Additive Manufacturing in Pharmaceuticals [1st ed. 2023] 9819924030, 9789819924035

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Subham Banerjee   Editor

Additive Manufacturing in Pharmaceuticals

Additive Manufacturing in Pharmaceuticals

Subham Banerjee Editor

Additive Manufacturing in Pharmaceuticals

Editor Subham Banerjee Department of Pharmaceutics National Institute of Pharmaceutical Education & Research (NIPER) Guwahati, Assam, India

ISBN 978-981-99-2403-5 ISBN 978-981-99-2404-2 https://doi.org/10.1007/978-981-99-2404-2

(eBook)

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Paper in this product is recyclable.

Preface

Industrial additive manufacturing (AM)/3D printing has reached a tipping point and is set to explode into the public. AM technology has evolved far beyond prototyping, quick tooling, trinkets, and toys, yet a few executives and engineers are unaware of this development. “AM” is the creation of long-lasting and secure items for sale in moderate to large volumes to actual customers. 3D printing is “ready to emerge from its niche position and become a viable alternative to conventional manufacturing processes in an expanding number of applications.” The applicability of the AM is increasing day by day in various fields including the pharmaceutical field. AM has provided a personalization front to the pharmaceutical industry where dosage development can be patient centric. If needed, 3D printed dosage form can be formulated with customized shape, size, and release characteristics on the patient bedside. Hailing from rapid prototyping and into biomedical field, 3D printing has convincingly revolutionized the pharmaceutical industry and its pace of innovation. 3D printing empowers the formulation design to new directions such as personalized medicine, controlled-released dosage form, organ-on-a-chip, as well as implants. Even until a few years ago, it was implausible to foresee the adoption of 3D printing in the formulation development pipeline such as preformulation to first-in-human (FIH). And now, 3D printing is being investigated to be used in frontline clinical trial setting to provide personalized service to the trial patients. Around 30,000 articles in technological literature have already been published discussing the futuristic application of 3D printing in the pharmaceutical field. The rapid progression of 3D printing in the pharmaceutical field is a result of an extensive amount of past research, driven by its vast application potential. In the visible way of the paradigm shift in AM, the pharmaceutical field also progressed and developed the levetiracetam-embedded oral dispersible tablets, Spritam, in 2015 using the binder jet technology. Spritam was the first and only drug-loaded 3D printed formulation that was approved by the U.S. Food and Drug Administration (FDA). Hence, Chap. 1 encapsulates the past and the present status of 3D printing in pharmaceuticals with an open-ended future application possibility. Known for its flexibility and ease of use, fused deposition modeling (FDM) has been one of the first 3D printing processes to be exploited for medical applications. In FDM 3D printing, feedstock material is fed to a heated nozzle where the feedstock is softened and deposited on a bed. The resulting 3D object is created in a layer-by-layer fashion by movement of either the nozzle or the bed along different v

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axes. Chapter 2 discusses the advantages and limitations of the FDM technique, its numerous applications in the medical field, and its future potential to become an established pharmaceutical manufacturing technique. In the pharmaceutical domain, stereolithography (SLA) 3D printing can offer the ability to rapidly fabricate dimensionally accurate drug-loaded excipients that are internally solid, cost-effective, and externally smooth. One of the principal benefits common to 3D printing technology is the ability to personalize medicine. The pharmaceutical SLA 3D printing domain is relatively new, and there is a huge scope for further development. Chapter 3 will start by providing a brief history of SLA 3D printing. This will be followed by the coverage of some of the earliest research in pharmaceutical SLA 3D printing. From there, the chapter will gradually build up to the latest findings in the domain. Then, the most cutting-edge and promising developments will be discussed. Finally, the challenges and future potential of the technology will be presented. Rapidly developing and evolving rapid prototyping technologies, as well as the emergence of 3D printable materials integrated with drug moieties, have enormous potential in the customization of dosage forms required for patients. Feature-rich functionalities of solid dosage forms such as desired control over porous internal architecture, complex geometry, and wide varieties of possible shapes and sizes, which are very difficult to achieve with mass manufacturing, are now possible with the use of selective laser sintering (SLS)-mediated rapid prototyping. Thus, the purpose of Chap. 4 is to discuss the basic fundaments of SLS, its potential pharmaceutical applications along with diverse processable materials, essential process parameters and their effect on SLS-mediated fabrication, setbacks for scaleup, regulatory consideration, and future aspects of SLS-mediated 3D printing in pharmaceuticals. Semisolid extrusion (SSE) consists of an extrusion-based 3D printing technique widely employed in food printing and bioprinting. In pharmaceutics, SSE is becoming the most explored technique to obtain solid dosage forms with specific characteristics, such as chewable, fast-dissolving, or gastro-floating tablets; polypills; oral and topical films; and rectal suppositories, among others. Due to this versatility, SSE has become a powerful tool to produce innovative dosage forms with clinical relevance for specific groups, including pediatric, geriatric, and veterinary populations, as personalized medicines. This is covered in Chap. 5. After two decades of foundational work, global interest remains ascendant for the AM of pharmaceuticals. At the forefront of this interest is binder jetting onto powder, which holds a unique position due to the early regulatory precedents established using this technology and also the diversity of materials it can process. Chapter 6 provides a technical foundation for binder jet printing of pharmaceuticals, with particular emphasis on its application to novel pharmaceutical dosage forms and future perspectives in the field. 4D printing is the potential evolution of AM by integrating the time variable. It can create dynamic structures which transfer a shape to another desired shape due to the influence of external stimulations. It has attracted the attention in healthcare with the noticeable advantages of the wide variety of materials used in the printing,

Preface

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unlimited design, and individual medical use. Chapter 7 represents the significant role of 4D printing in healthcare, which offers the recent 4D printing technology to the future directions of 4D printing in healthcare. Frist, a brief overview of 4D printing is introduced. Then, the process of 4D printing methods based on standardized categories of AM is illustrated. The suitable materials and advantages in each method are described to introduce a better way in the use of 4D printing. In addition, the materials used in 4D printing are reviewed with consideration on stimuli-responsive behaviors and types of initiate materials. Finally, the challenges and future trend of 4D printing are discussed. 4D printing for the development of pharmaceutical and drug delivery system is presented and deeply discussed in Chap. 8. Commercial launch of a pharmaceutical new chemical entity is an outcome of extensive financial and time commitments. Failure of drugs at late stage of clinical trials causes immense loss to the developer. Technological innovations that can provide reliable prediction of safety and efficacy of the molecules in the early phases of discovery process are of extreme importance for the pharmaceutical industry. Due to their ability to better mimic composition and anatomical characteristics of tissues over conventional two-dimensional monolayer cultures, three-dimensional (3D) models are increasingly proving beneficial. Successful development of such 3D models is expected to provide better physiological correlation compared to 2D culture, and the former may be used as a replacement for animal models. Among various other fabrication techniques, bioprinting is an advanced technique to fulfil the purpose of development of biomimetic constructs. Chapter 9 presents the fundamental aspects of bioprinting and discusses its application in different stages of drug discovery, like high-throughput screening and predictive in vitro safety. 3D printed drug product has to meet the standard of identity, strength, quality, and purity. To encourage the use of novel technology in drug product manufacturing including 3D printing, the FDA/CDER has established “Emerging Technology Program” to guide sponsors in identifying and resolving potential technical and regulatory challenges. Chapter 10 reviews the regulatory aspect of 3D printed drug products. In industrial fields, the application of machine learning and deep learning in AM is expected to be an effective method to optimize the manufacturing process, to control the quality of 3D printed objects, to detect defects in the objects, and to predict material properties. Machine learning may hold promise in solving the complex problems of drug manufacturing using 3D printers. Chapter 11 introduces the recent advancement of 3D printed medicine and the application of machine learning. Subsequently, it discusses about 3D printed medicines that use statistical approaches in the experimental methods. Finally, a possible future is embedded where “artificial intelligence pharmacists” will regularly use 3D printers in a clinical setting. The potential uses of AM are anticipated to have a promising future in the pharmaceutical industry. Researchers believe that AM is a groundbreaking pharmaceutical technology that may shape the future of many industries, including pharma. The vision of the studies and diligent work in the field of AM in pharmaceuticals can

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be seen day by day in terms of publications and in the pipeline of the pharmaceutical industry. The current medical research is the primary focus of this book, which also includes a thorough explanation of the applicability, restrictions, and regulatory considerations of AM in pharmaceuticals. Guwahati, India

Subham Banerjee, Ph.D.

Contents

1

History and Present Scenario of Additive Manufacturing in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Koyel Sen, Thomas G. West, and Bodhisattwa Chaudhuri

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Fused Deposition Modeling (FDM) of Pharmaceuticals . . . . . . . . . . . . . . . Silke Henry, Valérie Vanhoorne, and Chris Vervaet

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Stereolithography (SLA) in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . Prashanth Ravi and Parimal Patel

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Selective Laser Sintering (SLS) in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . 125 Tukaram Karanwad, Srushti Lekurwale, and Subham Banerjee

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Semi-Solid Extrusion (SSE) in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . 171 Nadine Lysyk Funk, Júlia Leão, Thayse Viana de Oliveira, and Ruy Carlos Ruver Beck

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Inkjet and Binder Jet Printing in Pharmaceuticals. . . . . . . . . . . . . . . . . . . . . 201 Thomas G. West and Jaedeok Yoo

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4D Printing: The Next Dimension of Healthcare in Cancer Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Atchara Chinnakorn, Wiwat Nuansing, Abbas Z. Kouzani, Mahdi Bodaghi, and Ali Zolfagharian

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4D Printing in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 Irene Chiesa, Amedeo Franco Bonatti, Aurora De Acutis, Gabriele Maria Fortunato, Giovanni Vozzi, and Carmelo De Maria

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Bioprinting in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Mansi Dixit, Nidhi Singh, Priyanka Das, and Pallab Datta

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Regulatory Perspective of Additive Manufacturing in the Field of Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Ziyaur Rahman, Naseem A. Charoo, Eman M. Mohamed, Mathew Kuttolamadom, and Mansoor A. Khan

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Contents

Machine Learning in Additive Manufacturing of Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Tatsuaki Tagami, Koki Ogawa, and Tetsuya Ozeki

Editors and Contributors

About the Editor Subham Banerjee, Ph.D. is an Associate Professor in the Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India. He is also a visiting staff faculty of the University of Texas (UT) at Austin, Texas, USA. In addition, he is also serving as a coordinator cum co-principal investigator of the “National Centre of Pharmacoengineering (state-ofthe-art facility)” funded under the Drugs and Pharmaceuticals Research Programme (DPRP), Department of Science and Technology (DST), Ministry of Science and Technology, Government of India. He has also served as an Assistant Professor in the same department at the NIPER, Guwahati. His research area focuses on pharmacoengineering including pharmaceutical additive manufacturing (AM), drug delivery engineering, and cutting-edge translational pharmaceutical research. He is the recipient of several prestigious national and international competitive awards, notably Gandhian Young Technological Innovation (GYTI) Award (2017) from Rashtrapati Bhavan (President’s Secretariat), New Delhi, India; Innovators Under-35 (2017) from MIT Technology Review, USA; NASI-Swarna Jayanti Puraskar (2020), Prayagraj, India, etc. He also bagged the first prize in 2020 for BIRAC-BRTC Mapping the Changemakers of the Northeast Region of India and many other prestigious recognitions, including several extramural research funds from various funding bodies in the Government of India. He has more than 9.5 years of teaching and research experience. He possesses 3 granted Indian patents, 2 granted Indian design patents, a 3D printed technologyderived product transferred to the industry, and 9 international book chapters and has published more than 90 research articles in peer-reviewed national/international journals. He is an active member/associate/fellow of the leading learned scientific societies of India and overseas as well. He is a “Member of the National Academy of Sciences (MNASc),” Prayagraj, India; “Associate of the Indian Academy of Sciences (IASc),” Bengaluru, India; “Associate of the West Bengal Academy of Science and Technology (AAScT),” Kolkata, India; “Member of the Royal Society of Chemistry (MRSC),” United Kingdom (UK); “Fellow of the Indian Chemical

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Society (FICS),” India; and “Executive Committee Member of the Controlled Release Society-Indian Local Chapter (CRS-IC),” Mumbai, India.

Contributors Subham Banerjee Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India Ruy Carlos Ruver Beck Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Mahdi Bodaghi Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK Amedeo Franco Bonatti Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy Naseem A. Charoo Succor Pharma Solutions, 216-Laboratory Complex, Dubai Science Park, Dubai, UAE Centric Compounding LLC, 216-Laboratory Complex, Dubai Science Park, Dubai, UAE Bodhisattwa Chaudhuri Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA Institute of Material Sciences, University of Connecticut, Storrs, CT, USA Irene Chiesa Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy Atchara Chinnakorn School of Physics, Institute of Science, Suranaree University of Technology (SUT), Nakhon Ratchasima, Thailand Priyanka Das Department of Pharmaceutics, Polymer-based Medical Devices, and Complex Drug Delivery Laboratory, National Institute of Pharmaceutical Education and Research Kolkata, Kolkata, India Pallab Datta Department of Pharmaceutics, Polymer-based Medical Devices, and Complex Drug Delivery Laboratory, National Institute of Pharmaceutical Education and Research Kolkata, Kolkata, India Aurora De Acutis Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy Carmelo De Maria Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy

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Thayse Viana de Oliveira Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Mansi Dixit Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, Kolkata, India Gabriele Maria Fortunato Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy Nadine Lysyk Funk Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Silke Henry Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium Tukaram Karanwad Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India Canberk Kayalar Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA Mansoor A. Khan Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA Abbas Z. Kouzani School of Engineering, Deakin University, Geelong, VIC, Australia Mathew Kuttolamadom College of Engineering, Texas A&M University, College Station, TX, USA Júlia Leão Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Srushti Lekurwale Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India Eman M. Mohamed Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, BeniSuef, Egypt Wiwat Nuansing School of Physics, Institute of Science, Suranaree University of Technology (SUT), Nakhon Ratchasima, Thailand Center of Excellent on Advanced Functional Materials (CoE-AFM), Suranaree University of Technology, Nakhon Ratchasima, Thailand Koki Ogawa Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan

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Tetsuya Ozeki Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan Parimal Patel Department of Mechanical & Aerospace Engineering, University of Texas at Arlington, Arlington, TX, USA Ziyaur Rahman Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA Prashanth Ravi Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA Koyel Sen Boehringer Ingelheim, Material & Analytical Sciences, Ridgefield, CT, USA Nidhi Singh Department of Pharmaceutics, Polymer-based Medical Devices, and Complex Drug Delivery Laboratory, National Institute of Pharmaceutical Education and Research Kolkata, Kolkata, India Tatsuaki Tagami Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan Valérie Vanhoorne Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium Chris Vervaet Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium Giovanni Vozzi Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy Thomas G. West Independent Consultant, Lawrenceville, NJ, USA Jaedeok Yoo FoundationLayers LLC, Princeton, NJ, USA Ali Zolfagharian School of Engineering, Deakin University, Geelong, VIC, Australia

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History and Present Scenario of Additive Manufacturing in Pharmaceuticals Koyel Sen, Thomas G. West, and Bodhisattwa Chaudhuri

Abstract

Additive manufacturing also called 3D printing has provided a personalization front to the pharmaceutical industry where dosage development can be patient centric. If needed, 3D printed dosage form can be formulated with customized shape, size, and release characteristics on the patient bedside. Hailing from rapid prototyping and into biomedical field, 3D printing has convincingly revolutionized pharmaceutical industry and its pace of innovation. 3D printing empowers the formulation design to new directions such as personalized medicine, controlled released dosage form, organ on a chip, as well as implants. Even until few years ago, it was implausible to foresee the adoption of 3D printing to formulation development pipeline such as preformulation to First-inHuman (FIH). And now, 3D printing is being investigated to be used in front line clinical trial setting to provide personalized service to the trial patients. Around 30,000 articles in technological literature have already been published discussing the futuristic application of 3D printing in pharmaceutical field. The rapid progression of 3D printing in the pharmaceutical field is a result of an extensive amount of past research, driven by its vast application potential.

