mol · L−)

Reference

Interestingly, a biomimetic electrochemical sensor was developed for detecting ketamine in biological fluids. This compound causes hallucinogenic and amnesia problems and is one of the most abused drugs worldwide. Its precise detection in real time has a relevant importance for avoiding serious health complications and criminal investigation efforts. In recent years, Fu et al. [90] developed an electrochemical MIM-based sensor having ketamine-poly(methacrylic acid)-imprinted membrane as recognition element. The device was applied for detecting ketamine in real saliva and urine samples of healthy volunteers via the standard addition method. Results evidenced a high detection and recovery value of the drug (near 100%) with respect to the initial content [90]. Magnetic molecularly imprinted membranes represent other promising sensing elements of innovative biomimetic sensors owing to their strong response to electrochemical signals and high ability to detect and remove the undesired analyte from the polluted site. Su et al. [88] developed a selective sensor toward acetaminophen depositing imprinted magnetic Fe3O4@SiO2-poly(4-vinylpyridine/methacrylic acid) on a surface of a magnetic carbon paste electrode under the action of a magnetic field (see Fig. 7.5). The adopted method ensured a large surface electrode area. As detecting platform, an electrochemical workstation was employed. In phosphate buffer, the sensor exhibited a linear dependence on the template concentration of the template, with a

7.4 Detection of drugs and biomolecules through MIM-based sensors

TEOS

4-VP+ MAA+AP MCPE

TEOS+AIBN Fe3O4

159

Fe3O4@SiO2 Extraction

Rebinding

Electrochemical station

MCPE Background solution

Fig. 7.5: Schematic representation of the acetaminophen-imprinted sensor developed by Su et al. (reprinted from ref. [88]. Copyright 2020, with the permission of Elsevier).

detection limit of 1.73 × 10−8 mol · L−1 and linearity between two ranges of concentration (6.0 × 10−8 to 5.0 × 10−5 mol · L−1 and 5.0 × 10−5 to 2.0 × 10−4 mol · L−1). The device was selective with respect to the similar compounds para-aminophenol and acetanilide. Furthermore, the evaluation of its performance in actual samples evidenced a good performance, confirming that the presence of interference in human serum and urine samples did not affect the detection of acetaminophen. Table 7.2 summarizes the results of these experiments. Tab. 7.2: Detection of acetaminophen in different samples with the acetaminophen-imprinted sensor was developed by Su et al. Sample

Tablet Granule Altapharma Oral liquid Serum

Urine

Declared or added

         

Detected by this method Found

Recovery (%)

RSD (%)

. . . . . . . . . .

– – – – . . . . . .

. . . . . . . . . .

Reproduced from ref. [88]. Copyright 2020, with the permission of Elsevier.

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Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

Another example of the successful application is the one-step production of glutathione-imprinted membrane by magnetic field directed self-assembly under magnetic field induction for the electrochemical detection of this antioxidant tripeptide [96]. In a different way, the microcontact imprinting allowed to produce a nanofilm for the selective recognition of myoglobin in human serum [101]. At this purpose, a poly(hydroxyethyl methacrylate-N-methacryloyl-L-tryptophan methyl ester) nanofilm was polymerized on a surface plasmon resonance gold chip. The detection limit in serum samples was 87.6 ng · mL−1. In selectivity studies, the sensor preferentially recognized the template protein with respect to lysozyme, cytochrome c, and bovine serum albumin, exhibiting a relative selectivity factor of 3.19, 3.81, and 5.59, respectively [101]. Molecularly imprinted nanotube membranes resulted applicability for also monitoring the urine level of the catecholamines dopamine, epinephrine, and norepinephrine [102]. The detection limit was 1.0 × 10−4 µmol · L−1, 6.87 × 10−5 and 1.33 × 10−4 ng · L−1, respectively, while the linearity range of the sensor was 0.50–300 μmol · L−1. The control of the presence of bacterial endotoxins in human serum is another application of MIM-based sensors. Endotoxins are components (lipopolysaccharides) of the external cell wall of Gram-negative bacteria and are present in blood during bacterial infection. Therefore, their diagnosis and treatment at the early stage of an infection are extremely important for avoiding the collapse of the immune system and the consequent death of the infected patient [103]. Molecularly imprinted nanofilms were created on the surface of a gold plasmon resonance chip using the endotoxin from Escherichia coli as template molecule [104]. In sensing studies performed in phosphate buffer pH 7.0, the change of sensor’s reflectivity allowed to confirm the endotoxin presence. In particular, an increase of endotoxin concentration determined a correspondent increase of the reflectivity. Furthermore, in selectivity studies carried out in the presence of the similar and competing compounds cholesterol and hemoglobin, the sensor exhibited a selective factor endotoxin/cholesterol of 5.73 and endotoxin/hemoglobin of 1.08. Figure 7.6 shows the different change of reflectivity of the imprinted and nonimprinted sensors. From the figure, it is evident that in the case of the imprinted sensor the response in reflectivity change was higher when endotoxin was present in the tested sample while the response was lower for solution containing only cholesterol and hemoglobin. The linearity range was from 0.5 to 100 ng · mL−1, while the low detection limit was 2.3 × 10−2 ng · mL−1. In addition, the nonimprinted sensor exhibited much lower reflectivity in all measurements without changing its behavior in the presence of endotoxin [104]. Recognition tests carried out on artificial plasma revealed a rapid response of the sensor and a high removal capacity of the detected endotoxin (from 98.36 to 98.73 ng · mL−1).

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7.5 MIM-based sensors for detecting additives and pollutants in food and water

A

B

4.5

ET ET+CHO+Hb CHO Hb CHO+Hb

4 3.5

0.8

ET ET+CHO+Hb CHO Hb CHO+Hb

0.7 0.6

%ΔR

%ΔR

3 2.5 2

0.5 0.4 0.3

1.5 1

0.2

0.5

0.1 0

0 0

120

240

360

480

Time (sec)

600

720

840

0

120

240

360

480

600

720

840

Time (sec)

Fig. 7.6: The selectivity studies of endotoxin imprinted surface plasmon resonance sensor (A) and its corresponding nonimprinted sensor (B) (the sample concentration was 50 ng mL–1 in all measurements). ET, endotoxin; CHO, cholesterol; Hb, hemoblobin (reprinted from ref. [104] Copyright 2021, with the permission of Elsevier).

7.5 MIM-based sensors for detecting additives and pollutants in food and water Various compounds used as food additives and in agriculture can contaminate soil, sea, rivers, lakes, and drinking water, representing a serious problem for the safeguard of our health and that of the fauna, flora, and of the environment. For example, pesticides, hormones, and chemicals can end up in the food chain through water and food. Therefore, the early and precise detection, monitoring, and removal of these contaminants from polluted sites are emergencies of the modern society. Today, in this unfortunate scenario, the employment of MIM-based sensors is extensively explored. For example, a voltammetric sensor able of selectively recognize nicotinic acid (used in medicine and as food additive) was fabricated through the synthesis of a thin imprinted membrane layer on the surface of a glassy carbon electrode [105]. The biomimetic sensor exhibited high recognition ability with respect to the structural analog benzoic acid and isonicotinic acid. Furthermore, it was able to assess the presence of nicotinamide in wahaha soft drink [105]. More recently, photoresponsive molecularly imprinted hydrogel-casting membrane permitted to detect traces of the antibiotic tetracycline in milk [106]. Also interesting is the possibility of monitoring the taurine level in food and beverages with biocompatible sensors based on MIMs. Taurine is an important β-amino acid for the function of many of our vital organs such as brain, cardiovascular and reproductive systems, and retina [107, 108]. Owing to its protective action toward oxidative destruction, it is used as nutrition enhancer in animal food and energy drinks. However, an excess of taurine in blood can cause gastrointestinal problems and hypertension. A molecularly imprinted electrochemical quartz crystal microbalance (EQCM) sensor was fabricated polymerizing a thin film of poly(L-methionine) through electrochemical

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Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

deposition on gold‐coated EQCM electrode using taurine as template molecule [107]. The sensor was used for detecting taurine in aqueous solutions and different milk samples. The maximum imprinting factor was 3.89. The scheme of the sensor preparation process is depicted in Fig. 7.7, while Fig. 7.8 shows the results of selectivity studies in aqueous solution of taurine and the competing compounds L-alanine, L-cysteine, D-aspartic acid, L-glutamic acid, and L-malonic acid.

O

CE H2N

RE

CH

C

OH

S

CH3

CH2 H2C

WE

n

Electropoly-merization Poly-(L-methionine) films

O H2N

Extraction

CH

S

CH3

OH

O

Rebinding Taurine

Cavities of taurine EQCM-MIP sensor Fig. 7.7: Schematic representation for the preparation of electrochemical molecularly imprinted polymer (MIP) sensor for taurine (reprinted from ref. [107] Copyright 2021, with the permission of John & Sons, Ltd.).

The interaction between the analytes and the recognition sites of the taurine-imprinted film determined a current change in the system. More in detail, a reduction of peak current proportional to the concentration of bounded analyte was observed. From Figure 7.8 the more pronounced current reduction upon the taurine binding [107] is evident.

7.5 MIM-based sensors for detecting additives and pollutants in food and water

163

–5

Current / μA

–4

Tau rine

–3 –2

L - al

L-g

ani n

e

luta

mic

D-a L-m L-c spa alo yst r nic acid tic aci acid eine d

–1

0 Interferrants Fig. 7.8: Differential pulse voltamogramm (DPV) currents for taurine and its different analogs (L‐cysteine, L‐alanine, L‐glutamic acid, L‐malonic acid, and D‐aspartic acid) in selectivity studies performed with the taurine-imprinted sensor developed by Singh et al. [107]. Voltage ranges from 0.6 to 1.0 V, scan rate 0.1 V s–1, amplitude 0.05 V, step potential 0.002 V, pulse width 0.0025 s, and pulse period 0.05 s (reprinted from ref. [107]. Copyright 2021, with the permission of John Wiley & Sons, Ltd.).

MIM-based sensors are also efficient devices for detecting and removing other undesired food contaminants such as pesticides. In this context, MIMs produced by combining the imprinting technology with the paper spray ionization permitted to detect and remove herbicides from apple, banana, and grape-extracted samples via the mass spectrometry method [109]. At this purpose, a thin imprinted layer was directly synthesized (via photo-copolymerization) on the surface of commercial cellulose membrane using methacrylic acid as functional monomer and monuron and 2,4,5-trichlorophenoxyacetic acid as dummy templates for diuron detection in fresh apple, banana, and grape methanolic extracts. For the herbicide diuron the low detection limit was lower than 0.35 µg · L−1, while for the 2,4-dichlorophenoxy acetic acid was lower than 0.65 µg · L−1. For both analytes, after the ionization the signal intensity of MIM was higher than the value registered for the corresponding NIM. Depending on the extracted matrix, the removal efficiency of MIM ranged from 96.4% to 116.9% for diuron and from 92.5% to 108.8% for the other detected analyte. In addition, in grape extract, the monuronimprinted membrane was able to discriminate diuron from the competing compounds atrazine and methomyl added to the samples, while the 2,4,5-trichlorophenoxyaceticimprinted membrane distinguished between the 2,4-dichlorophenoxy acetic acid and glyphosate [109]. Finally, tests on real samples with these membranes revealed the presence of diuron in three bananas (4.0, 6.5, and 9.9 µg L−1), while no traces of pesticides were found in other tested fruit [109]. The rapid detection of micotoxins in food (especially cereals and feedstuffs) represents another important application because the assessing of contamination even in trace is vital for our health. Choi et al. [110] developed a surface plasmon resonance sensor consisting of a poly(polypyrrole) film electropolymerized on a bare gold chip to detect deoxynivalenol, a mycotoxin produced mainly by Fusarium graminearum and causing gastrointestinal disorder. The concentration range

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Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

was 0.1–100 ng · mL−1. Deoxynivalenol was also efficiently detected with a new recent impedimetric sensor based on electropolymerized imprinted polymer layer of ophenylenediamine on the surface of screen-printed gold electrode. The sensor exhibited high sensitivity and stability and acceptable regeneration and was reused nearly 30 times without losing its affinity toward the target mycotoxin [111]. An ultrasensitive molecularly imprinted electrochemical platform consisting of an indium thin oxide electrode modified with graphene oxide and quantum dots heterojunction covered with a MIP film synthesized via photopolymerization allowed to quantify fumonisin B1, mainly produced by Fusarium species [112]. The employment of the sensor for testing real milk and maize samples containing three different concentration of standard fumonisin B1 revealed an optimal detection and recovery rate (from 94.03% to 106.41%) of the added toxin for each tested trial [112]. Another example is the development of a highly sensitive electrochemical sensor based on an MIP film for the detection of T-2 toxins in cereal grains [113]. Referring to water, the main polluting agents are pesticides even if pharmaceuticals and chemical substances used in industry represent other important contamination sources. For example, the large use of antibiotics is responsible for their presence in environmental waters and determines the onset of anitbiotic-resistant bacterial strains. Therefore, a continuous monitoring of these substances in waters is necessary, also with the aid of portable and cost-effective sensors. From this viewpoint, Ayankojo et al. [114] developed a portable electrochemical sensor to detect erythromycin in water by exploiting the synergistic effect of the combination of the high selective recognition capacity of an imprinted polymeric film with the compact nature of the screen-printed electrode. Kinetic recognition tests were carried out in the range of 12.8–40 µM erythromycin concentration. The detection limit was 0.1 nM while the low quantification limit was 0.4 nM. Sensing tests in tap water samples containing other antibiotics (sulfamethizole, amoxicillin, and ciprofloxacin) demonstrated a strong selectivity for erythromycin with respect to them. In a different work, a hybrid organic–inorganic amoxicillin MIP film was the sensing element integrated with a surface plasmon resonance sensor for the detection of this antibiotic [115]. The imprinted film was produced via the sol–gel technique and for ensuring its good adhesion to the sensor the 3-mercaptopropyl trimethoxysilane was involved in the sol preparation. The detection of bisphenol A in water was carried with an electrochemical sensor fabricated via the phase-inversion membrane formation on the surface of a titanium/titanium oxide electrode [116]. The process allowed the simultaneous membrane formation and the imprinting of its polymeric matrix made of poly(acrylonitrile-co-acrylic acid); the solvent was dimethyl sulfoxide. Figure 7.9 shows the SEM images of membranes having different thickness and the surface of the membrane with the thickness of 144 µm, which exhibited the better performance. As it is clear, the prepared membranes exhibited an asymmetric structure consisting of a finger-like macroporous layer supporting a thin top layer characterized of mesoporous structure. The sensor, applied on seawater and paper cup samples, exhibited recovery rates in the range 86–110% with low relative standard deviations of 1.3–3.2% and a low

7.5 MIM-based sensors for detecting additives and pollutants in food and water

165

Fig. 7.9: SEM images of bisphenol A molecularly imprinted films with different thicknesses of 92 µm (A), 144 µm (B) and 213 µm (C). SEM image of the surface of MIFs with the thickness of 144 µm (D) (reprinted from ref. [116]. Copyright 2018, with the permission of Elsevier).

detection limit equal to 1.3 nM. The linearity range was 4.4 nM to 0.13 mM. An excellent selectivity with respect to bisphenol A analogs was also observed. Figure 7.10 illustrates the sensor preparation process and the possible mechanism of bisphenol detection.

Fig. 7.10: Schematic illustration for the construction process and possible detection principle of the titanium/titanium oxide-MIM film-based sensor (reprinted from ref. [116]. Copyright 2018, with the permission of Elsevier).

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As it is shown in the figure, after the interaction between the sensing element (membrane) and the bisphenol A the intensity of the current signal increased. An electrochemical workstation registered this variation [116]. A novel plasticizer-free MIM-based potentiometric sensor was also able to successfully detect bisphenol A in lake water samples [117]. Its preparation entailed the copolymerization of the functional monomers methyl methacrylate and 2-ethylhexyl acrylate without plasticizer and the dispersion of the obtained copolymer into poly(vinyl chloride) matrix. Then, the mixture was drop-casted on a glass carbon electrode. Another undesired phenolic water contaminant is the 2,4-dichlorophenol. It is a member of the family of chlorophenols, a class of compounds often used in the production of pesticides, preservatives, and food biocides [118]. Liu et al. [118] demonstrated the possibility to simultaneously detect and remove 2,4-dichlorophenol from water by applying an electrochemical sensor based on a composite molecularly imprinted membrane/bipolar membrane introduced onto a palladium-coated titanium mesh electrode. The presence of the dual membrane system increased the efficiency of the electrode from 70% to 80% [118]. A plasticized composite MIM as sensing element of a potentiometric biomimetic sensor allowed the detection of dimethylamine, another pollutant of waters, soil, air, and biological fluids. Numerous industries entailing the production of rubbers, lubricants, plastic epoxy resins, pharmaceuticals, and propellants use this compound [119]. The simultaneous registration of both the sensor potential and the pH of the tested samples allowed to selectively assess the presence of dimethylamine as monovalent ion in soil extracts samples spiked with different standard concentrations of the targeted analyte and buffered with Trizma buffer solution at 5.0 mmol · L−1 and pH 7.1. The electrode showed high accuracy, a short response time (10 s), and stable potential evaluations (±0.5 mV) for over 2 months. The removal of dimethylamine from the tested samples ranged from 97.0% to 102.8% of the detected content. In addition, the sensors exhibited acceptable selectivity with respect to various basic organic and inorganic ions [119]. Some years before, D’Agostino et al. [120] produced a potentiometric sensor based on a MIM for detecting the triazinic herbicide atrazine in water, while an MIM-based sensor developed by Liu et al. [121] successfully detected the insecticide primicarb. Recently, measurements performed with a fluorescent lateral flow test strips based on an electrospun molecularly imprinted membrane made of nitrocellulose embedding an MIP imprinted with the pesticide triazophos led to reveal its trace residues in tap water [122]. The developed membrane achieved a low detection limit of 20 μg · mL−1 and was extremely stable and promising as an innovative system for the rapid detection of pesticides residues. The last example is than determination of traces of polycyclic aromatic sulfur heterocycles in seawater through imprinted polymeric thin film synthesized by in situ photopolymerization on a derivatized glass microscope slide and used as microextraction adsorbent [123]. The small size of the film and the easy preparation render it suitable for off-site and onsite environmental analysis when combined with a proper sensor device.

References

167

References [1] [2]

[3] [4] [5]

[6]

[7] [8] [9] [10]

[11] [12] [13] [14]

[15] [16]

[17] [18]

[19]

Noguera-Oviedo K, Aga DS. Lessons learned from more than two decades of research on emerging contaminants in the environment. J Hazard Mater 2016, 316, 242–251. Rajmohan KS, Chandrasekaran R, Varjani S. A review on occurrence of pesticides in environment and current technologies for their remediation and management. Indian J Microbiol 2020, 60, 125–138. Javaid M, Haleem A, Rab S, Singh RP, Suman R. Sensors for daily life: A review. Sensors Int 2021, 2, 100121, https://doi.org/10.1016/j.sintl.2021.100121. Ho CK, Robinson A, Miller DR, Davis MJ. Overview of sensors and needs for environmental monitoring. Sensors 2005, 5, 4–37. Patel BC, Sinha GR, Goel N. Introduction to sensors. In: Sinha GR, eds. Advanced modern sensors, physics, design, simulation and applications. Iop Publishing Ltd, Bristol, United Kingdom, 2020, 1–21. Zhou H, Wang Z, Zhao W, Tong X, Jin X, Zhang X, Chen W. Robust and sensitive pressure/strain sensors from solution processable composite hydrogels enhanced by hollow-structured conducting polymers. Chem Eng J 2021, 403, 126307, https://doi.org/10.1016/j.cej.2020.126307. Wu H, Dyson M, Nazarpour K. Arduino-based myoelectric control: Towards a longitudinal study of prosthesis use. Sensors 2021, 21, 763, https://doi.org/10.3390/s21030763. Nazemi H, Aashis J, Park J, Arezoo E. Advanced micro-and nano-gas sensor technology: A review. Sensors 2019, 19, 1285, https://doi.org/10.3390/s19061285. Adamo F, Attivissimo F, Carducci CGC, Lanzolla AML. A smart sensor network for seawater quality monitoring. IEEE Sensor J 2014, 15, 2514–2522. Kozitsina AN, Svalova TS, Malysheva NN, Okhokhonin AV, Vidrevich MB, Brainin KZ. Sensors based on bio and biomimetic receptors in medical diagnostic, environment, and food analysis. Biosensors 2018, 8, 35, https://doi.org/10.3390/bios8020035. Kaisti M. Detection principles of biological and chemical FET sensors. Biosens Bioelectron 2017, 15, 437–448. Algieri C, Drioli E, Guzzo L, Donato L. Bio-mimetic sensors based on molecularly imprinted membranes. Sensors 2014, 14, 13863–13912. Ertürk G, Bo M. Molecular imprinting techniques used for the preparation of biosensors. Sensors 2017, 17, 288, https://doi.org/10.3390/s17020288. Fraden J. Sensor characteristics handbook of modern sensors. Physics, designs and applications. 5th ed. Springer Cham Springer International Publishing Switzerland, 2016, https://doi.org/10.1007/ 978-3-319-19303-8_3. Patel S, Park H, Bonato P. A review of wearable sensors and systems with application in rehabilitation. J Neuro Eng Rehabil 2012, 21, 9–21. Usamentiaga R, Molleda J, Garcia DF, Granda JC, Rendueles JL. Temperature measurement of molten pig iron with slag characterization and detection using infrared computer vision. IEEE Trans Instrum Meas 2012, 61, 1149–1159. Zang Y, Zhang F, Di CA, Zhu D. Advances of flexible pressure sensors toward artificial intelligence and health care applications. Mater Horiz 2015, 2, 140–156. Liu Z, Zhu T, Wang J, Zheng Z, Li Y, Li J, et al. Functionalized fiber-based strain sensors: Pathway to next-generation wearable electronics. Nano-Micro Lett 2022, 14, https://doi.org/10.1007/s40820022-00806-8. Chen A, Zhang J, Zhao L, Rhoades RD, Kim DY, et al. Machine-learning enabled wireless wearable sensors to study the individuality of respiratory behaviours. Biosens Bioelectron 2021, 173, 112799, https://doi.org/10.1016/j.bios.2020.112799.

168

[20] [21] [22]

[23] [24] [25] [26] [27] [28] [29] [30] [31] [32]

[33]

[34] [35] [36]

[37]

[38]

[39] [40] [41]

Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

Piro B, Mattana G, Noël V. Recent advances in skin chemical sensors. Sensors 2019, 19, 4376, https:// doi.org/10.3390/s19204376. Swager TM, Mirica KA. Introduction: Chemical sensors. Chem Rev 2019, 119, 1–2. Compagnone D, Di Francia G, Di Natale C, Neri G, Seeber R, Tajani A. Chemical sensors and biosensors in Italy: A review of the 2015 literature. Sensors 2017, 17, 868, https://doi.org/10.3390/ s17040868. Stetter JR, Penrose WR, Yao S. Sensors, chemical sensors, electrochemical sensors, and ECS. J Electrochem Soc 2003, 150, 11–16. Hulanicki A, Staniseaw G, Folke I. Chemical sensors definitions and classification. Pure & Appl Chem 1991, 63, 1247–1250. Yi Z, Kun-Lin Y. Quantitative detection of phenol in wastewater using square wave voltammetry with pre-concentration. Anal Chimica Acta 2021, 1178, 338788, https://doi.org/10.1016/j.aca.2021.338788. Bakker E, Qin Y. Electrochemical sensors. Anal Chem 2006, 78, 3965–3984. Gruber P, Marques MPC, Szita N, Mayr T. Integration and application of optical chemical sensors in microbioreactors. Lab Chip 2017, 17, 2693–2712. Kirk TV, Szita N. Oxygen transfer characteristics of miniaturized bioreactor systems. Biotechnol Bioeng 2013, 110, 1005–1019. Sempionatto JR, Jeerapan I, Krishnan S, Wang J. Wearable chemical sensors: Emerging systems for on-body analytical chemistry. Anal Chem 2020, 92, 378–396. Chen C, Zhao XL, Li ZH, Zhu ZG, Qian SH, Flewitt AJ. Current and emerging technology for continuous glucose monitoring. Sensors 2017, 17, 182, https://doi.org/10.3390/s17010182. Bruen D, Delaney C, Florea L, Diamond D. Glucose sensing for diabetes monitoring: Recent developments. Sensors 2017, 17, 1866, https://doi.org/10.3390/s17081866. Zhang X, Gao C, Lu S, Duan H, Jing N, Dong D, et al. Anti-photobleaching flower-like microgels as optical nanobiosensors with high selectivity at physiological conditions for continuous glucose monitoring. J Mater Chem B 2014, 2, 5452–5460. Adeel M, Rahman M, Caligiuri I, Canzonieri V, Rizzolio F, Daniele S. Recent advances of electrochemical and optical enzyme-free glucose sensors operating at physiological conditions. Biosens Bioelectron 2020, 165, 112331, https://doi.org/10.1016/j.bios.2020.112331. Mello GPC, Simoes EFC, Crista DMA, Leitão JMM, Pinto da Silva L, Esteves da Silva JCG. Glucose sensing by fluorescent nanomaterials. Crit Rev Anal Chem 2019, 49, 542–552. Harper A, Anderson MR. Electrochemical glucose sensors. Developments using electrostatic asembly and carbon nanotubes for biosensor construction. Sensors 2010, 10, 8248–8274. Talarico D, Arduini F, Constantino A, Del Carlo M, Compagnone D, Moscone D, et al. Carbon black as successful screen-printed electrode modifier for phenolic compound detection. Electrochem Commun 2015, 60, 78–82. Spissu Y, Barberis A, Bazzu G, D’Hallewin G, Rocchitta G, Serra PA, et al. Functionalization of screenprinted sensors with a high reactivity carbonaceous material for ascorbic acid detection in fresh-cut fruit with low vitamin C content. Chemosensors 2021, 9, 354, https://doi.org/10.3390/ chemosensors9120354. Jemmeli D, Dridi C, Abbas MN, Dempsey E. Development of highly sensitive and selective bisphenol A sensor based on a cobalt phthalocyanine-modified carbon paste electrode: Application in dairy analysis. Anal Methods 2021, 13, 4674–4682. Valentini F, Roscioli D, Carbone M, Conte V, Floris B, Bauer EM, et al. Graphene and ionic liquids new gel paste electrodes for caffeic acid quantification. Sens Actuators B Chem 2015, 212, 248–255. Bhalla N, Jolly P, Formisano N, Estrela P. Introduction to biosensors. Essays Biochem 2016, 60, 1–8. Amine A, Mohammadi H, Bourais I, Palleschi G. Enzyme inhibition-based biosensors for food safety and environmental monitoring. Biosens Bioelectron 2006, 21, 405–1423.

References

[42] [43] [44] [45] [46] [47] [48]

[49]

[50] [51] [52] [53]

[54]

[55] [56]

[57] [58] [59] [60] [61]

[62] [63]

169

Hu L, Zou L, Qin Z, Fang J, Huang L, Wang P. A novel label-free bioengineered cell-based biosensor for salicin detection. Sens. Actuators B Chem 2017, 238, 1151–1158. De Carvalho CCCR. Enzymatic and whole cell catalysis: Finding new strategies for old processes. Biotechnol Adv 2011, 29, 75–83. Lei Y, Chen W, Mulchandani A. Microbial biosensors. Anal Chim Acta 2006, 568, 200–221. Rashid JIA, Yusof NA. The strategies of DNA immobilization and hybridization detection mechanism in the construction of electrochemical DNA sensor: A review. Sens Bio-Sens Res 2017, 16, 19–31. Updike S, Hicks G. The enzyme electrode. Nature 1967, 214, 986–988. Jolly P, Formisano N, Estrela P. DNA aptamer-based detection of prostate cancer. Chem Pap 2015, 69, 77–89. Jolly P, Formisano N, Tkac J, Kasak P, Frost C, Estrela P. Label-free impedimetric aptasensor with antifouling surface chemistry: A prostate specific antigen case study. Sens Actuators B 2015, 209, 306–312. Karimi-Maleh H, Orooji Y, Karimi F, Alizade M, Baghayeri M, Rouhi J, et al. A critical review on the use of potentiometric based biosensors for biomarkers detection. Biosens Bioelectron 2012, 184, 113252, https://doi.org/10.1016/j.bios.2021.113252. Grieshaber D, Mackenzie R, Vörös J, Reimhult E. Electrochemical biosensors. Sensor principles and architectures. Sensors 2008, 8, 1400–1458. Wilson GS, Gifford R. Biosensors for real-time in vivo measurements. Biosens Bioelectron 2005, 20, 2388–2403. Ozer T, Geiss BJ, Henry CS. Chemical and biological sensors for viral detection. J Electrochem Soc 2019, 167, 037523, https://doi.org/10.1149/2.0232003JES. Yadav S, Devi R, Bhar P, Singhla S, Pundir CS. Immobilization of creatininase, creatinase and sarcosine oxidase on iron oxide nanoparticles/chitosan-g-polyaniline modified Pt electrode for detection of creatinine. Enzym Microb Technol 2012, 50, 247–254. Dasgupta P, Kumar V, Patnam Krishnaswamy R, Bhat N. Serum creatinine electrochemical biosensor on printed electrodes using monoenzymatic pathway to 1-methylhydantoin detection. ACS Omega 2020, 5, 22459–22464. Song M, Lin X, Peng Z, Xu S, Jin L, Zheng X, et al. Materials and methods of biosensor interfaces with stability. Front Mater 2021, 7, 583739, https://doi.org/10.3389/fmats.2020.583739. Sharma TK, Ramanathan R, Rakwal R, Agrawal GK, Bansal V. Moving forward in plant food safety and security through nanobiosensors: Adopt or adapt biomedical technologies?. Proteomics 2015, 15, 1680–1692. Donato L, Drioli E. Imprinted membranes for sustainable separation processes. Front Chem Sci Eng 2021, 15, 775–792. Frasco MF, Truta LAANA, Goreti Sales MGF, Moreira FTC. Imprinting technology in electrochemical biomimetic sensors. Sensors 2017, 17, 523–551. Cieplak M, Kutne W. Artificial biosensors: How can molecular imprinting mimic biorecognition?. Treds Biotech 2016, 34, 922–941. Haupt K, Mosbach K. Molecularly imprinted polymers and their use in biomimetic sensors. Chem Rev 2000, 100, 7, 2495–2504. Parisi OI, Francomano F, Dattilo M, Patitucci F, Prete S, Amone F, et al. The evolution of molecular recognition: From antibodies to molecularly imprinted polymers (MIPs) as artificial counterpart. J Funct Biomater 2022, 13, 12, https://doi.org/10.3390/jfb13010012. Herrera-Chacón A, Cetó X, Del Valle M. Molecularly imprinted polymers – Towards electrochemical sensors and electronic tongues. Anal Bioanal Chem 2021, 413, 6117–6140. Bhakta S, Mishra P. Molecularly imprinted polymer-based sensors for cancer biomarker detection. Sens Actuators Rep 2021, 3, 100061, https://doi.org/10.1016/j.snr.2021.100061.

