Polymeric Nanoparticles 1588830640

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Encyclopedia of Nanoscience and Nanotechnology

www.aspbs.com/enn

Polymeric Nanoparticles Bobby G. Sumpter, Donald W. Noid, Michael D. Barnes Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA

Joshua U. Otaigbe University of Southern Mississippi, Hattiesburg, Mississippi, USA

CONTENTS 1. Introduction 2. Synthetic Routes for Polymeric Nanoparticles 3. Supercritical Fluid-Based Particle Production 4. Droplet and Aerosol Techniques 5. Gas Atomization Approaches 6. Dendrimers, Hyperbranched Polymers, or Star Polymers 7. Molecular Imprint Polymers 8. Simulation and Modeling of Polymer Particles 9. Applications of Polymer Particles 10. Polymer Particle Patent Review 11. Conclusions Glossary References

1. INTRODUCTION Science and technology continue to witness enormous attention focused on the production of new materials on the micrometer and nanometer scale that have tunable material, electrical, and optical properties. Polymer particles, polymer particle alloys, or polymeric composites provide one viable avenue for the production of these highly desired systems. Currently, polymer particles can be produced in a variety of ways, some of which allow easily controllable particle size and composition as well as a number of crucial physical properties [1–12]. In addition, recent results have shown that polymeric particles in the micro- to submicrometer range can be formed such that dynamical confinement effects result in interesting nanostructures and properties that cannot be produced using conventional methods [2]. ISBN: 1-58883-064-0/$35.00 Copyright © 2004 by American Scientific Publishers All rights of reproduction in any form reserved.

Polymer particle wires and arrays, “supramolecular particle structures,” have also been produced which offer another set of exciting possibilities [4]. These combined capabilities open the door to a variety of novel uses, such as electrooptic and luminescent devices, magnetic coatings, thermoplastics and conducting materials, hybrid inorganic–organic polymer alloys, polymer-supported heterogeneous catalysis, high-energy-density materials, information materials, and a whole host of applications in the biomedical field [6–16]. In this chapter we review some of the recent progress in the production and characterization of polymer particles and provide examples of a number of relevant applications. Our intent is to provide a general overview of the various areas and methods relevant to polymeric particles. Since there is a very large literature base for each of the topics discussed in the following sections, we have tried to provide some general references where more extensive literature citations can be found.

2. SYNTHETIC ROUTES FOR POLYMERIC NANOPARTICLES The synthesis of polymeric nanoparticles in large and homogeneous quantities has received considerable attention in polymer and materials science [17–73]. Much of the motivation has been derived from the incredibly broad and often unique applications of polymeric particles (see later sections for details). To date most of the synthetic production of polymer particles generally falls within two primary approaches. The first approach is based on the emulsification of the water-immiscible organic solution of the polymer by an aqueous phase containing a surfactant, followed by evaporation of the solvent. The second approach is based on the precipitation of a polymer after addition of a nonsolvent of the polymer. On the other hand, nanoparticles formed of natural macromolecules are generally obtained by thermal denaturing proteins (such as albumin) or by a gelification process, as in the case of alginates.

Encyclopedia of Nanoscience and Nanotechnology Edited by H. S. Nalwa Volume 8: Pages (873–903)

874 In the past, polymer latexes (suspensions or dispersions of polymer particles) were largely made by conventional emulsion polymerization but this method is mostly suitable for only radical homopolymerization of a narrow set of barely water-soluble monomers. To broaden the range of possible polymeric systems a number of new techniques for generating micro- and miniemulsions, phase inversions, secondary dispersions, and suspension polymerizations have been developed and successfully implemented. Figure 1 illustrates some of the types of polymerization methods available for producing polymer particles and the corresponding particle size range. We discuss a number of these techniques and their applicability to the production of polymeric nanoparticles. Our discussion is only meant to give a flavor of the various polymerization routes for producing polymer particles. There are a number of reviews and books dedicated to these methods and more complete details are better obtained from those references and references cited therein [17–26].

2.1. Emulsion Polymerization Emulsion polymerization as a conventional preparation method can make polymeric particles in the size range of 100–1000 nm, a range that has been gradually broadened [17, 18, 27–39]. For example, the seeded emulsion polymerization technique was developed to make latexes larger than 1000 nm, while the miniemulsion and microemulsion polymerizations were designed to prepare particles in the ranges 50–200 and 20–50 nm, respectively (see Fig. 1). Emulsion polymerization is a widely used industrial process for making coatings, paints, adhesives, and resins. Monomers used in emulsion polymerization are typically only sparingly soluble in water although a few percent of water-soluble co-monomers are often added to enhance stability. Both ionic, such as sodium dodecyl sulfate or sodium dodecyl benzene sulfonate, and nonionic surfactants are used to produce the emulsions. A typical polymer emulsion

Polymeric Nanoparticles

formulation contains a water-soluble initiator such as potassium persulfate, an organic phase consisting of monomers dispersed in 1–20 micrometer droplets, and a surfactant that is above its critical micelle concentration. The surfactant causes a high concentration of monomer-swollen micelles to form in the aqueous phase. As the system is heated, the initiator decomposes to give aqueous phase radicals that propagate with small amounts of monomer dissolved in the aqueous phase. The newly forming radicals become hydrophobic very quickly and enter the micelles where they initiate polymerization of particles. Particle nucleation continues until all of the micelles either have been nucleated to form polymer particles or have been dispersed. As long as there are monomer droplets in the system, homogeneous nucleation can continue to take place. Once the micelles have been depleted, the polymer particles continue to grow by using monomer diffusing through the aqueous phase. Particle growth is continued until all of the monomers in the aqueous phase have been depleted. One of the critical elements of emulsion polymerization is the formation of micelles which act as compartmentalized reaction chambers. This is how emulsion polymerization can produce reasonably small particles. Polymerization conducted in dispersed aqueous systems, such as suspension polymerization, produces relatively large polymer particles (20–1000
m).