K. Sen () Boehringer Ingelheim, Material & Analytical Sciences, Ridgefield, CT, USA T. G. West Independent Consultant, Lawrenceville, NJ, USA B. Chaudhuri Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA Institute of Material Sciences, University of Connecticut, Storrs, CT, USA © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals, https://doi.org/10.1007/978-981-99-2404-2_1

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Hence, this chapter encapsulates the past and the present status of 3D printing in pharmaceuticals with an open-ended future application possibility. Keywords

AM · Additive manufacturing · 3DP · 3D Printing · Pharmaceutical Sciences · Formulation development · Personalized medicine

1.1

Historical Foundation of AM Technologies for Pharmaceuticals

Although Additive Manufacturing (AM) is considered a new category of technology for pharmaceuticals, the underlying foundations of AM are more than four decades old. The genesis of modern AM is essentially 1984, when Chuck Hull filed the first patent application for stereolithography (SLA) (Hull 1986). Within 5 years, this was followed by the first patent application each for selective laser sintering (SLS) in 1986 (Deckard 1989), fused deposition modeling (FDM) in 1989 (Crump 1992), and the powder-liquid process now known as binder jetting in 1989 (Sachs et al. 1993). At the time, and for many years afterward, binder jetting itself was uniquely referred to as three-dimensional printing, 3D printing, and 3DP before those terms were adopted more widely across multiple forms of AM. Today 3D printing is a common umbrella term, sometimes synonymous with AM. The advent of modern AM was initially unrelated to pharmaceuticals. The technology was created in order to form physical prototypes quickly from computeraided designs, allowing for rapid design review and iteration without the delay or cost of creating traditional molds or tooling. Dedicated companies were set up for this purpose, including 3D Systems for SLA, Desk Top Manufacturing (DTM) Corp. for SLS, Stratasys for FDM, and Z-Corporation for binder jetting. Over time, DTM Corp and Z-Corp were acquired by 3D Systems. Other companies and technologies have since joined the field. The AM of pharmaceuticals first emerged as part of the binder jetting research at the Massachusetts Institute of Technology (M.I.T.) and later under licenses from M.I.T. to startup companies. Initially Therics, Inc. explored pharmaceutical use of binder jetting from 1993 to 2003 as part of a broader license for medical applications. Therics ultimately narrowed its license to medical devices, obtaining its first FDA 510(k) clearance in 2003 for TheriRidge bone substitute, a porous hydroxyapatite implant made using binder jetting. That clearance represents an early milestone for use of binder jetting in the manufacture of an FDA-regulated product for use inside human body. Aprecia Pharmaceuticals was formed later in 2003 and became the new exclusive licensee of binder jetting for pharmaceuticals, prioritizing novel equipment designs to enable pharma-specific scale and operations. In 2011, Aprecia opened its first centralized plant for scaled binder jetting, an essential step toward regulatory entrée in the pharmaceutical field. In 2015, the FDA-approved

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals

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Aprecia’s 505(b)(2) New Drug Application for Spritam , the first ever approval of a pharmaceutical product manufactured using a form of AM. Following this milestone, interest in AM of pharmaceuticals accelerated. Alongside binder jetting, other forms of AM have been applied to pharmaceuticals over time, with principal motivations for dosage form personalization, point-of-use manufacturing, and on demand manufacturing. Proof of concept research was performed to fabricate pharmaceutical dosage forms using FDM, SLS, SSE, SLA, etc. (Fina et al. 2017; Goyanes et al. 2014; Khaled et al. 2014; Wu et al. 2009). In 2014, FabRx Ltd. was formed with interest in multiple forms of AM for personalized pharmaceuticals. In 2015, Triastek Inc. was formed to commercialize its material extrusion deposition technology, MED™ 3D, intended for centralized manufacturing of novel dosage forms. In 2019, FabRx conducted the first clinical study with personalized pharmaceuticals via AM—chewable tablets made using semisolid extrusion (SSE). In 2020, FabRx introduced the first commercial platform for small-scale personalized pharmaceuticals, the M3DIMAKER™ , which is designed for use at clinical sites (Sertoglu 2020). CurifyLabs was formed, aimed at personalized medicine. Merck KGaA and AMCM/EOS announced a partnership for SLS-type AM of tablets (Schrimpf G Merck KGaA, Darmstadt, Germany and B. Braun Join Forces in the Development of Bioelectronic Devices n.d.). In 2021, Triastek received FDA clearance for their IND on product candidate T19 (Everett 2021; Trieste 2022). Aprecia introduced ZipCup™ (Z-Fill) orodispersible shells (Pollinger and West 2021). In 2022, CurifyLabs introduced MiniLab™ platform (SSE 3D printing) for potential personalized medicine to be used for developing human and veterinary dosage form (Ebrahim and Fahem 2022; Sjöholm et al. 2022). Triastek obtained FDA clearance on INDs for candidates T20 and T21. Aprecia introduced its Z-Form equipment design for binder jetting within blister packages (https://fi.linkedin.com/ posts/aprecia-pharmaceuticals_aprecia-introduces-z-form-flex-manufacturingactivity-6987723679329656832-D2Jw?trk=public_profile_like_view). Selected milestones in the AM of pharmaceuticals are illustrated in Fig. 1.1.

1.2

Overview of AM and Process Considerations for Use in Pharma

The AM technology umbrella is diverse. AM processes differ from one another in their capabilities for forming unit doses and in the type and extent of process stress applied to the units made. Likewise, the AM techniques also differ in the choice of materials that can be used and the types of structures that can be created most effectively. This section will provide a synopsis of these factors for the main families of AM applied to pharmaceuticals thus far. It will also mention some current practitioners for certain technologies.

Fig. 1.1 Foundations of AM for pharmaceuticals

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1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals

1.2.1

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Stereolithography (SLA)

SLA uses liquid resin as feedstock material, which undergoes localized photopolymerization when contacted by a directed energy source such as a laser. The printing process goes on to fabricate printed parts in layer-by-layer fashion onto a build platform, typically within a vat of resin. The advantage of SLA 3D printing of medicine is high resolution of the printing process compared to other printing processes. Thus, it is possible to introduce very fine and complex physical features into the dosage form. Moreover, due to the use of laser photo-cure mechanism designed for near room temperature operation, SLA imparts low localized thermal stress for short periods, which might make this process a candidate for some thermolabile drugs. API can be directly incorporated in the liquid resin prior to the printing process and therefore the drug can be entrapped in the printed dosage form. During SLA printing, the build platform submerges in the liquid resin tank and a UV laser initiates the cross linking of the liquid resin at the free surface according to the CAD image file. After each layer is completed, the build platform submerges further into the vat and the steps repeat until the desired height of the part is complete. After the part is extracted from the vat, additional post-SLA curing or other post-processing may be required. SLA requires a (i) photocrosslinkable polymer, (ii) hydrophilic polymer, (iii) photoinitiator apart from API for formulation development. However, the available number of photocrosslinkable polymers available for formulation development is limited such as Poly(ethylene glycol) diacrylate (PEGDA), poly(propylene fumarate)/diethyl fumarate (PPF/DEF), poly(ethylene glycol) dimethacrylate (PEGDMA), and poly(2-hydroxyethyl methacrylate) (pHEMA) (Wang et al. 2016). A photoinitiator goes through photolysis and changes into a primary radical or cation, thus initiating crosslinking process of the photopolymer and converting resin to solid. Most initiator used in SLA 3D printing are either monoacylphosphine oxide (MAPO) or bisacylphosphine oxide (BAPO) [Bao]. The ratio of photocrosslinkable polymer and hydrophilic polymer can be adjusted to modify the drug release (Bao et al. 2022; Wang et al. 2016). Although it is one of the oldest forms of AM, challenges remain in the use of SLA for pharmaceuticals. Due to the lack of FDA-approved photocrosslinkable polymer, SLA has more limited options for raw materials when compared to other AM options (Deshmane et al. 2021). Toxicity of residual initiator and monomer remain active topics for resin selection and design of any post-SLA processing.

1.2.2

Fusion Deposition Modeling (FDM)

In its original form, FDM combines a melt extrusion nozzle with X-Y-Z motion controls to provide for layer-by-layer deposition of the extrudate into a desired part shape according to preprogrammed machine instructions. Compared to other forms of AM, the parts produced are not automatically surrounded with support

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material that requires recycling or disposal, which can be advantageous for material efficiency. However, support structures can be extruded if a complex shape requires them. Classic FDM uses filament as a feedstock for the printing process. As few offthe-shelf FDM filament materials are of pharmaceutical grade (such as ABS, Nylon, ASA, PETG, etc.), pharmaceutical filament may need to be formed as a precursor step. Hence, powdered pharmaceutical excipients must be screened for suitable mechanical and thermal properties for filament formation. To bridge this gap, HME (or similar processes) have been introduced in combination with FDM, either as discrete sequential steps having a filament intermediate or as integrated apparatus that forego a filament stage. Thus, the excipient selection in HME-FDM process is driven by the processability requirement of HME and FDM. Apart from the API, and depending on the drug delivery goals, formulation development for FDM (or HME-FDM) typically includes: (i) thermoplastic polymer, (ii) disintegrant, and (iii) plasticizer. Thermoplastic polymers consist of polymer chains associated by intermolecular forces and are thermally shapeable by molding, extrusion, and sintering processes. The thermoplastic polymer forms the physical matrix of a dosage form in which the API would be embedded, and therefore has significant influence over drug release. Pharmaceutical thermoplastic polymers which can be directly used in FDM ® or HME-FDM include vinyl pyrrolidone and vinyl acetate copolymer (Kollidon VA64), polyvinyl alcohol (PVAl), poly-lactic acid (PLA), hydroxypropyl cellulose (HPC), and hydroxypropyl methyl cellulose (HPMC) (Fanous et al. 2021; Korte and Quodbach 2018; Than and Titapiwatanakun 2021). Other thermoplastics such as Eudragit based polymers have difficulty forming a flexible filament for FDM alone and require formulation aids. For example, Sadia et al. (Sadia et al. 2018) have successfully extruded FDM filament with Eudragit-E by incorporating plasticizer (Triacetin) and filler (tricalcium phosphate). The role of plasticizer in the formulation is to lower the overall Tg of the formulation during extrusion, leading to better mixing and lower brittleness in the filaments. Since 2020, the M3dimaker™ has been available from FabRx (London, United Kingdom). It is a small-scale FDM-type pharmaceutical compounding machine for making personalized medicines in a decentralized manner. It can be configured with specific print heads to perform filament extrusion, direct powder extrusion (single screw), or semisolid extrusion (SSE) and is positioned for research, drug development, and clinical practice (Markarian 2022). M3dimaker is largely aimed at individualized dosing for patients. MED™ 3D (Deng et al. 2019; Zheng et al. 2021) from Triastek (Nanjing, China) is another FDM-type technology that is able to work directly from API and excipient powders, forming parts with single or multiple extrusion nozzles. In contrast to FabRx, Triastek currently uses MED 3D in a centralized manner to develop and manufacture products for itself and its partners. The technology is primarily positioned to create modular tablet designs providing customized release profiles and bioavailability enhancement for clinical differentiation.

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1.2.3

7

Selective Laser Sintering (SLS)

SLS is a form of AM that fuses powder particles together layer-by-layer using a laser, a directed energy source. SLS requires powder as the input material, so powder preparation (blending, granulation, etc.) is a precursor step to pharmaceutical SLS. During SLS, a roller spreads a first thin layer of powder onto the build platform. The laser scans across the powder layer and sinters the powder in selected locations according to a 3D image file. Then the platform descends for the next powder layer, and sintering process repeats until the full part design is complete. SLS formulations mainly consist of two functional excipients: (i) thermoplastic polymer and (ii) laser absorbent/pharmaceutical grade colorant. Currently, Merck KGaA (Darmstadt, Germany) has partnered with AMCM/EOS (Starnberg, Germany) to provide an SLS platform for one step tablet production intended for clinical supply, commercial supply, tailored formulation, and product development (Merck Merck’s 3D Printing Overview n.d.; Schrimpf G Merck KGaA, Darmstadt, Germany and B. Braun Join Forces in the Development of Bioelectronic Devices n.d.).

1.2.4

Semi Solid Extrusion (SSE)

SSE printing process uses similar principles of printing as FDM, but using a semisolid working material instead of a melt. Like other AM, SSE requires CAD file loaded in the printer to start the printing process. SSE uses gel or paste as feedstock that is then extruded through a syringe, which can be heated if needed to aid material deposition. Versus FDM, SSE printing can be performed using lower temperatures (near ambient) making it suitable for thermolabile or thermo-sensitive compounds. Primary process considerations include viscosity of the raw material at ambient and at operating temperature, nozzle size, feed rate, and printing speed. A formulation advantage of SSE is that it can use either paste or gel. Paste (Seoane-Viaño et al. 2021a) feedstock can contain customary soluble and insoluble excipients in a water/ethanol mixture, whereas gel (Basit and Gaisford 2018) feedstock minimally contains gelling agent/water. Accordingly, an SSE formulation typically entails: (i) water insoluble polymer as release modifier and/or disintegrant and (ii) water-soluble polymer as matrix former and/or disintegrant. Hence, formulation development and excipient selection for SSE mainly depend on the desired properties of the final dosage form and the rheological properties of the semisolid feedstock to provide consistent deposition at the working conditions of the process. Recently, CurifyLabs (Helsinki, Finland) has introduced a small platform for personalized dosing named MiniLab which provides semisolid extrusion directly into blister packs, decreasing manual compounding work by 72%. According to the company, this technology has already been applied to serve patients at compounding pharmacies such as Finnish Oulu Central Pharmacy (Hanaphy 2022; Labs C CurifyOur Clients n.d.). The proposed deployment of this technology includes clinical trials (indicated to have started), compounding pharmacy, and veterinary medicine.

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Binder Jet 3D Printing (BJ3DP)

Inkjet/Binder Jet 3D printing requires two feedstocks—a powder mixture and a binder liquid (“ink”) which selectively binds the powder particles together during the printing process. Like other AM, the part design and feedstocks are loaded ahead of printing. During binder jetting, a roller spreads a thin powder layer on the build platform followed by selective deposition of the liquid onto the powder according to the part design. Then the platform descends, and the process repeats layer-bylayer until the entire part design is completed. After printing, the parts are dried and separated from loose, unprinted powder. Drying conditions are determined based on the materials, typically selecting the highest post-processing rate that does not adversely impact composition stability. BJ3DP formulation requires at least one powder and at least one liquid feedstock. The liquid may be solution or suspension. The powder may be a dry blend, granulation, or other coprocessed or engineered powder. The liquid is formulated for reliable jetting and powder binding and typically contains: (i) binding agent (usually polymer), (ii) surfactant, (iii) humectant, and (iv) aqueous or organic solvents (e.g., water, oil, ethanol). The powder mixture may contain: (i) binding agent soluble in the liquid, (ii) matrix or bulking agent as appropriate, and (iii) disintegrant, if necessary. The API may be incorporated either as part of the powder or as part of the liquid feedstock, or both. This optionality is a key difference versus other forms of AM. Using BJ3DP, Aprecia Pharmaceuticals (Blue Ash, Ohio, USA) (West and Bradbury 2019) has been a pioneer in AM of pharmaceuticals, obtaining the first ® regulatory approval of a 3D printed medicine (Spritam ) in 2015. Spritam is a uniquely high-dose (250–1000 mg) fast-disintegrating tablet exemplifying the ® company’s ZipDose family of formulations and is manufactured in a centralized plant using Aprecia’s proprietary scaled version of BJ3DP (Z-Free). Recently, Aprecia has introduced new technology, including equipment for printing dosage forms directly in blisters (Z-Form) and new pre-formed orodispersible shells that can be filled with more diverse payloads and assembled analogous to capsules (ZipCup™ /Z-Fill) (https://fi.linkedin.com/posts/aprecia-pharmaceuticals_apreciaintroduces-z-form-flex-manufacturing-activity-6987723679329656832-D2Jw? trk=public_profile_like_view) (Jonathan and Karim 2016; Pollinger and West 2022).