170

Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

[64] Crapnell RD, Hudson A, Foster CW, Eersels K, Van Grinsven B, Cleij JC. Recent advances in electrosynthesized molecularly imprinted polymer-sensing platforms for bioanalyte detection. Sensors 2019, 19, 1204, https://doi.org/10.3390/s1905120. [65] Song X, Xu S, Chen L, Wei Y, Xiong H. Recent advances in molecularly imprinted polymers in food analysis. Appl Polym Sci 2014, 131, 40766, https://doi.org/10.1002/APP.4076. [66] Zaidi SA. Development of molecular imprinted polymers-based strategies for the determination of dopamine. Sens Actuators B Chem 2018, 265, 488–497. [67] Sharma S, Singh N, Tomar V, Chandra R. A review on electrochemical detection of serotonin based on surface modified electrodes. Biosens. Bioelectron 2018, 107, 76–93. [68] Pacheco JC, Silva MSV, Freitas M, Nouws HPA, Delerue-Matos C. Molecularly imprinted electrochemical sensor for the point-of-care detection of a breast cancer biomarker (CA 15-3). Sens Actuator B Chem 2018, 256–905, https://doi.org/10.1016/j.bios.2020.112877. [69] Carneiro LP, Ferreira NS, Tavares AP, Pinto AM, Mendes A, Sales MGF. A passive direct methanol fuel cell as transducer of an electrochemical sensor, applied to the detection of carcinoembryonic antigen. Biosens Bioelectron 2021, 175, 112877, https://doi.org/10.1016/j.bios.2020.112877. [70] Abbasy L, Mohammadzadeh A, Hasanzadeh M, Razmi N. Development of a reliable bioanalytical method based on prostate specific antigen trapping on the cavity of molecular imprinted polymer towards sensing of PSA using binding affinity of PSA-MIP receptor: A novel biosensor. J Pharm Biomed Anal 2020, 188, 113447, https://doi.org/10.1016/j.jpba.2020.113447. [71] Pacheco JC, Rebelo P, Freitas M, Nouws HPA, Delerue-Matos C. Breast cancer biomarker (HER2-ECD) detection using a molecularly imprinted electrochemical sensor. Sens Actuators B Chem 2018, 273, 1008–1014. [72] Li W, Diao K, Qiu D, Zeng Y, Tang K, Zhu Y, et al. A highly-sensitive and selective antibody-like sensor based on molecularly imprinted poly (L-arginine) on COOH-MWCNTs for electrochemical recognition and detection of deoxynivalenol. Food Chem 2021, 350, 129229, https://doi.org/10.1016/ j.foodchem.2021.129229. [73] Seguro I, Rebelo P, Pacheco JG, Delerue-Matos C. Electropolymerized, molecularly imprinted polymer on a screen-printed electrode. A simple, fast, and disposable voltammetric sensor for trazodone. Sensors 2022, 22, 2819, https://doi.org/10.3390/s22072819. [74] Raziq A, Kidakova A, Boroznjak R, Reut J, Öpik A, Syritski V. Development of a portable MIP-based electrochemical sensor for detection of SARS-CoV-2 antigen. Biosens Bioelectron 2021, 178, 113029, https://doi.org/10.1016/j.bios.2021.113029. [75] Afzali Z, Mohadesi A, Karimi MA, Fathira F. A highly selective and sensitive electrochemical sensor based on graphene oxide and molecularly imprinted polymer magnetic nanocomposite for patulin determination. Microchem J 2022, 177, 107215, https://doi.org/10.1016/j.microc.2022.107215. [76] Ferreira Santos AC, De Araújo ORP, Moura FA, Khan S, Tanaka AA, Santana AEG, Et al. Development of magnetic nanoparticles modified with new molecularly imprinted polymer (MIPs) for selective analysis of glutathione. Sens Actuators B Chem 2021, 344, 130171, https://doi.org/10.1016/j. snb.2021.130171. [77] Hedborg E, Winquist F, Lundstroem I, Anderson LI, Mosbach K. Some studies on molecularly imprinted polymer membranes in combination with field-effect devices. Sens Actuators A 1993, 37–38, 796–799. [78] Piletsky SA, Parhometz YP, Lavryk NV, Panasyuk TL, El’Skaya AV. Sensors for low-weight organic molecules based on molecular imprinting technique. Sens Actuators B Chem 1994, 18–19, 629–631. [79] Piletsky SA, Panasyuk TL, Piletskaya EV, El’skaya AV, Levi R, Karube I, et al. Imprinted membranes for sensor technology: Opposite behavior of covalently and non-covalently imprinted membranes. Macromolecules 1998, 31, 2137–2140.

References

171

[80] Movsisyan NK, Vinciguerra M, Medina-Inojosa JR, Lopez-Jimenez F. Cardiovascular diseases in central and eastern Europe: A call for more surveillance and evidence-based health promotion. Ann Glob Health 2020, 86, 21, https://doi.org/doi:10.5334/aogh.2713. [81] Ezzati M, Obermeyer Z, Tzoulaki I, Mayosi BM, Elliott P, Leon DA. The contributions of risk factor trends and medical care to cardiovascularmortality trends. Nat Rev Cardiol 2015, 12, 508–530. [82] Piletsky SA, Piletskaya EV, Sergeyeva TA, Panasyuk TL, El’skaya AV. Molecularly imprinted selfassembled films with specificity to cholesterol. Sens Actuators B Chem 1999, 60, 216–220. [83] Ji J, Zhou Z, Zhao X, Sun J, Sun X. Electrochemical sensor based on molecularly imprinted film at Au nanoparticles-carbon nanotubes modified electrode for determination of cholesterol. Biosens Bioelectronics 2015, 66, 590–595. [84] Ciardelli G, Borrelli C, Silvestri D, Cristallini C, Barbani N, Giusti P. Supported imprinted nanospheres for the selective recognition of cholesterol. Biosens Bioelectron 2006, 21, 2329–2338. [85] Petcu M, Schaare PN, Cook CJ. Propofol-imprinted membranes with potential application in biosensors. Anal Chim Acta 2004, 504, 73–79. [86] Chen C, Chen Y, Zhou J, Wu C. A 9-vinyladenine-based molecularly imprinted polymeric membrane for the efficient recognition of plant hormone H-indole-3-acetic acid. Anal Chim Acta 2006, 569, 58–65. [87] Hassan SSM, Amr AE-GE, El-Naby HA, El-Naggar M, Kamel AH, Khalifa NM. Novel aminoacridine sensors based on molecularly imprinted hybrid polymeric membranes for static and hydrodynamic drug quality control monitoring. Materials 2019, 12, 203327, https://doi.org/10.3390/ma12203327. [88] Su C, Li Z, Zhang D, Wang Z, Zhou X, Liao L, et al. A highly sensitive sensor based on a computerdesigned magnetic molecularly imprinted membrane for the determination of acetaminophen. Biosens Bioelectron 2020, 148, 111819, https://10.1016/j.bios.2019.111819. [89] Salvo-Comino C, Rassas I, Minot S, Bessueille F, Rodriguez-Mendez ML, Errachid A, et al. Voltammetric sensor based on electrodeposited molecularly imprinted chitosan film on BDD electrodes for catechol detection in buffer and in wine samples. Mat Sci Eng C 2020, 110, 110667, https://doi.org/10.1016/j.msec.2020.110667. [90] Fu K, Zhang R, He J, Bai H, Zhang G. Sensitive detection of ketamine with an electrochemical sensor based on UV-induced polymerized molecularly imprinted membranes at graphene and MOFs modified electrode. Biosens Bioelectron 2019, 143, 111636, https://doi.org/10.1016/j.bios.2019.111636. [91] Ermolayeva TN, Farafonova OV, Bessonov OI. Synthesis and use of thin polymer films with molecular imprints of salbutamol in quartz crystal microbalance sensors. J Anal Chem 2019, 74, Suppl. 2, 1–8. [92] Alì IHMH. Sensitive electrochemical sensor for rapid determination of mebeverine hydrochloride and metronidazole benzoate selective molecular imprinted polymer in the PVC membrane. J Pure Appl Sci 2018, 31, 74–87. [93] Wang H, Qian D, Xiao X, Gao S, Cheng J, He B, et al. A highly sensitive and selective sensor based on a graphene-coated carbon paste electrode modified with a computationally designed boronembedded duplex molecularly imprinted hybrid membrane for the sensing of lamotrigine. Biosens Bioelectron 2017, 94, 663–670. [94] Abu-Dalo MA, Nassory NS, Abdulla NI, Al-Mheidat IR. Azithromycin-molecularly imprinted polymer based on PVC membrane for aithromycin determination in drugs using coated graphite electrode. J Electroanal Chem 2015, 751, 75–79. [95] Li S, Li J, Lin Q, Wei X. A molecularly imprinted sensor based on an electrochemiluminescent membrane for ultratrace doxycycline determination. Analyst 2015, 140, 4702–4707. [96] Zhu W, Jiang G, Xu L, Li B, Cai Q, Jiang H, et al. Facile and controllable one-step fabrication of molecularly imprinted polymer membrane by magnetic field directed self-assembly for electrochemical sensing of glutathione. Anal Chim Acta 2015, 886, 37–47.

172

[97]

[98] [99]

[100] [101] [102]

[103] [104]

[105] [106]

[107] [108] [109]

[110] [111]

[112] [113]

[114] [115] [116]

Chapter 7 Molecularly imprinted membranes as biomimetic receptors in sensors

Al-Mustafa JI, Abu-Dalo MA, Nassory NS. Liquid selective electrodes for dextromethorphan hydrobromide based on a molecularly imprinted polymer in PVC matrix membrane. Int J Electrochem Sci 2014, 9, 292–303. Ye N, Gao T, Li J. Hollow fiber-supported graphene oxide molecularly imprinted polymers for the determination of dopamine using HPLC-PDA. Anal Methods 2014, 6, 7518–7524. Sergeyeva TA, Gorbach LA, Piletska EV, Piletsky SA, Brovko OO, Honcharova AA, et al. Colorimetric test-systems for creatinine detection based on composite molecularly imprinted polymer membranes. Analy Chim Acta 2013, 770, 161–168. Chen YP, Liu B, Lian HT, Sun XY. Preparation and application of urea electrochemical sensor based on chitosan molecularly imprinted films. Electroanalysis 2011, 23, 1454–1461. Osman B, Uzun L, Besirli N, Denizli A. Microcontact imprinted surface plasmon resonance sensor for myoglobin detection. Mater Sci Eng C 2013, 33, 3609–3614. Qiu X, Hua Y, Guo H, Lu W. Preparation of a molecularly imprinted polymer nanotubes membrane and its application in the determination of catecholamines in urine samples. Chem J Ch Univ 2018, 39, 653–659. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol 2011, 6, 19–48. Çimen D, Aslıyüce S, Tanalp TD, Denizli A. Molecularly imprinted nanofilms for endotoxin detection using a surface plasmon resonance sensor. Anal Biochem 2021, 632, 114221, https://doi.org/10.1016/ j.ab.2021.114221. Yao L, Tang Y, Huang Z. Nicotinic acid voltammetric sensor based on molecularly imprinted polymer membrane‐modified electrode. Anal Lett 2007, 40, 677–688. Wang Q, Zhen L, Tang Q, Gong CB, Lam MHW, Ma CB, et al. Photoresponsive molecularly imprinted hydrogel casting membrane for the determination of trace tetracycline in milk. J Mol Recognit 2016, 29, 123–130. Singh AK, Singh M. Electrochemical and piezoelectric monitoring of taurine via electropolymerized molecularly imprinted films. J Mol Recogn 2017, 30, 2652, https://doi.org/10.1002/jmr.2652. Huxtable RJ. Physiological actions of taurine. Physiol Rev 1992, 72, 101–163. Pereira I, Rodrigues MF, Chaves AR, Vaz BG. Molecularly imprinted polymer (MIP) membrane assisted direct spray ionization mass spectrometry for agrochemicals screening in foodstuffs. Talanta 2018, 178, 507–514. Choi SW, Chang HJ, Lee N, Chun HS. A surface plasmon resonance sensor for the detection of deoxynivalenol using a molecularly imprinted polymer. Sensors 2011, 11, 8654–8664. Radi A-E, Eissa A, Wahdan T. Impedimetric sensor for deoxynivalenol based on electropolymerised molecularly imprinted polymer on the surface of screen-printed gold electrode. Int J Environ Anal Chem 2021, 101, 2586–2597. Mao L, Kailun J, Yao L, Xue X, Wen W, Zhang X, Wang S. Molecularly imprinted photoelectrochemical sensor for fumonisin B1 based on GO-CdS heterojunction. Biosens Bioelectron127, 2019, 57–63. Gao X, Cao W, Chen M, Xiong H, Zhang X, Wang S. A high sensitivity electrochemical sensor based on Fe3+-ion molecularly imprinted film for the detection of T-2 toxin. electroanalysis 2014, 26, 2739–2746, 10.1002/elan.201400237. Ayankojo AG, Reut J, Ciocan V, Öpik A, Syritski V. Molecularly imprinted polymer-based sensor for electrochemical detection of erythromycin. Talanta 2020, 209, 120502. Ayankojo AG, Reut J, Öpik A, Furchner A, Syritski V. Hybrid molecularly imprinted polymer for amoxicillin detection. Biosens Bioelectron 2018, 118, 102–107. Yang Q, Wu X, Peng H, Fu L, Song X, Li J, et al. Simultaneous phase-inversion and imprinting based sensor for highly sensitive and selective detection of bisphenol A.Talanta 2018, 176, 595–603.

References

173

[117] Liu K, Song Y, Song D, Liang R. Plasticizer-free polymer membrane potentiometric sensors based on molecularly imprinted polymers for determination of neutral phenols. Anal Chim Acta 2020, 1121, 50–56. [118] Liu X, Zhang Y, Chen R, Yu Y, Chen X, Zheng X, et al. 2,4-Dichlorophenol removal from water using an electrochemical method improved by a composite molecularly imprinted membrane/bipolar membrane. J Hazard Mater 2019, 377, 259–266. [119] Hassan SSM, Amr AEGE, El-Naby HA, Al-Omar MA, Kamel AH, Khalifa NM. Potentiometric PVCmembrane-based sensor for dimethylamine assessment using a molecularly imprinted polymer as a sensory recognition element. Polymers 2019, 11, https://doi.org/10.3390/polym11101695. [120] D’Agostino GD, Alberti G, Biesuz R, Pesavento M. Potentiometric sensor for atrazine based on a molecular imprinted membrane. Biosens Bioelectron 2006, 22, 145–152. [121] Liu H, Sun S, Du R, Gao B. Design and preparation of molecularly imprinted membrane with grafttype and constitution of potentiometric sensor of pesticides and its detection performance. J Instrum Anal 2015, 10, 1126–1133. [122] He Y, Hong S, Wang M, Wang J, El-Aty JAMA, et al. Development of fluorescent lateral flow test strips based on an electrospun molecularly imprinted membrane for detection of triazophos residues in tap water. New J Chem 2020, 44, 6026–6036. [123] Hijazi HY, Bottaro CS. Molecularly imprinted polymer thin-film as a micro-extraction adsorbent for selective determination of trace concentrations of polycyclic aromatic sulfur heterocycles in seawater. J Chromatogr A 2020, 1617, 460824, https://doi.org/10.1016/j.chroma.2019.460824.

Chapter 8 Ion-imprinted membranes 8.1 Introduction Ion-imprinted membranes (IIMs) combine the typical features of membrane separation and imprinting technologies for selectively recognize targeted ions instead of molecules. Owing to the presence of electrostatic interactions and metal complexes, they are effective in the recognition of anions, cations, and metalloids. Experimental investigations have demonstrated that they are useful for the detection and removal of contaminant ions from different matrices as well as for the recovery of high addedvalue metals, thus assuming significance in analytical chemistry, pollution control, water treatment, recycle of critical raw materials, and so on [1–4]. In particular, they are applicable in sensor technology and solid-phase extraction processes to assess the presence of toxic metals in food, beverages, and water and removing them from contaminated sites. In addition, they are applied the selective extraction of metal ions and rare earth metals from raw materials [1–5]. The preparation process of IIMs exploits the same synthetic strategies employed for the fabrication of MIMs (see previous chapters). However, this case envisages the use of ligands with specific coordination groups for creating recognition sites able of interacting with the template ion. For promoting the applicability of IIMs, studies on their production are increasing in parallel to the development of new polymeric materials, also with the aid of computational modeling for the choice of appropriate functional monomers, crosslinkers, and ligands [6]. However, it must be borne in mind that despite the fact that IIM’s production has increased in recent years, the number of works that deal with their production is still low, even if they are excellent ion separation systems. Therefore, hopefully, their large-scale production and application will be implemented precisely by virtue of their potential. This chapter deals with a general introduction to the ion-imprinted membranes and their application for selectively detecting and separating specific ions from others or recovery them from different matrices.

8.2 General aspects of ion-imprinted membranes Nowadays, the interest toward the specific recognition of ions is increasing rapidly and one efficient strategy to produce tailored recognition systems is the fabrication of ion-imprinted membranes. The advent of these smart membranes allowed overcoming the limit of traditional membranes in separating ions having similar radii and features. For example, a typical ion-exchange membrane only separates ions on the basis of their charge, while an IIM is capable of distinguishing ions having similar charge. https://doi.org/10.1515/9783110654691-009

8.2 General aspects of ion-imprinted membranes

175

Furthermore, the coordination and electrostatic interactions occurring in ion imprinting are compatible with aqueous media and stronger than the hydrogen bonds characterizing the molecular imprinting [1, 7]. Ions are characterized by a charge and have less functional groups with respect to molecules but in general exhibit similar chemical and physical properties. Usually, the preparation of IIMs involves the synthesis of an ion-imprinted polymer on the surface, into the matrix or in the pores of a membrane. The polymer synthesis is based on the same polymerization methods adopted in the production of MIPs. However, in this case, the size, the shape, and the charge of the targeted ion govern the formation of monomertemplate ion-ligand ternary complexes often stabilized by a crosslinker. The removal of the template ion after the polymerization leads to the formation of the selective recognition sites complementary to it [1, 6]. The presence of the ligand with specific coordination groups ensures the effectiveness of the imprinting process. In fact, owing to the small size and the scarcity of functional groups of ions, the only use of functional monomers is not efficacy for creating active recognition sites. The incorporation of the ligand into the nascent-imprinted membrane (or the covalent bound to it as well as its immobilization on the surface of a pre-existing membrane) leads to produce ion-ligand chelation and avoids the ligand leaching during the subsequent step of the template rebinding. Depending on the type of ion to imprint, the ligands contain electrodonor or electroreceiving atoms like oxygen, nitrogen, phosphorus, sulfur, azo-derivatives, calixarenes, and vinylated groups [1, 6–9]. The crown ethers (CEs), which are cyclic compounds consisting of a ring containing several ether groups able to bind alkali metal cations, represent one example of ligands. Other ligands are organophosphates, organic carboxylic acids, β-diketones, calixarene derivatives, and cyclodextrins [1–3]. The more used functional monomers for preparing metal-imprinted membranes are acrylic acid, methacrylic acid, methyl methacrylate, acrylamide, 2-vinylpyridine, 4-vinylpyridine, 1-vinylimidazole, tetraethoxysilane, and other similar compounds. Self-synthetic monomers like ethylenediamine-tetra-N-3-pyrrole-1yl) propylacetamide, tymine-3isocyanatopropyl-triethoxysilane, and 2,4-dioxopenthan-3-yl-methacrylate are also used [1–3]. The crosslinkers are typically used in molecular imprinting and they are chosen case by case in relation to the functional monomer. The types of targeted ions in preparing IIMs are metal ions, rare earth ions, and anions [1–3, 6]. On the basis of different methods used for their preparation IIMs are distinguished in filled IIMs, freestanding IIMs, hybrid IIMs, and composite IIMs. The filled IIMs have a sandwich-like structure consisting of two membrane layers containing an imprinted polymer as filler and previously synthesized. They are capable of separating simultaneously different target ions and are suitable for industrial application [1, 10]. Hybrid IIMs consist of membranes (prepared via the phase inversion) embedding the IIP in their matrix [1, 7, 11]. Freestanding IIMs are prepared by synthesizing an IIP on the surface of nanocomposites followed by a crosslinking step to obtain a three-dimensional porous structure [1, 12]. Finally, composite IIMs, which are prepared via the surface

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Chapter 8 Ion-imprinted membranes

imprinting, consist of a support membrane covered by a thin layer of IIP synthesized via grafting, coating, in situ polymerization, etc. Owing to the possibility of controlling the thickness of the polymer layer and the better exposure and accessibility of the recognition sites, these membranes are most promising with respect to the previous one [1, 2, 13, 14]. The application of the click chemistry also allows producing composite multilayered IIMs high separation efficiency [15]. Independent of the membrane type, for avoiding or reducing the employment of toxic ions the dummy-template and multitemplate imprinting processes are also applied [1, 6, 9, 16]. During the recognition process performed with an IIM, the small difference in solubility, size, and shape between the target ion and its analogs permit to separate it in a selective manner [6, 15]. The main parameter affecting the recognition process of IIMs is the pH. In fact, in the case of cation-imprinted membranes, at low pH value there is richness of protons that can occupy the recognition sites of the membrane, thus hindering the template binding. On the contrary, at high pH value, the abundance of anions can reduce the efficiency of anion-IMs. Other important parameters to consider are the temperature, the template-monomer, and temple-ligand ratio as well as the extraction time. For example, too short extraction time can lead to incomplete removing of the template ion, while an exacerbate extraction time can destroy the recognition sites [1]. Similar to MIMs, the separation mechanisms characterizing IIMs are the retarded permeation, the facilitated permeation, and the selective adsorption. From a general viewpoint, the permeation is characterized by a selective diffusive transport through the membrane matrix and/or its pores [5, 17]. Nowadays, for stimulating the applicability of IIMs, studies on their preparation are increasing in parallel to the production of new polymeric materials, also with the aid of the computational modeling for the appropriate choice of functional monomers, crosslinkers, and ligands as well as for the prediction of the ions’s adsorption-transport behavior [6, 7, 17–19]. In the last years, IIMs have been also prepared using ionic liquids, which are used as solvents and functional monomers. This is due to their dissolving capacity in aqueous environment, specific binding capacity, and controllable structure–activity [20]. Natural polymers such as sodium alginate, cellulose, and chitosan are also used as membrane forming material owing to their low cost, biodegradability, nontoxicity, and adsorption capacity toward tailored ions [21–24]. So far, despite the efforts done for producing IIMs applicable on large scale in a variety of fields and their high efficiency, they have not received the attention they deserve. This is confirmed by the data shown in Fig. 8.1, which summarizes the number of publications on affinity MIMs and IIMs until 2021. As can be seen, the advent of IIMs is more recent and the number of pubblication on IIMs is very low in comparison with the number of publishing on MIMs. For the scientific community this means that additional efforts are necessary for developing much more innovative IIMs able of selectively separate ionic species and ensure their launch into the market world. The following sections are devoted to the discussion of

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177

Fig. 8.1: Number of publications on affinity MIMs and IIMs until 2021 (reprinted from ref. [24]. Open access).

some examples of IIMs already developed for the specific recognition of different types of ions in monitoring pollution, water treatment, and recovery strategy.

8.3 Selective recognition of metal ions with IIMs The development of IIMs with specific recognition properties toward metals was focused mainly on the detection and separation of alkali metal ions and transition metal ions. However, some cases of IIMs prepared for the selective recognition of alkaline earth metals are also present in literature. Alkali metals are elements of the first group (IA) of the periodic table that form cations with “1+” charge owing to their tendency to lose valence electron. Owing to their small hydration radius they cannot be imprinted with the traditional ion imprinting polymerization strategies and requires specific complexing agents having ring-like/cup-like structure such as CEs and calixarenes, which are compatible with them [1, 7, 9, 15]. Furthermore, conventional functional monomers are combined with vinylated ligands [9, 15, 25, 26]. Alkaline earth metals are elements of the second group (IIA) of the periodic table. They are less reactive than the alkali metals, have two valence electrons in their highest-energy orbitals (ns2), and are ionized to form a “2+” charge [26, 27]. Transition metals are elements afferent to different groups exactly from IIIB to VIII. They have larger hydration radius with respect to alkali metals and therefore easily form coordination complexes with appropriate ligands. They include heavy metals, which exhibit a toxic action on humans and other living organisms and need to be removed from the environment [1, 7, 27–29]. Table 8.1 reports some recent examples of metal ion-imprinted membranes prepared via different routes [30–45]. As it is evident from this table, one of the most representative examples of imprinted alkali metal ions is lithium, which is largely used in metallurgy, ion battery industry, and pharmaceutical industry. In this context, the possibility of selectively

-(Allyloxy)methyl-crown-

Li+

Mg+

Ca+

Ag+

Glutaraldehyde

-crown--ether

-(Allyloxy)methyl-crown-

-Crown-ether (CE)

Itaconic acid

Ethylene glycol dimethacrylate

Composite regenerated Epichlorohydrin cellulose/sodium alginate (abbreviated ECH)

Cross-linked blended chitosan (CS)/polyvinyl alcohol (PVA)

Methacrylic acid

-Crown-ether (CE)

Li+

Li+

-(Allyloxy)methyl-crown-

Li+

-(Allyloxy)methyl-crown-

-Crown-ether (CE)

-Crown-ether (CE)

Li+

Retarded permeation

Selective adsorption

Separation mechanism

Mg+-imprinted nanoparticles embedded into a PVC membrane prepared via phase inversion

Phase inversion

Phase inversion

Surface imprinting of PDA/PES membrane

Surface imprinting of PDA/PVDF membrane

Selective adsorption

Selective adsorption

Selective adsorption

Retarded permeation

Retarded permeation

Hydrolysis polymerization using Retarded pDA/GO/PVDF as base membrane permeation

Surface imprinting of Ag/PDA/ PVDF membrane

Surface imprinting of SPPDA/PVDF membrane

Ligand/cross-linker Synthetic strategy

Cation Functional monomer/ polymer

. μmol/g

KCa+/Cu+ = . KCa+/Mg+ = .. KCa+/Zn+ = .

αAg+/K+ = . αAg+/Cu+ = . αAg+/Pb+ = .

βNa+/Li+ = . βK+/Li+ = .

βMg+/Li+ = .

βK+/Li+ = . βCa+/Li+ = . βMg+/Li+ = .

βMg+/Li+ = .

KLi+/Mn+ = . KLi+/Co+ = . KLi+/Ni+ = .

Selectivity coefficient

Tab. 8.1: Some examples of IIMs prepared for the selective recognition of alkali metals, alkaline earth metals, and transition metals.

[]

[]

[]

[]

[]

[]

[]

[]

Reference

178 Chapter 8 Ion-imprinted membranes

Polypyrrole

Methacrylic acid

Ni+

Ni+

Pb+

Chitosan

Cross-linked blended glutaric acid/chitosan (CS)/polyvinyl alcohol (PVA)

Acrylamide

Hg+

Pb+

Poly(ethyleneimine)

Cross-linked blended chitosan (CS)/polyvinyl alcohol (PVA)

Divinylbenzyltriethylenetetramine

Cu+

Cu+

Cu+

Surface imprinting of PAN membrane

Phase inversion

Polymerization of the Cu+chelating monomer complexes into PVDF membrane pores

Glutaraldehyde

Glutaraldehyde

Dithizone

Ferricyanide

One-step electrospinning

Phase inversion

Surface imprinting of PVDF membrane

Unipolar pulse electropolymerization

Bathophenanthroline Hg+-imprinted nanoparticles embedded into a PES membrane prepared via phase inversion

Epichlorohydrin

Glutaraldehyde

Divinyl benzene

Selective adsorption

Selectiv adsorption

Facilitated diffusive permeation

Selective adsorption

Retarded permeation

Facilitated diffusive permeation

Facilitated diffusive permeation

Facilitated diffusive permeation

αPb+/Ni+ = . αPb+/Cd+ = . αPb+/Zn+ = . αPb+/Cu+ = .

Not reported

αNi+/Co+ = .

αNi+/Ca+ = . αNi+/Na+ = . αNi+/K+ = .

αHg+/Zn+ = . αHg+/Pb+ = . αHg+/Cu+ = . αHg+/Cd+ = . αHg+/Cr+ = . αHg+/Co+ = .

(continued)

[]

[]

[]

[]

[]

[]

[]

αCu+/Ni+ = .

αCu+/Zn+ = .

[]

αCu+/Ni+ = .

8.3 Selective recognition of metal ions with IIMs

179

-Vinyl pyridine

,-Bipyridyl

Methacrylic acid

Pt+

Zinc+

As+

Cation Functional monomer/ polymer

Tab. 8.1 (continued)

-Vinylpyridine

As(III)-imprinted nanoparticles embedded into a PVC membrane prepared via phase inversion

Surface imprinting on poly (vinylidene fluoride) support

Phase inversion of blended PMMA-b-PVP/PVDF

Ligand/cross-linker Synthetic strategy

Retarded permeation

Facilitated permeation through diffusive transport

Selective adsorption

Separation mechanism

αZn+/Cu+ = .

αPt+/Cu+ = . αPt+/Ni+ = .

Selectivity coefficient

[]

[]

[]

Reference

180 Chapter 8 Ion-imprinted membranes

8.3 Selective recognition of metal ions with IIMs

181

recovering it from industrial wastewaters as well as from lake water, seawater, and other matrices offers a valid contribution in satisfying the ever-increasing demand for this metal. Sun et al. [33] developed lithium-imprinted macroporous membranes for separating Li+ from Mg2+. They used 2-(allyloxy) methyl-12-crown-4 as the functional monomer to synthesize an imprinted layer on the surface of PVDF membrane prepared via the phase inversion technique. The presence of pDA between the preexisting membrane and the imprinted layer ensured good interfacial adhesion of the membrane components. Membranes showed high stability and adsorption capacity and successfully separated Li+ from Mg2+ with a maximum selectivity factor of 4.42 [33]. In addition, selectivity studies carried out in a diffusion cell showed low Li+ and fast Mg2+ permeation, confirming the presence of the retarded permeation separation mechanism [33]. Figure 8.2 shows the permeation profile of Li+ and Mg2+ for both the imprinted membrane (IIMMs) and its corresponding nonimprinted membrane (NIMMs). 60

(a)

40

Ce (mg L-1)

Ce (mg L-1)

60

IIMMs to Li+ IIMMs to Mg2+

20

0

0

50

100 t (min)

150

200

(b)

40 NIMMs to Li+ NIMMs to Mg2+

20

0

0

50

100 t (min)

150

200

Fig. 8.2: Selectivity permeation performance of IIMMs (a) and NIMMs (b) toward Li+ and Mg2+ prepared by Sun et al. (reprinted from ref. [33]. Copyright 2017, with the permission of Elsevier).