2.1.1. Soap-Free Emulsion Polymerization In emulsion polymerization, surfactants play important roles such as maintaining the polymer particle stability, controlling the particle size, distribution, latex surface tension, and latex rheological properties. Clearly the choice and amount of surfactants significantly affect the polymer latex performance. For example, improper surfactant choice may lead to foaming, which in turn causes surface defects and decreased water resistance. Also the amount of the surfactants is the key factor to control new particle generation in the case of seeded polymerization. Unfortunately, surfactant molecules used in emulsion polymerization do not always stay tightly on the surface of particles but repetitively undergo desorption and absorption. These molecules are not easily removed from the final latex product and can often interfere with applications to systems that are not compatible with this type of latex contaminant. To overcome this type of problem, two techniques were developed, soap-free emulsion polymerization or the use of polymerizable surfactants [30, 31]. Soap-free emulsion polymerization can produce functional polymer particles in the submicrometer size range. Water is usually used as the continuous phase in soap-free polymerization. The polymer particles formed during soap-free emulsion polymerization retain their stability by electrorepulsive forces between ionic fragments on the particle surfaces or sequences.

2.1.2. Miniemulsion Polymerization

Figure 1. Particle size range achieved for different synthetic polymerization techniques.

Miniemulsion polymerization shares many of the fundamental principles with emulsion polymerization, most importantly compartmentalization [19, 32, 33]. Miniemulsions are specially formulated heterophase systems where stable nanodroplets of one phase are dispersed in a second

Polymeric Nanoparticles

continuous phase (see Fig. 2). This system is created by using an appropriate combination of high shear treatment, surfactants, and the presence of an osmotic pressure agent that is insoluble in the continuous phase. Nanodroplet stability is obtained by adding an agent that dissolves in the dispersed phase but that is not soluble in the continuous phase. A simple example is a typical oil–water miniemulsion, where oil, a hydrophobic agent, an emulsifier, and water are homogenized by high shear to obtain homogenous and monodisperse droplets in the size range of 30 to 500 nm. The generality and potential of the miniemulsion method lay in the fact that since each of the droplets is basically an individual batch reactor, a whole variety of polymerization reactions can be performed, thus significantly extending the profile of classical emulsion polymerization. Radical homopolymerization, copolymerization, catalytic chain transfer, controlled free radical polymerization, polyaddition reactions, metal catalyzed reaction, among others have all been utilized to produce polymer particles using the miniemulsion technique. Due to this large range of possible polymerization reactions and the nearly unlimited number of possible monomers that can be used for the formation of particles, a wide variety of polymeric particles have been produced using miniemulsion technology. Examples include numerous homopolymers, in particular polystyrene, poly(methyl methacrylate), poly(vinyl chloride), poly(acrylic acid), poly(n-methylol acrylamide), polyacrylonitrile, etc., polymer–polymer hybrids, encapsulated pigments, carbon black, and liquid, silica, and composite particles. A useful list of characteristics for determining if a system represents a miniemulsion has been compiled by Antonietti and Landfester [19]. They discuss seven items that should be present. (1) Dispersed miniemulsions in a steady state are stable against diffusional degradation but critically stabilized with respect to colloidal stability. (2) The interfacial energy between the oil and water phase is significantly greater than zero and the surface coverage of the droplets by surfactant molecules is incomplete.

875 (3) The formation of a miniemulsion requires high mechanical agitation to reach a steady state. (4) The stability of droplets against diffusional degredation originates from an osmotic pressure within the droplets that controls the solvent or monomer evaporation. (5) Polymerization occurs by droplet nucleation only. (6) The growth of droplets during polymerization can be suppressed. (7) The amount of surfactant or inherent surface stabilizing groups required to form a polymerizable miniemulsion is small compared to other polymerizations.

2.1.3. Microemulsion Polymerization Miniemulsions are defined by the mode of operation instead of a size range and are fairly easy to distinguish among most other heterophase polymerization methods. However, it can be confusing to find in the literature another method called microemulsion polymerization. Microemulsions are formed by mixing water, a hydrophobic compound, and suitable emulsifiers [20, 34, 35]. The medium is a multicomponent liquid that exhibits long-term stability, has low viscosity, and is optically transparent and isotropic. In microemulsions, the polymerization starts from a thermodynamically stable state that is spontaneously formed. This is generally achieved by using large amounts of specialized surfactants or mixtures that have an interfacial tension at the oil–water interface that is near zero. The microdroplets formed consist of a spherical organic core surrounded by a monomolecular shell of emulsifier molecules whose polar groups are in contact with the continuous aqueous phase. Initiation of polymerization is not simultaneously obtained in all of the microdroplets and therefore only some of the droplets contain the first polymer chains formed. These chains influence the stability of the microemulsion and can lead to an increase in the particle size and secondary nucleation. Latexes formed via microemulsions typically consist of relatively small polymer particles in the range of 5–50 nm but the particles are often mixed among numerous empty micelles. However, a variety of elaborate surfactants (mixtures of cationic and anionic salts) have been utilized to significantly alter the final polymer particle size, surfactant content, and distribution. The essential features of microemulsion polymerization are: (1) polymerization proceeds under nonstationary state conditions; (2) size and particle concentration increase throughout polymerization; (3) chain transfer to monomer/exit of transferred monomeric radical–radical reentry events are operative; and (4) molecular weight is independent of conversion and distribution of the resulting polymer broad. Microemulsion and inverse microemulsion polymerization have been used to produce a variety of polyacrylate latex particles, water-soluble nanoparticles, and conductive polymeric particles.