1.3

Current State of AM Technologies in Pharmaceutical Practice

Today the deployment of AM is still nascent and poised to impact key aspects of modern drug delivery practice as well as classical pharmacy practice over time (Park et al. 2021). For drug delivery, AM promises a new suite of options to

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9

control localized structure and composition of dosage forms, impacting many of the core drug delivery goals that have been recurring themes in the field. For pharmacy practice, AM offers new capabilities for extemporaneous preparation and individualization of dosage forms, potentially with dosing or release properties that are difficult to achieve using other manufacturing techniques. Accordingly, this section is structured to review several prominent pharmaceutical goals for AM use that cut across aspects of drug delivery and pharmacy practice. They center on frequent themes or motivations for introduction of AM into the pharmaceutical field. These goals for AM are as follows: 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6

Personalization, point of use, and on demand manufacturing Improving bioavailability of low solubility compounds (e.g., BCS II and IV) Modulating release kinetics of dosage forms Combining medications into a single dosage unit (“polypill”) Orodispersible dosage forms Others AM uses of note

Each goal will be discussed in turn, recognizing there can be some overlap or combinations of concepts in the examples cited. The type and extent of deployment of AM technologies differ across these goals, based in part on the strengths and weaknesses of each technology. The following subsections review the deployment of AM for each goal, highlighting the most mature usage thus far as an illustration of the state of the art.

1.3.1

Personalization, Point of Use, and On Demand Manufacturing

This section focuses on the potential for AM to change what is made, for whom it is tailored, where and how it is made, and also when it is made. Table 1.1 summarizes several ways that AM may be used to change the medication itself or the way in which it reaches the patient. Pursuing one or more of these goals in tandem can substantially impact the approach to AM equipment design and deployment. Figure 1.2 provides a conceptual representation of these effects on equipment design, illustrated with respect to the distance of the machine deployment from the patient. State of the Art Taken as a whole, the concepts of Table 1.1 are broad in scope. Even so, a few of these ideas have already reached a degree of practical deployment to benefit patients. Thus far two small-scale (desktop) AM systems are commercially available for pharmaceutical use: the M3dimaker FDM/SSE-type system from FabRx, and the MiniLab SSE-based system from CurifyLabs. Subject to any formulation or processing limitations, each of these systems is able to make dosage forms in various

When

How and where

For whom (Target Population)

What

Polypill. Dispersible form. Cancer patients. Conditions that require complex release profiles-circadian rhythm. Patients with difficulty in swallowing, CVD, HIV, etc. Rare diseases (Orphan Drug). Visually impaired. Traditional manufacturing plant, optionally operating differently using AM. Progressively closer to the patient, up to the point of care (hospital, pharmacy, clinic) Progressively closer to the time of use. More likely to be performed with greater proximity to the patient.

Geriatric Specific classes of patients (based on disease or disorder)

Decentralized Mfg (e.g., point of use) On demand (Extemporaneous)

Centralized Mfg

Pediatric

Markings

Organoleptics; Excipients

Unique structure or function of the dosage for particular patient groups or individuals. Unique release kinetics. Orodispersible forms. Implants. Size, shape, color, texture, smell, taste for patient acceptance or palatability. Exclusion of certain excipients due to patient allergy. Identifiers or reminders to the patient about identity, timing, or regimen. Personalized dosing (attractive dosage form, different dose loading). Dispersible form.

Combination of drugs in same dosage form matched to specific patient needs (FDC or Polypill) Unique strength and/or concentration of drug

Type of dosage form across routes of administration

Levels of the drugs (dose)

Aspects Number and choice of drugs

Table 1.1 Types of personalization, point of use, and on-demand manufacture of medicine that are possible using AM

Labs C Curify-Our Clients (n.d.)

Sertoglu (2020)

West and Bradbury (2019)

Karavasili et al. (2021) Saydam and Takka (2020)

Rautamo et al. (2020)

Shariff et al. (2020)

Januskaite et al. (2020)

Selected Refs Goh et al. (2021) Robles et al. (2019) Siyawamwaya et al. (2019), Maniruzzaman (2019) Maroni et al. (2017), Okwuosa et al. (2017)

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Patient

5

Number of Machines

6

Ease of Use

7

Cost per Unit

Onsite (Point-of-Use) Hospital or Clinic

Local Compounding Facility or Pharmacy

Regional Hub

11

1

Quality & Regulatory Compliance

2

Speed Matched to Demand

Size of Machine

3

Skill for Use

4

Centralized Plant

Distance From Patient

Fig. 1.2 Influence of proximity on the design and deployment of AM for pharmaceuticals

sizes, shapes, and colors, incorporating one or more drugs at dosages tailored to an individual patient. The small format of each is suited to decentralized use close to the point of care. The timing can be essentially on demand, with whatever lead time is needed to account for manufacturing speed and sequencing of orders for patients. CurifyLabs has indicated that MiniLab is in use at compounding pharmacies in Finland. At larger scale in a centralized manufacturing model, Aprecia’s ZipDose formulations use BJ3DP for a more general tailoring of dosage form and formulation to groups of patients with swallowing difficulties. The technology is largely positioned for high-dose medicines constituting some of the largest tablets and capsules. The first commercial example, SPRITAM, provides an easy-to-administer form of the drug levetiracetam, a highly prescribed first-line treatment for children and adults with epilepsy. The product has been marketed in U.S. since 2016. In clinical development, Triastek has received IND clearance for three product candidates (T19, T20, T21) using FDM-type AM to tailor release kinetics and/or bioavailability for specific therapies. T19 aims for chronotherapeutic delivery for rheumatoid arthritis (e.g., administration at night to provide coverage for morning symptoms). T20 seeks once-daily dosing for a cardiovascular and clotting disorder medication that is currently given twice daily. T21 is intended for colonic drug delivery in the treatment of ulcerative colitis while reducing systemic side effects. Discussion The personalization of 3D printed dosage forms can be performed in one or more of the following ways. The number and choice of drug. Using 3D printing, a dosage form can be personalized based on the requirement of an individual’s needs with respect to the choice of drugs and the number of drugs to be incorporated in one pill (polypill). 3D printing allows the creation of medicine with distinctive geometry which makes

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it easy for the patient to distinguish. 3D printing also has the potential to modify the flavor or make a chewable version of the medicine according to patient’s preference, thus increasing treatment adherence (Goyanes et al. 2019). For patients who need to administer multiple pills in one day, using a 3D printed polypill would reduce the common issue of dosing error or forgetting to take one or more pills, albeit with some risk of more severe impact if the polypill itself is missed. Levels of drug. 3D printing process (such as binder jet, FDM, etc.) allows the creation of non-standard doses of drug more easily than conventional techniques, especially for small batches. For orodispersible dosage forms specifically, relatively high drug loading (>60% w/w) has been demonstrated, which is difficult to achieve through legacy techniques such as freeze-drying or soft-compression. Moreover, using the consistency and droplet placement of inkjet 3D printing, a higher content uniformity can be achieved in extremely low drug loading (μg scale). Type of dosage form. For tablets swallowed intact, the architecture of dosage design can affect drug release in a dosage form. 3D printing process allows a medicine to be positioned internally with local excipients in such a way as to provide tailored drug release (progressive release, pulse release, delayed release, etc.). Alternate dosage forms such as orodispersibles or implants can be created having different capabilities than those from legacy techniques. Organoleptic properties. The size, shape, color, texture, smell, or taste of a printed tablets can be customized to provide a better match with a patient’s needs. Certain excipients can also be excluded based on the patient allergy history (e.g., mannitol instead of lactose), a frequent reason for compounding of medicines. Markings. Dosage forms can be marked a number of unique ways to provide reminders of drug identity or regimen. For example, for two similarly shaped and colored dosage forms, a customized marking could potentially benefit elderly patients in correctly identifying each medicine. Similarly, braille or other raised markings could be created for the vision-impaired. 3D printing of pharmaceutical medicine can potentially be deployed in three categories: i. centralized, ii. decentralized, and iii. on demand. Centralized and decentralized are intended in the spatial sense of equipment placement, whereas on demand refers to the temporal sense of equipment utilization. Centralized deployment is analogous to that of the conventional medicine supply chain, using a single point for mass-production and later distribution to wholesalers and local pharmacies or the point of use. For this arrangement, the manufacturing site is rarely near the patients, and significant inventory must be made in advance. Centralized deployment of 3D printing has already been demonstrated (Aprecia Pharmaceuticals) using the traditional regulatory process for new drug approval. In contrast, decentralized deployment involves the use of 3D printing at multiple small locations, typically closer to the patient, and is still at its nascent stage. For decentralized deployment, there is a requirement to be performed under the supervision of a registered pharmacist at a compounding facility in accordance with appropriate local regulations, which provides increased opportunity for those medicines to be produced on demand (such as at a hospital, clinical setting, and pharmacy). The implementation of decentralized 3D printing of medicine is lagging

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13

behind due to the lack of existing standardization process in the production process (Aquino et al. 2018). To illustrate this point, the first approval of an AM drug product made centrally (Spritam in 2015) occurred several years before availability of the first AM equipment designed for decentralized compounding (M3dimaker in 2020). In addition, the cost effectiveness of AM has been demonstrated for centralized deployment but for decentralized deployment it remains to be seen, based on an AM study across industries (Thomas and Gilbert 2015). Despite those uncertainties, there are signs of early adoption of AM for decentralized use. SSE was used in a hospital (decentralized) clinical study with different flavors and colors of chewable for children with rare metabolic diseases (Goyanes et al. 2019). SSE has also been explored to fabricate ODF in a vet clinical setting where the doses of prednisolone have been personalized for animals (Sjöholm et al. 2020). Also, as noted under State of the Art, two small pharmaceutical printers have recently come to market for decentralized use.

1.3.2

Improving Bioavailability for Low Solubility Compounds (e.g., BCS II and IV)

One of the pivotal steps in formulation development is to attain sufficient bioavailability of an API in a suitable dosage form for the patient group, most often via oral route. Unfortunately, most new drug substances in development (Peltonen and Hirvonen 2018) (~70%) do not meet high solubility criteria for the Biopharmaceutics Classification System (BCS) and are classified as BCS II or IV (low solubility) (Lindenberg et al. 2004). Increasing bioavailability for these compounds remains a significant priority for industry. Due to high cohesivity of their crystalline structure, these APIs exhibit low aqueous solubility. Various approaches have been investigated to increase the solubility of these poorly soluble APIs (Kanaujia et al. 2015) such as particle size reduction (Jennotte et al. 2020), nanocrystallization, amorphous solid dispersion (ASD) formation (Ayyoubi et al. 2021), and self-microemulsifying drug delivery system (SMEDDS). The best BA enhancement technique for these drugs differs case-by-case based on API properties, therapeutic goals, and commercial goals. Similarly, the compatibility of these techniques with each form of AM will depend on those factors as well as the respective physicochemical phenomena involved in each form of AM. State of the Art Thus far, AM technology has demonstrated early proof-of-principle for BA enhancement of BCS II and IV compounds. The existing research includes approximately 26 published studies, all based on in vitro results, encompassing 19 different APIs and making use of ~20 different functional excipients in concert with AM as part of an overall strategy for improved BA. To date, there do not appear to be any confirmed examples in the clinical development or commercial stage (Zema et al. 2017).

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Table 1.2 summarizes key examples for BA enhancement, grouped by the type of AM technology. Each AM technology is then discussed in more detail for this application.

1.3.2.1 FDM FDM and HME-FDM platforms have the capability of amorphizing low solubility drug crystals and mixing with thermoplastic polymer to form solid dispersions that are stable during storage. Incorporation of disintegrant in the formulation enables quick expansion and/or pore formation in the matrix once it encounters gastrointestinal fluids, hence faster disintegration, higher surface area, and more rapid dissolution of the amorphized API (Saydam and Takka 2020). Based on the desired drug release kinetics, the composition can be modified as well. For an IR dosage form, an IR polymer (or polymer plus plasticizer) for HME can be incorporated, along with a pore former/disintegrant. In contrast, for SR, one can avoid the disintegrant. The release kinetics of the printed tablets can be additionally improved by incorporating innovative design in the tablet image file such as channels (Sadia et al. 2018) or collapsible structure (Arafat et al. 2018; Korte and Quodbach 2018; Nukala et al. 2019). One can also extrude crystalline drug embedded filament to impart FDM-based supersaturation (Bandari et al. 2021; Buyukgoz et al. 2021) in the printed dosage form. Chitosan was included in one of the formulations to increase permeation and buccal adhesion of the film (Eleftheriadis et al. 2019). Orally disintegrating films (ODFs) with high surface area have also been used advantageously. Using FDM, low soluble APIs have been converted into ASD and loaded onto these films. 1.3.2.2 SLS The first SLS printing in pharmaceutical field was performed in 2017 (Fina et al. 2017) by Fina et al. using two types of thermoplastic polymer (Eudragit RL and Kollicoat IR) to create to different release properties of paracetamol in a 3D printed dosage form. Based on the expected lack of absorption of directed energy by the API and excipients (required to obtain adequate binding via SLS), a pharmaceutical grade colorant (Candurin Gold sheen) was incorporated in the formulation and has been used for pharmaceutical SLS ever since (Fina et al. 2017; Fina et al. 2018b; Januskaite et al. 2020; Thakkar et al. 2021a, 2021b; Trenfield et al. 2022). The function of thermoplastic polymers in SLS is similar to their application in FDM process that is as matrix former by melting and cooling/fusing to embed APIs by kinetic trapping. Unlike FDM, very few thermoplastic polymers have been explored so far. However, based on the published studies, one can fabricate IR or ASD-based ® dosage forms via SLS by using Kollidon VA64 (Allahham et al. 2020; Davis et al. 2021; Fina et al. 2018b; Thakkar et al. 2021a; Trenfield et al. 2022), Kollicoat IR (Januskaite et al. 2020), HPC (Trenfield et al. 2022), HPMC E55 (Fina et al. 2018b). Apart from the excipients above, SLS can incorporate process aids such as silicon dioxide as glidant (Davis et al. 2021) or mannitol as disintegrant (Allahham et al. 2020).