As you can see, in the case of imprinted membrane (a) the competing Mg2+ was accumulated in the permeate stream while Li+ was mostly retained by the membrane. In the case of the nonimprinted membrane (b), the permeation of Li+ was similar to that of Mg2+. Figure 8.3 shows the SEM images of the pristine PVDF membrane, the PVDFPDA membrane, and the final imprinted membrane. The original PVDF membrane exhibited a smooth macroporous surface (a, b), after the addition of pDA layer the membrane surface became rough (c, d), while in the case of the IIMs, the roughness increased much more (e, f). The retarded permeation separation mechanism also characterized multilayered Li+-imprinted membranes prepared using polyether sulfone as support membrane covered by a hydrophilic layer of SiO2 nanoparticles and a lithium-imprinted polymer layer synthesized using MA, 12-crown-4, and EGDMA as the functional monomer, the ligand, and the crosslinker, respectively [15]. The pDA was employed as the interfacial

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Fig. 8.3: SEM images of pristine PVDF macroporous membrane (a, b) pDA@PVDF macroporous membrane (c, d) and IIMs (e, f) (reprinted from ref. [33]. Copyright 2017, with the permission of Elsevier).

adhesion layer between the support membrane and the hydrophilic layer. The prepared imprinted membranes exhibited high binding capacity toward Li+ with respect to similar ions Na+ and K+ present in salt lake brines. The optimal selectivity factor Li+/Na+ and Li+/K+ was 1.85 and 2.07, respectively. Figure 8.4 shows a schematic representation of the different layers of the membrane and of the interaction between the 12-crown-4 and the template Li+ [15].

Fig. 8.4: Representation of a lithium-multilayered imprinted membrane and of the interaction between the ligand 12-crown-4 and template Li1+ (reprinted from ref. [15]. Copyright 2018, with the permission of Elsevier).

8.3 Selective recognition of metal ions with IIMs

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In permeation studies carried out with mix solutions of Li+, Na+, and K+, these membranes exhibited low permeation rate of Li1+ with respect to the competing ions. More in detail, the permeability rate was Na+ > K+ > Li+, while the permselectivity factor Na+/Li+ was 7.39 and that one of K+/Li+ was 9.86 [15]. In a different work, dual-IIMs were prepared using the cup-like oligomer calixarene as ligand and lithium and rubidium as template ions [16]. The authors demonstrated that changing the internal size of the oligomer is possible to achieve the selective separation of different ions. The separation of the targeted ions occurred via the selective adsorption. Recently, novel multilayered lithium-imprinted membranes were also developed by He et al. [46]. Other ion of interest in developing IIMs are the alkaline earth metals: calcium [35, 47, 48] and magnesium [36], the transition metal cadmium [14, 49], copper [22, 37, 38, 50– 54], lead [42, 43, 55, 56], mercury [39], nickel [40, 41], platinum [44], silver [25, 34], zinc [5], the semimetal arsenium [45, 57], and so on. Recently, Alidazeh and coworkers [36] developed an Mg2+-selective PVC membrane electrode dispersing Mg2+-poly (itaconic acid) nanoparticles (synthesized via the precipitation polymerization method and used as ionophores) into a PVC matrix. The membrane electrode was used to detect magnesium in different bottled mineral water and drinking water samples. The detection limit was 2.3 × 10−7 mol · L−1, while the linearity range was from 5 × 10−7 to 1 × 10−1 mol · L−1. The covalent modification of the imprinted nanoparticles with alkali chains allowed increasing the membrane selectivity owing to the block of a portion of carboxylic groups responsible of nonspecific interactions [36]. The application of the phase inversion membrane preparation technique allowed fabricating calcium-imprinted regenerated cellulose/sodium alginate membranes that removed selectively Ca2+ from aqueous solution containing also Cu2+, Mg2+, and Zn2+ [47]. In the framework of the transition metals, Wang et al. [34] developed Ag+-IMs. The scientists applied the phase inversion for obtaining blended chitosan (CS)/polyvinyl alcohol (PVA) membranes exhibiting selective adsorption capacity toward silver with respect other competing monovalent potassium and divalents copper and lead present in the same solutions [34]. The selective transport of iron was also obtained with Fe3+-IMs developed by Djunaidi et al. [58, 59] that used polyeugenol as functional polymer for preparing the membranes via the phase inversion technique. Interestingly, an electrochemical sensor based on in situ polymerized Pd2+-IIM at graphene-modified electrode surface was developed for palladium determination [60]. Pd2+-imprinted-azobenzene-modified chitosan membrane (Pd-IAzoCsM) fabricated by Di Bello and coworkers [61] allowed an efficient removal of palladium from aqueous solutions. Figure 8.5 shows the photographs of the synthesized imprinted membrane and of its corresponding nonimprinted membrane (NIMs) (NIAzoCsM) before and after a washing step with HNO3 0.5 M for removing the template ion after the membrane preparation procedure. The difference in color between the two membranes before the washing step was attributed to the presence of Pd2+ only in the imprinted one [61].

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Chapter 8 Ion-imprinted membranes

Fig. 8.5: Photographs of (Pd-IAzoCsM) and (NIAzoCsM) before (dried state) and after washing with HNO3 0.5 M (swelling state) (reprinted from ref. [61]. Open access).

Cr3+-imprinted membranes were able of removing Cr3+ [62] and Cr6+ [63] ions from water and wastewater in a selective manner. A nitrocellulose/poly(vinyl alcohol)-ionimprinted membrane was prepared using cupper as the template ion aiming at the determination of traces of this metal [54]. When the template interacted with the IM it aroused an ionic association with the fluoroscein anion allowing the emission of phosphorescence outside the recognition sites by electrostatic effects. The signal was proportional to the content of Cu2+. This novel sensing system allowed to successfully detecting copper traces in human hair and tea samples, proving high selectivity [54]. In a different case, the combination of ion imprinting technology with electrochemically switched ion exchange technology allowed fabricating cupper-imprinted membranes applied for the removal of low concentration of Cu2+ from aqueous solutions [53]. Membranes were prepared as thin films by unipolar pulse electropolymerization method using Cu2+ as template ion, potassium ferrocyanide as doping agent, pyrrole as cross-linker and conductor. During adsorption tests carried out in the presence of Cd2+, Zn2+, and Ni2+, the removal percentage of the template ion was higher with respect them. The selectivity factor Cu2+/Cd2+, Cu2+/Zn2+, and Cu2+/Ni2+ was 49.27, 26.52, and 30.16, respectively [53]. He et al. [56] applied the semiinterpenetrating polymer network technique for fabricating a Pb2+-imprinted PVA/PAA membrane for the selective removal of this heavy metal from contaminated water. In adsorption experiments the Pb-IM showed high binding capacity toward Pb (1.003 mmol · g−1) and was selective with respect to the competitor cadmium (Cd2+). The selectivity factor was 70.7. The adsorption was fast, reaching the equilibrium within 1.5 h and the process agreed the Langmuir isotherm model and the intraparticle pore-diffusion model [56]. In 2020, phase inversion membranes were successfully imprinted with mercury aiming the removal of this element (one of the most toxics) from simulated industrial wastewater [39]. Various membranes were prepared by dispersing different amounts of a previously synthesized Hg2+-imprinted polymeric particles into a poly(ether sulfone) matrix.

8.3 Selective recognition of metal ions with IIMs

185

From Fig. 8.6, it is possible to see that all the membranes exhibited an asymmetric structure consisting of a porous layer (finger-like macrovoids) supporting a thin dense layer.

Fig. 8.6: SEM images of the imprinted polymer (a), PES membrane (b), composite Hg2+-imprinted membrane with 2% (c), 2.5% (d), and 3.0% (e) IP and composite nonimprinted pristine membrane with 2.5% NIP (f) prepared by Esmali et al. (reprinted from ref. [39] Copyright 2020, with the permission of Elsevier).

Furthermore, the addition of polymer particles to the pristine PES allowed obtaining membranes that were more porous. This was confirmed by an increase of water permeability. During recognition experiments, membranes containing the 2.5% of IP particles exhibited the better performance in the selective adsorption and separation of mercury from other ions present in the same water samples. On the other hand, increasing IP content from 2.5% to 3.0% the agglomeration of polymer particles negatively affected the recognition properties (see Fig. 8.6e) [39]. The removal of arsenic from water samples with imprinted membranes was also achieved [57]. Membranes were prepared by means of different routes, and the more efficient resulted those prepared via “grafting from” of carboxymethyl cellulose using acrylamide as functional monomer and vinyl cysteine/zinc sulfide/titaniun oxide nanoparticles as capping agent (see Fig. 8.7).

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Chapter 8 Ion-imprinted membranes

Fig. 8.7: Schematic representation of the fabrication of As-IM via the “grafting-from” (GFM) approach (reprinted from ref. [57]. Copyright 2020, with the permission of Elsevier).

Permselectivity studies evidenced as this membrane retained As3+ with respect to other ions present in polluted water. Table 8.2 reports the permselectivity of As3+ and competing ions as well as the permeselectivity factor (β), expressed as the ratio between the flux of the competing ions and that one of the template. Tab. 8.2: Permselectivity of different ions through As3+ “grafting from” imprinted membrane [57]. Permeating ion +

As Na+ Cu+ Zn+ Cd+ Hg+ Pb+ Chloride Fluoride Nitrate Cyanide

Permeation flux · − (mg · cm− · s−)

Permselectivity factor (β)

. . . . . . . . . . .

. . . . . . . . . .

Readapted from ref. [57]. Copyright 2020, with the permission of Elsevier.

The presence of zinc sulfide conferred to the membrane an antibacterial activity due to the interaction between its positive charge and the negative charge of bacterial membrane [57]. Previously, As3+-imprinted membranes were also prepared using methacrylic acid as functional monomer for synthesizing imprinted nanoparticles subsequently embedded into a PVC membrane electrode prepared via the phase inversion [45]. The membrane resulted efficient in detecting arsenic in real hot spring water and urine samples. The lower detection limit was 5.0 × 10−7 mol · L−1. Other membranes prepared via “grafting to” and the conventional method resulted less efficient [57]. IIMs were also prepared for removing cadmium from food [64] and for the

8.4 IIMs for rare earth elements recognition

187

selective recognition of other metal ions such as Rh3+ [65, 66] and Pt4+ [67]; details can be found in the relative reported literature.

8.4 IIMs for rare earth elements recognition Rare earth elements (RERs) are 17 special members of the periodic table that include lanthanides (La–Lu), yttrium (Y), and scandium (Sc). They are co-constituents of minerals and are not present in nature as individual elements. Due to their electrical, magnetic, and optical properties, the interest of the modern industry toward them is in continuous increase. In fact, they play a key function in developing clean energy, high-tech manufacturing, and petrochemical engineering for enhancing product properties. In particular, owing to their ability to react with other elements forming compounds with specific chemical behaviors they find application in electronic, optical, magnetic, and catalytic fields [68–70]. However, the excessive use of REEs caused an increase of their environmental emission and costs. Therefore, from one side is important to find new sources and improve their extraction processes while, from the other side, it is essential to remove REEs from the polluted sites and recycle them for reducing their future supply risk and environmental problems [70, 71]. In this context, an increase of the recovery and recycling innovative separation strategies in the near future is hoped in order to have a good compromise between their market, potential benefits, and adverse effects on human and environmental health [72, 73]. Table 8.3 summarizes the main applications of the REEs [74]. Tab. 8.3: Main applications of REEs. Element

Atomic Application number

Lanthanium (La)

 Electron microscopic tracer, studio lighting, laptop batteries, camera lenses, and hybrid car batteries

Cerium (Ce)

 Carbon-arc lighting, TV color, screen, fluorescent lighting, and catalytic converter

Praseodymium (Pr)

 Nickel metal hydride (NiMH) in hybrid cars, glass goggles for glass blowers and welders, and high-intensity carbon arc lights

Neodymium (Nd)

 NIB magnets (computers, hand phones, medical equipment, motors, wind turbines, and audio systems) and specialized goggles for glassblowers

Promethium (Pm)

 Atomic batteries for space craft and guided missiles

Samarium (Sm)

 Magnets for headphones, small motors, and pickups for some electric guitars, absorber in nuclear reactors, and cancer treatment

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Chapter 8 Ion-imprinted membranes

Tab. 8.3 (continued) Element

Atomic Application number

Europium (Eu)

 Antiforgery marks on euro banknotes, nuclear reactor control rods, and compact fluorescent bulb

Gadolinium (Gd)

 Microwave, MRI, and color television picture tubes

Terbyum (Tb)

 Magnet for wind turbine and hybrid car motor and speaker UV light for euro banknotes

Dysprosium (Dy)

 Speakers, compact discs, and hard discs, medium source rare earth lamps (MSRs) within the film industry

Holmium (Ho)

 Yellow or red coloring for glass, cubic zirconia, nuclear reactor control rods, solid-state lasers for noninvasive medical procedures treating cancers, and kidney stones

Erbium (Er)

 Nuclear reactor control rods, coloring agent in glazes, and glasses. Laser for skin (remove tattoo)

Thulium (Tm)

 Laser, euro banknotes for its blue fluorescence under UV light to defeat counterfeiters

Ytterbium (Yb)

 Stress gauges to monitor ground deformations caused by earthquakes or underground explosions, catalyst, and fiber laser amplifiers

Lutetium (Lu)

 Catalyst, detectors in positron emission tomography

Yttrium (Y)

 Microwave filter, provide the red color in color television tubes, and hightemperature superconductor YBCO

Scandium (Sc)

 Aerospace industry components and for sports equipment such as bicycle frames, fishing rods, golf iron hafts, and baseball bats

Reprinted from ref. [74]. Open access.

Among the various membrane-based strategies applied for their separation from environmental water, wastes, wastewater, and other sites, IIMs are efficient systems that allow to overcome the problems of the chemical similarity of these elements and to separate them from each other. In addition, they offer the possibility of recovery low concentration level owing to their high efficiency [75, 76]. REEs-imprinted membranes are prepared with different methods. Liu et al. [77] developed a dysprosiumchitosan-imprinted membrane with interconnected 3D-macroporous structure via the immersion-precipitation method for the selective extraction of Dy3+ from water and separating it from competing ions with identical valence and radius (Nd3+, Pr3+, Tb3+, and Fe3+) present in the same samples [77]. The incorporation of silica particles into the imprinted membrane matrix determined the formation of the macroporus structure. Figure 8.8 illustrates the membrane preparation process.

8.4 IIMs for rare earth elements recognition

189

Fig. 8.8: The preparation process of Dy3+-imprinted 3D macroporous modified chitosan membrane (II-MAC) (reprinted from ref. [77]. Copyright 2017, with the permission of Elsevier).

In adsorption tests, the maximum imprinting factor (28.0) Dy3+ adsorpion (23.3 mg · g −1) were observed at pH 7.0 and 25 °C. In permeation studies, the separation of Dy3+ from interfering ions occurred via the retarded permeation mechanism [77]. After five consecutive adsorption–desorption cycles, the adsorption capacity was 91.6% of the initial observed value, thus confirming the good reusability of the prepared IIM (see Fig. 8.9).

Fig. 8.9: Regeneration of II-MAC over five cycles (reprinted from ref. [77]. Copyright 2017, with the permission of Elsevier).

Freestanding dual-template docking-oriented ionic-imprinted mesoporous films also resulted useful for the selective recognition and separation of neodymium (Nd3+) from praseodymium (Pr3+) [78]. In 2018 [79], the application of the dual-template imprinting strategy led to the production of IIMs capable of selectively recovery neodymium and dysprosium (Dy3+), which were used as template ions during the membrane formation. In acidic conditions (pH 4) the adsorption capacity of the membrane toward Dy3+ was 17.50 mg · g−1, while that one toward Nd3+ was 12.15 mg · g−1. More recently, Wu et al. [80] proposed a new three-dimensional (3D) basswood-based Nd3+-imprinted nanocomposite membranes having a multilevel structure. The process entailed the application of a two-

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Chapter 8 Ion-imprinted membranes

step temperature free radical polymerization procedure on a PDA/basswood-modified surface. Figure 8.10 shows the effect of pH on the rebinding capacity on the optimized imprinted membrane (3D-IIMs) and its corresponding NIMs.

Fig. 8.10: Effect of pH on the binding capacity of 3D-IIMs and their corresponding NIMs developed by Wu et al. [80] (reprinted from ref. [80]. Copyright 2021, with the permission of Elsevier).

As you can see, increasing the pH from 1.0 to 7.0, the binding capacity of the 3D-IIMs also increased, while in the case of NIMs the increase of binding capacity barely evident. This behavior suggested that at high acidic conditions some recognition sites were occupied by the protonation leading to low binding capacity. At pH 7.0 the binding capacity of the 3D-IIMs was 120.87 mg · g−1, while the imprinting factor was 3.78 [80]. Three-dimensionally interconnected macroporous chitosan films were also imprinted with gadolinium Gd3+ [81]. In this case the high affinity between the membrane and the template ion was due to coordination interactions between the carboxyl groups (–COO–) of Gd3+ and the amino groups (–NH2) of the imprinted membrane. More recently skilled Gd3+-imprinted mesoporous carboxymethyl chitosan films [82] and chitosan-based porous Gd3+-imprinted films with an interpenetrating network structure for efficient selective adsorption of gadolinium [12] were also developed. Yet, for preparing gadolinium-IMs, Cui et al. [83] developed a bionic facile strategy via interlaced stacking of one-dimensional Gd3+-imprinted carbon nanotubes (GICNTs) and two-dimensional pDA-modified graphene oxide (pDA@GO). Other REEs of interest in developing IIMs are europium [84–86] and yttrium [87–89]. For example, Eu3+-imprinted nanocomposite membranes based on graphene oxide and silicon dioxide end exhibiting antifouling properties allowed separating the template ion from its analogs [84]. In adsorption tests, the binding capacity of IIMs toward Eu3+ was higher with respect to that observed for the corresponding NIMs and competing ions. Table 8.4 shows the imprinting factor and the binding capacity of different membranes toward the investigated ions.

8.4 IIMs for rare earth elements recognition

191

Tab. 8.4: Parameters of selective rebinding experiments on Eu-IIMs and Eu-NIMs. Ions

Eu-IIMs Q (mg g ) -

+

Eu La+ Gd+ Sm+

. . . .

Eu-NIMs α – . . .

Q (mg g ) -

. . . .

IF α – . . .

. . . .

Reprinted from ref. [84]. Copyright 2018, with the permission of Elsevier.

From the table it is evident that the binding capacity of the imprinted membrane toward Eu3+ was one order of magnitude higher than the other cases. Permeation tests with a diffusion cell evidenced the presence of a retarded permeation of the Eu3+ ions through the membrane, while the competing ions permeated faster [84]. Figure 8.11 shows the schematic representation of the permselectivity mechanism.

Fig. 8.11: Schematic diagram of the permselectivity mechanism of Eu-IIMs toward europium ions. (pH = 7.0, 35 °C, 50 mg⸱L−1) (reprinted from ref. [84]. Copyright 2018, with the permission of Elsevier).

Burying membranes with and without Ag nanoparticles into natural soil for several days and evaluating the subsequent membrane decomposition by soil microorganisms allowed to assess the antifouling ability of membranes modified with Ag nanoparticles on their surface [84].

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8.5 IIMs toward inorganic anions Anion species are not toxic as such metals but their potential environmental pollution as well as the anthropogenic activity has to be taken into account. They are characterized by different shapes such as linear (OH–, N3–, CN–, SCN–, spherical (Br–, Cl–, F–, I–), triangular (NO3–, CO32–), tetrahedral (PO43–, SO42–, VO43–), octahedral (PF63–, [Fe(CN) 6]4–, [Co(CN)6]3–), and square planar ([PdCl4]2–, [Pt(CN)4]2–) [1, 6, 90]. The production of imprinted membranes for the selective recognition of anions is less widespread with respect to the fabrication of cation-imprinted membranes. This is because it is more difficult to imprint them. In fact, shapes that are more complex are in general larger than cations and have lower charge to radius ratio. Therefore, a higher degree of design for the construction of their complementary recognition sites is required. On the other hand, simple inorganic anions are too small or less functional and shape adapting than the other species and exhibit high affinity for polar solvents that interfere with the formation of the recognition sites during the imprinting process. For example, strong hydrogen bonds in the presence of water are formed [1, 6, 90]. In 1988, Dong et al. [91] fabricated one of the first sensors based on an anionimprinted polypyrrole film through electrochemical polymerization in aqueous solution using Cl– as the template anion. The imprinted film exhibited a fast recognition response and a detection limit of 3.5 × 10−5 M in linearity comparable with the values observed with chloride-selective traditional electrodes. Later, Dong and Che [92] developed a similar sensor for selective sensing chloride in serum. An imprinted film based on polypirrole was also produced for the discrimination of nitrate over anion larger than it, thus investigating the possibility of avoiding interferences with the detection [93]. The authors demonstrated as in the case of a commercial nitrate-selective sensor the lipophilic anions (ClO4– and I–), which are larger than nitrate sterically hindered the detection, while the imprinted sensor exhibited a selectivity higher four orders of magnitude [93]. In the third millennium, other IIMs were prepared using chloride, molybdate, nucleotidess, phosphate, and tungstate as template anions. In this context, a very recent paper [94] deals with the fabrication of nanostructured imprinted films exhibiting selective recognition capacity toward chloride anions. They exhibited a sensitivity threefold higher than the commercial sensing devices and were able to distinguish between chloride ions and interfering anions (carbonate, nitrate, and sulphate). In addition, selectivity studies versus the similar anions fluoride, bromide, and the hydroxyl group demonstrated the selective properties of the membranes. The selectivity coefficients calculated by the matched potentials method [95] toward SO42–, NO3–, HCO3–, Br–, F–, and OH– were −2.4, −2.1, −2.6, −2.0, −2.1, and −6.4, respectively. An electrochemical sensor based on nitrate-imprinted polyaniline matrix/copper nanoparticles was also efficient in the detection of nitrate in water [96]. The negative charge of NO3– can enhance the growth of algae, thus causing the problem of lakes and rivers eutrophication. In addition, high levels of nitrate in drinking water promote the occurrence of dangerous sicknesses like gastrointestinal and stomach tumors [97, 98]

8.5 IIMs toward inorganic anions

193

and methemoglobinemia [99]. Also, nitrate present in food is reduced to nitrite and the more toxic ammonia [100]. So, it is important to measure the level of nitrate in water and food. To this purpose, the Environmental Protection Agency limited the presence of this anion in drinking water at 10 mg · L−1 [101]. NO3– imprinted membranes based on polyaniline matrix/copper nanoparticles exhibited high sensitivity toward this anion. The detection linearity range of IIM in water was from 1.0 µM to 100 mM, while the detection limit was 3.1 × 10−7 mol · L−1. The application of sensor in well and real mineral water allowed removing from 95.5% to 98.7% of nitrate ions [96]. A Cr2O72– anionimprinted composite membrane was also prepared via grafting polymerization of the designed functional monomer N,N′-(ethane-1,2-diyl)bis(2-methylacrylamide) on the surface of nylon-6 membrane [102]. The highest binding capacity toward the template was obtained at pH 3.0. This was because the hydrogen ions present at acidic conditions protonated the nitrogen atoms on the membrane surface. At this pH, in permeation selectivity studies the Cr2O72– anions easily permeated the imprinted membrane with respect to the competing HPO42– anions and Cd2+, Cu2+, and Ni2+ cations. All the experimental results confirmed the efficacy of the specifically designed functional monomer for membrane fabrication [102]. The selective separation of molybdate anions was also achieved with a molybdate surface-imprinted membrane prepared via graft polymerization of the function monomer 1-vinylimidazole on the surface of a ceramic membrane activated with a SiO2 layer [103]. Figure 8.12 illustrates the interaction during the recognition process. The static adsorption capacity of the membrane toward the template anion was 6.9 µmol · g−1, while the selectivity factor molybdate(VI)/tungstate(VI) was 7.48. A good selectivity was also observed in permeation tests, evidencing the presence of the retarded permeation separation mechanism. A similar membrane was prepared using tungstate as the template anion [104]. In this case, the selectivity factor tungstate(VI)/ molybdate(VI) and tungstate(VI)/chromium(VI) was 15.5 and 19.7, respectively. The presence of polyethylenimine into the membrane endorsed the tungstate ion adsorption by electrostatic interactions. In conclusion, all the presented paragraphs discussed the efficiency of IIMs in the selective recognition of metal cations, RERs, and inorganic anions. However, it should be noted that although IIMs are excellent ionic separation systems their production is still limited, and therefore it is hoped that their large-scale production and application will be implemented in the near future of the research on this topic.

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Fig. 8.12: Chemical interaction between Mo(VI) anion and the recognition site of the molybdate-imprinted composite membrane prepared using 1-vinylimidazole as the functional monomer (reprinted from ref. [103]. Copyright 2017, with the permission of Elsevier).

References [1] [2] [3]

[4] [5] [6] [7]

Lu J, Qin Y, Wu Y, Meng M, Yan Y, Li C. Recent advances in ion imprinted membranes: Separation and detection via ion-selective recognition. Environ Sci Wat Res & Technol 2019, 5, 1626–1653. Fu J, Chen L, Li J, Zhang Z. Current status and challenges of ion imprinting. J Mat Chem A 2015, 3, 13598–13627. Shakerian F, Kim KH, Kwon E, Szulejko JE, Kumar P, Dadfarnia S, et al. Advanced polymeric materials: Synthesis and analytical application of ion imprinted polymers as selective sorbents for solid phase extraction of metal ions. Trend Anal Chem 2016, 83, 55–69. Kyzas GZ, Bikiaris DN. Molecular imprinting for high-added value metals: An overview of recent environmental applications. Adv Mater Sci Eng 2014, 932637, http://dx.doi.org/10.1155/2014/932637. Zhai Y, Liu Y, Chang X, Ruan X, Liu J. Metal ion small molecule complex imprinted polymer membranes: Preparation and separation characteristics. React Funct Polym 2008, 68, 284–291. Chen L, Dai J, Hu B, Wang J, Wu Y, Dai J, et al. Recent progresses on the adsorption and separation of ions by imprinting routes. Sep Purif Rev 2020, 49, 265–293. Donato L, Drioli E. Imprinted membranes for sustainable separation processes. Front Chem Sci Eng 2021, 15, 775–792.

References

[8] [9] [10]

[11] [12]

[13] [14]

[15]

[16]

[17] [18] [19]

[20]

[21]

[22] [23] [24] [25] [26] [27]

195

Mokhtar M, Dickson SE, Kim Y, Mekky W. Preparation and characterization of ion selective membrane and its application for Cu2+ removal. J Ind Eng Chem 2018, 60, 475–484. Kimaro A, Kelly LA, Murray GM. Molecularly imprinted ionically permeable membrane for uranyl ion. Chem Commun 2001, 1282–1283. Lehmann M, Brunner H, Tovar G. Molecularly imprinted nanoparticles as selective phase in composite membranes: Hydrodynamics and separation in nanoscale beds. Chem Ing Tech 2003, 75, 149–153. Yoshikawa M, Tharpa K, Dima SO. Molecularly imprinted membranes: Past, present, and future. Chem Rev 2016, 116, 11500–11528. Zheng X, Zhang Y, Bian T, Zhang Y, Zhang F, Yan Y. Selective extraction of gadolinium using freestanding imprinted mesoporous carboxymethyl chitosan films with high capacity. Cellulose 2019, 26, 1209–1219. Huang K, Chen Y, Zhou F, Zhao X, Liu J, Mei S, et al. Integrated ion imprinted polymers-paper composites for selective and sensitive detection of Cd (II) ions. J Hazard Mater 2017, 333, 137–143. Chen A, Zeng G, Chen G, Hu X, Yan M, Guan S, et al. Novel thiourea-modified magnetic ionimprinted chitosan/TiO2 composite for simultaneous removal of cadmium and 2,4-dichlorophenol. Chem Eng J 2012, 191, 85–94. Lu J, Qin Y, Zhang Q, Wu Y, Cui J, Li C, et al. Multilayered ion-imprinted membranes with high selectivity towards Li based on synergistic effect of 12-crown-4 and polyether sulfone. Appl Surf Sci 2018, 427, 931–941. Wang Y, Xu J, Yang D, Zhang T, Qiu F, Pan J. Calixarenes functionalized dual-imprinted mesoporous film for the simultaneous selective recovery of lithium and rubidium. Appl Organomet Chem 2018, 32, 4511, https://doi.org/10.1002/aoc.4511. Salehi E. Application of diffusive transport model for better insight into retardation mechanisms involved in ion-imprinted membrane transport. Chin J Chem Eng 2016, 24, 1161–1165. Salehi E, Madaeni V, Vatanpour V. Thermodynamic investigation and mathematical modelling of ion-imprinted membrane adsorption. J Membr Sci 2012, 389, 334–342. He LQ, Wang ZM, Li YJ, Yang J, Xiao XL, Liu Y. A novel electrochemical sensor modified with a computer-simulative magnetic ion-imprinted membrane for identification of uranyl ion. Sensors 2022, 22, 4410, https://doi.org/10.3390/s22124410. Zarrougui R, Mdimagh R, Raouafi N. Highly efficient extraction and selective separation of uranium (VI) from transition metals using new class of undiluted ionic liquids based on H-phosphonate anions. J Hazard Mater 2018, 342, 464–476. Li N, Yang H. Construction of natural polymeric imprinted materials and their applications in water treatment: A review. J Hazard Mater 2021, 403, 123643, https://doi.org/10.1016/j. jhazmat.2020.123643. Zhang W, Yun M, Yu Z, Chen D, Li X. A Novel Cu (II) ion imprinted alginate-chitosan complex adsorbent for selective separation of Cu (II) from aqueous solution. Polym Bull 2019, 76, 1861–1876. Zarghami S, Mohammadi T, Kazemimoghadam M. Diffusive transport of Cu (II) ions through thin ion imprinted polymeric membranes. Chem Pap 2014, 68, 1325–1331. Ratnaningsih E, Kadja GTM, Putri RM, Alni A, Khoiruddin K, Djunaidi MC, et al. Molecularly imprinted affinity membrane: A review. ACS Omega 2022, 7, 23009–23026. Shawky HA. Synthesis of ion-imprinting chitosan/PVA crosslinked membrane for selective removal of Ag (I). J Appl Polym Sci 2009, 114, 2608–2615. Lu Y, Sun D, Lu Y, Yan Y, Hu B. Zwitterion imprinted composite membranes with obvious antifouling character for selective separation of Li ions. Korean J Chem Eng 2020, 37, 707–715. Greenwood NN, Earnshaw A. Chemistry of the elements. 2nd ed. Elsevier, Butterworth-Heinemann, 1997, ISBN 978-0-08-037941-8.