2.1.4. Inverse Emulsions Figure 2. Fundamental principles involved in miniemulsion polymerizations.

The advantage gained by emulsion stabilization is not restricted to only direct micro- and miniemulsions but can easily be extended to inverse emulsions [21, 36, 37]. Polymer

Polymeric Nanoparticles

876 spheres in the nanometer range, below 200 nm in diameter, can be produced through this standard technique that involves the use of an inverse emulsion—a clear mixture of water in oil also containing a surfactant. The water-in-oil inverse emulsion contains pools of water surrounded by oil molecules. These water droplets can be used as miniature nanoreactors to produce nanoparticles by adding the right amount of monomer into the solution. The chemical thermodynamics governing the emulsion drives the monomer molecules added into the solution directly into the water droplets. The polymerization reaction occurs inside the water droplets, triggered by the addition of an appropriate initiator substance into the system. The microscopic polymerization process inside the tiny water droplet is similar to macroscopic polymerization. One advantage at this stage of particle formation is that drug molecules can be taken up and effectively encapsulated. The nanoparticles formed assume the spherical shape of the water droplet with the size of the resulting nanoparticle being restricted by the diameter of the water droplet. Applications of the inverse emulsion polymerization to micro- and miniemulsions are the most common. For miniemulsions, osmotic pressure is built up by an insoluble agent such as an ionic compound, in the continuous phase. The droplet size finds an equilibrium state which is characterized by a dynamic equilibrium rate between fusion and fission of the droplets and the droplet size seems to be only dependent on the quantity of the osmotic agent. There appears to be a zero effective droplet pressure that results from a balance between the osmotic pressure and the Laplace pressure. As such, inverse miniemulsions do not appear to be as critically stabilized as that for direct miniemulsions but instead are stable systems. Nevertheless, surfactants can be used in a relatively efficient manner for inverse miniemulsion polymerization, especially when compared to inverse microemulsion and inverse suspension polymerizations.

miniemulsion and suspension polymerization is that suspension polymerization utilizes much larger monomer droplets dispersed in the continuous phase.

2.2. Suspension Polymerization

2.4. Seeded Polymerization

Another polymerization method that has many similarities to the emulsion methods is suspension polymerization [22, 38]. In this synthetic method a water-insoluble monomer is dispersed in the continuous phase as liquid droplets via vigorous stirring. An oil-soluble initiator is used to begin polymerization inside the monomer droplets. Droplets are kept from adhesion and coalescence by the presence of a small amount of stabilizer. Nearly all of the nucleation occurs in the droplets which act as isolated batch polymerization reactors. The larger droplet size causes the droplet pressures to be much smaller which leads to Ostwald ripening at a considerably slower rate than in miniemulsions. The final polymer particle size has been found to depend on the stirring speed, volume ratio of the monomer to water, concentration of the stabilizer, the viscosity of both phases, and the design of the reaction vessel. When a properly designed reactor and well-stabilized suspension is used, monodisperse polymer particles can be produced. The final product is generally limited to polymeric particles in the size range of 20–2000
m. The main difference between

Polymerization based on using a previously formed polymer particle or one that is created during the process but altered by swelling followed by chemical reactions is usually referred to as seeded polymerization. Seeded polymerization can be accomplished using many of the previously discussed synthesis techniques, in particular emulsion and dispersion polymerization [23, 34–42]. Synthesis based on seeded polymerization can be used to produce porous polymer particles as well as composite, core–shell, and hollow structures. The porosity of the particles produced by a seeded polymerization technique has been found to be dependent on the molecular weight of the seed polymer. As the molecular weight of the seed increases, the porous particles produced can become macroporous. One drawback of seeded polymerization is that the final particle diameter is limited by the size of the initial polymer particle seed. Monodisperse submicrometer polymer particles are not easily obtained using seeded polymerization but particles from 1 to several hundreds of micrometers appear to be readily producible. For example, extremely uniform

2.3. Precipitation and Dispersion Polymerization Dispersion polymerization can be considered an intermediate technique between homogenous and heterogenous polymerizations [24, 39–43]. All reagents are initially soluble in the medium and produce an insoluble polymer which precipitates out as the polymerization proceeds. By using soluble polymer stabilizers, polymer particles can be produced. The particle stability is primarily controlled by steric effects. A good example of successful dispersion polymerization is the preparation of polyphenol particles. In this work, peroxidase-catalyzed dispersion polymerization was performed by using a water-soluble polymer stabilizer in aqueous 1,4-dioxane and poly(vinyl methyl ether) in a 40% phosphate buffer solution as a steric stabilizer. This work produced relatively monodisperse particles in the submicrometer range. Similar particles of m- and p-cresols and p-phenylphenol have also been produced using the same type of synthetic procedure. In precipitation polymerization, a polymer is generally precipitated out of solution by adding a nonsolvent of the polymer [25]. The primary polymer particles do not form into colloids but remain in a loose slurrylike form. This occurs since no stabilizer or block copolymer is added to the medium and therefore no steric barrier for particle stability is formed. Polymerization can occur in both the continuous and dispersed phase. Careful control of the kinetics can give polymer materials with a wide range of particle sizes (see Fig. 1). For example polymeric spherical particles with an average size of 160 nm have been prepared by precipitation of the particles which was facilitated by the increasing molecular weight of the polymer or from increased cross-linking.