Technology FDM

Ketoprofen (II) Rufinamide (II)

Griseofulvin (II)

Hydrochlorothiazide (IV)

Olanzapine (II)

Naproxen (II)

API (BCS Class) Lumefantrine (IV)

Kollidon VA 64-matrix (80% released in 50 min no pore formers) Polyethylene oxide ® Kollidon VA 64-matrix poloxamer 407 poloxamer 188-plasticizers triethyl citrate-plasticizer tricalcium phosphate-non-melting filler Eudragit E-matrix Disintegrant Sodium starch glycolate Croscarmellose sodium Crospovidone Kollicoat protect-moisture protection hydroxypropyl cellulose-matrix polyvinyl alcohol (PVA) HPMC Soluplus ® Kollidon VA64-matrix former ® Gelucire 48/16-solubility enhancer Triacetin -Plasticizer

®

Key Excipients Butylated methacrylate copolymer-Eudragit EPO-Matrix former hydrophilic xylitol-plasticizer maltodextrin-pore former

channeled tablet IR ASD (mix of all) IR 80% in 45 min

Supersaturated by FDM induce Amorphization

IR with perforated channels (minimal disintegrant effect observed due to perforated channels)

ASD (drug and kolli) loaded ODF (PEO)

ASD-stable formulation formed with hot melt extrusion and printed in stable form

Dosage form IR stable formulation formed with hot melt extrusion and printed in stable form

Table 1.2 Use of AM with BCS II and IV compounds involving BA enhancement

(continued)

Nukala et al. (2019) Saydam and Takka (2020)

Buyukgoz et al. (2021)

Sadia et al. (2018)

Kissi et al. (2021), Than and Titapiwatanakun (2021) Cho et al. (2020)

Reference Fanous et al. (2021)

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 15

SSE

Technology SLS

Fenofibrate (II)

Clarithromycin (II)

Tacrolimus (II)

Albendazole (II)

Ondansetron (II)

Gelucire 44/14 or Gelucire 48/16) and coconut oil HPMC EC Poloxamer PVP K30 Nano-caco3 Glyceride Triglyceride Tween 85 Kolliphor EL

HPC 3 grades Candurin HPBCD-tase masking ® Kollidon VA64-matrix Candurin Mannitol-disintegration PEG 1500/propylene glycol

Itraconazole (II)

®

Kollidon VA64 Candurin blend

®

Kollidon VA 64 Candurin

®

Key Excipients Copovidone VA64-matrix Candurin-absorbent Silicon dioxide-glidant

Indomethacin (II)

Indomethacin (II)

API (BCS Class) Ritonavir (II)

Table 1.2 (continued)

Emulsified lipid-based formulation for thermolabile compound and to be absorbed with lipid outer core

Fast release nano crystal with high drug loading (~50%w/w) provides fast release of poorly soluble drug SR-maximizing drug connection at onsite of action with lipid-based excipient Core-shell system SR where floating property of the tablet increases the residence time

ASD-stable formulation formed with twin-screw granulation and printed in stable form ASD-stable formulation with proper excipient ODF-provides quick disintegration and quicker drug release

IR stable formulation formed with Twin screw granulation and printed in stable form

Dosage form ASD Printing process parameters such as hatch spacing was tweaked to fully amorphized the drug

Johannesson et al. (2021). Li et al. (2018)

Seoane-Viaño et al. (2021b) Chen et al. (2021)

Lopez-Vidal et al. (2022)

Allahham et al. (2020)

Trenfield et al. (2022)

Thakkar et al. (2021a, 2021b)

Thakkar et al. (2021b)

Reference Davis et al. (2021)

16 K. Sen et al.

BJ3DP

Oxcarbazepine (II)

Ciprofloxacin (IV)

Naproxen (II)

Indomethacin (II)

Carvedilol (II)

Olanzapine (II)

Benzydamine HCl (II)

Maltodextrin Sorbitol HEC PEO Kollidon VA Poloxamer 188 Irgacure 2959 photocurable N-vinyl-2-pyrrolidone poly(ethylene glycol) diacrylate L -arginine PVP Polyvinylpyrrolidone, chitosan, HPMC Dextran sulfate (complexing agent) cellulose polyethylene glycol Povidone and HPC among potential binders Wickström et al. (2015)

ASD produces stable formulation with proper excipients ASD produces stable formulation by incorporating foreign substrate ASD using nanosuspension ink

IR high-dose orodispersible. Micronized crystalline API wet-gran’d ahead of BJ3DP

Clark et al. (2020)

ASD-with different geometry shows different release rate of low soluble API

Jacob et al. (2016a)

Cheow et al. (2015)

Hsu et al. (2013)

Cho et al. (2020)

Elbl et al. (2020)

ASD-stable formulation with proper polymer

ODF-stable drug loaded dispersion in layers

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 17

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1.3.2.3 SSE The typical formulation for SSE contains i. matrix former, ii. plasticizer, and iii. disintegrant. For low solubility APIs, SSE has shown feasibility for immediate release dosage forms and orally disintegrating films (ODF). For IR dosage forms, matrix formers such as Kollicoat IR, PVP, HPMC, HPC, PEG (Aita et al. 2019; Conceição et al. 2019; Li et al. 2019) have been used. For ODF, Kollidon VA64, lactose monohydrate and HPC (Cho et al. 2020; Elbl et al. 2020; Sjöholm and Sandler 2019; Yan et al. 2020a) have been used as adjuvant to load APIs onto the films. In addition, SSE has been explored with S-SMEDDS, API nanocrystal suspension printing, and floating core-shell system (CSS). SSE provides an innovative approach ® ® to incorporate lipid-based excipients such as Gelucire 44/14, Gelucire 48/16, and ® Kolliphor P 188 for S-SMEDDS formulation (Vithani et al. 2019). Due to SSE’s versatility, the ink medium can be selected from an emulsion-based system (e.g., solid lipid emulsion gel such as glyceride, triglyceride, etc.) to print thermolabile drug (Johannesson et al. 2021) to a suspension-based system (e.g., PEG1500/PPG ink medium to print nanocrystals using SSE (Lopez-Vidal et al. 2022)). 1.3.2.4 Inkjet Printing and BJ3DP Inkjet printing process has also been applied successfully to increase solubility or improve delivery of BCS II/IV APIs. The jetting of ink onto a preformed substrate used in the printing has enabled fabrication of ASD-based dosage forms for increased effective solubility. The stability of the amorphized drug in the matrix can be achieved by incorporating a proper polymer matrix former in the ink composition (such as Irgacure 2959, poly (ethylene glycol) diacrylate (Clark et al. 2020) or l-arginine, PVP, and HPMC) (Hsu et al. 2013; Wickström et al. 2015). Moreover, amorphous API can also be stabilized in the ink prior to the printing with complexing agent such as dextran sulphate (Cheow et al. 2015; Chou et al. 2021). For powder-based systems, BJ3DP has also made rapidly disintegrating tablets using granules containing a micronized crystalline API from BCS Class II. (Jacob et al. 2016a). In this example, the micronized API particles aid dissolution rate and the granules aid powder flow for BJ3DP.

1.3.3

Modulating Release Kinetics of Dosage Forms

AM technologies are among the newest tools in a multipronged pursuit: steady blood levels within a drug’s therapeutic window, ideally while reducing dosing frequency in a dosage form that is easy for a patient to take reliably. The oral route remains the most facile, with a goal of obtaining release patterns more tailored than those of conventional immediate release (IR) tablets and capsules. For certain therapeutic regimes, transdermal and implantable routes are also considered. Modulated or modified release (MR) encompasses many descriptors, including both fast (IR, accelerated, or intermediate) and slow release (sustained, delayed, tailored, continuous, pulsatile, progressive), alone or in combination (Fig. 1.3).

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals Fig. 1.3 Represents the basic release profiles of different released dosage form

19

Plasma Conc

Zero order release

Sustained release Conventional release Time

Building upon the composition-based approaches of prior MR techniques, AM offers increased control of structure and material placement, further refining the forms of MR that can be achieved. These capabilities differ based on the specific form of AM. State of the Art To date there is extensive research applying AM for MR. Although no MR products have been approved yet using AM, FDM-type AM appears to be at the most advanced stage of development for MR use. In particular, Investigational New Drug (IND) applications have been cleared by FDA in 2021 and 2022 for candidates T19, T20, and T21 using Triastek’s MED 3D (Melt Extrusion Deposition) technology. T19 is modular chronotherapeutic drug delivery system for rheumatoid arthritis that controls drug release based on the shape and internal geometric pattern of the tablet. It is administered at night and targets peak blood levels of drug in the morning when pain and joint stiffness are most acute. Triastek expects to file a New Drug Application (NDA) for T19 by 2023. Triastek candidate T20 is a new once-daily formulation of a drug for cardiovascular and clotting disorders that is presently given twice daily in other marketed forms (Everett 2021; Trieste 2022). T21 is intended for colonic drug delivery in the treatment of ulcerative colitis while reducing systemic side effects. In 2022, Triastek announced a partnership with Eli Lilly for targeting drug release in specific regions of the intestine to improve bioavailability (Triastek Inc 2022). Table 1.3 summarizes the key published examples for using AM to pursue dosage forms exhibiting MR kinetics. (Triastek candidates T19, T20, and T21 are not listed, as the identity of the APIs and formulation details are undisclosed as of this writing).

1.3.3.1 SLA Few studies have explored SLA for modulating release kinetics due to the limited availability of suitable raw materials. Thus far sustained release dosage forms (Krkobabi´c et al. 2019; Wang et al. 2016) have been fabricated. In both cases, the modified drug release has been achieved by optimizing the formulation composition

SLS

FDM

Technology SLA

PVAl, mannitol, PLA

Compartmental dosage unit PVAl single/double/triple reservoir PLA, PVAl, HPMC, KIR two compartment capsular device PVAl, SSG, HPMC infill patterns, and wall thickness PVP, Eudragit enteric shell core PVP,SSG, TEC,TCP, Channeled tablet Kollicoat IR ethyl cellulose Polyethylene oxide Eudragit RL Eudragit L Ethyl cellulose Kollicoat IR Lactose monohydrate, talc

Budesonide, paracetamol

Hydrochlorothiazide

Rifampicin and isoniazid Curcumin Acetaminophen

Lopinavir

Paracetamol

Amlodipine Theophylline Hydrochlorothiazide Paracetamol/Ibuprofen

Acetaminophen

Polymer Polyethylene glycol diacrylate (PEGDA) diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Photo initiator) Polyethylene glycol diacrylate (PEGDA) diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Photo initiator) PVAl

API 4-aminosalicylic acid Paracetamol

Table 1.3 Use of AM for modulating release from dosage forms

Fast and immediate

Tailored DR Delay release Accelerated release Fast and sustained release Fast , intermediates, and sustained release

CR Progressive DR Two pulse DR

MR-sustained release/Tailored release CR-zero order

Sustained release

Release type Extended-release profile

Hamed et al. (2021)

Fina et al. (2018a)

Obeid et al. (2021) Okwuosa et al. (2017) Sadia et al. (2018) Awad et al. (2019)

Goyanes et al. (2015a, 2015b) Gioumouxouzis et al. (2017) Genina et al. (2017) Russi and Gaudio (2021) Maroni et al. (2017)

Krkobabi´c et al. (2019)

Reference Wang et al. (2016)

20 K. Sen et al.

SSE

HPMC

HPMC Mannitol Xylitol HPC Croscarmellose sod

Glipizide

Levofloxacin

Levetiracetam

Cellulose acetate D-mannitol

Kollidon VA64

Paracetamol

Propranolol HCl

Powdered charcoal

Paracetamol

Immediate release by controlling the lattice cell size in the printing pattern

Modulating release kinetics by changing the hatch spacing in infill pattern Modulating release kinetics by changing porosity Modified sustained release profile by printing a shell with rate controlling polymer and optimizing the gap in between the shell inner wall and API tablet inside Modulating drug release kinetics were achieved by changing grid pattern and printing orientation along with conc of HPMC Controlled drug release of ophthalmic patches

(continued)

Cui et al. (2020)

Tagami et al. (2022)

Cui et al. (2019)

Algahtani et al. (2020)

Gueche et al. (2021)

Kulinowski et al. (2021)

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 21

Technology BJ3DP

PLGA P(FAD:SA)

Lactose MH MCC PVPK30

Amitriptyline HCl

HPMC PVP K-25 PVAc/PVP K-30 HPMC TEC PCL PLGA

Polymer HPC Ink (ethanol, water) PH301 (Additive) Eudragit E-100 Ink (ethanol) MCC Eudragit RL-PO Ink (Acetone) Ethyl cellulose

5-Fluorouracil Diclofenac

Ethinyl estradiol

Pseudoephedrine HCl

9-Nitrocamptothecin

Acetaminophen

Diclofenac sodium

Chlorpheniramine maleate

API Caffeine

Table 1.3 (continued)

Modulating release (by changing shape, dimensions, and conc of release retardant polymers.) Encapsulating potent active, core-shell Tunable near-zero order release, pH independent, human pilot PK 12 week+ continuous release from rod-shaped implant, rabbit PK study Conceptual implant releasing 4 pulses of 5-FU and continuous release of diclofenac IR

Dual pulsatile release and IR, ER)

Release type SSL-SFP IR SL-FP CR Delayed Release

Sen et al. (2020))

Monkhouse et al. (1997)

Lin et al. (2001)

Wang et al. (2006)

Rowe et al. (2002)

Yu et al. (2009)

Rowe et al. (2000)

Katstra et al. (2000)

Reference Infanger et al. (2019)

22 K. Sen et al.

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals

23

such as by tuning the ratio of photocrosslinkable polymer and hydrophilic excipient to control the dissolution rate of the drug.

1.3.3.2 FDM Developing controlled release or modified release formulations using FDM has been of interest for the past decade, leveraging FDM’s ability to process malleable thermoplastic polymer at high temperature and its ability to create complex, compartmentalized architectures. Thus, FDM can modulate release kinetics by optimizing formulation composition and also by optimizing the dosage form architecture. Compositionally, FDM uses a main thermoplastic polymer (such as polyvinyl alcohol, PVAl), a plasticizer, and an optional disintegrant (for IR or fast release). PVAl has been widely used as a main polymer for CR/MR dosage forms based on its suitable water solubility properties and its extrudability properties (Goyanes et al. 2015a). In some cases, PVAl has worked alone, but in other cases, a plasticizer such as mannitol, sorbitol, or HPMC has been added to aid extrusion (Ðuranovi´c et al. 2021; Gioumouxouzis et al. 2017; Wei et al. 2020). In addition to CR, various IR dosage forms have also been produced from PVAl by FDM that include plasticizer and disintegrant/pore former (Ðuranovi´c et al. 2021; Wei et al. 2020). For architecture-based release control, FDM can use infill patterns (Sadia et al. 2018), infill density (Obeid et al. 2021), shape of the tablets (Goyanes et al. 2015b), and internal compartments in the tablets (Genina et al. 2017; Russi and Gaudio 2021). Reducing infill pattern and infill density, adding disintegrant, and optimizing use levels can accelerate release and provide the ability to tailor release rate. Changing the overall shape of the tablet, a general capability of AM techniques, can be used to modify the release rate based on surface area to volume ratio. In addition, FDM can form one or more internal compartments for modified release (accelerated, progressive, two pulse dosage form (Maroni et al. 2017)). 1.3.3.3 SLS Similar to FDM, SLS can modulate release using composition and dosage form architecture. Compositionally, the MR research has focused on thermoplastic polymers recognized for pH- and time-dependent solubility (Awad et al. 2019; Fina et al. 2018a; Hamed et al. 2021). Kollidon IR and PEO have been used for immediate release components, whereas polymers such as ethyl cellulose have been applied to sustained release. The concentration of thermoplastic polymer is used to modulate release rates. When copovidone or powdered charcoal is used as a matrix former, a separate laser absorbent is not required (Gueche et al. 2021; Kulinowski et al. 2021). For architecture-based release control, the SLS infill pattern can be used to alter the extent of laser-based local binding. Specific patterns can be screened in combination with different polymers to elucidate release properties (Fina et al. 2018a). Hatch spacing can be used to alter the resulting local pore structure as part of modulating release rate (Kulinowski et al. 2021).