196

Chapter 8 Ion-imprinted membranes

[28] Dev VV, Nair KK, Baburaj G, Krishnan KA. Pushing the boundaries of heavy metal adsorption: A commentary on strategies to improve adsorption efficiency and modulate process mechanisms. Colloids Interface Sci Commun 2022, 49, 100626, https://doi.org/10.1016/j.colcom.2022.100626. [29] Qasem NAA, Mohammed RH, Lawal DU. Removal of heavy metal ions from wastewater: A comprehensive and critical review. Colloids Interface Sci Commun 2022, 49, 100626, https://doi.org/ 10.1016/j.colcom.2022.100626. [30] Li Z, He G, Zhao G, Niu J, Li L, B J, et al. Preparation of a novel ion-imprinted membrane using sodium periodate-oxidized polydopamine as the interface adhesion layer for the direction separation of Li+ from spent lithium-ion battery leaching solution. Sep Purif Sci 2021, 277, 119519, https://doi.org/10.1016/j.seppur.2021.119519. [31] Sun D, Meng M, Qiao Y, Zhao Y, Yan Y, Li C. Synthesis of ion imprinted nanocomposite membranes for selective adsorption of lithium. Sep Purif Technol 2018, 194, 64–72. [32] Cui J, Zhang Y, Wang Y, Ding J, Yu P, Yan Y, et al. Fabrication of lithium ion imprinted hybrid membranes with antifouling performance for selective recovery of lithium. New J Chem 2018, 42, 118–128. [33] Sun D, Zhu Y, Meng M, Qiao Y, Yan Y, Li C. Fabrication of highly selective ion imprinted macroporous membranes with crown ether for targeted separation of lithium ion. Sep Purif Technol 2017, 175, 19–26. [34] Wang X, Zhang L, Ma C, Song R, Hou H, Li D. Enrichment and separation of silver from waste solutions by metal ion imprinted membrane. Hydrometallurgy 2009, 100, 82–86. [35] Wang Y, Zhu S, Liao Y, Xiong X. A calcium ion-imprinted porous film prepared from a cellulosealginate composite. J Polym Res 2014, 21, 612, https://doi.org/10.1007/s10965-014-0612-3. [36] Alizadeh T, Akhoundian M, Hoseinnejad B. Synthesis of dodecanol-anchored nano-sized magnesium imprinted polymer and its application as an efficient ionophore in Mg2+-selective PVC membrane electrode. Anal Bioanal Electrochem 2021, 13, 436–456. [37] Mokhtar M, Dickson SE, Kim Y, Mekky W. Preparation and characterization of ion selective membrane and its application for Cu2+ removal. J Eng Chem 2018, 60, 475–484. [38] Deng H, Gao L, Zhang S, Yuan J. Preparation of a copper ion selective membrane by surface modified molecular imprinting. Ind Eng Chem Res 2012, 51, 14018–14025. [39] Esmali F, Mansourpanah Y, Farhadi K, Amani S, Rasoulifard A, Ulbricht M. Fabrication of a novel and highly selective ion-imprinted PES-based porous adsorber membrane for the removal of mercury (II) from water. Sep Purif Technol 2020, 250, 17183, https://doi.org/10.1016/j.seppur.2020.117183. [40] Du X, Zhang H, Hao X, Guan G, Abudula A. Facile preparation of ion-imprinted composite film for selective electrochemical removal of nickel (II) ions. ACS Appl Mater Interfaces 2014, 6, 9543–9549. [41] Vatanpour V, Madaeni SS, Zinandini S, Rajabi HR. Development of ion imprinted technique for designing nickel ion selective membrane. J Membr Sci 2011, 373, 36–42. [42] Lv X, Liu Y, Zhang J, Zhao M, Zhu K. Study on the adsorption behavior of glutaric acid modified Pb(II) imprinted chitosan-based composite membrane to Pb (II) in aqueous solution. Mater Lett 2019, 251, 172–175. [43] Li Y, Zhang J, Xu C, Zhou Y. Crosslinked chitosan nanofiber mats fabricated by one-step electrospinning and ion-imprinting methods for metal ions adsorption. Sci China Chem 2016, 59, 95–105. [44] Zeng J, Lv C, Liu G, Zhang Z, Dong Z, Liu JY, Wang Y. A novel ion-imprinted membrane induced by amphiphilic block copolymer for selective separation of Pt (IV) from aqueous solutions. J Membr Sci 2019, 572, 428–441. [45] Alizadeh T, Rashedi M. Synthesis of nano-sized arsenic-imprinted polymer and its use as As3+ selective ionophore in a potentiometric membrane electrode: Part 1. Anal Chim Acta 2014, 843, 7–17.

References

197

[46] He G, Li Z, Liu Y, Liu M, Zhu C, Zhang L, et al. A novel lithium ion-imprinted membrane with robust adsorption capacity and anti-fouling property based on the uniform multilayered interlayer. Desalination 2022, 539, 115973, https://doi.org/10.1016/j.desal.2022.115973. [47] Alizadeh T, Shamkhali AN, Hanifehpour Y, Joo SW. A Ca2+ selective membrane electrode based on calcium-imprinted polymeric nanoparticles. New J Chem 2016, 40, 8479–8487. [48] Rosatzima T, Andersson L, Wilhelm S, Masbach K. Preparation of Ca2+ selective sorbents by molecular imprinting using polymerisable ionophores. J Chem Soc Perkin Trans 1991, 1261–1265. [49] Xi Y, Shi H, Liu R, Yn X, Yang L, Huang M, et al. Insights into ion imprinted membrane with a delayed permeation mechanism for enhancing Cd2+ selective separation. J Hazard Mater 2021, 416, 125772, https://doi.org/10.1016/j.jhazmat.2021.125772. [50] Zheng X, Fan R, Zhao J. An ion-imprinted microporous polypropylene membrane for the selective removal of Cu (II) from an aqueous solution. Sep Sci Technol 2012, 47, 1571–1582. [51] Wang Z, Wang M, Wu G, Shen Y, He C. Ion imprinted sol–gel nanotubes membrane for selective separation of copper ion from aqueous solution. Microchim Acta 2010, 169, 195–200. [52] Li ZM, Liu JM, Liu ZB, Liu QY, Lin X, Li FM, et al. Preparation for nitrocellulose membrane-poly (vinyl alcohol)-ionic imprinting and its application to determine trace copper by room temperature phosphorimetry. Anal Chim Acta 2007, 589, 44–50. [53] Liu W, Lei ZA, Wang QM, Liu X, Yang Y. Construction of a novel ion imprinted film to remove low concentration Cu2+ from aqueous solution. Chem Eng J 2021, 411, 128477, https://doi.org/10.1016/j. cej.2021.128477. [54] Deng H, Zhao S, Meng Q, Zhang W, Hu B. A novel surface ion-imprinted cation-exchange membrane for selective separation of copper ion. Ind Eng Chem Res 2014, 53, 15230–15236. [55] Sun J, Wu L, Li Y. Removal of lead ions from polyether sulfone/Pb (II)-imprinted multi-walled carbon nanotubes mixed matrix membrane. J Taiwan Inst Chem Eng 2017, 78, 219–229. [56] He J, Liu A, Chen JP. Introduction and demonstration of a novel Pb (II)-imprinted polymeric membrane with high selectivity and reusability for treatment of lead contaminated water. J Colloid Interface Sci 2015, 439, 162–169. [57] Roy E, Patra S, Madhuri R, Sharma PK. A single solution for arsenite and arsenate removal from drinking water using cysteine@ZnS:TiO2 nanoparticle modified molecularly imprinted biofoulingresistant filtration membrane. Chem Eng J 2014, 304, 259–270. [58] Djunaidi MC. Synthesis of ionic imprinted polymer particles for selective membrane transport of Fe (III) using polyeugenol as the functional polymer. Orient J Chem 2016, 32(135), 77, http://dx.doi.org/ 10.13005/ojc/320107. [59] Djunaidi MC, Jumina J, Siswanta D, Ulbricht M. Selective transport of Fe (III) using polyeugenol as functional polymer with ionic imprinted polymer membrane method. Asian J Chem 2015, 27, 4553–4562. [60] Bai H, Wang S, Liu P, Xiong C, Zhang K, Cao Q. Electrochemical sensor based on in situ polymerized ion imprinted membranes at graphene modified electrode for palladium determination. J Electroanal Chem 2016, 771, 29–36. [61] Di Bello MP, Lazzoi MR, Mele G, Scorrano S, Mergola L, Del Sole R. A new ion-imprinted chitosanbased membrane with an azo-derivative ligand for the efficient removal of Pd (II). Materials 2017, 10, 1133–1148. [62] Chen JH, Li GP, Liu QL, Ni JC, Wu WB, Lin JM. Cr (III) ionic imprinted polyvinyl alcohol/sodium alginate (PVA/SA) porous composite membranes for selective adsorption of Cr (III) ions. Chem Eng J 2010, 165, 465–473. [63] Li P, Wang X, Wang G, Zhao L, Hong Y, Hu X, et al. Synthesis and evaluation of ion-imprinted composite membranes of Cr(VI) based on β-diketone functional monomers. RSC Adv 2021, 11, 38915–38924.

198

Chapter 8 Ion-imprinted membranes

[64] Amini MH, Alijani H, Beyki MH. Toxic cadmium selective sequestration from food samples using melamine anchored magnetic cellulose by surface imprinting route. Food Chem 2022, 396, 133688, https://doi.org/10.1016/j.foodchem.2022.133688. [65] Zeng J, Zhang Z, Zhou H, Liu G, Liu Y, Zeng L, Jian J, Yuan Z. Ion-imprinted poly(methyl methacrylatevinyl pyrrolidone)/poly (vinylidene fluoride) blending membranes for selective removal of ruthenium(III) from acidic water solutions. Poly Adv Technol 2019, 30, 1865–1877. [66] Zeng J, Zhang Z, Dong Z, Ren P, Li Y, Liu X. Fabrication and characterization of an ion-imprinted membrane via blending poly (methyl methacrylate-co-2-hydroxyethyl methacrylate) with polyvinylidene fluoride for selective adsorption of Ru (III). React Funct Polym 2017, 115, 1–9. [67] Zeng J, Lv C, Liu G, Zhang Z, Dong Z, Liu JY, Wang Y. A novel ion-imprinted membrane induced by amphiphilic block copolymer for selective separation of Pt (IV) from aqueous solutions. J Membr Sci 2019, 572, 428–441. [68] Drobniak A, Mastalerz M. Rare earth elements – A brief overview. Ind J Earth Sci 2022, 4, https://doi. org/10.14434/ijes.v4i1.33628. [69] Jordens A, Cheng YP, Waters KE. A review of the beneficiation of rare earth element bearing minerals. Miner Eng 2013, 97–114. [70] Balaram V. Rare earth elements: A review of applications, occurrence, exploration, analysis, recycling, and environmental impact. Geosci Front 2019, 10, 1285–1303. [71] Binnemans K, McGuiness P, Jones PT. Rare-earth recycling needs market intervention. Nat Rev Mater 2021, 6, 459–461, https://doi.org/10.1038/s41578-021-00308-w. [72] Grandell L, Lehtila A, Kivinen M, Koljonen T, Kihlman S, Lauri LS. Role of critical metals in the future markets of clean energy technologies. Renew Energy 2016, 95, 53–62. [73] Nelson JJM, Cheisson T, Rugh HJ, Gau MR, Carroll PJ, Schelter EJ. High- throughput screening for discovery of benchtop separations systems for selected rare earth elements. Commun Chem 2020, 3, https://doi.org/10.1038/s42004-019-0253-x. [74] Suli LM, Ibrahim WHW, Aziz BA, Deraman MR, Ismail NA. A review of rare earth mineral processing technology. Chem Eng Res Bull 2017, 19, 20–35. [75] Bashiri A, Nikzad A, Maleki R, Asadnia M, Razmjou A. Rare earth elements recovery using selective membranes via extraction and rejection. Membranes 2022, 12, 80, https://doi.org/10.3390/ membranes12010080. [76] Chen L, Wu Y, Dong H, Meng M, Li C, Yan Y, Chen J. An overview on membrane strategies for rare earths extraction and separation. Sep Purif Technol 2018, 197, 70–85. [77] Liu E, Xu X, Zheng X, Zhang F, Liu E, Li C. An ion imprinted macroporous chitosan membrane for efficiently selective adsorption of dysprosium. Sep Purif Technol 2017, 189, 288–295. [78] Zheng X, Zhang F, Liu E, Xu X, Yan Y. Efficient recovery of neodymium in acidic system by freestanding dual-template docking oriented ionic imprinted mesoporous films. ACS Appl Mater Interfaces 2017, 9, 730–739. [79] Zheng X, Zhang Y, Zhang F, Li Z, Yan Y. Dual-template docking oriented ionic imprinted bilayer mesoporous films with efficient recovery of neodymium and dysprosium. J Hazard Mater 2018, 353, 496–504. [80] Wu Y, Lin R, Ma F, Xing W, Pan J. Three-dimensional macroporous wood-based selective separation membranes decorated with well-designed Nd (III)-imprinted domains: A high-efficiency recovery system for rare earth element. J Colloid Int Sci 2021, 587, 703–714. [81] Zheng X, Liu E, Zhang F, Dai J, Yan Y, Li C. Selective adsorption and separation of gadolinium with three-dimensionally interconnected macroporous imprinted chitosan films. Cellulose 2017, 24, 977–988. [82] Liu E, Lin X, Zhang D, Xu W, Shi J, Hong Y. Preparation of an ion imprinted chitosan-based porous film with an interpenetrating network structure for efficient selective adsorption of Gd (III) new. J Chem 2012, 45, 725–734.

References

199

[83] Cui K, Gao B, Tai M, Su B. A facile bionic strategy towards Gd (III)-imprinted membranes via interlaced stacking of one-dimensional/two-dimensional nanocomposite materials. J Taiwan Inst Chem Eng 2019, 95, 652–659. [84] Lu J, Wu Y, Lin X, Gao J, Dong H, Li C, Qin Y, Wang L, Yan Y. Anti-fouling and thermosensitive ion-imprinted nanocomposite membranes based on grapheme oxide and silicon dioxide for selectively separating europium ions. J Hazard Mat 2018, 353, 244–253. [85] Chen J, Bai H, Xia J, Li Z, Liu P, Cao Q. Electrochemical sensor for detection of europium based on poly-catechol and ion-imprinted sol-gel film modified screen-printed electrode. J Electroanal Chem 2018, 824, 32–38. [86] Chen J, Bai H, Li Y, Zhang J, Liu P, Cao Q. Stripping voltammetric determination of europium via ultraviolet-trigger synthesis of ion imprinted membrane. Sens Act B: Chemical 2018, 271, 329–335. [87] Pan W, Chen L, Wang Y, Yan Y. Selective separation of low concentration rare earths via coordination-induced ion imprinted electrospun membranes. J Membr Sci 2022, 658, 120759, https://doi.org/10.1016/j.memsci.2022.120759. [88] Chen L, Wang Y, Dai J, Meng M, Dai X, Pan J. Ligand confinement and pure aqueous medium synthesis of novel ion imprinted membranes for advanced rare earth separation. Appl Surf Sci 2022, 588, 152862, https://doi.org/10.1016/j.apsusc.2022.152862. [89] Huang S, Luo F, Lai X. Novel potentiometric sensors of ion imprinted polymers for specific binding of yttrium (III). Asian J Chem 2014, 26, 6787–6790. [90] Wu X. Molecular imprinting for anion recognition in aqueous media. Microchim Acta 2012, 176, 23–47. [91] Dong S, Sun Z, Lu Z. Chloride chemical sensor based on an organic conducting polypyrrole polymer. Analyst 1988, 113, 1525–1528. [92] Dong SJ, Che GL. An electrochemical microsensor for chloride. Talanta 1999, 38, 111–114. [93] Hutchins RS, Bachas LG. Nitrate-selective electrode developed by electrochemically mediated imprinting/doping of polypyrrole. Anal Chem 1995, 67, 1654–1660. [94] Ruiz-Gonzalez A, Huang J, Xun C, Chhabra R, Lee R, Yizhong H, et al. Ultrasensitive and miniaturized ion sensors using ionically imprinted nanostructured films. Appl Mat Today 2022, 29, 101600, https://doi.org/10.1016/j.apmt.2022.101600. [95] Xiao KP, Bühlmann P, Nishizawa S, Amemiya S, Umezawa Y. A chloride ion-selective solvent polymeric membrane electrode based on a hydrogen bond forming ionophore. Anal Chem 1997, 69, 1038–1044. [96] Essousi H, Barhoumi H, Bibani M, Ktari N, Wendler F, Al-Hamry A, et al. Ion-imprinted electrochemical sensor based on copper nanoparticles-polyaniline matrix for nitrate detection. J Sen 2019, 4257125, https://doi.org/10.1155/2019/4257125. [97] van Zijderveld SM, Gerrits WJJ, Apajalahti JA, Newbold JR, Dijkstra J, Leng RA, et al. Nitrate and sulfate: Effective alternative hydrogen sinks for mitigation of ruminal methane production in sheep. J Dairy Science 2010, 93, 5856–5866. [98] Daniel WL, Han MS, Lee JS, Mirkin CA. Colorimetric nitrite and nitrate detection with gold nanoparticle probes and kinetic end points. J Am Chem Soc 2009, 131, 6362–6363. [99] Liang J, Zheng Y, Liu Z. Nanowire-based Cu electrode as electrochemical sensor for detection of nitrate in water. Sens Actuators B Chem 2016, 232, 336–344. [100] Badea A, Amine A, Palleschi G, Moscone D, Volpe G, Curulli A. New electrochemical sensors for nitrites and nitrates. J Electroanal Chem 2001, 519, 66–72. [101] Alahi ME, Mukhopadhyay SC, Burkitt L. Imprinted polymer coated impedimetric nitrate sensor for real-time water quality monitoring. Sens Actuators B Chem 2018, 259, 753–761.

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[102] Liu Y, Hu D, Hu X, Chen S, Zhao L, Chen Y, et al. Preparation and characterization of chromium(VI) ion-imprinted composite membranes with a specifically designed functional monomer. Anal Lett 2020, 53, 1113–1139. [103] Zeng J, Dong Z, Zhang Z, Liu Y. Preparation of a surface-grafted imprinted ceramic membrane for selective separation of molybdate anion from water solutions. J Hazard Mater 2017, 333, 128–136. [104] Dong Z, Zeng J, Zhou H, Lv C, Ma Y, Zeng J. Selective removal of tungstate anions from aqueous solutions by surface anion-imprinted ceramic membranes. J Chem Technol Biotechnol 2019, 94, 942–954.

Chapter 9 Molecular imprinting and controlled drug delivery 9.1 Introduction A controlled delivery device is a system releasing a drug under controlled rate for a specific time. The administration can take place via different routes such as oral dosage, injection, implantation, and ocular and transdermal delivery. Controlled drug delivery technology allowed great expansion, owing to its advantages over conventional dosage forms comprising patient’s compliance, enhanced therapeutic response, and depressed toxicity, as it is particularly important for drugs requiring administration over prolonged time. From these viewpoints, the synergic action of different strategies exploiting the efficacy and the integration of biological and pharmaceutical sciences allowed achieving maximum therapeutic benefits of drugs undergoing controlled release. Another input came from the development of different biocompatible polymeric materials that allowed the production of polymer-based matrices and membrane-controlled systems (from macroscale to nanoscale) for obtaining the desired release rates [1–3]. Some of the most employed materials used for their preparation are modified polyacrylonitrile, polyethylene, poly(methylmethacrylate), poly(ether imide), polysiloxanes, and polyurethanes. Other materials are the natural polymers such as cellulose derivatives, chitosan, polycaprolactone, polylactide, and polyhyaluronic acid esters, which are designed to be degraded into the body and physiologically adsorbed by it after having fulfilled their tasks. Different mechanisms (diffusion, swelling erosion, osmosis, and solvation) that may also coexist control the drug delivery rate from all these systems. In addition, for improving the release efficiency, external stimuli are used. In fact, these intelligent tools are stimuli-responsive, thus regulating the drug transport and release in response to external signals such as variation of pH and temperature, and the presence of biological molecules (biomarkers) or electromagnetic fields [1, 3, 5–8]. The literature reports a large number of publications on controlled drug delivery systems (CDDSs), and over the time, more and more efficient devices were developed. A great contribution became also by the advent of the molecular imprinting technology and of the advancement and integration of membrane technology with molecular biology, chemistry, materials and pharmaceutical sciences, which have led to the production of imprinted polymers and membranes suitable for application as drug delivery tools. More in detail, the production of intelligent macromolecular networks endowing specific and selective recognition and transport properties (as the imprinted materials) allowed the production of molecularly imprinted polymer (MIP)based and molecularly imprinted membrane (MIM)-based delivery systems highly specific toward targeted drugs. In fact, their ability of selectively bind the “template https://doi.org/10.1515/9783110654691-010

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drug” increases its loading and residence time into the imprinted matrices resulting in a sustained release. Furthermore, in the case of chiral drugs, their enantioselective properties allow delivering only the pharmaceutically active enantiomeric form [9–11]. This chapter deals with the introduction of the controlled delivery science and with a short presentation of MIPs used in controlled drug release, while more attention is devoted to the production and application of MIM-based delivery systems, owing to their great potential, even if further efforts are needed for making them known to an ever-wider industrial audience.

9.2 A small look at controlled drug administration The controlled drug delivery technology finds great application in the pharmaceutical industry for ensuring good drug bioavailability, promoting the necessary therapeutic profile, and drastically reducing side effects typical of the traditional administration forms (e.g., injected solutions and tablets). An extremely interesting aspect is the possibility of maintaining the level of the drug in the therapeutic range, thus avoiding overdosing or underdosing of the drug. Other important benefits are the reduction of the administration amount and frequency, and the improvement of the patient’s compliance [1, 3, 12, 13]. Figure 9.1 shows the fluctuations of the drug concentration in plasma with traditional dosage forms [1].

Fig. 9.1: Plasma drug concentration versus time after administration of traditional single dose (a), multiple doses (b), and increased single dose (c) (reprinted from ref. [1]. Open access).

9.2 A small look at controlled drug administration

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In the case of single-dose administration, the drug concentration allows reaching a peak in a short time and then immediately decreases. Multiple dosages determine the drug-level fluctuations of the drug concentration in time, often with values below the minimum efficacy level and above the toxicity level. The administration of a single dose higher than that required leads to exceeding the level of toxicity [1]. Figure 9.2 shows the drug concentration in blood during the traditional administration and the controlled delivery approach.

Fig. 9.2: Behavior of blood drug concentration during traditional dosing and controlled delivery (reprinted from ref. [5]. Copyright 2008, with the permission of Elsevier).

It is evident that in the case of controlled delivery, the drug concentration remains constant in the entire therapeutic range (below the minimum toxic level and above the minimum effective level), whereas dangerous fluctuations take place in the other case. An important aspect to highlight is that efficient CDDSs does not present the burst effect, which consists in the release of a too high drug concentration in a short time with possible harmful effects for the patients [3, 12, 14]. Both polymer-based and membrane-based drug delivery systems exhibiting welldefined release profile represent good efficient tools alternative to the conventional dosage forms. For their preparation, natural and synthetic polymeric materials as well as their combination or incorporating nanoparticles for producing nanostructured release devices are employed. Some of them are chitosan, poly(lactic acid), sodium alginate, cellulose derivatives, poly(methacrylic acid) derivatives, polyacrylonitrile, polyethylene, poly(ethylenevinyl acetate), poly[(D,L-lactide-co-glycolide)-co-polyethylene glycopoly(methylmethacrylate)], poly(etherimide), poly(vinyl alcohol), polysiloxanes, polyurethanes, and so on. The different administration routes include oral dosage, injection, implantation, pulmonary, rectal delivery, transdermal delivery, and vaginal/intrauterine delivery [1, 6, 14–22]. The release from these polymeric matrices occurs via diffusion, erosion, osmosis, and solvation. According to the Fickian diffusion, the transport of a drug through a polymeric matrix is governed by a concentration gradient within the system. For maintaining the constant release rate, this gradient must be constant over the release time. This is possible by increasing the drug loading above its solubility limit. Erosion is typical of biodegradable materials; it entails the degradation of the polymer matrix endowing the drug owing to a selective breaking of some chemical bonds of the macromolecular network via chemical

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or enzymatic reactions. The degradation rate of the material is an important factor to consider. For example, a very rapid degradation allows to the burst effect. The osmosis release allows the drug transport by the action of an osmotic pump. The drug is contained in a nucleus surrounded by a semipermeable membrane provided with an exit hole. When the system meets an aqueous fluid, the water passes through the membrane at a constant rate, dissolves the core, and promotes the outflow of the drug through the pore at a constant rate. Solvation entails releasing the drug because of the swelling of the polymer after the absorption of the solvent (e.g., water or biological fluids) [6, 23, 24]. Other useful strategies for enhancing the release performance are the use of external stimuli such as chemical signals, the employment of magnetic field, and ultrasound [7, 25]. Since the middle of the last century, the controlled delivery science had a great development from macroscopic scale to nanoscale applications. Table 9.1 reports the advancement in the production of CDDSs including development perspectives until 2040 [1, 24–27]. Tab. 9.1: Evolution of drug delivery systems from 1950 to 2040.

Drug delivery system Size scale

Macroscale

Microscale and nanoscale

Nanoscale (targeted delivery)

Implants (e.g., subcutaneous or intramuscular)

Reservoir DDS (e.g., oral tablets, drug-eluting stents, and catheters) Injected matrix or monolith depots (e.g., degradable microparticles and phase separation) Early nanoparticles and PEGylation DDS (e.g., polymeric micelles and liposomes)

Injected nanocarrier DDS (e.g., PEGylated drugs, PEGylated liposomes, PEGylated polymeric micelles, and polymer–drug conjugates)

Second generation Smart delivery system (–)

Third generation Modulated delivery system (–)

Zero-order release Smart polymers and hydrogels

On–off insulin release Targeted delivery

Peptide and protein delivery

Long-term delivery system

Nanoparticles

In vitro and in vivo correlation

Inserts (e.g., vaginal and ophthalmic) Ingested DDS (e.g., osmotic pumps and hydrogels) Topical DDS (e.g., skin patches) Drug delivery system Technologies

First generation Basics of controlled release (–) Oral delivery Transdermal delivery Drug release mechanism

Reprinted from ref. [1]. Open access.

9.2 A small look at controlled drug administration

205

The evolutionary process of these systems was accompanied by an increase in the number of drugs released in a controlled way and in the routes of administration. Some objectives pursued by third-generation technologies are the long-term delivery of macromolecules, the targeted delivery of drugs to specific sites, and the selfregulated drug release, thus improving greater effectiveness and further reducing all the systemic undesired side effects [24–28]. Some class of drugs used in the formulation of drug delivery systems are antiinflammatory, antidiabetic, antifibrotic, antiproliferative, antithrombotic, antibiotics, and so on. The preparation of CDDSs entails the loading (via incorporation or adsorption) of the drug to administer. The performance of these tools is evaluated in vitro and in vivo release studies under proper conditions. The transport of drugs through and from the polymeric matrix depends on different factors like crystallinity and ramification degree of polymeric chains, swelling degree, and leaching [13]. In in-vitro studies, the composition of the release medium must keep in mind the proposed administration route of the system. It must reproduce the in vivo conditions of pH and temperature, and its volume must be at least three times higher than that required for obtaining a saturated drug solution [11, 29]. Other important factors to study are the drug loading, the biocompatibility, the chemical stability, and the mechanical resistance (for membranes) of the polymeric materials. It must be noted that any small change in the formulation affects the solubility of the drug in the delivery medium and its bioavailability. The percentage of drug released by any system is calculated according to the following equation [12]: Drug releaseð%Þ = ðMt =Mi Þ · 100

(9:1)

where Mi and Mt represent the initial drug amount and the amount of drug released at time t, respectively. The continuous growth of the membrane science, the scientific research, and the pharmaceutical and material sciences together with the microelectronic engineering allowed a rapid advancement of the controlled delivery technology. In this scenario, the application of different mathematical models (zero-order kinetics, first-order kinetics, Higuchi model, and Bhaskar and Korsmeyer-Peppas models) for characterizing the drug release from the delivery forms assumed a relevant importance in designing and evaluating the performance of these systems [30–32]. These mechanisms may also cohabit in a single delivery system. According to the zero-order kinetics, the release of a drug occurs by diffusion, in virtue of its infinite dose in the formulation. In this case, the amount of drug released increases directly proportional to the release time. The equation of the zero-order release model is Qt = Q0 + K0 t

(9:2)

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where Q0 and Qt are the initial amount of drug in the system and the amount of drug released at time t, respectively. K0 is the zero-order constant. The zero-order model defines the release of a therapeutic agent from matrix tablets and transdermal delivery tools [3, 12, 33]. The first-order kinetic model describes the release of water-soluble drugs [3, 12, 34]. It is expressed as follows: −logð1 − Mt =M∞ Þ = kt =2.303

(9:3)

where Mt is the drug amount delivered at time t, while M∞ is the drug amount released after infinite time; k is the release rate constant [3, 12, 34]. The Higuchi model refers to the release of a drug via diffusion from solid matrices (thin films via matrix tablets) containing water-soluble drugs [3, 34, 35]. It is described by the following equation: ðMt =M∞ Þ = kH t1=2

(9:4)

where kH represents the Higuchi dissolution constant. According to this equation, the drug delivery rate decreases in proportion to the square root of time. This model considers several assumptions: the initial drug concentration into the system is above its solubility limit, the diffusion takes place only in one direction, the diffusion is constant, the drug size is smaller than the release matrix thickness, and the swelling and the dissolution of the polymer matrix are insignificant [3, 34, 35]. The Korsmeyer-Peppas semiempirical model interprets the release from polymeric systems having different geometries (sheets, cylinders, spheres, disks, and polydisperse microspheres) [3, 12, 36, 37]. According to this model, between the fractional drug release and the release time, there is an exponential correlation. The equation describing this model is as follows: logðMt =M∞ Þ = log k + n log t

(9:5)

where k is the release constant endowing the geometry and the structure of the dosage form, and n is the diffusive exponent describing the drug release type. A value of n < 0.5 indicates a Fickian release similar to the Highuchi’s model; if n = 0.5 a pure diffusion-Fickian controlled drug release operates, while for 0.5 < n < 1, a combination of the erosion of the polymeric chains and of pure diffusion occurs (anomalous). Finally, when n = 1, the release is governed by the swelling-controlled drug release or by the erosion (non-Fickian) [3, 12, 36, 37]. The equation of the Bhaskar model, which describes the diffusion of a drug from resins and inorganic particles, is as follows [12, 38]: −logð1 − Mt =M∞ Þ = Bt0.65 where B is the kinetic constant.