Polymeric Nanoparticles

polymeric particles have been successfully produced using the seeded polymerization techniques. In a rather elaborate study, a repeated seeded emulsion polymerization in a nongravitational field was used to generate uniform polymeric microspheres up to 100
m in size. Ugelstad et al. performed a two-step swelling technique and achieved similar results [42, 43]. This method is characterized by the use of an oligomer of extremely low solubility in water as an effective swelling agent. In order to produce larger particles, from 0.5 to 100
m, which have applications in areas such as polymer coating emulsions that are resistant to shear thinning, Ito et al. used a seeded emulsion polymerization procedure [47]. Controlled coagulation induced by the formation of secondary polymers with opposite charge to the surface of the seed particles was achieved. They studied and characterized the effects of agitation rate, size of the polymer seed particles, and the pH or the reaction mixture. A variety of seeded polymerization methods have been used to produce monodisperse micrometer-sized polymeric particles. Many of these studies were based on using a swelling stage during the overall process. For example, a dynamic selling method makes the seed polymer absorb a large amount of swelling monomers by treating the monomer soluble in the medium with slow, continuous, dropwise addition of water. Many of the conventional emulsion and dispersion seeded polymerization techniques use seed particles consisting of linear polymers for the initial swelling stage. This is due to difficulty associated with preparing micrometer-sized seed particles with a crosslinked network structure. Some success has been reported in using a two-stage swelling process of cross-linked seed particles. The effect of seed cross-linking on monomer swelling and final particle morphology reveals a strong dependence. Core–shell composite polymer particles can also be efficiently produced using seeded polymerization. A seeded dispersion polymerization method was reported to yield micrometer-sized monodisperse polymethyl methacrylate (PMMA)/polystyrene (PS) composite particles consisting of a PMMA core and a PS shell. This study suggested that seeded dispersion polymerization, in which almost all monomers and initiators exist in the medium with seed particles having higher glass transition temperature than polymerization temperature, has an advantage for producing core–shell polymer particles. In particular, polymer layers tend to accumulate in their order of formation, even if the morphology is unstable thermodynamically.

2.5. Self-Assembly of Block and Ionic Polymers Surfactant-free polymeric nanoparticles, something that is extremely difficult to achieve via most synthetic routes, can be produced by taking advantage of the self-assembly of block copolymers and ionomers in a selective solvent [26, 53–73]. Self-assembly of block copolymers can be successfully induced by a variety of methods including chemical reaction, polymer–polymer complexation, microphase inversion, temperature control, and a microwave method. Most of these techniques produce core–shell nanoparticles

877 but have the advantage that nanoparticles are surfactantfree. In addition, core–shell structures are often desirable for many uses in biomedicine (see later sections). Poly(styrene-block-(2,-bis-[4-methoxyphenyl]oxycarbonyl) styrene) nanoparticles have been prepared via self-assembly by using temperature control. The particles are formed with a core–shell structure by using temperature and p-xylene as a solvent. The temperature-induced self-organization is achieved due to the solubility of the rod-shaped poly([4methoxyphenyl]oxycarbonyl)styrene block in p-xylene (soluble above 100
C). Temperature controlled selforganization was also used to produce nanoparticles of poly(N -isopropylacrylamide) (PNIPAM) grafted with short poly(ethylene oxide) chains. Both of these polymers are soluble in water at room temperature, but at higher than 32
C, PNIPAM becomes hydrophobic and undergoes an intrachain coil-to-globule transition and an interchain aggregation to form nanoparticles. By controlling the formation conditions, interchain association can be completely suppressed and a single-chain core–shell nanoparticles are formed. -- -caprolactone) Core–shell poly(ethylene oxide-block-C (PEO-b-PCL) diblock copolymer nanoparticles that are stable in water have also been produced using a microphase inversion technique. In this work, tetrahydrofurane was used as the primary solvent which was suddenly replaced by a nonsolvent, water. This leads to the aggregation of the water insoluble polymeric block, PCL, and to the formation of a core, while the soluble block, PEO, formed a protective corona. Since these core–shell nanoparticles have been shown to be biodegradable in the presence of Lipase PS, they have important applicability to drug delivery. Complexation between multiple polymer blocks has been used to generate stable core–shell nanoparticles. Polyacrylate and PMMA can be complexed with hydroxyl-containing polystyrene [PS–(OH)] in toluene to form insoluble particles. Successful implementation of this concept was achieved by using poly(styrene–block–methyl methacrylate) diblock copolymer complexed with hydroxyl containing polystyrene. Complexation of the PMMA block and the PS–(OH) led to an insoluble core, while the soluble PS blocks prevent macroscopic precipitation. The final product was stable nanoparticles whose particle size could be regulated by the initial concentrations of the two components and by the mixing order. Microwave irradiation can also be used to facilitate the formation of polymeric nanoparticles. Stable polystyrene nanoparticles were formed by using microwave radiation in the presence of potassium persulfate in water. This method substantially reduces the reaction time (factor of 20) and produces narrowly distributed nanoparticles. Particle size can be controlled by varying the monomer-to-initiator weight ratio.

2.6. Polyanionic Solution-Based Both continuous and batch processes have been developed which use a polyanionic solution that is atomized into a swirling polycationic solution to form polymeric nanoparticles [74–81]. This method of production is often referred to as titration since a sequential addition of one polymer into another is performed. By varying the ratios of

878 polyanion to polycation, a variety of nanoparticle compositions can be produced. One advantage of this method is that all solutions are made using water as a solvent which eliminates the possibility of having trace amounts of organic solvents of surfactants within the nanoparticles (a serious problem for medical applications). The polyanionic method is intimately effective for generating core–shell nanoparticles. In a typical process, the anionic solution (droplet-forming) forms the core and the cationic solution (receiving solution) forms the corona or shell. This is the most common setup and is often referred to as the standardized system; however, there are examples of the reverse where a droplet-forming cationic solution is mixed with an anionic receiving solution. A typical batch system is composed of a needle connected to a syringe that is inserted into an ultrasonic hollow titanium probe with a conical tip. The probe is connected to a transducer and power generator which is used for nebulizing the solution. An anionic polymer solution is introduced into the syringe and slowly extruded through the needle and the probe tip where it is atomized by the transducer. The atomized anionic mist is released into air above a container of the cationic solution which is vigorously swirled during the reaction (1–2 min). As mentioned previously the anionic solution is generally used as the droplet-forming internal phase mixture (core polymer) and the cationic solution is used as the receiving batch mixture (corona or shell polymer). A reverse system simply uses the same setup but introduces a cationic mixture into the syringe to form the mist that is received by an anionic solution. The batch system described can be modified into a continuous system by using two inflow lines, one for the anionic solution and one for the cationic solution, and one overflow line to keep the receiving bath volume constant. This mode of operation produces nanoparticles of similar quality to the batch system.