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K. Sen et al.

1.3.3.4 SSE Like other AM, SSE can use a combination of compositional control (rate controlling polymers) and architectural control (e.g., infill pattern or design) to achieve MR. Polymers such as HPC, HPMC, and cellulose acetate have been explored with SSE to achieve release rates ranging from immediate to sustained release. Changing the infill pattern, lattice cell size, and printing orientation of a rate controlling polymer have also successfully tailored the drug release in an SSE dosage form (Cui et al. 2020; Cui et al. 2019). In addition , encapsulating a BCS I drug inside a rate controlling polymer chamber has provided sustained release in certain instances (Algahtani et al. 2020). Beyond oral dosage forms, ophthalmic patches designed by SSE for clinical trial setting have shown drug release primarily dependent upon the water uptake of the incorporated polymer (Tagami et al. 2022). 1.3.3.5 BJ3DP BJ3DP has also shown CR and MR capability by integrating rate controlling polymer in the formulation and compartments into the dosage design. For example, the release rate of acetaminophen was modulated by changing the tablet shape (doughnut) and the concentration of rate controlling polymer. Here, acetaminophen was embedded in HPMC matrix and coated with ethyl cellulose to create a constant rate of surface erosion during dissolution (Yu et al. 2009). Also, diclofenac sodium embedded in rate controlling polymer was used to demonstrate four specific type of release patterns: instant release followed by continuous release; continuous release from subdividing (breakaway) units; enteric dual pulsatory (two pulse release in gastric pH); and dual pulsatory (two pulse release on two different pH -acidic and gastric) (Rowe et al. 2000). Caffeine tablets were made using BJ3DP with different grades of HPC to produce immediate release and extended-release dosage form (Infanger et al. 2019). Near-zero order release of pseudoephedrine hydrochloride was demonstrated from BJ3DP tablets having modular core/shell (reservoir-like) structure tunable by changing the ratio of Kollidon SR and HPMC, supported by pilot biostudy results (Wang et al. 2006). For implantable systems, conceptual designs for 12-week continuous release of ethinyl estradiol (Lin et al. 2001) and for combined continuous and pulsatile release (diclofenac and 5-fluorouracil, respectively) (Monkhouse et al. 1997) have been demonstrated using degradable polyesters.

1.3.4

Combining Medications into a Single Dosage Unit (“Polypill”)

A polypill can be defined as a dosage form containing two or more active ingredients. Although the term “polypill” has a specific lineage related to cardiovascular disease (Gioumouxouzis et al. 2017; Wald and Law 2003), in broader usage it can refer to any multidrug dosage form used to treat disease. In practice, that means one pill replaces several. This approach reduces pill count and simplifies dosing schedule, with associated benefits to patient adherence. When manufactured centrally, the dose levels of each drug are preset, and such fixed-dose combination

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals

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Fig. 1.4 Examples of “Polypill” design using AM (Khaled et al. 2015a; Pereira et al. 2019)

(FDC) products are widely made today by traditional means, predominantly for two-drug and three-drug regimens. In this context, AM is most often seen as enabling much greater flexibility for polypill manufacture, including the number and levels of drugs that can be incorporated. This section will focus on polypill composition and design using AM. Flexible manufacturing aspects of AM are already separately addressed in Sect. 1.3.1. State of the Art Although various research groups have shown the possibility of using AM to fabricate polypills (Keikhosravi et al. 2020), this specific application has yet to achieve a regulatory approval. An initial preclinical study explored the behavior of two anti-tuberculosis drugs in a polypill showing promising results (Khaled et al. 2015a; Pereira et al. 2019) (Fig. 1.4). Additionally, a pilot study was conducted to understand the preferences of patients regarding aesthetics, practicality, and acceptability of dosage form designs (Fastø et al. 2019). The future aspect of polypharmacy has been discussed predominantly for the clinical setting or at the point of care (Trenfield et al. 2021) (Table 1.4).

1.3.4.1 SLA SLA has not yet been explored extensively for polypill work. However, a recent study showed the potential feasibility of polypill fabrication using SLA to incorporate six APIs (paracetamol, caffeine, naproxen, chloramphenicol, prednisolone, and aspirin) into one single dosage form (Robles et al. 2019). Another study illustrated the importance of avoiding photopolymer drug degradation in fabricating a polypill with four API (irbesartan, atenolol, hydrochlorothiazide, and amlodipine) (Xu et al. 2020). The SLA polypill has been optimized thus far by dosage form design (APIs stacked on top of each other). 1.3.4.2 FDM The contribution of FDM in polypill prototyping is extensive, including strategies based on dosage form design and on formula composition. Dosage form design has been used in the following ways: by building a multicompartment chamber separated by divider to physically inhibit interaction between two incompatible

SLS

FDM

Technology SLA

Ibuprofen-IR Paracetamol-SR

Amlodipine and lisinopril

Polyethylene oxide Candurin Kollicoat IR-IR Ethyl Cellulose -SR

PVA-IR Ethylene-vinyl acetate copolymer-ER

PVA

Lisinopril dihydrate, indapamide, rosuvastatin calcium and amlodipine besylate Pramipexole-IR levodopa, benserazide-ER

Aspirin and simvastatin

Irbesartan, atenolol, hydrochlorothiazide, and amlodipine

Polymer Polyethylene glycol diacrylate (PEGDA) diphenyl(2,4,6trimethylbenzoyl)phosphine oxide (Photo initiator) PEG300 Polyethylene glycol diacrylate (PEGDA) diphenyl(2,4,6trimethylbenzoyl)phosphine oxide (Photo initiator) Eudragit L100-55 and PEG 6000(with api)

API Paracetamol, caffeine, naproxen, chloramphenicol, prednisolone, and aspirin

Table 1.4 Examples of AM use to create “Polypills”

2 in 1 dose Miniprintlets with control release

Two compartment polypill (Two API separated removing incompatibility issues and thermal sensitivity problem by integrating with melt casting) 4 in 1 polypill where water was used as plasticizer to reduce printing temp (two drug crystalline and two amorphous) 3 in 1 polypill with customize release to treat Parkinson’s disease ( gastric floating capabilities) 2 in 1 dose

Cylindrical

Design Cylinder shape and ring shaped polypill

Trenfield et al. (2020) Hypertension Awad et al. (2019) Antipyretic

Windolf et al. (2022) Parkinson’s

Pereira et al. (2019) CVD

Keikhosravi et al. (2020) CVD

Xu et al. (2020) Hypertension

Reference and Therapy Robles et al. (2019) Antipyretic

26 K. Sen et al.

SSE

PEG 6000 HPMC-SR Mannitol MCC SSG Cellulose acetate (Change in design to make IR release by mixing SSG and mannitol and introducing holes) Hydroxyethyl cellulose Ethoxylate Cellulose acetate Phthalate

Captopril-osmotic pump nifedipine, glipizide-SR

Aspirin, hydrochlorothiazide-IR Pravastatin Atenolol Ramipril-ER Efavirenz Tenofovir Disoproxil Fumarate Emtricitabine

Proprietary craft blend

Caffeine-ER Vit B1,B3,B6-IR

Multicompartment dosage design 5 in 1 dose with two independently controlled and well-defined release profiles 3 in 1 loaded together and in separate layers

2 compartments with core-shell design 4-in-1 oral polypill with multiple release profiles Multicompartment dosage design Captopril-zero order Rest—1st order release

(continued)

Siyawamwaya et al. (2019) anti-HIV

Khaled et al. (2015b) CVD

Khaled et al. (2015a) hypertension of diabetic patient

Goh et al. (2021) Dietary Supplement

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 27

Technology BJ3DP (Combined material jetting/standalone) Powder Mix MCC Mannitol PVP Sucralose Ink IPA PVP Glycerin Powder Mix Lactose PVP K-25 Ink#1 PVP K-17 Ink#2 both drugs PVP K-17

Levetiracetam (powder) Pyridoxine HCl (ink)

Chlorpheniramine maleate and Pseudoephedrine HCl (in same ink)

Polymer Hydrophilic hyaluronic acid, hydrophobic PEG

API Lisinopril, Spironolactone

Table 1.4 (continued)

2 in 1 rapidly disintegrating tablet having reinforced top and bottom regions (drug free). Both drugs deposited in central region.

Multicompartment structure dispersible tablet

Design Preform tablet composed of two attachable compartments

Yoo et al. (2002) Cough/cold

Hong et al. (2021) Anti-epileptic

Reference and Therapy Acosta-Vélez et al. (2018) Hypertension

28 K. Sen et al.

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drugs (Keikhosravi et al. 2020); by changing the architecture of the dosage form to extend multiple drug release in the GI tract with two drug release kinetics (mini-floating polypill) (Windolf et al. 2022); by engineering drug release behavior based on physicochemical properties, e.g., successfully printing two crystalline and two amorphous drugs in a single dose (Pereira et al. 2019). An example formulation-based technique is the incorporation of water as a plasticizer to reduce the operating temperature and enabling FDM of amorphous and thermally sensitive drug. Otherwise, polypills have the same compositional requirements as for other solid oral dosage forms by FDM. Most often, PVA, Eudragit, and PEG have been used as thermoplastic polymer for FDM polypills.

1.3.4.3 SLS Fabrication of polypill using SLS has not been properly explored yet. A couple of studies used two drugs loaded into one dosage unit. SLS polypills have been fabricated by directly incorporating the customary ingredients into the powder blend for SLS (APIs, thermoplastic polymer, and laser adsorbents such as Candurin). Two drugs polypill exhibiting two release behaviors was achieved by loading drug in two thermoplastic polymers enabling IR and SR property (Awad et al. 2019; Trenfield et al. 2020). 1.3.4.4 SSE Compared to the other AM, SSE has been investigated extensively for polypill fabrication. A two compartmental core-shell design has been developed to deliver dietary supplements (caffeine and four grades of Vitamin B) which exhibits different release properties (Goh et al. 2021). A multicompartment dosage platform has been developed to load antihypertensive and CVD drugs with IR and SR behaviors (Khaled et al. 2015a, 2015b). Apart from multicompartment designs, multiple drugs have been printed onto the same dosage form in separate layers using SSE as well (Siyawamwaya et al. 2019), exhibiting higher drug release compared to the corresponding commercial dosage form for HIV treatment. Although compartments have been used for SSE polypills, excipients have maintained a critical function to provide personalized release properties of the drug such as HPMC, cellulose acetate phthalate for SR and PEG 6000 for IR. 1.3.4.5 BJ3DP The application of BJ3DP in polypill production has not been properly explored. A multicompartment structure of levetiracetam-pyridoxine hydrochloride (LEV-PN) dispersible tablet has been developed wherein the pyridoxine hydrochloride has been added to the ink and deposited into the middle nest layer of the tablet (Wang et al. 2021). In some of the earliest BJ3DP work, a two-drug orodispersible tablet of chlorpheniramine maleate and pseudoephedrine hydrochloride was demonstrated (Yoo et al. 2002).

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1.3.5

K. Sen et al.

Orodispersible Dosage Forms

Orodispersibles can be defined as dosage forms that disintegrate rapidly when placed in the oral cavity. These dosage forms provide ease of administration, faster drug release, and the potential for quicker onset of action for certain drugs. Orodispersibles can be either orally disintegrating tablets (ODTs) or orally disintegrating films (ODFs) having low total mass and disintegrating without liquid (FDA Guidance for Industry 2008), or they can be larger units specifically designed to disintegrate in the mouth in response to added liquid. Orodispersibles made by AM are mainly prototyped as ODT and ODF. The quick disintegration in orodispersibles has been achieved primarily by higher specific surface area of loosely bound particles and dissolution of water-soluble excipients or water-soluble drug substances within the dosage form’s structure.

1.3.5.1 State of the Art Orodispersible dosage forms are the most mature area of AM use for pharmaceuticals thus far. The first drug approval incorporating AM was in 2015 for Spritam (levetiracetam), an orodispersible dosage form made using a proprietary scaled form of binder jetting in a centralized plant by Aprecia Pharmaceuticals. Spritam is an example from a category of formulations referred to as ZipDose technology, which can incorporate chosen drugs at high doses (e.g., 1000 mg) and high total mass while retaining fast-disintegrating properties when administered directly in the mouth with a sip of liquid. Aprecia already offers development and manufacturing services for partners using this technology. Aprecia has also recently introduced ZipCup™ (ZFill) technology, which entails orodispersible shells that can be filled with diverse dry payloads similar to capsules, but can still disintegrate in the mouth with a sip of liquid. Apart from binder jetting, a recent clinical example of orodispersibles is warfarin film fabricated using SSE and inkjet technology. The film was precast using SSE, and the drug was loaded using inkjet printing. The ODF was administered to patients using naso-gastric tube at a hospital ward at HUS Pharmacy in Finland (Öblom et al. 2019) as an on-demand patient specific dose (Table 1.5). 1.3.5.2 FDM Among orodispersibles, FDM work has mainly focused on orodispersible films (ODFs) which are more practical to fabricate than ODTs due to the characteristics of the FDM process. These studies mainly use three ingredients: film former, support materials, and API. PEO and PVA have been used as the main film forming agents in ODF fabrication. In some cases, a backing substrate for the film such as poloxamer (Jamróz et al. 2017) or ethyl cellulose has been used to modify the properties of the film to aid handling by the user (Eleftheriadis et al. 2019). 1.3.5.3 SLS SLS has been investigated significantly for fabrication of ODTs, including orodispersible Printlets™ from FabRx. An ODT formulation using SLS requires API,

SSE

SLS

Technology FDM

Prednisolone

Levocetirizine HCl

Paracetamol

Ondansetron

Paracetamol

Chitosan

API Aripiprazole Olanzapine

Key Excipients PVA-film former PEO-film former Kollidone VA64-ASD former Poloxamer 407, Poloxamer 188-solubility enhancer PVA-film base Ethylcellulose-film base Kollidon VA64HPMCCandurin Cyclodextrin-drug loader Kollidone VA64-Binder Mannitol Candurin Kollidon VA64 Candurin HPMC-film former Maltitol Sucralose Pregelatinized Starch PEO, HPC-Viscosity modifier

Table 1.5 Examples of AM use to create orodispersible dosage forms

Vet ODF

ODT(Brailied for visually impaired patient) ODF

ODT

ODT

Mucoadhesive film

Dosage form ODF ASD ODF

(continued)

(Sjöholm et al. 2020)

(Yan et al. 2020b)

(Awad et al. 2020)

(Allahham et al. 2020)

(Fina et al. 2018a)

(Eleftheriadis et al. 2019)

Reference (Jamróz et al. 2017) (Cho et al. 2020)

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 31

SPRITAM (Levetiracetam)

BJ3DP

Topiramate

Oxcarbazepine

Triiodothyronine (T3) & Thyroxine (T4) Hydrochlorothiazide Enalapril maleate Captopril

Levetiracetam

Quinapril hydrochloride, clotrimazole

API Hydrochlorothiazide

Technology

Table 1.5 (continued)

Mannitol Maltitol MCC Mannitol HPC PVP Mannitol MCC HPC PVP

Key Excipients PVP K30 Croscarmellose sodium Lactose MH Mannitol MCC PVP Microcrystalline Cellulose HPMC PVP (Powder bed) Mannitol PVP VA64 Microcrystalline cellulose HPMC Propylene Glycol PEG 400

Tablet for Oral Susp. (can be taken in mouth w/ sip of liquid)

Tablet for Oral Susp. (can be taken in mouth w/ sip of liquid)

(Jacob et al. 2016b)

(Jacob et al. 2016a)

(Lee et al. 2003)

(Thabet et al. 2018)

ODF ODT

(Wang et al. 2021)

(Basit and Gaisford 2018)

(Kozakiewicz-Latała et al. 2022)

(Aprecia Pharmaceuticals 2021)

Reference (Eduardo and Ana 2021)

ODF

ODT

ODT

Tablet for Oral Susp (can be taken in mouth w/ sip of liquid)

Dosage form Pediatrics ODT

32 K. Sen et al.

1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals

33

thermoplastic polymer, and a laser adsorbent (such as Candurin). The ratio of API and thermoplastic polymer is used to modify the disintegration properties of ODTs generated by SLS. In some cases, Kollidon VA64 (Fina et al. 2018a) and HPMC have been used as matrix formers for ODTs. In one study, mannitol (Allahham et al. 2020)was added to act as a pore former.