(9:6)

9.2 A small look at controlled drug administration

207

Membranes applied in controlled-diffusion drug delivery tools exhibit high efficiency [39–47]. They may have a dense or a microporous structure and exist as reservoir or matrix systems. A reservoir system consists of a membrane that surrounds a central core containing the drug in a dispersed or suspended form. In the second case, the drug distribution arises uniformly into the entire polymeric matrix. For membrane-controlled diffusion release, the rate-limiting step is the diffusion of drug through the polymeric matrix in the presence of a dense structure or through the membrane pores in the case of a microporous structure [47]. The diffusion coefficient depends on the void volume existing between the polymer chains and on the pore size, respectively, as well as on the drug dimensions. The transport mechanism can be studied case by case by fitting the experimental data with the mathematical models. Semipermeable membranes used in prostheses for intravitreal delivery and eluting stents for intravascular therapy I glaucoma treatment allowed a prolonged drug diffusion of diclofenac sodium as a model drug [48]. Another example is the employment of membrane systems in the transdermal release of lipid-lowering agents [49], analgesics [3], and anti-inflammatory drugs [12]. The transdermal drug delivery (by means of patches, ointments, creams, etc.) allows to bypass the gastrointestinal tract, thus eluding both the degradation by the gastric acids and the first-pass drug metabolism in the liver, typical of the oral administering route. In addition, delivering drug through the skin permits to control the release rate continuously for an extended time [49–54]. Donato and coworkers developed mixed matrix membranes as potential patches for the transdermal delivery of the lipidlowering drug gemfibrozil for the treatment of dyslipidemia [49]. Flat-sheet membranes were prepared via the phase inversion embedding hydrophilic zeolite particles (NaX) into a polydimethylsiloxane polymeric matrix. Characterizations of these membranes evidenced the absence of erosion, low swelling degree, and moisture uptake. The presence of the zeolite fillers allowed modulating the release rate of gemfibrozil. Studies on percutaneous permeations through the stratum corneum of the ear rabbit skin (in a Franz diffusion cell) with membranes containing 12 wt% of zeolites and a drug-loading degree of 2.6 wt% revealed a constant release of gemfibrozil in time, allowing a linear kinetic profile fulfilling the zero-order model [49]. Polyacrylonitrile-based membranes as potential tools for pulsatile pump delivery of antibacterial and antifungal agents [55] and for the release of anticancer tamoxifen [56] have also been produced. As it is clear, there are many studies and applications in the controlled release sector. The common goal has become the production of highly innovative formulations for customized releases. A deeper discussion concerning the different formulation and mechanisms regulating the drug delivery (release studies) is beyond the scope of this chapter, which deals with the general features of these systems and with the application of MIT for improving their performance. Therefore, detailed information concerning their variety and the mathematical modeling describing the release kinetics can be found in the already cited literature.

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9.3 Molecular imprinting technology in drug delivery purposes MIT plays an important role in the development of systems equipped with specific receptors capable of modulating the rate of administration of a drug, especially in improving drug loading and release rate profile for the sustained release of therapeutic agents, as well as the enantioselectivity when administering chiral drugs [9, 10, 57–59]. Langer and Peppas [60] first highlighted the efficacy of combining polymeric materials with imprinting technology as an innovative strategy for CDDS development. However, for a long time, a small part of research interest was focalized on this topic, with an increased attention only in recent years. So, macromolecular polymeric networks (i.e., polymer and membranes) exhibiting specific selective (and enantioselective) recognition and transport properties were produced successfully for application in controlled drug delivery [57, 60–62]. This is because the employment of imprinted materials increases the control of the beneficial release dosage, and argues the smart release of a drug in response to external stimuli. Furthermore, it must be highlighted that the action of drugs commonly take place via a molecular recognition and therefore the MIT is useful for enhancing the loading capacity of the materials to the template drug, owing to the presence of localized specific recognition sites available for interacting with it properly by virtue of this mechanism [62–64]. Imprinted materials applied as CDDSs are mostly prepared via the noncovalent synthetic method. In particular, the production of increasingly smaller imprinted polymer particles leads to a reduction in the heterogeneity of the recognition sites typical of noncovalent imprinting, thus favoring the development of release systems with improved performance in terms of binding capacity and release control. In the case of covalent imprinting, the necessity of cleaving the chemical bonds between the recognition sites of the polymeric matrix and the template allows a slow drug binding and release kinetics [60, 65, 66]. In addition, the number of functional monomers suitable for this synthetic approach is restricted. The preparation of imprinted materials (both polymers and membranes) for delivery purposes entails the incorporation of the interested drug into the polymeric matrix or its adsorption via interaction with its complementary recognition sites of the polymeric matrix. The choice of the more appropriate functional monomer (acidic, neutral, or basic) to use depends on the physicochemical properties of the drug. This choice is also strategic for introducing stimulus responsiveness into the imprinted material for achieving a remote control of the system [60, 65, 66]. Figure 9.3 illustrates the stimuli-responsive release of a drug loaded on an imprinted matrix upon the application of specific release prompts [67]. An important factor affecting the drug delivery from imprinted matrices is the displacement of the drug from the recognition sites and its transport through the polymeric network. From this viewpoint, the binding, the release profile, and the selectivity are in strict relation with the availability and a fair stiffness degree of the recognition sites. More specifically, a trade-off between their flexibility and rigidity is required to achieve a rapid balance between loading and release of the template

9.3 Molecular imprinting technology in drug delivery purposes

209

Fig. 9.3: Stimuli-responsive drug release from an imprinted matrix after applying a specific external stimulus (reprinted from ref. [67]. Open access).

drug. Another aspect to consider is that sometimes the hydrophilic groups of comonomers used during the synthesis affect the swelling degree of the polymeric material and therefore the recognition efficiency and the release behavior [13]. For example, in developing paracetamol-poly(methacrylic acid)-imprinted particles, Puoci et al. used glycidyl methacrylate as prohydrophilic comonomer. The swelling of this MIP was much higher (40%) than that one observed in the case of MIP synthesized only with methacrylic acid (7%). Release studies performed in simulated gastric fluids revealed a release of 60% after 5 h with respect to the initial drug content, while the release from the corresponding nonimprinted polymer was about 90% [68]. Table 9.2 summarized some published reviews dealing with the application of imprinted polymeric materials in the controlled drug delivery. They refer to polymers used as such (as micro- and nanomaterials), incorporated into membranes or applied as thin layers on their surface. Tab. 9.2: Some published reviews on the application of imprinted materials in controlled delivery. Title

Year Reference

Advances in molecularly imprinted polymers as drug delivery systems



[]

Advances of molecularly imprinted polymers (MIP) and the application in drug delivery 

[]

Perspectives of molecularly imprinted polymer-based drug delivery systems in ocular therapy



[]

Molecular imprinting: a useful approach for drug delivery.



[]

Developments of smart drug-delivery systems based on magnetic molecularly imprinted polymers for targeted cancer therapy: a short review



[]

Perspectives of molecularly imprinted polymer-based drug delivery systems in cancer therapy



[]

Molecularly imprinted polymers based drug delivery devices: A way to application in modern pharmacotherapy. A review.



[]

210

Chapter 9 Molecular imprinting and controlled drug delivery

Tab. 9.2 (continued) Title

Year Reference

Molecularly imprinted polymers: novel discovery for drug delivery.



[]

Latest trends in molecular imprinted polymer based drug delivery systems



[]

Molecular imprinted polymers as drug delivery vehicles



[]

The use of molecularly imprinted polymers for dermal drug delivery



[]

Molecularly imprinted polymers in drug delivery: state of art and future perspectives.



[]

Mimicking biological delivery through feedback-controlled drug release systems based  on Molecular imprinting

[]



[]

Stimuli-responsive molecularly imprinted polymers for drug delivery

An example of the efficacy of MIT in the production of CDDSs for the sustainable release comes from the development of aminoglutethimide-poly(methacrylic acid) crowding-assisted imprinted polymer by means of the free-radical precipitation polymerization method [80]. As a crowding agent, PS was added to the pre-polymerization mixture. The release profile of MIP during in vitro release studies followed the zeroorder kinetics, while for the corresponding NIP, a rapid release occurred. The release times were 18 h and 10 h, respectively. Furthermore, in vivo studies on rats revealed that this system yielded a significantly high relative bioavailability (266.3%) with respect to commercial tablet, while in the case of NIP it was much lower (57%) [80]. The concentration of aminoglutethimide in plasma as a function of time for the different studied cases is shown in Fig. 9.4. For MIP1-PS, the maximum concentration level of aminoglutethimide was higher (263.2 ng · mL−1 ) with respect to NPI1-PS (178.8 ng · mL −1) and commercial tablet (57.0 ng · mL−1). Furthermore, in the case of imprinted formulation, the maximum concentration value was reached within 2 h, while in the case of nonimprinted polymer and commercial tablet, it was reached within 0.5 h. These results confirmed the suitability of MIT in producing MIPs as drug-controlled release vehicles [80]. Norell et al. [81] published the first paper dealing with the potential application of MIPs as sustained-release carriers. They used methacrylic acid as a functional monomer and the methyl xanthine theophylline as a model drug. Release studies performed in phosphate buffer at pH 7.0 have shown a slow decrease in the release rate when using MIP compared to the case of NIP [81]. Among the other various papers dealing with the development of MIPs for controlled delivery purposes, some of them can be found in the literature [81–91] and in reviews listed in Tab. 9.2, while the production and application of MIM-based controlled delivery systems is more deeply discussed in the next section.

9.4 MIMs in controlled drug delivery

211

Fig. 9.4: The plasma rats’ concentration profile of aminoglutethimide during release studies performed with the crowding-assisted MIP1-PS (molar ratio of template/functional monomer/cross-linker: 0.1/0.5/ 1.5), its corresponding nonimprinted polymer (NIP1-PS), and commercial tablet of aminoglutethimide (tablet AG) (reprinted from ref. [80]. Copyright 2015, with the permission of Elsevier).

9.4 MIMs in controlled drug delivery As already introduced, imprinted materials are useful for application in controlled drug delivery. However, until now little attention has been devoted to the MIM-based devices. Moreover, it is important to underline that the release systems based on imprinted membranes are more efficient and advantageous than MIPs, also considering the critical issues of drugs released from hydrophilic matrices [92]. This is because the loading capacity and mass transfer rate of MIPs are lower with respect to those exhibited by membranes. Therefore, the employment of MIPs for producing membranes allows exploiting the advantages of both imprinting and membrane technologies for achieving large-scale buildup and application of highly efficient CDDSs. A significant example of the potential of imprinted membranes in controlled delivery technology is the employment of electrospun nanofiber membranes. The formulation of nanofiber-based drug delivery systems is ad hoc performed for each specific drug to administer, considering the drug features, the drug loading, the release time, and the type of administration (i.e., oral, topical, transmucosal, and transdermal) for achieving the desired therapeutic effect [93–95]. In general, imprinted electrospun nanofiber membranes for controlled-release purposes are prepared via three different routes: – The entrapment of a presynthesized MIP into the nascent nanofibers by its addition to the electrospinning solution. – The direct addition (via dispersing or dissolution) of the template drug into the casting polymer solution containing a functional monomer (one or more) complementary to it.

212

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The surface imprinting via the synthesis of an MIP layer on the surface of nanofibers or surface immobilization of MIP particles previously synthesized.

The first method (see Fig. 9.5) is largely applied. It entails the use of MIP particles having size from nanometric to micrometric range, even if the challenge is the production of smaller and smaller-sized controlled nanoparticles for promoting their easy entrapping into the nanofibers and avoiding particle aggregation. Two important aspects of this method are the realization of a homogeneous MIP particles distribution into the nanofibers and the preservation of the recognition sites. From this viewpoint, the production of nanofiber membranes endowing MIPs (MIP-NFs) allows the exploitation of intrinsic properties of nanofibers (i.e., high surface area and mechanical resistance, and flexibility of surface features) and of the selective recognition effect of the imprinted process for enhancing more drug loading degree and better controlling its release rate [96–98].

Fig. 9.5: Scheme of the production of electrospun imprinted nanofibers by entrapping MIP particles (imprinted with the template drug) into the nascent nanofibers (reprinted from ref. [96]. Open access).

The second route is simpler but presents the problem of the complete template drug removal from the obtained nanofiber membranes. This problem is overcome by the third method [96–98]. The diameter of electrospun nanofibers ranges from tens of nanometers to up to micrometric size. Zaheidi et al. [99] produced polycaprolactone-based electrospun nanofibers endowing dexamethasone-imprinted poly(methacrylic acid) nanoparticles synthesized via the precipitation polymerization method. Dexamethasone is a synthetic glucocorticoid having an anti-inflammatory activity. Furthermore, its use involves the treatment of the primary immune thrombocytopenia and perioperative immunosuppression of cardiac replacement, for averting rejection and conserving the function of the implant function. It suffers a short half-life (about 2–5 h) in biological fluids and

9.4 MIMs in controlled drug delivery

213

drops dramatically its effectiveness when applied to natural organs of the human body. Therefore, the development of systems useful for promoting a sustainable release of this drug is a challenge. In this perspective, hybrid imprinted poly(caprolactone)/poly(methacrylic acid) nanofibers exhibited a sustainable release of dexamethasone over 4 days when tested in in-vitro release studies. More in detail, poly(ε-caprolactone) nanofibers containing MIP nanoparticles synthesized at monomer/template ratio of 6:1 released about 60% of the initial drug content in 4 days. On the other hand, poly (ε-caprolactone) nanofibers alone exhibited an initial burst release leading at 80% of released drug after 10 h. Finally, nanofibers containing nonimprinted polymer nanoparticles release about 70% of the initial drug content after 24 h. The release data of imprinted nanofibers fitted the Higuchi model [99]. Transmission electron microscopy analysis demonstrated the dispersion of dexamethasone-imprinted poly(methacrylic acid) nanoparticles along the length of nanofibers (see Fig. 9.6). MIP nanoparticles

(a)

600 nm

(b)

600 nm

Fig. 9.6: Transmission electron microscopic images of electrospun poly(ε-caprolactone) nanofibers (a) and dexamethasone-poly(caprolactone)/poly(methacrylic acid)-imprinted nanofibers (b) (reprinted from ref. [99]. Copyright 2017, with the permission of Springer Nature).

In another case, magnetic-imprinted polycaprolactone-based nanofibers having an average diameter of 857 ± 390 nm resulted in efficient sustained release of rosmarinic acid as a potential therapeutic agent in cancer and other disease treatments [100]. Magnetic properties were conferred by adding magnetite (iron(II and III) oxides) to the electrospinning solution containing also the dissolved template drug. Similar to other magnetic systems, rosmarinic acid-imprinted nanofibers were activated by an external magnetic field [100]. In vitro release studies evidenced an initial burst release followed by a slow release until reaching a plateau from both imprinted and control nanofibers. However, in the case of imprinted nanofibers, the burst release was less pronounced. Furthermore, after 6 h, they exhibited a lower cumulative release with respect to the controls (46% ± 3% and 73% ± 5%, respectively) [100] and reached the plateau after 10 h. These results mean that the imprinting process conferred to the nanofibers the capacity of retarding the delivery of rosmarinic acid in the release medium. Figure 9.7 shows the profile of the release of rosmarinic acid from the prepared membranes.

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Cumulative release (%)

90

A

80 70 60 50 40 30 20 10

1

0

Cumulative release (%)

60

2

3 4 Times (hr)

5

6

7

B

50 40 30 20 10 0 0

5

10

15

20

25

30

Times (hr) Fig. 9.7: Cumulative release profile of rosmarinic acid from magnetic control beaded nanofibers over a period of 6 h (A) and molecularly imprinted magnetic beaded nanofibers over a time of 24 h (B) (reprinted from ref. [100]. Open access).

The combination of controlling drug delivery nanofibers with biodegradable natural polymers is a good strategy for producing biodegradable release systems. For example, combining bacterial cellulose nanofibers with the natural polymer xanthan, Dima and coworkers developed diosgenin surface-imprinted membranes applied in controlled delivery of diosgenin, which has anticancer and anticholesterol functions [101]. The efficiency of imprinted bacterial cellulose nanofiber membranes in the controlled release of the antibiotic gentamycin was also demonstrated [102]. MIMs used in drug delivery are also prepared via phase inversion with tailored polymers having chemical complementarity to the template drug or endowing in the membrane matrix a presynthesized imprinted polymer as in the case of nanofibers. Interestingly, the fabrication of quercetin-imprinted bacterial cellulose flat-sheet membranes for achieving the sustained release of this bioactive compound entailed the exploitation of this technique [103]. The addition of the template molecules to the dope solution allowed creating the recognition sites directly into the bacterial cellulose matrix. Diffusion, swelling, and erosion were the mechanisms controlling the

9.4 MIMs in controlled drug delivery

215

quercetin release [103]. The cryogelation is another useful method for producing MIM-based controlled delivery tools [104]. MIMs are also intelligent enantioselective release systems. One example of their application is the transdermal delivery of S-propranolol, a beta-blocker used in the treatment of hypertension [105–108]. This enantiomeric form is 100–130 times more active than its opposite enantiomer R-propanolol. The release of S-propranolol was achieved with tailored enantioselective MIMs prepared by different methods. Suedee and coworkers [105] prepared a transdermal patch incorporating a chitosan gel formulation containing racemic propranolol into an S-propranolol-imprinted composite membrane obtained by copolymerizing the surface of cellulose membrane with a thin MIP layer of poly(methacrylic acid). In vivo release studies performed on the rat skin for 48 h revealed that MIM promoted the facilitated release of the template enantiomer. Furthermore, S-propranolol plasma concentration profile from patch was similar to that one from a gel formulation consisting only of S-propranolol applied on the skin. On the contrary, the release from the gel formulation alone containing racemic propranolol was not stereoselective. Confocal laser scan microscopy carried out with both enantiomeric forms of propranolol supported these results. Figure 9.8 shows the permeability profiles of R-propranolol and S-propranolol enantiomers released from the S-propranolol gel formulation and the patch formulation containing racemic propranolol [105]. Similar patches produced using poloxamer 407 (an amphiphilic block polymer) as drug reservoir instead of chitosan were not stereoselective and exhibited much lower release rate of both enantiomers (40% of the initial drug loading). These results demonstrated that the nature of the gel used as a drug reservoir in patch formulation has an active role in controlling the delivery of drug. In fact, the higher release observed with chitosan (60% of the initial loading degree) was due to the repulsive effect of positive charge of chitosan and propranolol. Yet, cellulose-based S-omeoprazole-imprinted membranes exhibited different release rates and enantioselective behavior in response to pH stimulus. More in detail, at pH simulating the gastric tract (1.2), no release was observed owing to the drug degradation, while at pH simulating the intestinal tract (6.8), the release amount of S-omeoprazole was higher than that of its opposite isomer, and increased more at pH 8.0. These results emphasize the possibility of developing a pH-responsive enantioselective-controlled delivery device for this drug [109]. All these studies confirm the potential of MIMs in drug delivery systems with controlled feedback. However, despite their great advantages, there are yet only few studies on their application in this field. Therefore, it is hopeful that in very near future they can receive the attention they deserve, especially for the possibility of realizing a sustained drug release with respect to polymeric scaffolds, which are often affected by the burst release and have less effectiveness.

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Fig. 9.8: Plasma concentration profile of propranolol enantiomers in rats following transdermal application of a gel formulation containing 0.75 mg of S-propranolol and an MIM-based patch containing 1.5 mg of racemic propranolol (adapted from ref. [105]. Copyright 2008, with the permission of Elsevier).

References [1] [2] [3] [4] [5]

[6] [7]

Adepu S, Ramakrishna S. Controlled drug delivery systems: Current status and future directions. Molecules 2021, 26, 5905, https://doi.org/10.3390/molecules26195905. Vigata M, Meinert C, Hutmacher DW, Bock N. Hydrogels as drug delivery systems: A review of current characterization and evaluation techniques. Pharmaceutics 2020, 12, 1–45. Donato L, Barbaro G, Drioli E, Algieri C. Controlled release of tramadol from mixed matrix membranes. J Memb Separ Technol 2012, 1, 137–144. Prabaharan M. Review paper: Chitosan derivatives as promising materials for controlled drug delivery. J Biomat Appl 2008, 23, 5–36. Stamatialis DF, Papenburg BJ, Girones M, Saiful S, Bettahalli SNM, Schmitmeier S, Wessling M. Medical applications of membranes: Drug delivery, artificial organs and tissue engineering. J Membr Sci 2008, 308, 1–34. Langer R. Polymer-controlled drug delivery systems. Acc Chem Res 1993, 26, 537–542. Zhang H, Jackson JK, Chiao M. Microfabricated drug delivery devices: Design, fabrication, and applications. Adv Funct Mater 2017, 27, 1703606, https://doi.org/10.1002/adfm.201703606.

References

[8] [9] [10] [11] [12] [13]

[14] [15]

[16]

[17] [18] [19] [20] [21] [22]

[23]

[24] [25] [26] [27]

217

Alvarez-Lorenzo C, Concheiro A. Smart drug delivery systems: From fundamentals to the clinic. Chem Commun 2014, 50, 7743–7765. Zaidi SA. Molecular imprinting: A useful approach for drug delivery. Mater Sci Energy Technol 2020, 3, 72–77. Hilt JZ, Byrne ME. Configurational biomimesis in drug delivery: Molecular imprinting of biologically significant molecules. Adv Drug Deliv Rev 2004, Sep 22, 56, 1599–1620. Oncel P, Cetin K, Topcu AA, Yavuz H, Denizli A. Molecularly imprinted cryogel membranes for mitomycin C delivery. J Biomater Sci Polym 2017, 6, 519–531. Algieri C, Drioli E, Donato L. Development of mixed matrix membranes for controlled release of ibuprofen. Appl Polym Sci 2013, 128, 754–760. Ruela ALM, Pereira GR. Design and evaluation of molecularly imprinted polymers as drug delivery systems. In: Tiwari A, Uzun L, eds. Advanced molecularly imprinting materials. Wiley-Scrivener, Beverly, 2017, 413–454. Huang X, Brazel CS. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J Control Release 2001, 73, 121–136. Piacentini E, Bazzarelli F, Poerio T, Albisa A, Irusta S, Mendoza G, Sebastian V, Giorno L. Encapsulation of water-soluble drugs in poly (vinyl alcohol) (PVA)-microparticles via membrane emulsification: Influence of process and formulation parameters on structural and functional properties. Mater Today Commun 2020, 24, 2020, 100967, https://doi.org/10.1016/j. mtcomm.2020.100967. Albisa A, Piacentini E, Sebastian V, Arruebo M, Santamaria J, Giorno L. Preparation of drug-loaded PLGA-PEG nanoparticles by membrane-assisted nanoprecipitation. Pharm Res 2017, 34, 2017, 1296–1308. Formoso P, Muzzalupo R, Tavano L, Nicoletta FP. Nanotechnology for the environment and medicine. Mini Rev Med Chem 2016, 16, 668–675. Valenta C, Auner BG. The use of polymers for dermal and transdermal delivery. Eur J Pharm Biopharm 2004, 58, 279–289. La Zara D, Sun F, Zhang F, Franek F, Sivars KB, Horndahl J, et al. Controlled pulmonary delivery of carrier-free budesonide dry powder by atomic layer deposition. ACS Nano 2021, 15, 4, 6684–6698. Purohit TJ, Hanning SM, Wu Z. Advances in rectal drug delivery systems. Pharm Dev Technol 2018, 23, 942–952. Ham AS, Rohan LC, Boczar A, Yang L, Buckheit KW, Buckheit RW Jr. Vaginal film drug delivery of the pyrimidinedione IQP-0528 for the prevention of HIV infection. Pharm Res 2012, 29, 1897–1907. Pacheco MS, Kano GE, Paulo LA, Lopes PS, de Moraes MA. Silk fibroin/chitosan/alginate multilayer membranes as a system for controlled drug release in wound healing. Int J Biol Macromol 2020, 152, 803–811. Peppas NA, Caldorera-Moore ME, Steichen SD. Historical survey of drug delivery devices. In: Liy S, Siegel RA, eds. Drug-device combination for chronic diseases. John Wiley & Sons, Inc, Hoboken, New Jersey, 2016, 39–65. Yun YH, Lee BK, Park K. Controlled drug delivery: Historical perspective for the next generation. J Control Release 2015, 219, 2–7. Coelho JF, Ferreira PC, Alves P, Cordeiro R, Fonseca AC, Góis JR, et al. Drug delivery systems: Advanced technologies potentially applicable in personalized treatments. EPMA J 2010, 1, 164–209. Timko BP, Kohane DS. Drug-delivery systems for tunable and localized drug release. Isr J Chem 2013, 53, 728–736. Guo MX. Dissolution testing: In vitro characterization of oral controlled release dosage forms. Wiley, Hoboken, NJ, USA, 2010.

218

Chapter 9 Molecular imprinting and controlled drug delivery

[28] Stevenson CL, Langer R. Development of combination product drug delivery systems. In: Liy S, Siegel RA, eds. Drug-device combination for chronic diseases. John Wiley & Sons, Inc, Hoboken, New Jersey, 2016, 66–87. [29] Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm 2010, 67, 217–223. [30] Janapareddi K, Jasti BR, Li X. Evolution of controlled drug delivery systems. In: Wang B, Hu L, Siahaan TJ, eds. Drug delivery: Principles and applications. 2nd ed. John Wiley & Sons, Inc., 2016, 336–352. [31] Peppas NA, Narasimhan B. Mathematical models in drug delivery: How modeling has shaped the way, we design new drug delivery systems. J Control Release 2014, 190, 75–81. [32] Siepmann J, Siepmann F. Mathematical modeling of drug delivery. Int J Pharm 2008, 364, 328–343. [33] Freitas MN, Marchetti JM. Nimesulide PLA microspheres as a potential sustained release system for the treatment of inflammatory diseases. Int J Pharm 2005, 295, 201–211. [34] Ruela ALM, Figueiredo EC, Pereira GR. Molecularly imprinted polymers as nicotine transdermal delivery systems. Chem Eng J 2014, 248, 1–8. [35] Higuchi TJ. Mechanism of sustained medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. Pharm Sci 1963, 84, 1464–1477. [36] Prasanthi NL, Manikiran SS, Rao RN. Effect of solubility of the drug on the release kinetics from hydrophilic matrices. Int J Pharm Tech Res 2010, 2, 2506–2511. [37] Peppas NA. Analysis of Fickian and non-Fickian drug release from polymers. Pharm Acta Helv 1985, 60, 110–111. [38] Shafiei SS, Solati-Hashjin M, Samadikuchaksaraei A, Kalantarineja R, Asadi-Eydivand M, Osman NAA. Epigallocatechin gallate/layered double hydroxide nanohybrids: Preparation, characterization, and in vitro anti-tumor study. Plos One 2015, 10, 0136530, https://doi.org/10.1371/journal.pone.0136530. [39] Tentor F, Siccardi G, Sacco P, Demarchi D, Marsich E, Almdal K, et al. Long lasting mucoadhesive membrane based on alginate and chitosan for intravaginal drug delivery. J Mater Sci: Mater Med 31 2020, 25, https://doi.org/10.1007/s10856-020-6359-y. [40] Feng Z, Zheng Y, Zhao L, Zhang Z, Sun Y, Qiao K, Xie Y, Wang Y, He W. An ultrasound-controllable release system based on waterborne polyurethane/chitosan membrane for implantable enhanced anticancer therapy. Mater Sci Eng C Mater Biol Appl 2019, 104, 109944, https://doi.org/10.1016/j. msec.2019.109944. [41] Hu S, Qin Z, Cheng M, Chen Y, Liu J, Zhang Y. Improved properties and drug delivery behaviors of electrospun cellulose acetate nanofibrous membranes by introducing carboxylated cellulose nanocrystals. Cellulose 2018, 25, 1883–1898. [42] López-Cebral R, Peng G, Reys LL, Silva SS, Oliveira JM, Chen J, et al. Dual delivery of hydrophilic and hydrophobic drugs from chitosan/diatomaceous earth composite membranes. J Mater Sci: Mater Med 29 2018, 21, https://doi.org/10.1007/s10856-018-6025-9. [43] Li JJ, Yang YY, Yu DG, Du Q, Yang XL. Fast dissolving drug delivery membrane based on the ultrathin shell of electrospun core-shell nanofibers. Eur J Pharm Sci 2018, 122, 195–204. [44] Hu X, Liu S, Zhou G, Huang Y, Xie Z, Jing X. Electrospinning of polymeric nanofibers for drug delivery applications. J Control Release 2014, 185, 12–21. [45] Mândru M, Costantin C, Vlad S, Butnaru M, Lebrun L, Popa M. Characteristics of polyurethanebased sustained release membranes for drug delivery. Cent Eur J Chem 2013, 11, 542–553. [46] Shaikh RP, Pillay V, Choonara YE, du Toit LC, Ndesendo VM, Bawa P, Cooppan S. A review of multiresponsive membranous systems for rate-modulated drug delivery. AAPS PharmSciTech 2010, 11, 441–459. [47] Mabrouk M, Rajendran R, Soliman IE, et al. Nanoparticles and nanoporous-membrane-mediated delivery of therapeutics. Pharmaceutics 2019, 11, 294, https://doi.org/10.3390/ pharmaceutics11060294.

References

219

[48] Wischke C, Neffe AT, Hanh BD, Kreiner CF, Sternberg K, Stachs O, et al. A multifunctional bilayered microstent as glaucoma drainage device. J Control Release 2013, 172, 1002–1010. [49] Donato L, Guzzo L, Drioli E, Algieri C. Mixed matrix membranes as potential transdermal devices for gemfibrozil release. J Appl Polym Sci 2015, 132, 1–8. [50] Ramadon D, McCrudden MTC, Courtenay AJ, Donnelly RF. Enhancement strategies for transdermal drug delivery systems: Current trends and applications. Drug Deliv Transl Res 2022, 12, 758–791. [51] Jeong WY, Kwon M, Choi HE, Kim KS. Recent advances in transdermal drug delivery systems: A review. Biomater Res 2021, 25, 24, https://doi.org/10.1186/s40824-021-00226-6. [52] Amit A, Shubhangi D, Ajazuddin, Giri TK, Saraf S, Saraf S, et al. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release 2012, 164, 26–40. [53] Palmer BC, DeLouise LA. Nanoparticle-enabled transdermal drug delivery systems for enhanced dose control and tissue targeting. Molecules 2016, 21, 1719, https://doi.org/10.3390/ molecules21121719. [54] Ruela ALM, Perissinato AG, Lino MES, Mudrik PS, Pereira GR. Evaluation of skin absorption of drugs from topical and transdermal formulations. Braz J Pharm Sci 2016, 52, 527–544. [55] Verma V, Balasubramanian K. Experimental and theoretical investigations of Lantana camara oil diffusion from polyacrylonitrile membrane for pulsatile drug delivery system. Mater Sci Eng 2014, 42, 292–300. [56] Nie HL, Ma ZH, Fan ZX, Branford-White CJ, Ning X, Zhu LM, et al. Polyacrylonitrile fibers efficiently loaded with tamoxifen citrate using wet-spinning from co-dissolving solution. Int J Pharm 2009, 21, 4–9. [57] Liu R, Poma A. Advances in molecularly imprinted polymers as drug delivery systems. Molecules 2021, 26, 3589, https://doi.org/10.3390/molecules26123589. [58] Braga MEM, Yanez F, Alvarez-Lorenzo C, Concheiro A, Duarte CMM, Gil MH, et al. Improved drug loading/release capacities of commercial contact lenses obtained by supercritical fluid assisted molecular imprinting methods. J Control Release 2010, 48, 102–104. [59] Suksuwan A, Lomlim L, Rungrotmongkol T, Nakpheng T, Dickert FL, Suedee R. J Appl Polym Sci 2015, 132, 41930, https://doi.org/10.1002/app.41930. [60] Langer R, Peppas NA. Advances in biomaterials, drug Delivery, and bionanotechnology. AIChE J 2003, 49, 2990–3006. [61] Brannon-Peppas L. Mimetic drug delivery systems for release with specific molecular triggers. Drug Deliv Technol 2009, 9, 30–37. [62] Alvarez-Lorenzo C, Concheiro A. Molecularly imprinted materials as advanced excipients for drug delivery systems. Biotechnol Annu Rev 2006, 12, 225–268. [63] Zaidi SA, Venkatesh S, Byrne ME, Peppas NA, Hilt JZ. Applications of biomimetic systems in drug delivery. Expert Opin Drug Deliv 2005, 2, 1085–1096. [64] Byrne ME, Hilt JZ, Peppas NA. Recognitive biomimetic networks with moiety imprinting for intelligent drug delivery. J Biomed Mat Res A 2008, 84, 137–147. [65] Da Silva MS, Casimiro T. High affinity polymers by molecular imprinting for drug delivery. In: De Souza Gomes A, eds. Polymerization. IntechOpen Publisher, London, UK, 2012, 145–162. [66] Prescott M, Battad J, Wilmann PG, Rossjohn J, Devenish RJ. Recent advances in all-protein chromophore technology. In: El-Gewely MR, eds. Biotechnology annual review. 1st ed. Elsevier, The Netherlands, 2006, 31–66. [67] Sanadgol N, Wackerlig J. Developments of smart drug-delivery systems based on magnetic molecularly imprinted polymers for targeted cancer therapy: A short review. Pharmaceutics 2020, 12, 831, https://doi.org/10.3390/pharmaceutics12090831. [68] Puoci F, Iemma F, Cirillo G, Curcio M, Parisi OI, Spizzirri UF, et al. New restricted access materials combined to molecularly imprinted polymers for selective recognition/release in water media. Eur Polym J 2009, 45, 1634–1640.