2.7. Polyelectrolyte Complexes Polymeric nanoparticles formed from macroscopic homogeneous colloidal systems can be prepared by aggregates of a high molar mass polyion species of weak charge density (called the host) with a much shorter lower mass macromolecular counterion (called guest) [82, 83]. Through continuous addition of the guest reactant, polymer nanoparticles form as colloidal particles that aggregated and precipitate. By altering the ratio of the host to guest, a variety of compositions can be produced. This technique is similar to the polyanionic solution based methods described previously and share similar advantages. In particular, multipolymeric water-soluble mixtures of two interacting pairs enable a template assembly of the nanoparticles. There is no use of organic solvents or surfactants and the process offers a high flexibility in choosing reacting pairs.

3. SUPERCRITICAL FLUID-BASED PARTICLE PRODUCTION Supercritical fluids (SCFs) are substances that are above their critical temperature and critical pressure [84]. These substances often have densities and solvating capabilities

Polymeric Nanoparticles

similar to those of a typical liquid but have diffusivity and viscosity comparable to that of gases, making them ideal solvents. These unique properties provide great promise as a versatile, environmentally acceptable replacement for conventional solvents. Indeed SCFs have been used fairly extensively for extractions, in particular for coffee and tea decaffeination, natural product extraction, and chromatography. More recent applications of SCF technology have been in the area of processing such as mixing, impregnation, encapsulation, reaction, crystal growth, etc. [85–97]. The most used SCF has been carbon dioxide (CO2 . This is primarily because supercritical carbon dioxide (scCO2  has an easily achievable critical point of 31.1
C and 73.8 bars and is nontoxic, cheap, nonflammable, and environmentally acceptable and may be recycled. The use of SCFs in polymer science has begun to witness an increase in popularity and a number of successful production techniques for polymeric particles have been reported [75–87]. Recently polymer-based nanoparticles have been produced by these alternative methods using supercritical fluid technology. Particles that have been produced using SCF technology tend to have characteristics that are strongly influenced by the properties of the solute, the type of SCF used, and the processing parameters (such as flow rate of solute and solvent phase, temperature and pressure of the SCF, pre-expansion temperature, nozzle geometry, and the use of coaxial nozzles). For example, polymer properties such as polymer concentration, crystallinity, glass transition temperature, and polymer composition are important factors that determine the final morphology of the particles. An increase in the polymer concentration can lead to the formation of less spherical and fiberlike particles. In an antisolvent process, the rate of diffusion of antisolvent gas is higher in a crystalline polymer compared to an amorphous polymer leading to high mass transfer rates in crystalline polymers that produces high supersaturation ratios and small particles with a narrow size distribution. Since SCFs act as plasticizers for polymers by lowering their glass transition temperatures Tg, polymers with a low Tg tend to form particles that become sticky and aggregate together. A change in polymer chain length, chain number, chain composition, and branching ratio can alter polymer crystallinity and thus the particle morphology. Core–shell particle structures can be produced by using an intimate mixture under pressure of the polymer material with a core material either before or after SCF solvation of the polymer, followed by an abrupt release of pressure which leads to solidification of the polymeric material around the core material. This technique has been successfully used to microencapsulate infectious Bursal Disease virus vaccine in a polycaprolactone or a poly(lactic-co-glycolic acid) matrix. There have been a reasonable number of drug and polymeric microparticles prepared using SCFs as both solvents and antisolvents. Particles from 5 to 100
m were the first to be produced using an array of solutes including lovastatin, polyhydroxy acids, and mevinolin. Further work in the past decade has lead to the simultaneous co-precipitation of two solutes, a drug, an excipient, and poly(lactic acid) (PLA) particles of lovastatin and naproxen. In these studies, supercritical CO2 was passed through an extraction vessel containing a mixture of drug and polymer, and the CO2

Polymeric Nanoparticles

containing the drug and the polymer was then expanded through a capillary tube. In another process, PLA and clonidine were dissolved in methylene chloride, and the mixture was expanded by supercritical carbon dioxide to precipitate polymeric drug particles. Similar to polymeric particles produced using SCF technology, the properties of the drugs such as solubility and partitioning of the drug into SCF determine the properties of the particles formed. For example, if the drug is soluble in a SCF under the operating conditions, it will then be extracted into the SCF and will not precipitate out. It has been observed that steroids with log P (the log of the partition coefficient) values between 1.6 to 3.9 formed spherical nonporous particles, whereas steroids with log P of 4.2 or 4.3 were extracted out into the SCF. The properties of the drugs also play an important role during encapsulation of a drug in a polymer matrix. There are strong influences of the properties of the drug on the drug loading. PLA-microparticle formation using an antisolvent process with supercritical CO2 indicated that an increase in log P decreases the loading efficiency as well as release rate, possibly because lipophilic drugs can be entrained by supercritical CO2 during SCF precipitation. Nucleation and growth rate influence the effective encapsulation and morphology of the particles. If the initial nucleation and growth rate of the drug is rapid and the polymer precipitation rate is relatively slow, then the drugs can form needles encapsulated in polymeric coat. SCF technology is currently claimed to be useful in producing particles in the 5 to 2000 nm range. U.S. Patent 6, 177, 103 describes a process that rapidly expands a solution of the compound and phospholipid surface modifiers in a liquefied gas into an aqueous medium, which may contain the phospholipid. By expanding into an aqueous medium, particle agglomeration and growth are prevented, thereby producing particles of a narrow size distribution. An additional step may be required to remove the aqueous phase if the final product is a dry powder. To achieve commercial success, the methods or techniques developed need to be scaled up to produce batch quantities for conducting further research or for marketing the product. The advances in the understanding of the mechanism of supercritical particle formation and SCF mass transfer are forming the basis for efficient scale-up of the laboratory-scale processes. While many laboratory investigators were only able to produce milligrams of the product, a scaled process that was capable of producing 200 g of biodegradable PLA particles in the size range of 6 to 50
m has been developed. Cost of manufacturing at the pilot scale with SCF technology has been claimed to be comparable to several conventional techniques, such as single-stage spray drying, micronization, crystallization, and milling batch operations. Thus from the perspective of scale-up, SCF technology appears to offer some advantages. The processing equipment can be a single stage, totally enclosed process that is free of moving parts and constructed from highgrade stainless steel, allowing easy maintenance. It offers reduced solvent requirements and particle formation occurs in a light-, oxygen-, and possibly moisture-free atmosphere, minimizing these often confounding factors.