1.3.5.4 SSE SSE has been used to develop both ODTs and ODFs. The thickness of ODF has been limited to a range of 0.6 to 1 mm, whereas ODTs of 1.4–1.6 mm in thickness have been demonstrated. Orodispersible formulations made by SSE typically contain API, binder (ODT) or film former (ODF), and disintegrant. Some studies with SSE used a water-soluble film former to load API and fabricate ODFs (Sjöholm et al. 2020). In other studies, pregelatinized starch and croscarmellose sodium have been added to attain quick disintegration (Eduardo and Ana 2021; Yan et al. 2020b). Binder/film formers such as HPMC, PVP K30, and PEO have been used in the previous studies. 1.3.5.5 BJ3DP BJ3DP has been used for making orodispersibles since the late 1990s (Yoo et al. 2002). To this day, the precision and accuracy of the jetting process remain attractive for depositing low-dose drugs using a liquid carrier. For ODTs, the drugs can be incorporated via the jetted liquid, via the dry powder that is spread, or both. Much higher dosing is possible for drugs incorporated using the powder route. Drugs can also be jetted onto ODTs after they are formed. Conversely, for ODFs inkjet printing has been used to deposit drugs onto preformed films made either by AM or by conventional techniques. For ODTs, BJ3DP uses hydrophilic excipients such as lactose, mannitol, and microcrystalline cellulose as part of the powder blend (Kozakiewicz-Latała et al. 2022; Basit and Gaisford 2018). To aid tablet binding, BJ3DP also uses watersoluble binding agents such HPMC and PVP as part of the powder blend, the jetted liquid, or both. For ODFs, inkjet printing requires a preformed film which can be made from water-soluble polymers such as PEG or HPMC (with glycerol) (Alomari et al. 2018; Thabet et al. 2018). Ink formation can either be by direct mixing of drug with water (Thabet et al. 2018) or with an appropriate solvent system (e.g., ethanol:DMSO:PG) to aid solubilization of the drug (Alomari et al. 2018).

1.3.6

Other AM Uses of Note

Localized Drug Delivery AM can facilitate localized drug delivery by making novel systems (Chakka and Salem 2019) such as drug-eluting implants (Liaskoni et al. 2021; Stewart et al. 2020), BIOCAGE implants (Son et al. 2017), bladder devices (Xu et al. 2021), and drug-eluting contact lenses (Mohamdeen et al. 2022). AM has improved the design

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K. Sen et al.

of devices such as mucoadhesive reservoirs that attain longer delivery time (Vaut et al. 2020). SLA and FDM are the categories of AM explored predominantly in this area. Anticounterfeiting AM has also been investigated to aid anticounterfeiting techniques. Using the exceptional capability of inkjet printing, unique QR codes can be printed on tablet surfaces using “smart inks” to track individual tablets (Trenfield et al. 2020). Internal 3D patterns or codes made using chemical markers have also been demonstrated with BJ3DP (Shariff et al. 2020). Masking API Taste AM has also been applied to taste-masking of drugs in dosage forms. Taste-masking is often necessary in order to achieve sufficient palatability of an oral formulation, especially for pediatric populations, and most often to cover bitter sensations (Wang et al. 2020). The forms of AM evaluated thus far are HME integrated FDM for donut-shaped tablets (Wang et al. 2020), Starmix dosage form (Scoutaris et al. 2018), fruit chews (Tabriz et al. 2021) for pediatric patients, and BJ3DP for instant dissolving tablets [172] and large-format orally disintegrating tablets including use of coated API (Jacob et al. 2016b; Wang et al. 2021). Bioprinting-Organ on a Chip 3D bioprinting is a specialized area of AM gaining popularity in the medical field. It fabricates tissues and organs using “bioinks” formulated to deposit living cells and biomaterials (e.g., collagen, cellulose, and agarose) that help mimic the cell’s normal environment while creating scaffolds for the cells to grow into the tissue or organ (Jamróz et al. 2018; Kassem et al. 2022). Apart from its main uses in tissue and organ replacement, certain 3D bioprinting processes are relevant to early-stage drug discovery and development such as organ on a chip (OoC) for toxicological screening. OoC is a platform in which one or more organs can be mimicked based on the inclusion of microfluidic channels and engineered tissue. By emulating the microenvironment and tissue-specific functions, OoC can approximate the physiological response to drug exposure. This approach has the long-term potential to reduce or replace early animal studies over time (e.g., heart (Zhang et al. 2016), liver (Bhise et al. 2016), etc.).

1.4

Conclusions

With its growing body of work, Additive Manufacturing (AM) has exposed the pharmaceutical industry to new possibilities for drug development. In one sense, AM promises an eventual revolution in formulation design by addressing longstanding needs such as improved bioavailability of low solubility compounds, modulated release kinetics, polypills, and orodispersible forms. In another sense, it has shown the immense potential of personalization to change the way medicine

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is deployed to impact patients’ lives. Although the vast majority of AM use cited in this chapter has been carried out in an academic or laboratory setting, both BJ3DP and FDM-type AM have already obtained early regulatory traction in a centralized manufacturing format, encompassing one 505(b)(2) approval and three IND clearances, collectively. In addition, both FDM and SSE have begun clinical usage in smaller decentralized formats, including the compounding pharmacy context. Accordingly, following the existing examples of regulated pharmaceutical use, AM holds tremendous potential for greater practical deployment to benefit progressively more patients in the near future. Acknowledgments The authors wish to thank Jaedeok Yoo (FoundationLayers, LLC) for contributing key concepts and review comments to Fig. 1.2.

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a focus group study among healthcare professionals. Pharmaceuticals 12:229. https://doi.org/ 10.3390/pharmaceutics12030229 Robles-Martinez P, Xu X, Trenfield SJ, Awad A, Goyanes A, Telford R, Basit AW, Gaisford S (2019) 3D printing of a multi-layered polypill containing six drugs using a novel stereolithographic method. Pharmaceuticals 11:274. https://doi.org/10.3390/pharmaceutics11060274 Rowe CW, Katstra WE, Palazzolo RD, Giritlioglu B, Teung P, Cima MJ (2000) Multimechanism oral dosage forms fabricated by three dimensional printingTM . J Control Release 66:11–17. https://doi.org/10.1016/s0168-3659(99)00224-2 Rowe C, Wang C, Monkhouse D (2002) Theriform technology. In Rathbone M (ed) Modifiedrelease drug delivery technology. Marcel Dekker Inc. https://doi.org/10.1201/9780203910337 Russi L, Gaudio CD (2021) 3D printed multicompartmental capsules for a progressive drug release. Ann 3d Print Med 3:100026. https://doi.org/10.1016/j.stlm.2021.100026 Sachs EM, Haggerty JS, Cima MJ, Williams PA (1993) Three-dimensional printing techniques. U.S. Patent 5,204,055, filed Dec. 8, 1989 and issued Apr. 20, 1993. https://patents.google.com/ patent/US5204055A/ Sadia M, Arafat B, Ahmed W, Forbes RT, Alhnan MA (2018) Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets. J Control Release 269:355–363. https://doi.org/10.1016/j.jconrel.2017.11.022 Saydam M, Takka S (2020) Improving the dissolution of a water-insoluble orphan drug through a fused deposition modelling 3-Dimensional printing technology approach. Eur J Pharm Sci 152:105426. https://doi.org/10.1016/j.ejps.2020.105426 Schrimpf G Merck KGaA, Darmstadt, Germany and B. Braun Join Forces in the Development of Bioelectronic Devices (n.d.). https://www.emdgroup.com/en/news/bioelectronics-bbraunneuroloop-29-06-2021.html#. Accessed 10 Sep 2022 Scoutaris N, Ross SA, Douroumis D (2018) 3D printed “Starmix” drug loaded dosage forms for paediatric applications. Pharm Res 35:34. https://doi.org/10.1007/s11095-017-2284-2 Sen K, Manchanda A, Mehta T, Ma AWK, Chaudhuri B (2020) Formulation design for inkjet-based 3D printed tablets. Int J Pharm 584:119430. https://doi.org/10.1016/j.ijpharm.2020.119430 Seoane-Viaño I, Januskaite P, Alvarez-Lorenzo C, Basit AW, Goyanes A (2021a) Semi-solid extrusion 3D printing in drug delivery and biomedicine: personalised solutions for healthcare challenges. J Control Release 332:367–389. https://doi.org/10.1016/j.jconrel.2021.02.027 Seoane-Viaño I, Ong JJ, Luzardo-Álvarez A, González-Barcia M, Basit AW, Otero-Espinar FJ, Goyanes A (2021b) 3D printed tacrolimus suppositories for the treatment of ulcerative colitis. Asian J Pharm Sci 16:110–119. https://doi.org/10.1016/j.ajps.2020.06.003 Sertoglu K (2020) Fabrx launches the m3dimaker for personalized medicine 3d printing. https:/ /3dprintingindustry.com/news/fabrx-launches-the-m3dimaker-for-personalized-medicine-3dprinting-170695/. Accessed 11 Nov 2022 Shariff Z, Kirby D, Missaghi S, Rajabi-Siahboomi A, Maidment I (2020) Patient-centric medicine design: key characteristics of oral solid dosage forms that improve adherence and acceptance in older people. Pharmaceuticals 12:905. https://doi.org/10.3390/pharmaceutics12100905 Siyawamwaya M, du Toit LC, Kumar P, Choonara YE, Kondiah PPPD, Pillay V (2019) 3D printed, controlled release, tritherapeutic tablet matrix for advanced anti-HIV-1 drug delivery. Eur J Pharm Biopharm 138:99–110. https://doi.org/10.1016/j.ejpb.2018.04.007 Sjöholm E, Sandler N (2019) Additive manufacturing of personalized orodispersible warfarin films. Int J Pharm 564:117–123. https://doi.org/10.1016/j.ijpharm.2019.04.018 Sjöholm E, Mathiyalagan R, Prakash DR, Lindfors L, Wang Q, Wang X, Ojala S, Sandler N (2020) 3D-printed veterinary dosage forms—a comparative study of three semi-solid extrusion 3D printers. Pharmaceuticals 12:1239. https://doi.org/10.3390/pharmaceutics12121239 Sjöholm E, Mathiyalagan R, Wang X, Sandler N (2022) Compounding tailored veterinary chewable tablets close to the point-of-care by means of 3D printing. Pharmaceuticals 14:1339. https://doi.org/10.3390/pharmaceutics14071339 Son AI, Opfermann JD, McCue C, Ziobro J, Abrahams JH, Jones K, Morton PD, Ishii S, Oluigbo C, Krieger A, Liu JS, Hashimoto-Torii K, Torii M (2017) An implantable micro-caged device

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Fused Deposition Modeling (FDM) of Pharmaceuticals Silke Henry, Valérie Vanhoorne, and Chris Vervaet

Abstract

A shift in treatment strategy from generalized to personal healthcare has sparked the interest for flexible production techniques capable of producing patient-specific dosage forms. Fused deposition modeling could be utilized for such personalized treatment, and its interest has grown rapidly, with over 350 published papers in the field of pharmaceutical science in the last decade. The advantages of the technique are indeed manifold. Apart from being desktopsized, FDM has also been praised for its simplicity and cost-effectiveness. The aim of this chapter is to summarize 10 years of research on pharmaceutical FDM 3D-printing in a concise and comprehensive way. Therefore, this chapter first provides information about the FDM 3D-printing equipment and its process mechanism. Next, the typical formulation constituents and specific characterization techniques for the printed dosage forms will be discussed. Finally, a variety of possible pharmaceutical applications like oral therapies, transdermal or transmucosal films and implants will also be reviewed. Keywords

Fused deposition modeling · Fused filament fabrication · Solid dosage forms · Drug delivery · Personalised healthcare · Additive manufacturing

S. Henry · V. Vanhoorne · C. Vervaet () Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium e-mail: [email protected]; [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals, https://doi.org/10.1007/978-981-99-2404-2_2

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Introduction

Pharmaceutical production processes are generally focused on mass production of dosage forms, suiting the average patient in the population. Recently, a shift in treatment strategy was initiated moving generalized healthcare towards personalization. Such treatment personalization is only possible if a versatile production technique able to create high-quality unique dosage forms is developed. Additive manufacturing or 3D-printing is such an innovative production technique with seemingly unlimited flexibility, capable to produce any wanted end-product in a layer-by-layer fashion (Auriemma et al., 2022; Henry et al., 2021a). Additive manufacturing or 3D-printing is an umbrella term encompassing a variety of 7 different printing techniques which are all classified as computeraided design (CAD), utilizing an in-silico model to drive production. These printing techniques are binder jetting, material jetting, vat photo-polymerization, sheet lamination, directed energy deposition, powder bed fusion and material extrusion. Material extrusion is characterized by the deposition of a material through an orifice to create semi-solid strands which solidify on the build plate. The material extrusion technique includes both semi-solid extrusion and fused deposition modeling (FDM). The semi-solid technique utilizes gels or pastes and pressure-assisted microsyringes, while FDM utilizes thermoplastic starting materials which are deposited in a molten state (Awad et al., 2018; Auriemma et al., 2022). The FDM 3D-printing technique was developed in 1988 by S. Scott Crump, after he attempted to create a 3D-object using a glue gun. Following commercialization by the company Stratasys, the technique was named fused deposition modeling (FDM) (Ligon et al., 2017). After expiration of the patent, the technique became commonly known as fused filament fabrication (FFF) (Shaqour et al., 2020). The popularity of the FDM or FFF technique is apparent by its use in many industries like rapid prototyping, manufacturing or tooling of specific applications in for example the aircraft industry (Wang et al., 2019), automotive industry (Yadav et al., 2019), electronic devices (MacDonald et al., 2014), architecture (Gosselin et al., 2016) and microfluidics (Pranzo et al., 2018). To suit this broad extent of applications, a variety of materials have been developed like glass fiber reinforced polypropylene (Carneiro et al., 2015), acrylonitrile butadiene styrene (ABS)-based nanocomposite material (Ceretti et al., 2022), ABS-based material containing metallic filler (Masood and Song, 2004) or sustainable feedstock materials (Fico et al., 2022). At present, FDM 3D-printing is also the most broadly investigated 3Dprinting technique in healthcare since it is cheap and easy-to-use. As a result, it is excellently suited to provide on-site production of personalized dosage forms (Ligon et al., 2017). The printing technique has been used to produce for example dental devices (Dawood et al., 2015), scaffolds for tissue engineering (Zein et al., 2002) or customized prosthetics (Barrios-Muriel et al., 2020). This chapter will focus on the use of FDM to produce drug delivery devices containing active pharmaceutical ingredients (API).