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[69] He S, Zhang L, Bai S, Yang H, Cui Z, Zhang X, et al. Advances of molecularly imprinted polymers (MIP) and the application in drug delivery. Eur Polym J 2021, 143, 110179, https://doi.org/10.1016/j. eurpolymj.2020.110179. [70] Bodoki AE, Iacob BC, Dinte E, Vostinaru O, Samoila O, Bodoki E. Perspectives of molecularly imprinted polymer-based drug delivery systems in ocular therapy. Polymers 2021, 13, 3649, https:// doi.org/10.3390/polym13213649. [71] Bodoki AE, Iacob BC, Bodoki E. Perspectives of molecularly imprinted polymer-based drug delivery systems in cancer therapy. Polymers 2019, 11, 2085, https://doi.org/10.3390/polym11122085. [72] Luliński P. Molecularly imprinted polymers-based drug delivery devices: A way to application in modern pharmacotherapy. A review. Mater Sci Eng C 2017, 76, 1344–1353. [73] Dhanashree S, Priyanka M, Manisha K, Vilasrao K. Molecularly imprinted polymers: Novel discovery for drug delivery. Curr Drug Deliv 2016, 13, 632–645. [74] Zaidi SA. Latest trends in molecular imprinted polymer-based drug delivery systems. RSC Advances 2016, 6, 88807–88819. [75] Zaid SA. Molecular imprinted polymers as drug delivery vehicles. Drug Deliv 2016, 23, 2262–2271. [76] Suedee R. The use of molecularly imprinted polymers for dermal drug delivery. Pharm Anal Acta 2013, 4, 264, https://doi.org/10.4172/2153-2435.1000264. [77] Puoci F, Cirillo G, Curcio M, Parisi OI, Iemma F, Picci N. Molecularly imprinted polymers in drug delivery: State of the art and future perspectives. Expert Opin Drug Deliv 2011, 8, 379–1393. [78] Kryscio DR, Peppas NA. Mimicking biological delivery through feedback-controlled drug release systems based on molecular imprinting. AIChE J 2009, 55, 1311–1324. [79] Puoci F, Iemma F, Picci N. Stimuli-responsive molecularly imprinted polymers for drug delivery: A review. Curr Drug Deliv 2008, 5, 85–96. [80] Tang L, Zhao CY, Wang XH, Li RS, Yang JR, Huang YP, et al. Macromolecular crowding of molecular imprinting: A facile pathway to produce drug delivery devices for zero-order sustained release. Int J Pharm 2015, 496, 822–833. [81] Norell MC, Andersson HS, Nicholls IA. Theophylline molecularly imprinted polymer dissociation kinetics: A novel sustained release drug dosage mechanism. J Mol Recognit 1998, 11, 98–102. [82] Park SY, Kim SY, Kang JH, Kim HS, Shin US. Design of thermoresponsive hydrogels by controlling the chemistry and imprinting of drug molecules within the hydrogel for enhanced loading and smart delivery of drugs. Mol Syst Des Eng 2021, 6, 286–292. [83] Li F, Lian Z, Song C, Ge C. Release of florfenicol in seawater using chitosan-based molecularly imprinted microspheres as drug carriers. Mar Pollut Bull 2021, 173, 113068, https://doi.org/10.1016/j. marpolbul.2021.113068. [84] Yan F, Liu Y, Han S, Zhao Q, Liu N. Bimatoprost imprinted silicone contact lens to treat glaucoma. AAPS PharmSciTech 2020, 21, 63, https://doi.org/10.1208/s12249-020-1622-1626. [85] Parisi OI, Ruffo M, Malivindi R, Vattimo AF, Pezzi V, Puoci F. 2020. Molecularly imprinted polymers (MIPs) as theranostic systems for sunitinib controlled release and self-monitoring in cancer therapy. Pharmaceutics 2020, 12, 41, https://doi.org/0.3390/pharmaceutics12010041. [86] Bai J, Zhang Y, Chen L, Yan H, Zhang C, Liu L, et al. Synthesis and characterization of paclitaxelimprinted microparticles for controlled release of an anticancer drug. Mat Sci Eng C 2018, 92, 338–348. [87] Liu XL, Yao HF, Chai MH, He W, Huang YP, Liu ZS. Green synthesis of carbon nanotubes-reinforced molecularly imprinted polymer composites for drug delivery of Fenbufen. AAPS PharmSciTech 2018, 19, 3895–3906. [88] Zhang K, Guan X, Qiu Y, Wang D, Zhang X, Zhang HA. pH/glutathione double responsive drug delivery system using molecular imprint technique for drug loading. Appl Surf Sci 2016, 389, 1208–1213.

References

221

[89] Ruela ALM, de Figueiredo EC, de Araújo MB, Carvalho FC, Pereira GR. Molecularly imprinted microparticles in lipid-based formulations for sustained release of donepezil. Eur J Pharm Sci 2016, 93, 114–122. [90] Lu XF, Shi YF, Lv HL, Fu YY, Ma D, Xue W. Preparation and characterization of molecularly imprinted poly(hydroxyethyl methacrylate) microspheres for sustained release of gatifloxacin. J Mat Sci Mat Med 2014, 25, 461–1469. [91] Allender CJ, Richardson C, Woodhouse B, Heard CM, Brain KR. Pharmaceutical applications for molecularly imprinted polymers. Int J Pharm 2000, 195, 39–43. [92] Maderuelo C, Zarzuelo A, Lanao JM. Critical factors in the release of drugs from sustained release hydrophilic matrices. J Control Release 2011, 154, 2–19. [93] Kajdiča S, Planinšeka O, Gašperlina M, Kocbek P. Electrospun nanofibers for customized drugdelivery systems. J Drug Deliv Sci Technol 2019, 51, 672–681. [94] Stoddard RJ, Steger AL, Blakney AK, Woodrow KA. In pursuit of functional electrospun materials for clinical applications in humans. Ther Deliv 2016, 7, 387–409. [95] Hu X, Liu S, Zhou G, Huang Y, Xie Z, Jing X. Electrospinning of polymeric nanofibers for drug delivery applications. J Control Release 2014, 185, 12–21. [96] Patel KD, Kim HW, Knowles JC, Poma A. Molecularly imprinted polymers and electrospinning: Manufacturing convergence for next-level applications. Adv Funct Mater 2020, 30, 2001955, https:// doi.org/10.1002/adfm.202001955. [97] Zaidi SA. Recent developments in molecularly imprinted polymer nanofibers and their applications. Anal Methods 2015, 7, 7406–7415. [98] Hunley M, Tong TE. Electrospinning functional nanoscale fibers: A perspective for the future. Polym Int 2008, 57, 385–389. [99] Zahedi P, Fallah-Darrehchi M, Nadoushan SA, Aeinehvand R, Bagheri L, Najafi M. Morphological, thermal and drug release studies of poly (methacrylic acid)-based molecularly imprinted polymer nanoparticles immobilized in electrospun poly (ε-caprolactone) nanofibers as dexamethasone delivery system. Korean J Chem Eng 2017, 34, 2110–2118. [100] Saad EM, El Gohary NA, El-Shenawy BM, Handoussa H, Klingner A, Elwi M, et al. Fabrication of magnetic molecularly imprinted beaded fibers for rosmarinic acid. Nanomaterials 2020, 10, 1478, doi:10.3390/nano10081478. [101] Dima SO, Dobre T, Stoica-Guzun A, Oancea F, Jinga SI, Nicolae CA. Molecularly imprinted biomembranes based on cellulose nano-fibers for drug release and selective separations. Macromol Symp 2016, 359, 124–128. [102] Tamahkar E, Bakhshpour M, Denizli A. Molecularly imprinted composite bacterial cellulose nanofibers for antibiotic release. J Biomat Sci Polym 2019, 30, 450–456. [103] Jantarat C, Attakitmongkol K, Nichsapa S, Sirathanarun P, Srivaro S. Molecularly imprinted bacterial cellulose for sustained-release delivery of quercetin. J Biomat Sci Polym Ed 2020, 31, 1961–1976. [104] Bakhshpour M, Yavuz H, Denizli A. Controlled release of mitomycin C from PHEMAH–Cu(II) cryogel membranes. Artif Cells Nanomed Biotechnol 2018, 46, 946–954. [105] Suedee R, Bodhibukkana C, Tangthong N, Amnuaikit C, Kaewnopparat S, Srichana T. Development of a reservoir-type transdermal enantioselective controlled delivery system for racemic propranolol using a molecularly imprinted polymer composite membrane. J Control Release 2008, 129, 170–178. [106] Jantarat C, Tangthong N, Songkro S, Martin JP, Suedee R. S-propranolol imprinted polymer nanoparticle-on-microsphere composite porous cellulose membrane for the enantioselectively controlled delivery of racemic propranolol. Int J Pharm 2008, 349, 212–225.

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Chapter 9 Molecular imprinting and controlled drug delivery

[107] Bodhibukkana C, Srichana T, Kaewnopparat S, Tangthong N, Bouking P, Martin GP, et al. Composite membrane of bacterially-derived cellulose and molecularly imprinted polymer for use as a transdermal enantioselective controlled-release system of racemic propranolol. J Control Release 2006, 113, 43–56. [108] Suedee R, Srichana T, Martin GP. Evaluation of matrices containing molecularly imprinted polymers in the enantioselective-controlled delivery of β -blockers. J Control Release 2000, 66, 135–147. [109] Suedee R, Jantarat C, Lindner W, Viernstein H, Songkro S, Srichana T. Development of a pHresponsive drug delivery system for enantioselective-controlled delivery of racemic drugs. J Control Release 2010, 142, 122–131.

Chapter 10 Cyclodextrins as recognition tools 10.1 Introduction Cyclodextrins (CDs) are macrocyclic compounds consisting of sugar units joined to form a cone shape exhibiting an inner hydrophobic cavity and an outer hydrophilic surface. On the basis of the number of monomeric units, they are distinguished as α-, β-, and γ-CDs containing six, seven, and eight units, respectively. The peculiar structure of CDs permits them to form inclusion complexes with guest molecules (or ions) and acting as molecular recognition elements [1–3]. In this context, their biocompatibility and biodegradability allow their applications in numerous fields both in native state and as CD derivatives. In addition, they are used as such or cross-linked to form polymers; they are employed as surface-functionalizing agents, or entrapped in membranes [2–5]. In particular, some fields of application are chromatographic separation, solid-phase extraction, membrane science, sensor technology, biotechnology, and drug delivery [2–8]. Interestingly, in the field of separations, the combination of the typical characteristics of CDs and of membrane processes allows producing advanced separation systems [5, 9]. The presence of an asymmetric center in the structure of CDs allows also their employment in chiral separations, enantioselective synthesis, and regioselective reactions [2, 3]. Moreover, the exploitation of CDs in the imprinting technology leads to produce MIPs, IIPs, MIMs, and IIMs, thus improving the separation effectiveness of similar ions and molecules. This is because the multiple interactions of CDs with guest molecules afford many recognition sites. Furthermore, the presence of hydroxyl functions ensures their good adaptability in aqueous environment. Also important is the possibility of replacing the hydroxyl groups with other chemical functions in order to modulate and better control the solubility, the application, and the recognition performance of these materials [6, 10]. This chapter deals with CDs as recognition elements. It also discusses their use in the development of CDbased membranes, in the production of imprinted polymers and imprinted membranes, as well as their applications.

10.2 Cyclodextrins as recognition elements CDs are macrocyclic oligosaccharides (obtained by enzymatic degradation of starch) consisting of six to eight D-glucopyranoside units linked to α-1,4. Their structure comprises a hydrophobic cavity surrounded by a hydrophilic outer surface. More precisely, they are rings having a thoroidal or truncated cone shape consisting of glucose units linked covalently by atoms of oxygen and kept fit through hydrogen bonds between secondary hydroxylic functions on the outer wall of the cone. This particular https://doi.org/10.1515/9783110654691-011

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organization confers them the ability of housing molecules and ions and form inclusion complexes through host–guest interactions such as hydrogen bonds, electrostatic interactions, and Van der Waals forces [1–4]. In addition, owing to the existence of many hydroxyl groups inside or outside, CDs are willing to add new functional groups, which can confer them new functionalities and features. Figure 10.1 shows their chemical and tridimensional structure.

Fig. 10.1: Chemical (a) and tridimensional (b) structure of cyclodextrins (reprinted from ref. [1]. Copyright 2018, with the permission of Springer Nature).

Owing to their high versatility, biocompatibility, and biodegradability, CDs find their applications in a wide variety of sectors. In this context, they are used in native state or as CD derivatives, as such or cross-linked for polymer synthesis, as coating or surfacefunctionalizing agents, as well as trapped in membranes to improve separation performance of chromatography, solid-phase extraction, membrane-based separation processes, and sensing systems [1, 2, 4, 11]. Furthermore, the presence of an asymmetric center in their structure permits to use CDs as chiral selectors in enantioselective synthesis, regioselective reactions and enantioseparation [2, 3]. Their application fields include biotechnology [7], food science [12], pharmacy, biology, cosmetics, and medicine [13], and remediation technologies [14–16]. CDs are also used in developing MIPs, MIMs, IIPs, and IIMs for achieving separations at molecular and ionic levels [5, 6, 10]. However, it is necessary to point out that CDs are also able to form noninclusion complexes. In fact, the hydroxyl groups of their external part can form hydrogen bonds with other molecules that make them capable of forming molecular structures with lipophilic compounds [1].

10.2 Cyclodextrins as recognition elements

225

Owing to their low cost and high suitability to form inclusion complexes with a widespread type of guests, the most used one in all application fields is β-CD [1–3]. Among the different applications, the possibility to form CD/drug complexes allows an improvement in drug bioavailability. Some papers reported the application of CDs as nanooral drug delivery systems and demonstrated their potential in promoting an intelligent passage of molecular drugs and biopharmaceuticals through the gastrointestinal tract [8, 17, 18]. The main advantage of these systems is their multifunctionality. In this context, they protect drugs from specific and nonspecific interactions in the physiological media. Furthermore, they enhance the drug permeability interacting with the biological membranes and modulate the rate and the site of the drug release [8, 19]. Various CD-based nanosystems, such as CD–self-assemblies, amphiphilic CD–nanosystems, CD–polymer conjugates, and CD-based nanosponges and nanofibers, have been developed for drug delivery purposes. For example, some studies have demonstrated that the drug CD–nanoassemblies enhance the aqueous solubility and the gastric permeability of drug [20, 21]. Instead, Unal et al. [22] demonstrated the capacity of amphiphilic CDs to load high drug amount through incorporating them into both the CD central cavity and their aliphatic chains. In addition, CD-based polymers with CDs adsorbed on the surface of nanoparticles or entrapped/incorporated within the polymer nanoparticles allow overcoming the problem of low drug loading of various polymeric nanoparticles [8, 18, 23]. Some examples of CD–polymer conjugates are CD–chitosan [24–26], CD–dextrans [27], and CD–methacrylates [28]. For example, chitosan/β-CD microspheres loaded with theophylline are useful for the pulmonary sustained delivery of this drug [25]. Cytotoxicity studies revealed a high theophylline loading and encapsulation efficiency. Interestingly, a CD-based delivery system allowed controlling the release rate of curcumin and vanillin [26]. The exogenous β-CD glycosyltransferase (β-CGTase) and the amyloglucosidase (AG) have been employed as congenerous substitutes of the endogenous maltase-glucoamylase secreted in the small intestine. During release studies in in-vitro-simulated small intestine, the enzymatic hydrolyzation of the β-CD–guest complexes promoted the release of curcumin and vanillin. In particular, the variation of βCGTase in the presence of an excess AG allowed modulating the guest release rates in the desired time destroying the limits of traditional enteric-coated tablets [26]. Recently, Haimhoffer et al. [29] investigated the carrier properties of solid-insoluble CD polymer of irregular shape (β-CDPIs), CD microbeads (β-CDPBs), and CD-based polymer microspheres in micro-sized controlled drug delivery systems. Results of these innovative studies confirmed the possibility of using insoluble CD matrix systems for oral drug delivery. Both carriers were capable of extracting curcumin and estradiol from aqueous solutions. In the case of curcumin, the loading efficiency ranged from 71.5% to 90.5% while that of estradiol ranged from 74.0% to 99.8%, indicating as the estradiol was almost completely complexed by βCDPIs. Additionally, dissolution experiments permitted to assess the presence of a prolonged release of estradiol from β-CDPBs [29]. β-CDs can find their application also in textile industry in the sectors of pretreatment, spinning, dyeing, finishing, and wastewater treatment [1, 30]. For example, CDs can be an alternative to surfactants in removing dyes used for coloring textile fibers [31–34]. Carpignano et al. [31] demonstrated the possibility of

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reducing the environmental impact of the exhausted baths of dyeing polyester fibers by employing β-CD as a substitute for the commercial synthetic surfactants ethofor RO 40, ethoxylated castor oil, and avolan IS [31]. The process allowed obtaining inclusion complexes of dye-β-CD without any other auxiliary additive. The presence of β-CD did not affect the dyeing efficiency. CDs are also helpful in removing organic micropollutants and heavy metals from dyeing wastewater as well as adsorbents for removing residual dyes [35–37]. In 2021, Saifi et al. [38] synthesized three β-CD inclusion complexes with the oil orange SS azo dye as a host molecule via the coprecipitation method and evaluated their application in water purification. Analytical investigations confirmed the encapsulation of the dye within the hydrophobic cavity of β-CD through hydrophobic–hydrophobic interaction. The formation of these complexes in industrial and lake water confirmed their purification. The employment of CDs and their derivatives in food science and human nutrition also gave important results, as it is the case of the complexation of cholesterol, toxins, and bioactive compounds [12, 39]. Figure 10.2 illustrates the most representative applications of CDbased materials in food science [39].

Fig. 10.2: The most representative current applications of CD-based materials in food science (reprinted from ref. [39]. Open access).

A recent industrial scale-up process developed by Alonso et al. [40] permitted to reduce cholesterol content in raw cow’s milk by a simple treatment with β-CD at 4 °C. The removal of the inclusion complexes of cholesterol-β-CD was realized with a centrifugal

10.3 Cyclodextrin-based membranes

227

separator. The entire proposed process allowed to remove 90% of the initial cholesterol content. The resulting cream was employed for the production of a low cholesterol butter [40]. Another example of recent application is the removal of cholesterol and for the first-time low-density lipoprotein (bad cholesterol) from solutions containing them with β-CD-modified poly(2-hydroxyethyl methacrylate-glycidyl methacrylate) grafted onto cellulose nanocrystals [41]. The novel adsorbent material permitted to remove about 99% of the initial content of compounds. Selectivity studies carried out using hydrocortisone and 17-β-estradiol as interfering compounds showed a higher adsorption of cholesterol accordingly. This was attributable to the hydrophobic nature of cholesterol over hydrocortisone and estradiol. However, authors reported that the achieved selectivity was not sufficient for the practical application of the proposed system that needs an improvement about this important aspect [41]. Differently insoluble β-CD beads resulted in the removal of mycotoxin alternariol from commercial red wine and tomato juice samples [42]. After an incubation time of 30 min with the imprinted beads in optimized conditions, the reduction in the mycotoxin content was about 50% and 85% of the initial value in tomato juice and red wine, respectively. This difference was due to the presence of fibers in tomato juice samples. However, the β-CD-based beads were not able to bind selectively the mycotoxin [42]. Other papers dealt with the application of CDs as complexing agents of flavonoids, resveratrol, and other bioactive compounds [43–46]. However, it is important to undertake more in-depth studies on their selective properties at the molecular and ionic levels by carrying out experimental studies on this aspect.

10.3 Cyclodextrin-based membranes Among the various CD-based adsorbent materials, membranes are tools combining the advantages of membrane science with the special features of CDs. Considering also the environmental friendliness of CDs and membrane processes, this integration resulted remarkably advantageous in various applications, exploiting the aptitude of CDs to form complexes, their inherent chirality, and enzyme-like behavior. In this context, the most important is their use for improving selectivity, permeability, and antifouling properties of membranes applied in water treatment and organic solvent nanofiltration for removing pollutants via adsorption and inclusion complexation [5, 9, 47]. For example, the employment of CDs allowed reducing membrane biofouling, which is an important parameter that negatively affects the membrane performance, as it is the case of the largely used cellulose acetate (CA) membranes, which are hydrophilic and require an accurate control of fouling. In this context, nanocomposite CA membranes, prepared via phase inversion and containing β-CD-stabilized silver nanoparticles, exhibited antibacterial activity and biofouling resistance [48]. After 12 h of incubation with Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213 cultures, almost 100% of the cells were inhibited. Furthermore, the presence of β-CD allowed preventing about

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90% of E. coli biofilm. In a different work [49], hydroxypropyl-beta-CD was used for removing biofoulants from the surface of RO membranes demonstrating their cleaning efficiency [49]. More recently, Xu et al. [50] immobilized the hydrophilic β-CD via crosslinking with GA on a PVDF membrane surface (premodified with PDA) and subsequently formed host–guest complexes with the bactericide enrofloxacin for reducing membrane biofouling. Dynamic biofouling experiments under cross-flow filtration proved the efficacy of the dual functionalization of the membrane, which exhibited higher water permeability, higher bacterial resistance, and lower protein adsorption in comparison with the pristine PVDF membrane. This behavior was due to the enhancement of the membrane hydrophilicity in the presence of β-CD and to the antibacterial action of the enrofloxacin complexed with the β-CD. The membrane containing 1.8% of β-CD exhibited an increase in the permeate flux of about 75.73%, while the reduction in BSA adsorption was 54.83%. Furthermore, the adhesion of bacterial cells used as membrane contaminants reduced to about 75% [50]. An increase in permeability was also achieved in the case of RO membranes prepared via interfacial copolymerization of βCD with m-phenylenediamine/trimesoyl chloride [51] as well as for thin-film composite membranes prepared through the integration of phase inversion with the interfacial polymerization using β-CD as monomer [52]. Furthermore, the use of β-CD as a coating layer for the surface of hydroxylated PVDF-based hollow fibers allowed obtaining nanofiltration composite membranes with enhanced permeate flux and antifouling properties [53]. The process involved the interfacial polymerization and the layer-by-layer method: firstly, a polyamide layer was synthesized for the PVDF membrane surface using polyethylenimine and isophthaloyl dichloride. Then, the composite membrane was modified with a β-CD coating layer, thanks to the chemical reaction between β-CD and the acyl chloride residues on the membrane surface (see Fig. 10.3).

Fig. 10.3: Schematic diagram of the preparation process of polyethylenimine/isophthaloyl dichloride/βCD/PVDF hollow-fiber composite NF membrane (reprinted from ref. [53]. Open access).

10.3 Cyclodextrin-based membranes

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Adams et al. [54] applied the phase-inversion technique for preparing blended polysulfone/β-CD-polyurethane membranes that resulted in efficient removal of cadmium from water. FT-IR analyses evidenced hydrogen bond interactions between polysulfone and β-CD-polyurethane, thus confirming their compatibility. The addition of the modifying agent to the pristine polysulfone determined an increase in water flux without affecting the membrane rejection. Membranes containing 5% and 8% of β-CDpolyurethane exhibited the best performance. For these membranes, the permeate fluxes were 342 L · m−2 · h−1 and 122 L · m−2 · h−1, respectively. The rejections were 70% and 65%, respectively. The permeate flux and the rejection observed in the case of the simple polysulfone membrane, prepared under the same conditions but without the addition of the modifying agent, were 12.93 L · m−2 · h−1 and 68%, respectively [54]. Polyester/polyamide-containing β-CD synthesized on a PES-supporting membrane exhibited an increase in the water flux of 68% with respect to its corresponding membrane prepared without β-CD [55]. Furthermore, in filtration experiments carried out with Na2 SO 4 /NaCl mixed solution, the membrane showed high rejection toward Na2SO4 (up to 95.8%) and lower rejection (1.1%) toward NaCl salts. This result indicates that the developed membrane is an efficient tool for divalent/monovalent anion separations. The synthetic process was the interfacial polymerization method, which involved the incorporation of β-CD into a mixture of piperazine (PIP) and bisphenol F, the subsequent immersion of the moistened membrane in a trimesoyl chloride solution, and the final heating step. Figure 10.4 shows the scheme of the process.

Fig. 10.4: Synthesis of the TFC NF membrane via IP of bisphenol F, PIP, β-CD, and trimesoyl chloride (reprinted from ref. [55]. Copyright 2019, with the permission of Elsevier).

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The application of the electrospinning is another strategy that permits to produce CD-based nanofibers highly efficient in water treatment. Some examples of application are the removal of dyes [56–59], heavy metals, and polycyclic aromatic hydrocarbons from water [60–62]. In the field of chiral separations, innovative nanocomposite membranes prepared with ethylenediamine-β-CD and graphene oxide (GO) exhibited high water permeability as well as excellent stability and enantioselective separation properties in the resolution of (DL)-tryptophan (Trp) (100% of ee) and (R,S)-propranolol (Prop) (75.34% of ee) [63]. This performance derived from the synergistic action of the CD and GO acted as a chiral selector and enhanced mechanical properties and membrane’s permeability, respectively. The modification of nafion membranes by cationic CD derivatives resulted in another efficient strategy for achieving good enantioselective separation properties. In this context, Gaálováa et al. [64] fabricated nafion117® membranes modified with three different cationic CD derivatives containing bis(methyl imidazolium) (MIM2) as a cationic anchor covalently bound to the CD unit with or without spacer. In pressuredriven separation experiments carried out in order to resolve the racemic tryptophan in water, all the membranes showed a preferential adsorption of the L-enantiomer, while the opposite isomer permeated faster than the membranes. The membranes modified in the presence of the spacer tetraethylene glycol and diethylene glycol exhibited the best performance. This was because their presence favored the interaction of CD–template enantiomer [64]. Recently, thin composite membranes produced by crosslinking CD nanofilm on a vermiculite layer allowed separating xylene isomers [65]. Other applications include the food sector and the sensor technology. As an example, Cassano et al. [66] synthesized polyacrylonitrile hollow-fiber membranes containing triacetyl-β-CD for the removal of pesticides imazalil, thiabendazole, and o-phenylphenol from citrus essential oils. Membranes were prepared via the dry–wet spinning technique. Morphological characterizations evidenced the presence of two layers consisting of finger-like macrovoids and an intermediate sponge-like structure. Filtration experiments carried out with lemon essential oil removed 49.7% of imalazil and 48.9% of thiabendazole in the permeate fraction, while the removal of o-phenylphenol and chlorpyrifos was not significant. In the case of treatment of orange essential oil, the removal of imalazil reached 53%, while that of o-phenylphenol was lower than 5%. The treatment of mandarine essential oil obtained similar results [66]. In a different work, Fontananova et al. [67] prepared polyether ether ketone membranes entrapping O-octyloxycarbonyl-β-CD via the diffusioninduced phase separation and applied them in the removal of the flavonoid naringin from aqueous solution. The presence of CD into the polymeric matrix improved its permeability and recognition performance. About sensor technology, a potentiometric sensor for the detection and recovery of the antiarrhythmic drug procainamide was fabricated by incorporating α-, β-, and γ-CD (as ionophers) into a polyvinyl chloride-based membrane matrix in the presence of dioctyl phthalate (DOP) or o-nitrophenyl octylether as plasticizer [68]. Detection studies with aqueous solutions showed a good sensor response in the pH range 4–8. At this interval, for the α-, β-, and γ-CD-based membranes, the linearities were

10.3 Cyclodextrin-based membranes

231

1 × 10−3 to 8.0 × 10−6 M, 1 × 10−3 to 7 × 10−6 M, and 1 × 10−3 to 8 × 10−6 M, while the low detection limits were 2.4 × 10−6 M, 2.12 × 10−6 M, and 2.4 × 10−6 M, respectively. Ionselective β-CD-based membrane electrodes are also efficient in determining midodrine hydrochloride in pharmaceutical formulations (tablets) and pure drug ingredients [69]. An important result was the determination of the intact drug in the presence of up to 10% of its degradation product and the selective detection in the presence of organic and inorganic interferents. The earlier discussed papers represent a part of the existing literature on CD-based membranes. Table 10.1 summarizes some other applications in the last decade [70–84]. Tab. 10.1: Some examples of application of CD-based membranes in the last decade. Membrane material

Preparation method

Membrane Application Type

Reference

Hydroxypropyl-β-CD-poly(etherblock-amide)/polysulfone

Dip coating and cross-linking reaction

Thin-film composite

Organic solvent nanofiltration

[]

β-CD/chitosan

Phase inversion

Thin-film composite

Protein adsorption

[]

β-CD/poly(-hydroxyethyl methacrylate-co-ethylene dimethylacrylate

Polymerizationinduced phase separation

Thin-film composite

Removal of steroid hormone

[]

β-CD/polyvinyl chloride

Phase inversion

Thin-film composite

Removal of ibuprofen and progesterone

[]

PA/amino-β-CD PA/diethylamino- Interfacial β-CD polymerization

Thin-film composite

Removal of MgSO and fouling-resistant

[]

Benzyl-β-CD/cellulose triacetate

Phase inversion

Thin-film composite

Separation of ethylenediamine from ammonia

[]

Polyethylenimine/α-, β-, and γCDs

Interfacial polymerization

Thin-film composite

Organic solvent nanofiltration

[]

β-CD-PVDF

Interfacial polymerization

Thin-film composite

Fouling-resistant

[]

β-CD-polyurethane

Phase inversion

Mixed matrix

Removal of humic acid

[]

β-CD-polycaprolactone

Electrospinning

nanofibers

Controlled release of naproxen

[]

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Chapter 10 Cyclodextrins as recognition tools

Tab. 10.1 (continued) Membrane material

Preparation method

Membrane Application Type

Reference

PA/amino-α- and β-CDs

Interfacial polymerization

Thin-film composite

Removal of NaCl

[]

α-, β-, and γ-CDs/polyethylene

Electrospinning

Nanofibers

Removal of phenanthrene

[]

α-, β-, and γ-CDs/poly(vinyl alcohol)

Coprecipitation and Nanofibers electrospinning

Inhibition of bacterial growth

[]

β-CD/chitosan/poly(vinyl alcohol) Electrospinning

Nanofibers

Control release of salicylic acid

[]

β-CD-polysulfone

Mixed matrix membrane

Removal of endocrine-disruptive chemicals

[]

Phase inversion

As it is evident, CD-based membranes find their applications in various processes and are prepared by means of different strategies. As cited earlier, an improvement in membrane performance in molecular and ionic separation processes could be useful by exploiting the characteristics of CDs in the development of both imprinted polymers and membranes. The following sections will discuss this latter aspect.