879

4. DROPLET AND AEROSOL TECHNIQUES Many nonsynthetic methods for producing polymeric particles are based on nebulization or piezoelectric droplet generation of very dilute polymer solutions [98–111]. Over the last several years, advances in microdroplet production technology for work in single-molecule detection and spectroscopy in droplet streams has resulted in generation of droplets as small as 2–3
m with a size dispersity of better than 1%. In the context of polymer particle generation, droplet techniques are attractive since particles of essentially arbitrary size (down to the single polymer molecule limit) can be produced by adjusting the size of the droplet of polymer solution, or the weight fraction of the polymer in solution. While droplet production in the size range of 20–30
m (diameter) is more or less routine (several different ondemand droplet generators are now available commercially), generation of droplets smaller than 10
m remains nontrivial especially under the added constraint of high monodispersity. Small droplets ( 3
m). In addition, polymeric particles have also found some applications in xerographic toners and as expandable beads for commodity materials. Polymeric particles are also one of the main constituents of polymer colloids, a class of polymers manufactured in the form of fine dispersions of polymer particles in aqueous or nonaqueous media. This class of polymers has found wide commercial applications in synthetic rubber (for tires, running shoes, and so on; Teflon, neoprene for fan belts and wet suits), surface coatings, paints, adhesives, impact modifiers, soil conditioners, toners for image development,

891 and the biomedical and biotechnical fields. Polymer colloids is one of the largest areas of polymer research and includes emulsion polymerization of acrylic monomers to form latex paints, suspension polymerization of divinylbenzene and comonomers to form ion-exchange and other porous resins, and micro- and miniemulsion polymerization to form submicrometer spheres for biodiagnostic uses. We have not included a specific section on polymeric or functional polymer colloids but have discussed many of the applications and synthetic production methods relevant to this field. A good source to get a more complete view on functional polymer colloids is provided in [309].

9.3.1. Supported Catalysts Supported homogeneous and heterogeneous catalysts are used extensively in industrial manufacturing of fine chemicals such as drugs, perfumes, pesticides, food additives, petrochemicals, etc. [309–312]. The use of inorganic catalyst supports such as activated carbon, silica, silica gel, alumina, etc. unfortunately provide little flexibility for tailoring which often leads to catalysts that do not have satisfactory selectivity. Organic polymer supports, on the other hand, provide a much larger degree of flexibility for tailoring. Cross-linked polymers with specific properties are widely used as catalyst supports since they are inert, nontoxic, nonvolatile, and often recyclable. Specific control over catalytic and complexing ability of ligands can be induced and the amount of metal present on the surface of such catalysts is very small, which is of economic significance in the case of expensive catalytic metals such as Ru and Pd. For these reasons, polymer supported catalysts have generated a considerable amount of interest in research. Examples can be found in selective hydrogenation of polyunsaturated cycloolefines and unsaturated carbonyl compounds where a functional polystyrene-supported metal (Ru, Rh, Pd) catalyst was successfully produced. In addition a number of applications have used commercially available resins as supports and ligands to produce effective polymer-supported catalysts. Again, the advantage of using polymer supports is the possibility to influence product selectivity by support and ligand composition. This applies to both homogeneous and heterogeneous catalyst systems. Clearly, polymeric particles offer notable advantages for catalyst supports due to their high surface area to volume ratio, a crucial element for efficient catalysis. In addition, the intimate control of particle size and composition provides flexible parameters for tailoring the selectivity of the supported catalyst.

9.3.2. Ion Exchange Resins Ion exchange is a process whereby anions or cations from solution replace anions or cations held on a solid sorbent [313]. The exchange process is reversible in that the exchanged ions can be released by treating the sorbent with a suitable stripping reagent. Natural soils contain solids with charged sites that exchange ions, and certain minerals called zeolites are quite good exchangers. Ion exchange also takes place in living materials because cell walls, cell membranes, and other structures have charges. Ion exchange materials

Polymeric Nanoparticles

892 include silicates, phosphates, flourides, humus, wool, proteins, cellulose, alumina, glass, and many others. The first industrial ion exchangers were inorganic aluminum silicates, used for softening water and treating sugar solutions. Later it was discovered that sulfonated coal was a relatively effective ion exchange material, but these types of materials are fragile and useful only under restricted operating conditions. Now nearly all ion exchange applications use synthetic polymer resins. Ion exchange resins are polymers with electrically charged sites where ions may replace others [313]. These synthetic ion exchange resins are usually cast as porous beads with considerable external and pore surface where ions can attach. Absorption plays an important role whenever there is a large surface area and if a substance is adsorbed to an ion exchange resin, no ion is liberated. Polystyrene-based ion exchange resins are the most common. These are generally insoluble spherical or irregular porous particles grafted with negatively (sulfonic or carboxylic) or positively (quarternary, tertiary, secondary, or primary amino) charged groups and the particles generally have excellent chemical, mechanical, and in most cases thermal stability. Typical applications of polymer particle-based ion exchange resins have included: water treatment, sugar refinement, preparation and purification of pharmaceuticals, catalysts, etc.