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Fig. 2.1 Different steps in the production of an FDM 3D-printed dosage form, starting from an in-silico model. (Reprinted with permission under the open access CC BY 4.0 license from Jamróz et al. 2018)

2.2

Process Technology and Principles of Printing

Fused deposition modeling (FDM) has a rather simple operating mechanism with equipment generally being desktop-sized. The general operating mechanism is similar to all FDM 3D-printers, illustrated in Fig. 2.1. Individual differences might however occur, for example, in terms of feeding behaviour. Firstly, a digital model is constructed using computer-aided design (CAD) software. This model is saved as a stereolithographic (.stl) file, where the surface of the model is transformed into small triangles (Cailleaux et al., 2021). Secondly, the in-silico model is imported in the printing or slicer software, where printing parameters can be freely chosen based on the desired outcome. The desired object will be saved, generating a set of instructions readable by the printer (g-code) (Trenfield et al., 2018). Thirdly, a feed and printable formulation in the form of a filament is chosen, consisting of a drug dispersed into a thermoplastic material. This feedstock filament is fed towards a heated nozzle, molten and deposited on a platform. Nozzle and build platform can move along a different axis to create a 3D-object in a layer-by-layer fashion (Turner et al., 2014).

2.2.1

Fused Deposition Modeling Equipment

FDM 3D-printing is a fairly new production technique, but it has known a swift rise in the number of applications. The first industrial prototype of an FDM printer was developed by Stratasys in 1992. The machine, the so-called 3D Modeler, utilized only plastics and waxes as starting material. In 2011, one of the first reports of pharmaceutical FDM 3D-printing appeared, when wound dressings containing an

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Fig. 2.2 On the left, an overview of the set-up of a generic FDM 3D-printer, utilizing a direct extrusion mechanism. A detailed overview of the extruder with feeding gears and nozzle is presented on the right. (Reprinted with permission from Parulski et al. 2021)

antibacterial agent were printed and evaluated in vivo (Teo et al., 2011). In 2014, one of the first reports of FDM 3D-printing for oral drug delivery occurred, describing the development of a fluorescein loaded polyvinyl alcohol (PVA) tablet (Goyanes et al., 2014). While all FDM printers possess a largely identical working principle, small differences in set-up exist in terms of movement, feedstock diameter, feed mechanism, print enclosure and number of nozzles. The set-up of a generic FDM 3D-printer is illustrated in Fig. 2.2, and possible variations on this generic type are discussed below. • Movement system: Nearly, all FDM printers used in pharmaceutical research utilize the Cartesian coordinate system with movement of the extruder head and build platform along the X-, Y- and Z-axis. Other less common types include a delta head, polar system or robotic arm. • Feedstock diameter: Printers are developed to work with a filament diameter of either 1.75 or 2.85 mm. Smaller filament diameters could be preferred in pharmaceutical manufacturing due to a shorter residence time inside the liquefier and nozzle, hence reducing the thermal load on the API (Gottschalk et al., 2021) and impact of diameter inhomogeneities on the printed dosage form (Quodbach et al., 2021). • Enclosure: Only a small subset of printers is built within a temperature-controlled enclosure, minimizing thermal gradients and subsequent warping of the printed object. Smaller scale printers used in pharmaceutical production mostly do not operate in a full enclosure but utilize only a heated build platform. While this is cost-effective, this approach impedes the use of materials with high melt temperatures and the production of large-scale objects. • Feed mechanism: Two subtypes exist within the class of FDM 3D-printers based on the feeding mechanism. The first subtype contains a direct drive extruder, with the feeding gears positioned directly above the extruder head as depicted

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Fig. 2.3 Set-up of the Bowden feed mechanism in a fused deposition modeling 3D-printer. (Reprinted with permission from Tlegenov et al. 2018)

in Fig. 2.2. This system provides superior feed control, which is beneficial for flexible materials. As a result however, the extruder head is somewhat heavier, resulting in vibrations which might hamper continuous flow from the nozzle and cause imperfections in the printed object (Fuenmayor et al., 2018). An example of a commercialized, non-GMP printer using this principle is the Prusa i3 MK3S. The second subtype, a Bowden printer, has the driver gears positioned apart from the extruder head as depicted in Fig. 2.3. This system enables higher print speeds with less vibrations but requires more fine-tuning for specialty filaments (Fuenmayor et al., 2018). An example of a commercialized, non-GMP printer using the Bowden principle is the Ultimaker S3. In general, the direct extrusion mechanism is preferred over the Bowden system to allow for a wider material selection while minimizing stress on the feedstock material (Prasad et al., 2019; Lamichhane et al., 2019; Fuenmayor et al., 2018). However, reports were recently made of modified Bowden printers utilizing a smaller feeding tube, rigid guide and piston feeding to enable wider material selection (Gottschalk et al., 2021). • Nozzle: A printer mostly has one nozzle but might consist of multiple extruders each with their own nozzle to enable for easy multi-material printing. This principle was used successfully to construct for example a polypill for the treatment of cardiovascular diseases (Pereira et al., 2019). Another approach enabling multi-material printing has been demonstrated by Windolf et al. (2022). A single extruder and nozzle was utilized where different filaments are consecutively fed and washed out by means of a cleaning tower (Windolf et al., 2022).

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The Printing Process

The extrusion head of a generic FDM 3D-printer contains a feeding mechanism, liquefier and nozzle assembled onto a gantry with build platform. The starting material, a filament, is pinched by roller grips and pushed further inside the extrusion head. This feeding mechanism might be incompatible with certain feedstock materials as it might crush or bend filaments due to the exerted pressure. Next, the feedstock enters the heated liquefier and is molten. The amount of melt inside the channel will depend on both the feed rate and heat flux. Finally, the melt flows out of the nozzle due to the piston action of the unmolten filament above the liquefier zone. Consequently, the melt is deposited on the build platform where it solidifies. The surface of the build platform is crucial as it should enable sufficient but not excessive adhesion of the object to the build platform. During melt flow out of the nozzle, the motion of the extrusion head and build platform are controlled by stepper motors, enabling the production of a 3D-object. The printing step could be followed by a smoothing step using mechanical abrasion, chemical smoothing with solvent vapors or surface coating (Turner et al., 2014) although this is typically not pursued when producing biocompatible pharmaceutical dosage forms.

2.2.2.1 Mass Flow During Fused Deposition Modeling 3D-Printing Feeding of the feedstock filament is controlled by rotation of the roller grips above the liquefier to obtain a well-defined constant volumetric flow rate. This feed rate can be expressed as v=

.

Q W ×H

(2.1)

where v is the linear feed velocity of the filament, Q the volumetric flow rate of the melt, W the road width and H the slice thickness of the deposited strand. The force required to achieve this volumetric flow by pushing the melt out of the nozzle depends on the pressure drop (.P) and cross-sectional area of the feedstock filament (A): F = P × A

.

(2.2)

Since polymer melts generally display pseudoplastic behaviour, their viscosity depends on the imposed shear rate and temperature of the process. A minimum process temperature is required for extrusion, since excessive viscosity will lead to an excessive pressure drop which will consecutively block the extruder. The pressure drop (.P) over the extruder head is directly proportional to the viscosity (.η) and volumetric flow rate (Q): P =

.

8×Q×L×η  4 π × D2

(2.3)

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where the length of the nozzle (L) and the diameter of the nozzle (D) represent equipment design variables (Henry et al., 2021a). From Eq. 2.3, it becomes clear that the size of the nozzle is an important process variable, since it controls the pressure drop and hence the resolution, occurrence of print failures and acceptable process conditions of a specific formulation (Henry et al., 2021a). Moreover, nozzle size determines the mass average of the printed object and its mass variation (Macedo et al., 2022).

2.2.3

Material Processability

As mentioned previously, the 3D-printing process utilizes roller grips to pinch and push the filament forward through the extruder. The flow behaviour of the melt exiting the extruder is in turn mainly dictated by its rheological behaviour. As a result, this printing technique inherently poses limitations on the materials that can be used as feedstock.

2.2.3.1 Feedability In terms of feedability, constraints are mainly related to the mechanical behaviour of the feedstock. The filament should be able to withstand the loads imposed by the feeding gears with minimal deformation. If the filament is incompatible with the printing gears, passage towards the heated nozzle is impeded which results in the occurrence of print failures as can be seen in Fig. 2.4. Feeding Failures Print failures due to feedability issues can be classified into brittleness, flexibility and softness. Brittleness occurs when filaments break inside the print head due to the transversally applied stress of the gears, as noted when (Korte et al., 2018) attempted to print theophylline-loaded Eudragit RL (Korte et al., 2018). Flexibility of the filament becomes an issue when the filament is not deformed or broken between the gears but buckles above the liquefier, hence impeding the piston action of the filament to push the melt out of the nozzle. This was observed by Genina et al. (2016) when attempting to print elastic ethylene vinyl acetate grades (Genina et al., 2016). Problems regarding filament softness are observed when the filament is deformed and flattened between the gears, often occurring for higher drug-loaded filaments in combination with increased process temperature. This was observed by Aho et al. (2019) when attempting to print polycaprolactone with 70% (m/m) indomethacin at higher temperatures (Aho et al., 2019). This phenomenon seems especially problematic when the filament has a low glass transition temperature and/or melting temperature and if high pressure is required to advance the filament towards the nozzle (Henry et al., 2021a).

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Fig. 2.4 Illustration of an FDM extruder head, presenting the feeding mechanism by means of roller grips and highlighting (a) defective feeding due to low toughness and subsequent deformation, (b) defective feeding due to brittleness and (c) flawless passage through the gears. (Reprinted with permission from Lima et al. 2022)

It must be noted that different nomenclature was sometimes used in research articles. The nomenclature used in the first column of Table 2.1 refers to the failure modes described in the cited articles, rather than the measured mechanical parameters. Screening Tests Several tests have been developed to screen formulations, enabling to test their feedability without the need to go through trial-and-error iterations on the printer. Most of these tests utilize a texture analyser, generating a force–displacement curve which is mostly converted towards a stress–strain curve taking into account the diameter and length of the investigated specimen. Zhang et al. (2017) utilized a 3-point bend test to investigate brittleness, expressed as stiffness, which was the ratio between the breaking stress and breaking distance (Zhang et al., 2017). This 3-point bend test is most commonly used to evaluate the feeding behaviour by comparing the breaking stress and flexural modulus (Prasad et al., 2019; Than and Titapiwatanakun, 2021). Alternative tests have also been developed like elongational tests (Goyanes et al., 2016; Henry et al., 2021a; Samaro et al., 2020; Macedo et al., 2020), compressive fracturability tests (Gültekin et al., 2019; Nasereddin et al., 2018) and indentation tests (Gioumouxouzis et al., 2020). Different screening parameters can be deducted from these mechanical tests and compared between formulations to predict printing failures, as summarized in Table 2.1.

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Table 2.1 Examples of printing failures observed due to feedability issues between the gears and their characterization test Failure mode Observation Brittleness Breakage

Screening parameter Distance at break (3PB) Distance at break (compression) Bending force (compression) Strain at break (elongation) Breaking force (3PB)

Flexibility

Bending and blocking

Softness

Deformed filament

Reference Korte et al. (2018), Gottschalk et al. (2021), Wei et al. (2020) Gültekin et al. (2019) Oladeji et al. (2022)

Macedo et al. (2020) Zhang et al. (2017), Prasad et al. (2019) Breaking force (elongation) Isreb et al. (2019) Indentation hardness (DMI) Gioumouxouzis et al. (2018) Tensile energy (elongation) Henry et al. (2021a) Flexural modulus (3PB) Samaro et al. (2021), Omari et al. (2022), Ilyés et al. (2019) Breaking force Oladeji et al. (2022) (compression) Breaking force (elongation) Lima et al. (2022), Yang et al. (2018) Elastic modulus Verstraete et al. (2018), Henry (elongation) et al. (2021a) Elastic modulus (DMI) Gioumouxouzis et al. (2018) Maximal stress (modified Zhang et al. (2019), Cri¸san et al. 3PB) (2022) Toughness (AUC, modified Xu et al. (2020) 3PB)

3PB .= three-point bend test, DMI .= dynamic micro indenter, AUC .= area under the curve

In general, a load is applied to a material during a screening test and its deformation measured. Initially, the material will behave elastically, meaning it will return to its original shape if the load is removed. The modulus of elasticity or Young’s modulus represents the stiffness of the material and is the ratio between stress and strain in this initial linear portion of the stress–strain curve. Printing failure due to flexibility is associated with a low elastic or flexural modulus. After the elastic deformation, plastic deformation will be initiated. The ductility of a material represents the ability for plastic deformation prior to fracture (Samaro et al., 2020). Brittleness failure is usually associated with low distance (or strain) and force (or stress) at break (Korte et al., 2018). Additionally, a low indentation hardness could reveal brittle fracture (Gioumouxouzis et al., 2018). The toughness is calculated from the area under the curve until fracture and represents the energy needed to fracture the material (Xu et al., 2020). In conclusion, an acceptable filament should possess adequate mechanical properties which means a sufficient stiffness, toughness and ductility (Samaro et al.,

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2020). It is unfortunately difficult to stipulate universally applicable numerical values for these screening parameters, distinguishing between (non-)feedable filaments due to the variety of applied tests, variety of utilized printers and modifications of the printer as reported among research articles. To this end, artificial intelligence has been exploited to build a predictive tool for feedability and ideal production parameters, utilizing a balanced dataset of 1594 drug-loaded formulations from inhouse and literature-mined data (Ong et al., 2022; Elbadawi et al., 2020).

2.2.3.2 Flowability Following successful passage through the printer gears, the polymer is fed towards the heated liquefier and nozzle. Here, the polymer melts and the resulting molten strand is deposited onto the build plate. Successful melting and deposition requires adequate rheological and thermal properties to achieve consistent melt flow at acceptable process temperatures, hence ensuring qualitative end-products (Pietrzak et al., 2015). The thermoplastic polymers employed as feedstock for FDM 3Dprinting are either amorphous, characterized by a glass transition temperature (Tg), or semi-crystalline, containing an additional melting temperature (Tm) (Parulski et al., 2021). Apart from the Tg and Tm, other material parameters like thermal conductivity and specific heat capacity are equally important for the printing process (Azad et al., 2020). Part strength of the end-product, for example, will depend on layer fusion and bonding mechanisms (Parulski et al., 2021). Flowability Failure The process temperature will have to be sufficiently high, to ensure that the polymer is in a molten state, but preferably it also remains below the degradation temperature of all formulation constituents (Pietrzak et al., 2015). As described in Eq. 2.3, the required pressure to push the melt out of the nozzle depends on the viscosity of the melt, which in turn depends on the process temperature (Solanki et al., 2018). As a result, the minimal processing temperature depends on the maximum pressure attainable within the 3D-printer head, which is generally higher than the processing temperature on a hot-melt extruder. This results from the smaller nozzle opening, shorter residence time and absence of shear mixing in the printer head (Azad et al., 2020). During the printing process itself, the melt is subjected to relatively high shear at the narrow print nozzle, and as a result, the shear rate dependency of the melt viscosity is crucial (Turner et al., 2014). This shear rate dependency is described by the degree of (non-)Newtonian behaviour. In general, polymers utilized for HME and FDM ideally display non-Newtonian shear-thinning behaviour, meaning their viscosity decreases at higher shear rate. This behaviour is beneficial since it enables the melt to be pushed through the nozzle while regaining its structural properties after deposition on the build plate (Azad et al., 2020). The viscosity of the melt after deposition should indeed be sufficient to support the weight of the consecutively deposited molten layers, which is problematic if the polymer has a too low viscosity as was noted by Kempin et al. (2018) when attempting to print PEG 6000 (Kempin et al., 2018).