10.4 Cyclodextrins and imprinting technology The employment of CDs in the development of imprinted materials is effective in creating high-affinity recognition sites within their matrix or on their surface. This is because the multiple interactions of CDs with guest molecules afford many recognition sites, thus improving the imprinting efficacy. In addition, owing to the hydroxyl groups of CDs, these materials exhibit good adaptability in aqueous medium. Sometimes, the replacement of the hydroxyl groups of CDs by other chemical functions such as acryloyl, allyl, vinyl, and silyl allows to better control the solubility, the recognition performance, and the application field. All these features render the CD-based imprinted material promising for application in food and medical industry, as well as in other different sectors [6, 10]. Some authors discussed about the employment of CDs or their derivatives as functional monomers, ligands, and modifiers in developing imprinted polymers applied in different areas as selective separation tools [10, 85–87]. About these applications, the preparation of naringin-imprinted polymers using β-CD as a functional monomer allowed obtaining good recognition properties [88]. Polymers were prepared via solution polymerization and emulsion polymerization using two different cross-linkers (hexamethylene diisocyanate and epichlorohydrin). Experimental investigations demonstrated

10.4 Cyclodextrins and imprinting technology

233

that the produced polymers exhibited good recognition ability toward naringin and were selective with respect to the interfering similar compound dihydrochalcone. The better performance was exhibited by the polymer prepared via emulsion polymerization with hexamethylene diisocyanate as a cross-linker, which had the larger average pore diameter. This result confirmed the key role played by the polymer porosity in the recognition performance. The maximum observed binding capacity toward the template was 50.13 μmol · g−1, while the selectivity factor template/homologue was 1.53 [88]. Lysozyme-imprinted silica beads synthesized using acryloyl-β-CD as functional monomer, in the presence of acrylamide as an assistant monomer, reulted capable of selectively recognizing lysozyme. More in detail, a column packed with the imprinted beads separated the enzyme from avidin, bovine serum albumin, cytochrome c, and methylated bovine serum albumin [89]. Later, a forchlorfenuron-imprinted polymer synthesized using β-CD as the monomer (in the presence of 1,6-hexamethylene diisocyanate as the cross-linking agent) allowed to detect and efficiently remove forchlorfenuron from both ethanol solution and real spiked fruit samples [90]. Forchlorfenuron is a cytokinin used for stimulating the growth of vegetables and fruits. The specific recognition of the imprinted polymer toward the template was due to the synergistic effect of inclusion interactions promoted by the cross-linker and hydrophobic interactions of the inner cavity of β-CD. Figure 10.5a shows these interactions, while Fig. 10.5b shows the binding capacity exhibited by the MIP and its corresponding NIP toward the template and its structural analogues paclobutrazol, thidiazuron, and 2,4-dichlorophenoxyacetic acid.

Fig. 10.5: Schematic demonstration of molecular imprinting and rebinding of forchlorfenuron (a) and binding capacities for forchlorfenuron and other analogues exhibited by forchlorfenuron-β-CD-imprinted polymer in ethanol solution. The concentration of the analyte was 1.0 × 10−3 mol · L−1 (reprinted from ref. [90] Copyright 2017, with the permission of Springer Nature).

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Chapter 10 Cyclodextrins as recognition tools

As it is evident in Fig. 10.5a, authors speculated that one template molecule interacted with two β-CDs. In addition, in Fig. 10.5b the high binding capacity exhibited by MIP toward forchlorfenuron with respect to NIP and other analytes is evident. In strawberry samples added with 0.05, 0.1, and 0.5 mg · kg−1 of forchlorfenuron, its removal was 90.3%, 84.5%, and 90.8%, respectively. Another example is the recent development of α-CD (α-CD)-based imprinted polymer for the selective removal of the endocrine-disrupting dibutyl phthalate (DBP) from water [91]. Authors used the cross-linker tetrafluoroterephthalonitrile in the presence of α-CD monomer and the template for synthesizing a porous polymeric network of αCD capable of capturing DBP via the formation of host–guest complexes. The imprinting factor (2.6) was higher than the one exhibited by other MIPs reported in the literature [91]. The application of the DBP-α-CD-MIP on lake and tap water allowed removing about 90% and 91% of the compound, respectively. Differently, an imprinted electrochemical sensor based on a thin film of β-CD aldehyde and prepared through the surface imprinting strategy was capable of detecting the carcinogen ethyl carbamate (used as a template in the synthetic process) in Chinese yellow wines in a selective manner [92]. The recognition process entailed two different steps: the fast combination of the imprinted sites of the membrane with the template followed by the rearrangement of template molecules on the electrode surface and its physical adsorption. The performance of the sensor was similar to that of the traditional more expensive gas chromatography-spectrometry method. The low detection limit was 5.86 µg · L−1. Instead, the employment of bismethacryloyl-β-CD and methacrylic acid as double functional monomers permitted the synthesis of a glycyrrhizic acid-imprinted polymer [93]. The novel fabricated MIP showed a high recognition performance in the solid-phase extraction of glycyrrhizic acid from liquorice roots in aqueous media. The imprinting factor was 3.77, while the adsorption capacity was 69.3 mg · g−1. Other examples of MIPs based on CDs (and their derivatives) applied in extraction and separation processes are listed in Tab. 10.2 [94–110]. Tab. 10.2: Examples of MIPs based on CDs in extraction and separation processes. Template

Functional monomer

Binding capacity (mg · g−)

Fenthion

β-CD

.

.–.

[]

Carbendazim

β-CD

.

.–.

[]

 β-Estradiol

Acryloyl chloride-modified β-CD

.

–

[]

Benzimidazole

Acryloyl-β-CD and methacrylic acid with silanized multiwalled carbon nanotubes

. × −

.–.

[]

Recovery rate (%)

Reference

10.4 Cyclodextrins and imprinting technology

235

Tab. 10.2 (continued) Template

Functional monomer

Copper(II)

β-CD/maleic anhydride

Triclosan

N-Alkenyl-β-CDs/methacrylate

-Aminopyridine

Maleic anhydride-β-CD and methacrylic acid

Cadmium(II)

β-CD/acrylamide

Cytochrome c

Binding capacity (mg · g−)

Recovery rate (%)

. .

Reference

[] .–

[]

.

[]



[]

Vinyl-β-CD

.

[]

Bisphenol A

-Vinylpyridine and silanized β-CD

.

.

[]

Clenbuterol hydrochloride

Allyl-β-CD/methacrylic acid

.

.

[]

Kelthane Pyridaben

Methyl methacrylate Methyl methacrylate

 

.–. .–.

[]

Remazol red

Acrylamide

.

.

[]

Deltamethrin

Bis(--O-butanediacid monoester)-β-CD

.–.

[]

Thorium(IV)

Acryloyl-β-CD

.

.

[]

Bilirubin

β-CD

.

.

[]

Creatinine

Methacrylic acid-β-CD

.

[]

In the field of drug delivery, Trotta et al. [111] developed CD-based nanosponges for the controlled delivery of L-DOPA. For this purpose, authors cross-linked β-CD with 1,1ʹ-carbonyldiimidazole. Another example is the employment of β-CD as a functional monomer for producing an MIP capable of delivering the medicinal ingredient aesculin in a controlled manner [112]. Other examples are the pH-responsive release of the alkaloid and anticholinergic atropine [113] and the delayed release of the strong bactericide allyl isothiocyanate [114] for food preservation. The development of imprinted membranes containing CDs as recognition elements have also proven to be a useful strategy for improving membrane separation efficiency at molecular and ionic levels. The field of application ranges from sensor technology to membrane separation processes in numerous areas. In 2016, Cheng and Dong [115] fabricated a fluorescent sensor employing quinoline-modified vinyl-β-CD and acrylamide as monomers for the selective recognition of spermidine in complex samples. Figure 10.6a shows the chemical structure of the template and of its similar compounds, while Fig. 10.6b shows the fluorescent sensitivity of both the imprinted and nonimprinted sensor toward spermidine and the interfering analytes.

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Chapter 10 Cyclodextrins as recognition tools

Fig. 10.6: Chemical structure of spermidine and its similar compounds (a) and fluorescent sensitivity of imprinted and nonimprinted sensors toward them (b) (reprinted from ref. [115]. Copyright 2016, with the permission of the Royal Society of Chemistry).

The interactions of membrane template involved both the occurrence of hydrogen bonding and the formation of inclusion complexes. The imprinting factor was 3.87, while the detection linearity range of the imprinted sensor was from 5 × 10−7 to 1 × 10−4 mol · L−1. Later, magnetic microspheres modified with 6-mercapto-β-CD were employed as a carrier in developing cinchonine-imprinted membranes, which were applied for detecting the chiral cinchonine in serum samples [116]. The detection occurred, thanks to an increase in the electrochemiluminescence intensity upon the interaction of membrane– template molecules. The concentration of the detected cinchonine was from 1 × 10−10 to 4 × 10−7 mol · L−1. The removal rate of the alkaloid from the samples was in the range of 98.2–107.6%. Another example is the determination of the anticancer drug mitoxantrone with MIP film fabricated through the electrochemical polymerization of β-CD on the surface of a glassy carbon electrode [117]. Tests were carried out on pharmaceutical formulations and spiked urine samples. The proposed method was one-step preparation. Upon binding, cyclic voltammetry scans without using any solvent permitted an ease template removal from the film. Shin and Shin [118] employed acryl β-CD and acrylamide as bifunctional monomers for producing an imprinted hydrogel membrane capable of selectively recognizing bisphenol A via the color-change response mechanism. For this purpose, the synthesis of blue polydiacetylene through UV photopolymerization on both membrane surfaces was carried out in order to confer them a blue color. The presence of template molecules interacting with the membrane determined a color change from blue to red. This change was due to the membrane contraction after the interaction with the template molecules during the rebinding process. The intensity of red increased with the increase in the amount of bisphenol A bounded by the membrane. Figure 10.7a illustrates the proposed color change mechanism, while Fig. 10.7b shows the color change of the imprinted membrane in the presence of different concentrations of bisphenol A. Finally, Fig. 10.7c shows the color of the nonimprinted membrane in the presence of 50 mM of bisphenol A with respect to the control membrane [118].

10.4 Cyclodextrins and imprinting technology

237

Fig. 10.7: Change color mechanism of CD-based bisphenol A (BPA)-imprinted hydrogel membrane (a). Color change of the imprinted membrane in the presence of different concentrations of BPA (b) and color of the nonimprinted membrane in the presence of 50 mM BPA (c) (reprinted from ref. [118]. Copyright 2019, with the permission of Springer Nature).

The lower detection limit of BPA was 0.1 mM, while the imprinting factor was 6.68. About the selective separations, recent enoxacin-imprinted membranes fabricated via grafting of β-CD on the surface of modified PVDF support membrane exhibited high binding capacity (21.25 mg · g−1) toward this antibiotic and were able to selectively separate it from the environmental sewage [119]. The recognition sites were created via the sol–gel surface imprinting using 3-aminopropyltriethoxysilane as the functional monomer and tetraethoxysilane as the cross-linker. The presence of β-CD conferred antifouling properties to the membrane, thus improving its performance. Ciprofloxacin-imprinted membranes containing β-CD exhibited antifouling properties, high stability, and retarded permeation separation mechanism, allowing a facile permeation of competing similar compounds than the template [120]. From this last viewpoint, the permselectivity factors of norfloxacin/ciprofloxacin, enrofloxacin/ciprofloxacin, and ofloxacin/ciprofloxacin were 1.57, 1.68, and 1.83, respectively [120]. A composite MIM consisting of a thin hydrophilic layer of glycidyl-methacrylate-β-CD and a support membrane of polyethersulfone was prepared through the grafting-from method using di(2-ethylhexyl)phthalate as the template molecule [121]. The presence of hydrophilic and hydrophobic components of glycidyl-methacrylate-β-CD ensured an improvement of membrane hydrophilicity and of recognition performance via hydrophobic interactions with the internal hydrophobic cavity of β-CD. Filtration experiments demonstrated the existence of a retarded permeation separation mechanism.

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As it is evident, the publications dealing with imprinted membranes containing CDs are still few. However, considering their special properties and the high potential of imprinting and membrane technologies, an increase in the production of CD-based IMs in the near future is expected.

References [1] [2]

[3]

[4] [5] [6] [7] [8] [9]

[10]

[11]

[12] [13] [14] [15] [16] [17]

Crini G, Fourmentin S, Fenyvesi E, Torri G, Fourmentin M, Morin‑Crini N. Cyclodextrins, from molecules to applications. Environ Chem Lett 2018, 16, 1361–1375. Donato L, Mazzei R, Algieri C, Piacentini E, Poerio T, Giorno L, Gugliuzza A, eds. Smart membranes and sensors: Synthesis, characterization, and applications. 1st ed. Scrivener Publishing, Beverly Ma. Wiley, 2014, 281–282. Fontananova E, Di P, Curcio E, Giorno L, Drioli E. Functionalization of polymeric membranes by impregnation and in situ cross-linking of a PDMS/β-cyclodextrin network. J Incl Phenom Macrocycl Chem 2007, 57, 537–543. Przybyla MA, Ylmaz G, Becer R. Natural cyclodextrins and their derivatives for polymer synthesis. Polym Chem 2020, 11, 7582–7602. Trotta F. Cyclodextrin in membranes. In Drioli E, Giorno L, eds. Encyclopaedia of membranes. Springer, Berlin, Heidelberg, 2016, https://doi.org/10.1007/978-3-662-44324-8_2044. Gentili A. Cyclodextrin-based sorbents for solid phase extraction. J Chromatogr A 2020, 1609, 460654, https://doi.org/10.1016/j.chroma.2019.460654. Singh M, Sharma R, Banerjee UC. Biotechnological applications of cyclodextrins. Biotechnol ADV 2022, 20, 341–359. Adeoye O, Cabrel-Marques K. Cyclodextrin nanosystems in oral drug delivery: A mini review. Int J Pharm 2017, 531, 521–531. Chabalala MB, Seshabela BC, Hulle SWV, Mamba BB, Mhlanga SD, Nxumalo EN. Cyclodextrin-based nanofibers and membranes: Fabrication, properties and applications. In Arora P, Dhingra N, eds. Cyclodextrin. A versatile ingredient. IntechOpen, 2018, https://doi.org/10.5772/intechopen.74737. Zhao X, Wang Y, Zhang P, Lu Z, Xiao Y. Recent advances of molecularly imprinted polymers based on cyclodextrin. Macromol Rapid Commun 2021, 42, 2100004, https://doi.org/10.1002/ marc.202100004. Tchoffo R, Ngassa GBP, Doungmo G, Kamdem AT, Tonlé IK. Surface functionalization of natural hydroxyapatite by polymerization of β-cyclodextrin: Application as electrode material for the electrochemical detection of Pb (II). Environ Sci Pollut Res 29, 2022, 222–235. Fenyvesi É, Vikmon M, Szente L. Cyclodextrins in food technology and human nutrition: Benefits and limitations. Crit Rev Food Sci Nutr 2016, 56, 1981–2004. Crini G, Aleya L. Cyclodextrin applications in pharmacy, biology, medicine, and environment. Environ Sci Pollut Res 2022, 29, 167–170. Yadav M, Thakore S, Jadeja R. A review on remediation technologies using functionalized cyclodextrin. Environ Sci Pollut Res 2022, 29, 236–250. Fenyvesi É, Sohajda T. Cyclodextrin-enabled green environmental biotechnologies. Environ Sci Pollut Res 2022, 29, 20085–20097. Alsbaiee A, Smith BJ, Xiao L, Ling YH, Helbling DE, Dichtel WR. (2016) Rapid removal of organic micropollutants from water by a porous β-cyclodextrin polymer. Nature 2016, 529, 190–194. Real DA, Bolaños K, Priotti J, Yutronic N, Kogan MJ, Sierpe R, et al. Cyclodextrin-modified nanomaterials for drug delivery: Classification and advances in controlled release and bioavailability. Pharmaceutics 2021, 13, 2131, https://doi.org/10.3390/pharmaceutics13122131.

References

[18] [19]

[20] [21] [22]

[23] [24]

[25]

[26] [27] [28] [29]

[30]

[31] [32] [33]

[34] [35]

[36] [37]

239

Zhang J, Ma PX. Cyclodextrin-based supramolecular systems for drug delivery: Recent progress and future perspective. Adv Drug Deliv Rev 2013, 65, 1215–1233. Haimhoffer Á, Rusznyák A, Réti-Nagy K, Vasvári G, Váradi J, Vecsernyés M, et al. Cyclodextrins in drug delivery systems and their effects on biological barriers. Sci Pharm 2019, 87, 33, https://doi. org/10.3390/scipharm87040033. Ryzhakov A, Thi TD, Stappaerts J, Bertoletti L, Kimpe K, Sá Couto AR, et al. Self-assembly of cyclodextrins and their complexes in aqueous solutions. J Pharm Sci 2016, 30, 1–14. Jansook P, Kurkov SV, Loftsson T. Cyclodextrins as solubilizers: Formation of complex aggregates. J Pharm Sci 2010, 99, 719–729. Unal H, D’Angelo I, Pagano E, Borrelli F, Izzo A, Ungaro F, et al. Core–shell hybrid nanocapsules for oral delivery of camptothecin: Formulation development, in vitro and in vivo evaluation. J Nanopart Res 2015, 17, 42, https://doi.org/10.1007/s11051-014-2838–8. Gref R, Duchêne D. Cyclodextrins as “smart” components of polymer nanoparticles. J Drug Deliv Sci Technol 2012, 22, 223–233. Trapani A, Lopedota A, Franco M, Cioffi N, Leva E, Garcia-Fuentes M, et al. A comparative study of chitosan and chitosan/cyclodextrin nanoparticles as potential carriers for the oral delivery of small peptides. Eur J Pharm Biopharm 2010, 75, 26–32. Zhang WF, Zhou HY, Chen XG, Thang SH, Zhang JJ. Biocompatibility study of theophylline/chitosan/ β-cyclodextrin microspheres as pulmonary delivery carriers. J Mater Sci: Mater Med 2009, 20, 1331–1330. Zheng D, Xia L, Ji H, Jin Z, Bai Y. A Cyclodextrin-based controlled release system in the simulation of in vitro small Intestine. Molecules 2020, 25, 1212, https://doi.org/10.3390/molecules25051212. Amiel C, Wintgens V, Nielsen TT, Larsen KL. Tailorable polymeric assemblies based on host/guest interactions between modified dextrans. Macromol Symp 2012, 317–318, 75–81. Kettel MJ, Schaefer K, Pich A, Moeller M. Functional PMMA nanogels by cross-linking with cyclodextrin methacrylate. Polymer 2016, 86, 176–188. Haimhoffer Á, Vas A, Árvai G, Fenyvesi É, Jicsinszky L, Budai I, et al. Investigation of the drug carrier properties of insoluble cyclodextrin polymer microspheres. Biomolecules 2022, 12, 931, https://doi. org/10.3390/biom12070931. Bezerra FM, Lis MJ, Firmino HB, Da Silva JGD. de Cassia Siqueira Curto Valle R, Borges Valle JA. et al. The role of β-cyclodextrin in the textile industry. Rev Mol 2020, 25, 3624, https://doi.org/10.3390/ molecules25163624. Carpignano R, Parlati S, Piccinini P, Savarino P, Giorgi MRD, Fochi R. Use of β-cyclodextrin in the dyeing of polyester with low environmental impact. Color Technol 2010, 126, 201–208. Cireli A, Yurdakul B. Application of cyclodextrin to the textile dyeing and washing processes. J Appl Polym Sci 2006, 100, 208–218. Kacem I, Laurent T, Blanchemain N, Neut C, Chai F, Haulon S, et al. Dying and antibacterial activation with methylene blue of a cyclodextrin modified polyester vascular graft. J Biomed Mater Res Part A 2014, 102, 2942–2951. Dardeer HM, El-sisi AA, Emam AA, Hilal NM. Synthesis, application of a novel azo dye and its inclusion complex with β-cyclodextrin onto polyester fabric. Int J Text Sci 2017, 6, 79–87. Hu X, Hu Y, Xu G, Li M, Zhu Y, Jiang L, et al. A green synthesis of a magnetic β-cyclodextrin polymer for rapid removal of organic micro-pollutants and heavy metals from dyeing wastewater. Environ Res 2020, 180, 108796, https://doi.org/10.1016/j.envres2019108796. Xu MY, Jiang HL, Xie ZW, Li ZT, Xu D, He FA. Highly efficient selective adsorption of anionic dyes by modified β-cyclodextrin polymers. J Taiwan Inst Chem Eng. 2020, 108, 114–128. Zhou Y, Hu Y, Huang W, Cheng G, Cui C, Lu J. A novel amphoteric β-cyclodextrin-based adsorbent for simultaneous removal of cationic/anionic dyes and bisphenol A. Chem Eng J 2018, 341, 47–57.

240

Chapter 10 Cyclodextrins as recognition tools

[38] Saifi A, Joio PJ, Singh AP, Kumar K. Complexation of an azo dye by cyclodextrins: A potential strategy for water purification. ACS Omega 2021, 6, 4776–4782. [39] Matencio A, Navarro-Orcajada S, García-Carmona F, López-Nicolás JM. Applications of cyclodextrins in food science. A review. Trends Food Sci Technol 2020, 104, 132–143. [40] Alonso L, Calvo MV, Fontecha J. A scale-up process for the manufacture of reduced-cholesterol butter using beta-cyclodextrin. Food Process Eng 2019, 42, e13009, https://doi.org/10.1111/ jfpe.13009. [41] Köse K, Mavlan M, Uzun L, Youngblood JP. Cholesterol removal via cyclodextrin-decoration on cellulose nanocrystal (CNC)-grafted poly (HEMA-GMA) nanocomposite adsorbent. Cellulose 2021, 28, 471–487. [42] Fliszár-Nyúl E, Szabó Á, Szente L, Poór M. Extraction of mycotoxin alternariol from red wine and from tomato juice with β-cyclodextrin bead polymer. J Mol Liq 2020, 319, 114180, https://doi.org/ 10.1016/j.molliq2020114180. [43] Wang R, Ding B, Liang J. Interaction poses, intermolecular forces, dynamic preferences between flavonoids and maltosyl-β-cyclodextrin. J Mol Liquids 2022, 346, 117068, https://doi.org/10.1016/ jmolliq2021117068. [44] Lucas-Abellán C, Fortea MI, Gabaldon JA, Jorge JA, Núñez-Delicado E. Complexation of resveratrol by native and modified cyclodextrins: determination of complexation constant by enzymatic, solubility and fluorimetric assays. Food Chem 2008, 111, 262–267. [45] Pinho E, Grootveld M, Soares G, Henriques MC. Cyclodextrins as encapsulation agents for plant bioactive compounds. Carbohydr Polym 2014, 101, 121–135. [46] López-Miranda S, Guardiola L, Hernández-Sánchez P, Núñez-Delicado E. Complexation between oleanolic and maslinic acids with native and modified cyclodextrins. Food Chemistry 2018, 240, 139–146. [47] Kozlowski CA, Sliwa W. The use of membranes with cyclodextrin units in separation processes: Recent advances. Carbohydr Polym 2008, 74, 1–9. [48] Andrade PF, de Faria AF, Quites FJ, Oliveira SL, Alves OL, Arruda MAZ, et al. Inhibition of bacterial adhesion on cellulose acetate membranes containing silver nanoparticles. Cellulose 2015, 22, 3895–3906. [49] Alayande AB, Kim LH, Kim IS. Cleaning efficacy of hydroxypropyl-beta-cyclodextrin for biofouling reduction on reverse osmosis membranes. Biofouling 2016, 32, 359–370. [50] Xu S, Wang P, Sun Z, Liu C, Lu D, Qi J, et al. Dual-functionalization of polymeric membranes via cyclodextrin-based host-guest assembly for biofouling control. J Membr Sci 2019, 569, 124–136. [51] Zhao Y, Wang S, Yi Z, Zhou Y, Gao C. Increasing the performance of reverse osmosis membranes via the interfacial copolymerization of β-cyclodextrin with m-phenylenediamine/trimesoyl chloride. Desalin Water Treat 2018, 136, 150–156. [52] Liu Y, Zhu J, Zheng J, Gao X, Wang J, Wang X, et al. A facile and scalable fabrication procedure for thin-film composite membranes: Integration of phase inversion and interfacial polymerization. Environ Sci Technol 2020, 54, 1946–1954. [53] He Y, Miao J, Jiang Z, Tu K, Yang H, Chen S, et al. Improving the anti-fouling property and permeate flux of hollow fiber composite nanofiltration membrane using beta-cyclodextrin. Sci Rep 2019, 9, 12435, https://doi.org/10.1038/s41598-019-48908-5. [54] Adams FV, Nxumalo EN, Krause RWM, Hoek EMV, Mamba BB. Preparation and characterization of polysulfone/β-cyclodextrin polyurethane composite nanofiltration membranes. J Membr Sci 2012, 405–406, 291–299. [55] Tang YJ, Shen BJ, Huang BQ, Zhan ZM, Xu ZL. High permselectivity thin-film composite nanofiltration membranes with 3D microstructure fabricated by incorporation of beta cyclodextrin. Sep Purif Technol 2019, 227, 115718, https://doi.org/10.1016/j.seppur.2019.115718.

References

[56]

[57]

[58]

[59]

[60]

[61]

[62] [63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

241

Wei ZZ, Liu YL, Hu HM, Yu JY, Li FX. Biodegradable poly (butylene succinate-co-terephthalate) nanofibrous membranes functionalized with cyclodextrin polymer for effective methylene blue adsorption. RSC Adv 2016, 6, 108240–108246. Zhao R, Wang Y, Li X, Sun BL, Wang C. Synthesis of beta-cyclodextrin-based electrospun nanofiber membranes for highly efficient adsorption and separation of methylene blue. ACS Appl Mat Int 2015, 7, 26649–26657. Xiao N, Wen Q, Liu QW, Yang QB, Li YX. Electrospinning preparation of betacyclodextrin/glutaraldehyde crosslinked PVP nanofibrous membranes to adsorb dye in aqueous solution. Chem Res Chin Univ 2014, 30, 1057–1062. Teng M, L F, Zhang B, Taha AA. Electrospun cyclodextrin-functionalized mesoporous polyvinyl alcohol/SiO2 nanofiber membranes as a highly efficient adsorbent for indigo carmine dye. Colloids Surf A: Physicochem Eng Asp 2011, 385, 229–234. Topuz F, Holtzl T, Szekely G. Scavenging organic micropollutants from water with nanofbrous hypercrosslinked cyclodextrin membranes derived from green resources. Chem Eng J 2021, 129443, https://doi.org/10.1016/j.cej.2021.129443. Celebioglu A, Topuz F, Yildiz ZI, Uyar T. Efficient removal of polycyclic aromatic hydrocarbons and heavy metals from water by electrospun nanofbrous polycyclodextrin membranes. ACS Omega 2019, 4, 7850–7860. Celebioglu A, Topuz F, Uyar T. Water-insoluble hydrophilic electrospun fbrous mat of cyclodextrinepichlorohydrin polymer as highly effective sorbent. ACS Appl Polym Mater 2018, 1, 54–62. Bai X, Ke J, Qiu X, Liu H, Ji Y, Chen J. Ethylenediamine-β-cyclodextrin modified graphene oxide nanocomposite membranes for highly efficient chiral separation of tryptophan and propranolol enantiomers. Sep Purif Technol 2022, 290, 120833, https://doi.org/10.1016/j.seppur.2022.120833. Gaálováa J, Michel M, Bourassia M, Ladewing BP, Kasal P, Jindřich J, et al. Nafion membranes modified by cationic cyclodextrin derivatives for enantioselective separation. Sep Purif Technol 2021, 266, 118538, https://doi.org/10.1016/j.seppur.2021.118538. Liu S, Li W, Chen C, Chen J, Wu X, Wang J. Ultrathin cyclodextrin nanofilm composite membranes for efficient separation of xylene isomers. J Membr Sci 2022, 644, 120165, https://doi.org/10.1016/j. memsci.2021.120165. Cassano A, Tasselli F, Conidi C, Drioli E, Timpone R, D’Avella M, et al. PAN hollow fibre membranes with triacetyl-b-cyclodextrin for the removal of pesticides from citrus essential oils. Sep Purif Technol 2013, 116, 124–130. Fontananova E, Basile A, Cassano A, Drioli E. Preparation of polymeric membranes entrapping bcyclodextrin and their molecular recognition of naringin. J Inclusion Phenom Macrocyclic Chem 2003, 47, 33–37. AlRabiah A, Homoda A, Bakheit A, Mostafa GAE. Cyclodextrin potentiometric sensors based on selective recognition sites for procainamide: Comparative and theoretical study. Open Chem 2019, 17, 1222–1234. Elzanfaly ES, Zaazaa HE, Merey HA. Ion selective phosphotungstate and β-cyclodextrin based membrane electrodes for stability-indicating determination of midodrine hydrochloride. Acta Chim Slov 203, 257, 60, 256–262. Jia M, Liang Y, Liu Z, Liu Y, Zhang X, Guo H. Hydroxypropyl-β-cyclodextrin-incorporated pebax composite membrane for improved permselectivity in organic solvent nanofiltration. RSC Adv 2022, 12, 16893–16902. Zhao J, Dou X, Tang Q, Qiu P, Li J, Gou D, et al. Preparation of chitosan/β-cyclodextrin composite membrane and its adsorption mechanism for protein. Res Square 2022, https://doi.org/10.21203/ rs.3.rs-1657852/v1.