9.3.3. Calibration Standards and Chromatography Polymer particles, in particular, polystyrene particles, which can be produced with quality size standards are often used for calibration of flow cytometers, particle and hematology analyzers, confocal laser scanning microscopes, and zetapotential measuring instruments. In addition, monodisperse polymer particles provide advantages for support materials in high performance liquid chromatography [314–317]. By using precise sized polymer particles, uniform packing of the chromatographic columns can be achieved and allows operation under lower pressures with an associated high efficiency of separation capacity. Another example of the advantage of using monodisperse polymer particles is in size exclusion chromatography. Size exclusion chromatography (SEC), is commonly used to obtain molecular weight distributions of polymers. Many biopolymers, including a large number of polysaccharides, have very large hydrodynamic sizes that may prevent an efficient use of SEC. By using macroporous, highly monodisperse polymer particles the range of molecular sizes accessible for aqueous SEC has been extended toward larger values.

9.4. Rheological Fluids Viscosity control can be achieved by using particles whose volume changes with environmental conditions [318–333]. For example, the volume of carboxylated latex particles increases with increasing pH so that the viscosity of the dispersion increases [318]. Ethyl acrylate-methacacrylic acid copolymer latex is one of the most popular thickeners. Other variables used to influence viscosity have been temperature, poly(N -isopropylacrylamide) particles, and electric fields [318, 319].

9.4.1. Electrorhelogical Fluids The use of electric fields to control viscosity of polymer particle-based fluids is known as electrorhelogical fluids [318]. These fluids are composed of particles from 1 to 100
m in diameter that are suspended in a nonconducting liquid. The particles align themselves into structures along the direction of an applied electric field which dramatically changes its rheological properties. This is similar to a sol–gel transition but one that is controlled with an electric field. The extent of the alignment of polymeric particles has been found to depend mainly on the difference in dielectric constants of the liquid medium and the particle. Poly(methacrylic acid) particles in various media, paraffin oil, poly(dimethyl siloxane), chlorinated paraffin, and transformer oil, were also found to give increasing yield stress as a function of increasing particle diameter up to 900 nm. Applications of these fluids are expected to be mainly in the area of mechanical devices such as novel switches, actuators, clutches, etc.

9.4.2. Magnetorheological Fluids Magnetorheological (MR) fluids are considerably less well known than electrorheological (ER) fluids. Both fluids are noncolloidal suspensions of polarizable particles having a size on the order of a few micrometers that respond to external MR or ER fields with a change in rheological behavior [318–333]. Typically, this change is manifested by the development of a yield stress that monotonically increases with applied field. Interest in magnetorheological fluids originates from their ability to provide simple, quiet, rapid-response interfaces between electronic controls and mechanical systems [318–333]. Many researchers believe magnetorheological fluids have the potential to radically change the way electromechanical devices are designed and operated. The magnetorheological response of MR fluids results from the polarization induced in the suspended particles by application of an external field. The interaction between the resulting induced dipoles causes the particles to form columnar structures, parallel to the applied field. These chainlike structures restrict the motion of the fluid, thereby increasing the viscous characteristics of the suspension. The mechanical energy needed to yield these chainlike structures increases as the applied field increases resulting in a field dependent yield stress. In the absence of an applied field, MR fluids exhibit Newtonian-like behavior. While the commercial success of ER fluids has remained relatively elusive, MR fluids have seen an increasing commercial success. A number of MR fluids and various MR fluid-based systems have been commercialized including an MR fluid brake for use in the exercise industry (stationary bikes), a controllable MR fluid damper for use in truck seat suspensions, and an MR fluid shock absorber for oval track automobile racing.

10. POLYMER PARTICLE PATENT REVIEW There has been a relatively large number of patents on production methods and applications of polymer micro- and nanoparticles (on the order of 400 from 1996 to 2002).

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A similar trend has been witnessed in the dendrimer and hyperbranched polymer area: approx. 433 patents issued during 1996–2000 on uses and production of dendrimers with an incredible growth rate giving a projection of well over 1000 patents before 2005. Such vibrant activity is clear evidence of the importance and applicability these materials to a broad range of fields. We provide a brief overview of some relevant patents in the area of polymer particles. The purpose is to give a brief overview of the various types of patent disclosures issued, not to discuss all of the various patents. Intricate details of the patents we discuss can best be obtained from the actual patent disclosures and supporting literature contained therein. A continuous process for the preparation of inorganic and organic bead polymers using a static micromixer was disclosed by Eisenbeiss et al. [334]. According to this invention the bead polymers obtainable by the process have a very uniform particle size distribution, which can be set in a range of between 0.1 and 300
m. The process is based on the mixing of liquid streams of suitable, usually immiscible component solutions in a micromixer, giving spherical particles in a continuous procedure with extremely improved volume yield, large particle yield with particle size range which can be set to a specific value, simplified temperature program, and reduced consumption of chemicals. A composite paramagnetic particle and method for production was recently disclosed [335]. In one aspect of the invention, a particle comprised of a multitude of submicrometer polymer bead aggregates covalently cross-linked to each other to form larger diameter particles is presented. Distributed throughout the composite paramagnetic particle are vacuous cavities. Each submicrometer polymer bead has distributed throughout its interior and surface submicrometer magnetite crystals. In another aspect of the invention, composite particles are produced by using high energy ultrasound during polymerization of one or more vinyl monomers. In one embodiment, high energy ultrasound is used during an emulsification step and during the early stages of the polymerization process to produce micrometer sized composite paramagnetic particles. The particles according to the invention exhibit a high percent magnetite incorporation and water and organic solvent stability. A method reported for the preparation of polymer particles includes: (a) forming an organic phase by dissolving a polymer material in a solvent; (b) dispersing the organic phase in an aqueous phase comprising a particulate stabilizer and homogenizing the resultant dispersion, thereby forming spherical particles having a selected particle and uniform particle size distribution; (c) following the homogenizing, adding a particle shape-modifying surface active material to the spherical particles; and (d) removing the solvent, thereby producing irregularly shaped polymer particles having mainly the same selected particle size and distribution as the spherical particles [336]. A process has been reported for the preparation of polyvinylarene polymer particles by suspension polymerization, where (a) vinylarene monomers are suspended in an aqueous medium to yield a suspension; (b) the temperature of the suspension is adjusted to a temperature above 50
C, at which temperature an initiator is added; (c) subsequently, the reaction temperature is increased by 5 to 30
C