242

[72]

[73]

[74]

[75]

[76]

[77] [78]

[79]

[80]

[81]

[82] [83] [84]

[85] [86] [87] [88] [89]

Chapter 10 Cyclodextrins as recognition tools

Dong Z, Tagliavini M, Darmadi J, Trouillet V, Schäfer AI, Levkin PA. Regeneration of β-cyclodextrin based membrane by photodynamic disulfide exchange. Steroid hormone removal from water. Adv Mater Interfaces 2020, 7, 1902100, https://doi.org/10.1002/admi.201902100. Moulahcene L, Skiba M, Bounoure F, Benamor M, Milon N, Hallouard F, et al. New polymer inclusion membrane containing β-cyclodextrin polymer: Application for pharmaceutical pollutant removal from wastewater. Int J Environ Res Public Health 2019, 16, 414, https://doi.org/10.3390/ ijerph16030414. Mbuli BS, Mhlanga SD, Mamba BB, Nxumalo EN. Fouling resistance and physicochemical properties of polyamide thin-film composite membranes modified with functionalized cyclodextrins. Adv Polym Technol 2017, 36, 249–260. Amor FIEH, Nasser II, Baatout Z, Teka S, Jaballah N, Donato L, et al. New polymer inclusion membranes containing modified β-cyclodextrin: Application to molecular facilitated transport. J Appl Chem 2016, 5, 435–445. Heng M, Zhang H, Li Y, Xue Y, Pei F, Wang J, et al. Tunable solvent permeation properties of thin film nanocomposite membrane by constructing dual-pathways using cyclodextrins for organic solvent nanofiltration. ACS Sustain Chem Eng 2015, 3, 1925–1933. Yu Z, Pan Y, He Y, Zeng G, Shi H, Di H. Preparation of a novel anti-fouling β-cyclodextrin–PVDF membrane. RSC Adv 2015, 5, 51364, https://doi.org/10.1039/C5RA04894J. Adams FV, Nxumalo EN, Krause RWM, Hoek EMV, Mamba BB. Application of polysulfone/ cyclodextrin mixed matrix membranes in the removal of natural organic matter from water. Phys Chem Earth 2014, 67–69, 71–78. Canbolat MF, Celebioglu A, Uyar T. Drug delivery system based on cyclodextrin naproxen inclusion complex incorporated in electrospun polycaprolactone nanofibers. Colloids Surf B Biointerfaces 2014, 115, 15–21. Mbuli BS, Nxumalo EN, Krause RW, Pillay VL, Oren Y, Linder C, et al. Modification of polyamide thinfilm composite membranes with aminocyclodextrins and diethylamino-cyclodextrins for water desalination. Sep Purif Technol 2013, 120, 328–340. Kayaci F, Aytac Z, Uyar T. Surface modification of electrospun polyester nanofibers with cyclodextrin polymer for the removal of phenanthrene from aqueous solution. J Hazard Mater 2013, 261, 286–294. Kayaci F, Ertas Y, Uyar T. Enhanced thermal stability of eugenol by cyclodextrin inclusion complex encapsulated in electrospun polymeric nanofibers. J Agric Food Chem 2013, 61, 8156–8165. Bazhban M, Nouri M, Mokhtari J. Electrospinning of cyclodextrin functionalized chitosan/PVA nanofibers as a drug delivery system. Chin J Polym Sci 2013, 31, 1343–1351. Choi SH, Chung JW, Priestley RD, Kwak SY. Functionalization of polysulfone hollow fiber membranes with amphiphilic β-cyclodextrin and their applications for the removal of endocrine disrupting plasticizer. J Membr Sci 2012, 409–410, 75–81. Lay S, Ni X, Yu H, Shen S. State-of-the-art applications of cyclodextrins as functional monomers in molecular imprinting techniques: A review. J Sep Sci 2016, 39, 2321–2331. Feng F, Liu ZM, Xu ZG. Novel β-cyclodextrin functional monomers and its application for molecularly imprinted polymers. Adv Mater Res 2015, 1101, 256–260. Karoyo AH, Wilson LD. Nano-sized cyclodextrin-based molecularly imprinted polymer adsorbents for perfluorinated compounds. A Mini Rev Nanomater 2015, 5, 981–1003. Ma X, Chen Z, Chen R, Zheng X, Chen X, Lan R. Imprinted β-cyclodextrin polymers using naringin as template. Polym Int 2011, 60, 1455–1460. Zhang W, Qin L, He XW, Li WY, Zhang YK. Novel surface modified molecularly imprinted polymer using acryloyl-β-CD and acrylamide as monomers for selective recognition of lysozyme in aqueous solution. J Chromatogr A 2009, 1216, 4560–4567.

References

243

[90] Cheng Y, Nie J, Li Z, Yan Z, Xu G, Li H, et al. A molecularly imprinted polymer synthesized using βcyclodextrin as the monomer for the efficient recognition of forchlorfenuron in fruits. Anal Bioanal Chem 2017, 409, 5065–5072. [91] Dolai J, Ali H, Jana NR. Molecular imprinted poly-cyclodextrin for selective removal of dibutyl phthalate. ACS Appl Polym Mater 2020, 2, 691–698. [92] Guo M, Hu Y, Wang L, Brodelius PE, Sun L. A facile synthesis of molecularly imprinted polymers and their properties as electrochemical sensors for ethyl carbamate analysis. RSC Adv 2018, 8, 39721–39730. [93] Tang W, Du W, Guo P, Wu N, Du K, Xu C, et al. Molecularly imprinted solid phase extraction using bismethacryloyl-β-cyclodextrin and methacrylic acid as double functional monomers for selective analysis of glycyrrhizic acid in aqueous media. J Chromatogr Sci 2017, 55, 166–173. [94] Farooq S, Chen B, Gao F, Muhammad I, Ahmad S, Wu H. Development of molecularly imprinted polymers for fenthion detection in food and soil samples. Nanomaterials 2022, 21, 2129, https://doi. org/10.3390/nano12132129. [95] Farooq S, Nie J, Cheng Y, Bacha SAS, Chang W. Selective extraction of fungicide carbendazim in fruits using β-cyclodextrin based molecularly imprinted polymers. J Sep Sci 2020, 43, 1145–1153. [96] Wang X, Liu H, Sun Z, Zhao S, Zhou Y, Li J, et al. Monodisperse restricted access material with molecularly imprinted surface for selective solid‐phase extraction of 17 β-estradiol from milk. J Sep Sci 2020, 43, 3520–3533. [97] Liang G, Guo X, Tan X, Mai S, Chen Z, Zhai H. Molecularly imprinted monolithic column based on functionalized β-cyclodextrin and multi-walled carbon nanotubes for selective recognition of benzimidazole residues in citrus samples. Microchem J 2019, 146, 1285–1294. [98] Cao Y, Li J, Liu J, Liu H, Jiang Y, Zhang H. Preparation and characterisation of a novel copperimprinted polymer based on β-cyclodextrin copolymers for selective determination of Cu2+ ions. Polym Int 2019, 68, 694–699. [99] Liu Y, Liu Y, Liu Z, Hu X, Xu Z. β-cyclodextrin molecularly imprinted solid-phase microextraction coatings for selective recognition of polychlorophenols in water samples. Anal Bioanal Chem 2018, 410, 509–519. [100] Zhang W, Zhu Z, Zhang H, Qiu Y. Selective removal of the genotoxic compound 2-aminopyridine in water using molecularly imprinted polymers based on magnetic chitosan and β-cyclodextrin. Environ Res Public Health 2017, 14, 991, https://doi.org/10.3390/ijerph14090991. [101] Zhu F, Li L, Xing J. Selective adsorption behavior of Cd (II) ion imprinted polymers synthesized by microwave-assisted inverse emulsion polymerization: Adsorption performance and mechanism. J Hazard Mater 2017, 321, 103–110. [102] Zhang X, Zhang N, Du C, Guan P, Gao X, Wang C, et al. Preparation of magnetic epitope imprinted polymer microspheres using cyclodextrin-based ionic liquids as functional monomer for highly selective and effective enrichment of cytochrome c. Chem Eng J 2017, 317, 988–998. [103] Yuan Y, Liu Y, Teng W, Tan J, Liang Y, Tang Y. Preparation of core-shell magnetic molecular imprinted polymer with binary monomer for the fast and selective extraction of bisphenol A from milk. J Chromatogr A 2016, 1462, 2–7. [104] Lay S, Yu HN, Hu BX, Shen SR. Using molecularly-imprinted polymers as the extracted sorbents of clenbuterol ahead of liquid chromatographic determination. J Zhejiang Univ Sci B 2016, 17, 465–475. [105] Li S, Xu M, Wu X, Luo J. Synergetic recognition and separation of kelthane and pyridaben base on magnetic molecularly imprinted polymer nanospheres. J Sep Sci 2016, 39, 4019–4026. [106] Kyzas GZ, Lazaridis NK, Bikiaris DN. Optimization of chitosan and β-cyclodextrin molecularly imprinted polymer synthesis for dye adsorption. Carbohydr Polym 2013, 91, 198–208. [107] Xu ZF, Wen G, Kuang DZ, Zhang FX, Tang SP. Selective separation of deltamethrin by molecularly imprinted polymers using a β-cyclodextrin derivative as the functional monomer. J Env Sci Health B 2013, 48, 336–343.

244

Chapter 10 Cyclodextrins as recognition tools

[108] Ji X, Liu H, Wang L, Sun Y, Wu Y. Study on adsorption of Th (IV) using surface modified dibenzoylmethane molecular imprinted polymer. J Radioanal Nuclear Chem 2013, 295, 265–270. [109] Yang Y, Long Y, Cao Q, Li K, Liu F. Molecularly imprinted polymer using β-cyclodextrin as functional monomer for the efficient recognition of bilirubin. Anal Chim Acta 2008, 606, 92–97. [110] Tsai HA, Syu MJ. Synthesis of creatinine-imprinted poly (β-cyclodextrin) for the specific binding of creatinine. Biomaterials 2005, 226, 2759–2766. [111] Trotta F, Caldera F, Cavalli R, Soster M, Riedo C, Biasizzo M, et al. Molecularly imprinted cyclodextrin nanosponges for the controlled delivery of L-DOPA: Perspectives for the treatment of Parkinson’s disease. Expert Opin Drug Deliv 2016, 13, 1671–1680. [112] Zhao L, Wang XL, Ma L, Shang PP, Huang YP, Liu ZS. Improving affinity of β-cyclodextrin-based molecularly imprinted polymer using room temperature ionic liquid. Eur Polym J 2019, 116, 275–282. [113] He Y, Zeng S, El-Aty AMA, Hacimuftuoglu A, Yohannes WK, Khan M, Sh Y. Development of watercompatible molecularly imprinted polymers based on functionalized β-cyclodextrin for controlled release of atropine. polymers 2020, 12, 130, https://doi.org/10.3390/polym12010130. [114] Huang YA, Zeng X, Zhu Q, Lu K, Xu Q, Ye C. Development of an active packaging with molecularly imprinted polymers for beef preservation. Packag Technol Sci 2018, 31, 1–8. [115] Cheng Y, Dong X. Preparation of a molecularly imprinted fluorescent chemosensor using quinoline modified vinyl-β-cyclodextrin and acrylamide as monomers for the selective recognition of spermidine. Anal Methods 2016, 8, 5838–5842. [116] Yuan X, Tan Y, Wei X, Li J. Chiral determination of cinchonine using an electrochemiluminescent sensor with molecularly imprinted membrane on the surfaces of magnetic particles. Luminescence 2017, 32, 1116–1122. [117] Liu Y, Wei M, Hu Y, Zhu L, Du J. An electrochemical sensor based on a molecularly imprinted polymer for determination of anticancer drug mitoxantrone. Sens Actuators B 2018, 255, 544–551. [118] Shin MJ, Shin JS. A molecularly imprinted polymer undergoing a color change depending on the concentration of bisphenol A. Microchim Acta 2019, 187, 44, https://doi.org/10.1007/s00604-0194050-0. [119] Wu J, Gao J, Hou Z, Xing W, Dai J, Yan Y, et al. Accelerating the design of β-CD-PVDF-based molecularly imprinted nanocomposite membrane for selective separation: A surface functional monomer-directing strategy. Nano 2020, 15, 2050138, https://doi.org/10.1142/S1793292020501386. [120] Lu J, Qin YY, Wu YL, Chen MN, Sun C, Han ZX, et al. Mimetic-core-shell design on molecularly imprinted membranes providing an antifouling and high-selective surface. Chem Eng J 2021, 417, 128085, https://doi.org/10.1016/j.cej.2020.128085. [121] Ahmadi H, Javanbakht M, Akbari-adergani B, Shabanian M. β-cyclodextrin based hydrophilic thin layer molecularly imprinted membrane with di (2-ethylhexyl) phthalate selective removal ability. J Ind Eng Chem 2020, 89, 416–427.

Index 12-crown-4 181–182 17β-estradiol 85 1-naphthol 45 1-vinyl-3 butylimidazolium chloride 45 1-vinyl-3-ethyl acetate imidazolium chloride 45, 118 1-vinyl-3sulfopropyl-imidazolium 109 1-vinylimidazole 10, 175, 193 2,4-dichlorophenoxyacetic acid 36, 59 2,4-dihydroxybenzoate 46 2-aminopyrimidine 64 2D imprinting 55–56 2-ethylhexyl acrylate 166 3D imprinting 55 4,4-methylenedianiline 64 4-chlorophenoxyacetic acid 59 4-vinylbenzoic acid 19 absolute configuration 129 absorbance 149, 153 abuser 99, 147, 156 acesulfame 95 acetaminophen 158 acetoside 36 acrylic copolymers 33, 61, 64 active pharmaceutical ingredient 64, 81, 84, 90 adenosine monophosphate 57 adsorber 36 adsorption layer 66 affinity binding 82, 85 affinity biosensors 151 affinity chromatography 108 affinity separation 81–82, 99 affinity-imprinted membranes 81–82 AFM 44, 69, 139 agarose 87 aggregation 13, 107–108, 113, 212 agriculture 59, 69, 84, 87, 137, 147, 161 alkaloids 128–129, 136 allyl isothiocyanate 235 alternative molecular imprinting 54, 57, 59, 66, 71 aminoglutethimide 210 amnesia 158 amphiphilic 215, 225 amylase 40, 120 analgesic 207 anchoration 69 antibiotics 36, 84, 86, 90, 95, 147, 164, 205 https://doi.org/10.1515/9783110654691-012

antidoping 115 antifouling 191 antigen 5, 7, 151, 154 anti-inflammatory 36, 81, 84, 93–94, 96, 128, 133, 212 antioxidant 81 antiviral 93, 105 aptamer 110–111, 148, 152 aquaculture 85 arsenium 183 asparaginase 19 asymmetric 61, 128, 130, 137, 164, 185, 223–224 asymmetry 129 atenolol 43 atom transfer radical polymerization 15, 45, 67 ATRP 15, 45, 69, 90, 118 azobisdimethylvaleronitrile 12 azobisisobutyronitrile 12 backfiltration 86 basswood 189 beads 15, 113, 225, 227, 233 benzophenone 67 benzoylperoxide 12 bidirectional filtration 86 bimodal 118 binding affinity 36, 41–42 binding kinetics 8, 15, 18, 55, 66, 74, 107 bioanalysis 107 bioavailability 202, 205, 210, 225 biocompatibility 117, 120, 205, 223–224 biodegradability 176, 223–224 biodegradable 47, 203, 214 biofouling 227–228 biologically active compounds 90, 129 biomass-based approach 47 biomimetic sensors 148, 153, 155, 158 bionic 190 bioproducts 81 biosensing 20 bismethacryloyl-β-cyclodextrin 234 blend 33, 61, 74, 85, 183, 229 boronate 8 boronic acid 7, 19, 111, 118, 150 bulk imprinting 108, 110 burst effect 203–204

246

Index

calcium alginate 117 calcium chloride 45, 139 calixarenes 175, 177 carbamazepine 19 carbonaceous 18 carbonyldiimidazole 235 carboxylic group 61, 72, 89, 105, 106, 183 carotenoids 93 cascade filtration 139 cathinone 68, 99 CDDSs 201, 203, 205, 208, 210 cell culture 42 cell wall 160 cellular adhesion 117 cellular receptors 132 charge density 71, 107 chiral selector 127, 129–130, 224, 230 chiral separations 65, 130, 223, 230 chirality 127–128, 130, 227 chloramphenicol 61 chromatographic separation 1, 7, 223 cinnamic acid 46 citrinin 45 Clarene® 120 cleanup 86, 95 clinical diagnosis 147, 156 clofibric acid 68 coagulation temperature 61 combinatorial chemistry 13 complementarity 5, 42, 214 composite membrane 67, 133 concanavalin A 112 concentration gradient 31, 203 conducting polymers 148, 152 conductivity 18, 45, 149, 154–155 cone 223 conformational state 109 congenerous 225 contact angle 44, 69 continuous operation mode 33, 127, 130 controlled radical polymerization 15, 57 convection 31, 36 copper 183–184, 192–193 core–shell 17, 19, 108, 111 covalent immobilization 68, 110 covalent imprinting 8, 12, 208 COVID-19 154 critical raw materials 174

cross-flow filtration 67, 97, 228 cross-reactivity 107 crowding agent 210 crown ethers 6, 130, 175, 177 cryogelation 119, 215 cryopolymerization 119 crystallization 35 C-terminus 108, 113 cyclododecyl 2,4-dihydroxybenzoate 46 cypermethrin 69 cyromazine 88 cytokinin 233 dead-end filtration 94, 134 deep eutectic solvent 19, 47 degradation 147, 151, 203, 207, 215, 223, 231 delayed release 235 deltamethrin 13 denaturation 82, 85, 105–106, 119, 153 dengue virus protein 113 deoxynivalenol 154, 163 derivatization 111 desalination 33 dexamethasone 212–213 diameter 31, 43, 58, 71, 212–213, 233 dibutyl phthalate 234 diclofenac 68–69, 207 dielectric constant 47 diffusion coefficient 47, 207 diffusive transport 31, 176 diffusivity 31–32, 47, 55 dimethoate 88 dimethyl sulfoxide 19, 164 Dioscorea 64 diosgenin 64, 214 dip coating 85 disease 121, 152 disinfectants 87 dispersion 14, 71, 166, 213 distillation 32, 35 dithiocarbamate 67 divinylbenzene 7, 12 DMAEMA 10, 113 DNA 5, 105, 151, 153 dope solution 57, 59, 61, 93, 157, 214 D-phenylalanine 138 driving force 31–32 drug discovery 147, 152

Index

D-tryptophan

45, 131, 137, 139, 141 dual-imprinting 121 dummy template 13, 45, 70, 87, 110, 163 dynamic molecular recognition 5 dysprosium 188–189

eco-friendly 17, 47 ecosystem 81, 84 electric charge 137 electric field 71 electrical field 31 electrical signal 147–148 electroactive 67, 154, 156 electrodialysis 32 electrodonor 175 electroreceiving 175 electrospray deposition 71 electrospraying 71 electrostatic interactions 32, 174–175, 224 elemental microanalysis 43 emodin 19, 97 emulsion polymerization 14, 69, 112, 232 enantiomeric excess 130–131, 140 enantioselective separation 128, 134–135, 230 endocrine disruptor 35, 48, 69 endogenic 156 endotoxins 156, 160 enoxacin 237 entrapment 151, 211 enzyme biosensors 151 enzyme–substrate interaction 7 epitope imprinting 108, 113, 121 erosion 201, 203, 206, 214 Escherichia coli 19, 160, 227 ethylene glycol dimethacrylate 12, 59 ethylene imine 85 europium 190 exogenic 156 exogenous 225 ferulic acid 46, 95 fibronectin 117 Fickian diffusion 203 filled IIMs 175 filler 47, 87, 175, 207 flavonoids 93, 227 florescence 149 fluorescence 46, 118, 121, 150, 153 folding 106, 111

folic acid 95 food control 152 food safety 7 forensic science 20, 152 Fourier-transform infrared spectroscopy 43 free radical 16, 20, 57, 67, 190 free radicals 14 free-standing 57 freestanding 175, 189 Freundlich 41 fungicide 87 Fusarium graminearum 163 gadolinium 190 gel-type 10 glass carbon electrode 68, 166 glycidyl methacrylate 209 glycoside 94 grafting from 67, 185 grafting to 186 grafting-from 237 graphene oxide 97, 121, 154, 164, 190, 230 green chemistry 45, 47, 139 grinding 14 hallucinogen 158 hand in glove model 5 harsh 7, 74 health care 30, 148 herbs 90 heterogeneous 8, 14, 33, 41 hexamethylene diisocyanate 232 hierarchical imprinting 109–110 homogeneous 8, 41–42, 48, 108, 212 homolog 115 homologue 6, 30, 88, 233 hormones 90, 95, 106, 129, 161 HPLC 20, 87, 95, 99, 135 humidity 65, 148 hydration radius 177 hydrogen bonding 72, 89, 236 hydrolysis 16, 19 hydrophilicity 47, 69, 228, 237 hydrophobic interactions 8, 106, 233, 237 imalazil 230 immersion precipitation 59 immunoassay 68 immunostimulant 45

247

248

Index

immunosuppression 212 impedance 149 implantable 149, 152 implantation 201, 203 imprinting effect 15, 46, 64, 70 in situ cross-linking polymerization 57, 66 in situ polymerization 15, 57 inclusion complexes 223–224, 226, 236 indoles 93 induced fit 5 inertia 47, 117 iniferter 12, 15–16 injection 201, 203 inorganic anions 192–193 input 81–82, 149, 201 intensity 41, 46, 118, 148, 163, 166, 236 interfacial 112, 181, 228–229 intermolecular interactions 13 interpenetrating network 190 interpenetrating polymer network 57, 184 interpenetration 67 intravitreal 207 ion-exchange 174 ionic interactions 10, 70 ionic liquids 45, 47, 115, 150, 176 ionic strength 1, 6, 105, 107 ionopher 230 isoelectric point 67, 107, 137, 140 isoquercitrin 19 isotherm 41, 96, 184 kinetic model 41, 206 Korsmeyer-Peppas 206 Langmuir 41, 48, 96, 184 lanthanides 187 layer-by-layer 228 leaching 13, 175, 205 L-glutamic acid 114, 131, 162 L-glutaraldehyde 129 lincomycin 69 lipid-lowering agent 68, 207 liquid droplets 71 liquid membrane 32, 43, 73, 85 liquid–liquid demixing 59 liquid–liquid extraction 87, 127 lock-and-key 7 lock-and-key model 5 lovastatin 46

L-phenylalanine

137–138, 155 131, 160 L-tyrosine 74, 131 luminescence 149, 236 L-tryptophan

macrocyclic 223 magnesium 106, 183 magnetic field 70, 90, 158, 160, 204, 213 magnetic force 70 magnetic nanoparticles 15, 110, 154 magnetic nuclear resonance 43 market 21, 132, 176 mass transfer 15, 55, 108, 112, 119, 155 mass transport 32 m-cresol 74 mechanical resistance 18, 33, 205, 212 mechanical strength 66 membrane bulk 55, 65 membrane operations 30, 32 mercury 183–185 mesoporous 164, 189–190 metabolism 93, 117, 136, 207 metalloids 174 methacrylamide 93, 110, 118 methemoglobinemia 193 methyl methacrylate 10, 166 methylene blue 90 metoprolol 68–69 micelles 15 microcontact imprinting 108, 113, 160 microfiltration 32, 69 microgel 10 microwave 13, 17, 34 mineral oil 14 MINFMs 71–72 mixed matrix 73, 86, 121, 207 modification degree 70 molecular dynamic 13 molecular memory 59 molecular recognition 6 molecular sieve 31 molecular simulation 19 molecular weight 16, 47, 57, 105, 107 molybdate 192–193 monolayer 41, 55, 96, 108 multilayered 69, 176 multisite binding 70 multistep swelling polymerization 15 multitemplate imprinting 46, 176

Index

(N,N-diethyl) aminoethyl methacrylate 57 N,N-methylene bisacrylamide 118 N,N′-methylenebis(acrylamide) 67 N-(4-vinyl)-benzyl iminodiacetic acid 109 nafion117® 230 nanocomposites 44, 175 nanoencapsulation 71 nanofiltration 32, 64, 227–228 nanosheets 154 nanospheres 44 nanosponges 235 nanostructure 18 nanostructured 68, 71, 152, 192, 203 natural polymers 45, 176, 201, 214 N-isopropylacrylamide 113, 115, 149 nitrate 192–193 noncovalent binding 33 noncovalent imprinting 8, 12, 208 nonflammability 45, 47 nonsolvent-induced phase separation 59 nonsuperimposable 128–129 norfloxacin 44, 237 N-terminus 108–109, 113 nucleotide 57, 131, 192 o-aminophenol 68 octahedral 192 ocular 201 oligonucleotide 111 oligosaccharides 223 oligourethane acrylate 57 omega-3 fatty acids 93 optical code 150 optically active 127–129 oral dosage 201, 203 ordered pore structure 65 osmosis 33, 201, 203–204 osmotic pressure 106 output signal 148, 151 oxidation 17–18, 36 oxytocin 113 paclitaxel 61 palladium 166, 183 patch 207, 215 pathogen 113 P(E-co-VA) 61 (P(e-co-VA)) 40, 121 peptide bond 105

peptide fragment 108 percutaneous 207 perfluorocarbons 14 periodic table 177, 187 permeate flux 47, 64, 228–229 permeation separation factor 130–131 permselectivity factor 74, 96, 183, 237 peroxides 12, 67 pervaporation 32, 54 phenolic acids 93 phenylalanine-glycine 109 phosphatidylcholine 40, 61 photo-copolymerization 93, 118, 133, 163 photodegradation 90 photoinitiator 67 photopolymerization 99, 164, 166, 236 photosensitive 67 physical adhesion 67 physical–chemical 54, 137 piperazine diarylamide 110 planar 55, 113 plasticizer 166, 230 platinum 152, 183 PMMA 57, 65 podophyllotoxin 42 polarized light 127–129 polyamide 33, 47, 228–229 polyaniline 73, 152, 192–193 polybenzimidazole 61 polycarbonate 33 polycondensation 16 polycyclic aromatic hydrocarbons 89 polyethersulfone 33 polyethylene glycol 57, 120 poly(ethylene terephthalate) 72 poly(ethylene-co-vinyl alcohol) 40 polyethylenimine 69, 193, 228 polymeric networks 7, 208 polymethylmethacrylate 57 polysaccharide 130, 160 polysiloxane 117, 201, 203 polystyrene 33, 61, 65 polysulfone 33 polyurethane 57, 201, 203, 229 polyvinyl alcohol 57, 72, 183 polyvinylidene fluoride 33, 46, 135 pore size distribution 14 porogen 9, 19, 47 porosity 55, 59, 64, 74, 120, 233

249

250

Index

portable sensor 154 potassium ferrocyanide 184 potassium persulfate 12 precipitation polymerization 14, 20, 70, 154, 183, 210, 212 pressure gradient 31–32 pressurized hot water 13, 48 primary amines 64 primary structure 106 print molecule 6, 30 process intensification 30, 35, 48, 54 protein imprinting 12, 105, 107–108, 112, 121 protein-substructural imprinting 108 proteomic 114–115 protons 176 pseudo-second-order 86 purity 4, 109, 135 p-xylene 54 quantification 151–152, 164 quantum mechanic 13 quaternary structure 106, 108 quercetin 35, 93 raceme 129–130 Radix Puerariae lobatae 94 RAFT 15 Raman spectroscopy 43 random distribution 35, 65 rare earth element 187, 193 rare earth metals 174 rebinding 8, 12–13, 40, 48, 105, 107, 120, 175, 190, 236 recovery rate 72, 87, 95, 99, 164 recycle 19, 47, 64, 81, 84, 174, 187 redox initiator 12, 67 regenerated cellulose 44–45, 74, 86, 118, 183 regeneration 164 rejection 64, 212, 229 removal efficiency 163 renewable 45 reservoir 207, 215 reverse osmosis 32 reversible addition-fragmentation chain transfer 15 ribonuclease A 109 RNA 5 roughness 44, 64, 69, 139, 181

S-amlodipine 135, 135 sandwich 73–74, 175 SARS-CoV-2 154 scaffold 64, 67, 112, 117, 121, 215 scandium 187 scanning electron microscopy 44 Scatchard analysis 41, 86 Schiff’s base 8 secondary structure 106, 113–114 seed polymerization 14 selective barrier 31, 66 selective layer 55 selective recognition properties 4, 67, 135 selective separation 84 selective separations 81, 237 self-assembly 73, 90, 156, 160 self-polymerization 86 self-supported 45, 56, 141 semicovalent 48, 94, 111 semicovalent imprinting 8 sensing element 147–149, 152, 156, 158, 164, 166 sensitivity 1, 6, 148, 150, 152–154, 156, 164, 192–193, 235 shrinking 36 sieving 14 silver 97, 154, 183, 227 smart membranes 30, 35, 42, 174 S-naproxen 36, 133, 135 sodium alginate 33, 45, 139, 183 sodium dodecyl sulfate 107 sol-gel imprinting 74, 108 solid-phase microextraction 83, 99 solubility-diffusion 31–32 solvation 201, 203–204 solvent evaporation-induced phase inversion 59 solvent extraction 1, 7 sol–gel imprinting 74, 121 sol–gel protein imprinting 108 specific binding capacity 40, 64, 82, 88, 112, 114, 176 specific interactions 4, 6, 33, 40, 149, 183 specific surface area 44, 55, 71 specificity 1, 5–6, 21, 33, 59, 82, 90, 107–109, 133, 147, 151–152, 156 spermidine 235 spherical 14, 192 spongy-like 65 square planar 192 static molecular recognition 5 stereoisomers 127

Index

stereoselective 127, 129–130, 135, 215 steric hindrance 129 sterols 93 stigmasterol 64 stimuli-responsive 18, 42, 208 subcutaneous 19, 149 sulfadiazine 86 sulfamonomethoxine 86, 96 sulfur group 89 supramolecular 5 supramolecular structures 4 surface functionalization 57, 66 surfactant 14 suspension polymerization 14 swelling degree 12, 205, 207, 209 tamoxifen 207 target compound 6 taurine 161–162 tebuconazole 72 temperature gradient 31–32 template 18 template analogue 13, 45 template immobilization 108–110 terapeptide 113 tertiary structure 106 tetracycline hydrochloride 61 tetrahedral 192 tetramodal 119 tetrapeptide 57, 112 therapeutic range 202–203 thermoresponsive 42, 115 thiabendazole 95, 230 thrombocytopenia 212 thymopentin 45 transdermal delivery 201, 203, 206–207, 215 transducer 147–151, 153, 155 transmembrane pressure 64 transport phase 66

251

transport rate 119 triallyl isocyanurate 12 triangular 192 triazophos 166 trimodal 118 ultrafiltration 32 ultrasound 13, 34, 204 vancomycin 68–69, 99 vapor pressure 45 veterinary medicine 84, 87 vinyl-3-carboxylmethyl-imidazolium chloride 109 vinylated group 175 viruses 4, 35, 105, 147, 152 viscosity 45, 47 vitamins 30, 35, 90, 106 waste reduction 84 wearable sensors 148 while 2-acrylamido-2-methylpropanesulfonic acid 67 X-ray photoelectron spectroscopy 43 xylene 230 yttrium 187, 190 zearalenone 46 zeolites 73, 82, 207 zero-order 205, 207, 210 zinc sulfide 185–186 α-aminic function 106 α-amylase 120 α-cyclodextrin 234 α-helix 106, 113 β-shifts 106