893 per hour until a temperature of at least 120
C is reached; and (d) the temperature is retained at least 120
C until the polymerization is complete [337]. Wu describes polymer particles made from copolymers of multifunctional (meth)acrylate monomer and multifunctional aromatics [338]. He also described methods of improving the compression characteristics of (meth)acrylate polymer particles by copolymerizing with a multifunctional (meth)acrylate monomer a multifunctional aromatic monomer. The particles are of a size, are of a uniformity, and contain physical characteristics that make them ideally suitable for use as spacers in liquid crystal display devices. Particles of a copolymer of a vinyl arene and a copolymerizable compound containing a polar moiety and a vinyl moiety containing water may be prepared by forming a mixture of monomers and small amounts of water and polymerizing under agitation to 20 to 70% conversion and then suspending the mass in water and finishing the polymerization. The resulting polymer beads contain finely dispersed water which is useful as an environmentally acceptable blowing agent [339]. An aqueous microemulsion polymerization procedure is described in which very small colloidal polymer particles are produced from tetrafluoroethylene monomer. The polymerization procedure involves adding a free radical initiator to a mixture of a microemulsion of at least one liquid saturated organic compound, and tetrafluoroalkyl ethylene [340]. A composition that includes a plurality of microcapsules each with one to five particles in a liquid droplet, and a complex coacervation induced shell encapsulating the liquid droplet and the one to five particles, has been reported [341]. There is also a composition comprised of a plurality of microcapsules each including a single particle in a liquid droplet, and a complex coacervation induced shell encapsulating the liquid droplet and the single particle. The authors also describe an encapsulation process [342] that includes (a) forming an emulsion composed of a continuous phase comprising a liquid, a cationic material, and an anionic material, and a disperse phase composed of a plurality of droplets of a second liquid, wherein a number of the droplets includes therein one to five particles; and (b) inducing complex coacervation of the cationic material and the anionic material. A polymer packing material suitable for liquid chromatography and a method for producing it was described by Kimura et al. [343]. The polymer packing material was based on polymer particles with a styrene skeleton and had a monodispersed particle distribution that could be obtained by hydrophilic treatment of an inner surface of a micropore existing in a fine pore of the polymer packing material, or subsequent introduction of a hydrophobic group into the inner hydrophilic surface by chemical modification. A method for producing the polymer packing material suitable for liquid chromatography includes the step of polymerizing glycerol dimethacrylate as a cross-linking agent and 2-ethylhexl methacrylate as a monomer according to a two-step swelling polymerization process. Alternatively, the producing method includes the step of cross-linking and polymerizing only glycerol dimethacrylate to form a polymer and introducing the hydrophobic group into the polymer by

894 chemical modification to form a shell around each of the droplets [343]. An inorganic dispersant having a high specific surface area and a high surface activity which comprises a calcium phosphate type compound having a specific particle composition, particle shape, particle size and dispersibility, and specific surface area was recently disclosed. When used as a suspension polymerization stabilizer, it provides polymer particles having a uniform and sharp particle size distribution, and when the polymer particles are contained in an unsaturated polyester resin composition and a toner composition, the obtained compositions have excellent quality [344]. A seeded microemulsion polymerization procedure in which colloidal polymer particles are produced from tetrafluoroethylene or tetrafluoroethylene/comonomer or other polymerizable monomers was described by Wu. The particles have an average diameter between 1 to 100 nm. A microemulsion is formed of a liquid monomer in water and a gaseous monomer is added either before or after polymerization is initiated [345]. An efficient method was disclosed for obtaining polymer particles by evaporating an organic solvent while maintaining a solution of a polymer in the organic solvent in contact with polymer particles, using a simple apparatus and a simple procedure. The polymer particles (powder) produced by the method have a small particle diameter, a high bulk density, and a small amount of residual solvent. The method includes introducing the organic solvent solution of the polymer into a particle producing zone which does not substantially contain steam, wherein an atmosphere is maintained in which the organic solvent is vaporizable and the particles are stirred. The organic solvent is evaporated, while maintaining the solution in contact with the polymer particles [346]. A phase inversion process for preparing nanoparticles and microparticles has been reported. The process involves forming a mixture of a polymer and a solvent, wherein the solvent is present in a continuous phase, and introducing the mixture into an effective amount of a nonsolvent to cause the spontaneous formation of microparticles [347]. Microspheres have been prepared by providing a solution of the polymer and of the active principal in a waterimmiscible solvent which is more volatile than water and mixing with an aqueous solution of the surface-active agent, followed by evaporation of the solvent [348]. Biocompatible microspheres containing one or more active principals, a biodegradable and biocompatible polymer and a surfaceactive agent which is also biodegradable and biocompatible, contain less than 10 ppm of heavy metals. A method of making polymeric particles having a predetermined and controlled size and size distribution is described by M. Nair, Z. R. Pierce, and C. Sreekumar (U.S. Patent 4, 833, 060, 1989). This disclosure describes a process which comprises dissolving a polymer in a solvent immiscible in water to form a solution, forming a suspension of small droplets of said solution in water containing a promoter which is water soluble and silica particles having an average particle size of from 0.001 to 1
m by high shear agitation. The promoter affects the hydrophilic/hydrophobic balance of the silica particles in the water suspension, removing the

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solvent from the droplets and separating the solidified polymer particles from the water. Otaigbe et al. [349] described a method for making polymer microparticles, such as spherical powder and whiskers (a whisker is defined here as a polymer microfiber of