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After forcing the polymer melt through the narrow print nozzle, the polymer chains will relax elastically and die swelling will occur. Die swell means that the road width of the molten strand will expand above the nozzle diameter. If this expansion of the road width is considerable, it has a detrimental effect on the resolution and topography of the printed object. The extent of die swell is a material property depending on for example molecular weight (Ilyés et al., 2019) and prior knowledge might help to optimize process conditions in order to minimize this die swell (Elbadawi, 2018; Aho et al., 2019). Screening Tests Different tests are available to characterize the thermal and rheological behaviour of the melt. The glass transition temperature and melt temperature can be determined using differential scanning calorimetry (DSC) or thermal gravimetric analysis (TGA). The rheological behaviour of the material describes its resistance to flow (Azad et al., 2020) and can be investigated using various tests like a melt flow index analyser, a capillary rheometer or rotational rheometer.

• Melt flow index analyser: A melt flow index analyser is a simple measurement providing information about the amount of melt flowing out of a heated capillary at a certain temperature but provides limited additional information (Samaro et al., 2020) and might not represent the true value of the viscosity especially for polymers displaying considerable non-Newtonian behaviour (Aho et al., 2015). • Capillary rheometer: A capillary rheometer can provide more detail of the polymer melt flow behaviour at a high shear rate regimen, although corrections are needed to achieve true shear stress and viscosity values (Aho et al., 2015). • Rotational rheometer: Rotational rheometers with a parallel-plate or cone-plate geometry are the most popular rheological instrument. They can be run in either rotation (steady-state rotational shear (SSRS)) or oscillation (small-amplitude oscillatory shear (SAOS)) mode (Aho et al., 2015). Dependency of the viscosity on the applied shear can be investigated using SAOS experiments although the high-shear regimen as assessed during 3D-printing cannot be attained. Combining SSRS and SAOS experiments by means of the Cox–Merz principle might deliver information of higher shear rate regimes up to 700 s.−1 (Azad et al., 2020). Oscillatory frequency sweep experiments revealed that the viscosities should be in the order of 10.3 Pa.s at the shear rate of printing (Elbadawi et al., 2020). An oscillatory temperature sweep could also provide information about the dependency of the viscosity on the processing temperature (Azad et al., 2020). In addition, polymers ideally display Maxwellian behaviour, which means the polymer melt behaves mainly as a viscous liquid with negligible elasticity. To this end, the behaviour of the storage and loss moduli in function of the angular shear rate should be investigated. Maxwellian behaviour means the storage modulus (G. ) is directly proportional to the angular shear rate (w) at low frequencies and the

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Fig. 2.5 Illustration of printing failures associated with high min/max ratio of the viscosity (i.e. non-Maxwellian behaviour) with resulting tablet quality. (Reprinted with permission from Samaro et al. 2021)

elastic modulus (G.") proportional to .w 2 . Non-Maxwellian behaviour means the melt displays marked elasticity and the moduli are less dependent on the angular shear rate. As a result of non-Maxwellian behaviour, the difference between the minimal and maximal viscosities during the frequency sweep is high. As the shear rate fluctuates rapidly during 3D-printing, this correlates with a high variation in viscosity changes and resulting required pressure drop, a phenomenon that has been associated with printing failures as can be seen in Fig. 2.5 (Samaro et al., 2021; Serdeczny et al., 2020). Ambiguity exists in the literature, as sometimes the opposite was mentioned, stating non-Maxwellian behaviour being advantageous (Cicala et al., 2018). In conclusion, the interplay of thermal and rheological properties governs the flowability of a certain feedstock material. A series of printing failures associated with these properties with their screening test are mentioned in Table 2.2. A printable formulation ideally combines Maxwellian behaviour with acceptable flow energy and viscosity at the printing temperature.

2.2.3.3 Stability Storage conditions might alter printability of the filaments due to absorption of moisture. As water acts as a plasticizer, it might render filaments suddenly (un)printable or can alter drug–polymer interactions initiating for example recrystallization in an amorphous solid dispersion (Henry et al., 2021a; Macedo et al., 2020). Water in the filament can also evaporate during the printing process generating air bubbles which distort the object. Additionally, a large amount of water content could also induce microbial contamination (Chaudhari et al., 2021). Some examples include the reporting by Tan et al. (2020) of brittleness in hydroxypropyl cellulose filament if left unprotected from moisture (Tan et al., 2020). Viidik et al. (2021) also stressed the need for proper storage of the feedstock material as they noted changes in crystallinity of indomethacin and theophylline

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Table 2.2 Examples of printing failures observed due to flowability issues related to thermal and rheological properties with their characterization test Failure mode Excessive viscosity

Observation Screening parameter Nozzle blockage Dynamic viscosity

Reference Henry et al. (2021a)

(temperature sweep, SAOS) (frequency sweep, SAOS) Elbadawi et al. (2020), Zhang et al. (2019), Novak et al. (2018) Melt flow index Samaro et al. (2020), Genina et al. (2016) Melt flow index Alhijjaj et al. (2019)

Poor print quality Non-Maxwellian Insufficient flow Moduli .∼ w behaviour Max/min. ratio (frequency sweep, SAOS) Excessive flow Print speed Arrhenius activation energy energy limitation (frequency sweep, SAOS) Insufficient Deposition of Melt flow index viscosity droplets Excessive Complex modulus material (temperature sweep, SAOS) deposition

Henry et al. (2021a) Samaro et al. (2021) Henry et al. (2021a) Genina et al. (2016) Lima et al. (2022)

SAOS .= Small amplitude oscillatory shear, .w = angular frequency (rad/s)

when the filament was stored for three months at 40 ◦C and 75% relative humidity. In comparison, filament stored in a refrigerator at 0% humidity displayed stability over the whole investigated time frame (Viidik et al., 2021). Ayyoubi et al. (2021) have shown recrystallization of nifedipine when a mini-caplet made from ethyl cellulose was stored at higher humidity levels (Ayyoubi et al., 2021). In conclusion, optimization of storage conditions is vital to ensure stability of the produced feedstock materials and reproducibility of the produced dosage forms.

2.2.3.4 Enhancing Printing Performance The constraints placed on the materials compatible with FDM 3D-printing limit the portfolio of processable pharmaceutical polymers. Several approaches have been investigated to overcome these limitations. Firstly, adaptations of the feeding mechanism might reduce the force applied on the filament resulting in less stringent constraints on the mechanical properties. For example, the construction of a rigid polylactic acid (PLA) guide combined with its use as a piston enabled printing of very brittle polymers (Gottschalk et al., 2021). Another adaptation involved a change of the original, high-pressure gear wheels by smooth and toothless 3Dprinted ones as can be seen in Fig. 2.6, hence enabling the printing of brittle materials (Abdelhamid et al., 2022). Secondly, decreasing the pressure drop by

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Fig. 2.6 Illustration of fractured feedstock material utilizing unmodified printer equipment (a) with the original (b, left) gears in comparison with the adapted, toothless gears (b, right). (Reprinted with permission from Abdelhamid et al. (2022))

optimizing process temperature, nozzle size and production speed might enable printing of troublesome materials (Henry et al., 2021a; Koutsamanis et al., 2021) Thirdly, blending of carrier polymers or the addition of processing aids might dramatically influence the mechanical properties and flow behaviour of the melt (Azad et al., 2020), as will be discussed in the next section.

2.2.4

Alternative Feedstock Materials

The FDM or FFF technique requires filaments with acceptable mechanical and optimal rheological properties which limit the materials compatible with this technique (Henry et al., 2021a). While the approaches mentioned in the previous section might broaden the portfolio of printable materials, limitations still exist. For example, Prasad et al. (2019) noticed printing failures with Affinisol™ 15LV filaments containing 25–45 wt% paracetamol due to softness of the filaments (Prasad et al., 2019). Samaro et al. (2021) noticed print failures of ethylene-vinyl acetate filaments with 9 or 25% vinyl acetate content due to a high initial viscosity and a high viscosity variation in a frequency sweep (Samaro et al., 2021). Various efforts were made to develop innovative extruder heads for direct extrusion additive manufacturing (DEAM), using alternative feedstock materials like powder and pellets with less material restrictions. For example, Goyanes et al. (2019) utilized a FabRx single-screw powder printer (Fig. 2.7) to process amorphous dispersions of itraconazole in different grades of hydroxypropyl cellulose (Goyanes et al., 2019). Boniatti et al. (2021) utilized the DEAM technology to produce

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Fig. 2.7 FabRx direct single-screw powder extruder designed to enable single-step 3D-printing, avoiding filament fabrication. (Reprinted with permission from Goyanes et al. 2019)

praziquantel-loaded Kollidon VA64 printlets from both powder, pellets and milled pellets on the M3DIMAKER™ printer (Boniatti et al., 2021). Feuerbach and Thommes (2021) have developed a single-screw extruder head to successfully print pharmaceutical grade polymers in powder form, which were troublesome to process on a traditional printer (Feuerbach and Thommes, 2021). Samaro et al. (2021) investigated the use of DEAM using powder and pellets of ethylene-vinyl acetate with 50% wt metoprolol tartrate. It was noticed that material flowability presented a restricting factor for successful printing at higher drug loads (Samaro et al., 2021). The direct extrusion process using powders will have to overcome some challenges like dealing with poor powder flowability, electrostatic forces, insufficient userfriendliness or difficulty in cleaning of all printer parts (Samaro et al., 2021; Boniatti et al., 2021). In addition, direct extrusion using pellets might suffer from noncontinuous flow with inconsistent pellet size (Boniatti et al., 2021). More in-depth studies investigating a wider range of materials utilizing the DEAM technology are certainly needed. Triastek has developed a novel 3D-printing technique called melt extrusion deposition (MED™), avoiding the need for filament production as it integrates a hotmelt extruder and 3D-printer to produce printed dosage forms in one step. Multiple printing stations can be used to develop compartmental core-shell structured tablets, a concept called 3D-printing formulation by design (3DPFbD) (Zheng et al., 2021). A similar approach to the melt extrusion deposition was utilized to produce tablets containing mefenamic acid dispersions in Soluplus (Prasad et al., 2020). Another printing technique, Arburg plastic freeforming or droplet deposition, combines principles from both material extrusion and material jetting and has recently been used to produce pharmaceutical dosage forms. The starting material

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can either be pellets or dried granules produced by wet granulation methods (McDonagh et al., 2022). The technique has successfully been used to produce dapivirine-releasing vaginal rings from polyurethanes (Welsh et al., 2019), tablets containing hypromellose acetate succinate, polyethylene oxide and paracetamol (Zhang et al., 2021) and printlets from Eudragit EPO loaded with paracetamol (McDonagh et al., 2022).

2.3

Materials Used in Fused Deposition Modeling 3D-Printing

The starting material for a pharmaceutical FDM process is a drug-loaded filament, generated by either filament impregnation or extrusion. Filament impregnation incorporates the drug or active pharmaceutical ingredient (API) into commercially available polymeric carriers by means of soaking the carrier into a saturated API solution or dispersion before printing (Tagami et al., 2019). The same approach was performed to load drugs directly into printed, polymeric tablets (Beck et al., 2017). However, the impregnation method suffers from numerous drawbacks like the use of toxic solvents, limited drug loading capacity and long duration of the process (Shaqour et al., 2020). A major advantage of hot-melt extrusion is the fact that the use of solvents or water is optional (Crowley et al., 2007). Therefore, most reported studies employ hot-melt extrusion (HME) to transform a polymer/drug mix into a printable filament (Shaqour et al., 2020). Either powder or pellets are selected as staring material and fed to the extruder, where heat is utilized to melt the material. A ram or screws are used to push the material towards a die, as illustrated in Fig. 2.8. Ram extrusion utilizes a movable arm or ram to generate pressure and push the product through the die of the hot-melt extruder (Kempin et al., 2017, 2018). This method generates extrudates with highly consistent diameter but generally suffers from poor mixing capability. Screw extrusion, on the other hand, utilizes a single or twin rotating screw and generates more shear stress, resulting in more intense mixing (Crowley et al., 2007). In pharmaceutical production processes, the use of a twin screw extruder is generally preferred over a single screw since the latter provides less mixing. Hence, employment of a single-screw extruder necessitates excellent homogenization of the powder blend using for example grinding and mixing, solvent casting or melt mixing (Shaqour et al., 2020; Martin, 2016; Goyanes et al., 2015). Twin screws can have a non-intermeshing or intermeshing set-up made for co- or counter-rotation and are generally modular with different sections facilitating feeding, melting and metering. The possibility to change the screw design enables selecting appropriate process conditions based on the product requirements (Crowley et al., 2007). FDM 3D-printing is a volume-controlled production technique, and hence a consistent and correct diameter of the filament feedstock is crucial to fabricate dosage forms with controlled and consistent mass (Macedo et al., 2022). In order to maximize diameter consistency when employing a twin screw extruder, process settings should be optimized to minimize pressure fluctuations and maximize the barrel filling degree (Ponsar et al., 2020; Chamberlain et al., 2022). Additionally, a

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Fig. 2.8 Illustration of an extrusion set-up utilizing powdered or pelletized starting material to create drug-loaded filaments which are consecutively used in FDM 3D-printing. (Reprinted with permission from Cailleaux et al. 2021)

melt pump between barrel and die might optimize filament diameter consistency by stabilizing melt fluctuations (Quodbach et al., 2021; Fuenmayor et al., 2018). The production of a filament with a correct diameter might be impaired by a process called die swell. Most polymers undergo die swell upon leaving the extruder die since the polymer chains are compressed and forced through this narrow die, after which the melt relaxes and swells to a larger-than-desired diameter. The extent of die swell depends on the process settings of the extruder and on the viscoelastic material characteristics of the specific polymer. Die swelling can be reduced by decreasing the shear to which the polymer is subjected for example by increasing the die temperature. In most cases, however, a self-winding roller is placed after the die to wind and stretch the melt in order to achieve a correct diameter (Quodbach et al., 2021; Samaro et al., 2020).

2.3.1

Carrier

Most research focuses on the use of polymer-based excipients for FDM 3D-printing. Hence, the properties of the formulation are often mainly determined by the material properties of the polymer in which the API is embedded. The most commonly used polymers in FDM 3D-printing are listed below with comments on their processability and possible applications. Blends of different polymers are often

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made to enhance the mechanical properties of the resulting filament or to modify its release behaviour (Shi et al., 2021). Other feedstock materials have also been investigated, like lipid-based excipients which presented technical challenges due to their brittle nature (Abdelhamid et al., 2022) or novel polyester-based thermoplastic elastomers (Koutsamanis et al., 2021).

2.3.1.1 Cellulose Derivatives Cellulose derivatives like hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethyl cellulose (EC) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS) are commonly used in FDM 3D-printing as they are biocompatible and generally possess favorable mechanical properties. The material properties and solubility of these derivatives strongly depend on the type of modification and substitution degree of the polymer (Zamboulis et al., 2022; Azad et al., 2020). Ethyl cellulose for example is insoluble in water and hence could be used for sustained-release products. On the other hand, HPMC swells when in contact with water, resulting in a drug release mechanism relying on diffusion through the swollen layer in combination with erosion of the hydrated polymer (Pereira et al., 2020). Cellulose derivatives are particularly popular to produce zero-order release gastroretentive floating devices. For example, Giri et al. (2020) utilized HPC in combination with theophylline to create tablets with a floating capability of up to 10 h (Giri et al., 2020). Zhao et al. (2020) created a floating tablet with air chambers, utilizing HPMC to create a drug-loaded core surrounded by an insoluble shell of polylactic acid containing an air chamber as can be seen in Fig. 2.9 (Zhao et al., 2022).

Fig. 2.9 Intragastric floating sustained-release tablets consisting of a drug-loaded core utilizing hydroxypropyl cellulose. Different sizes in air chambers resulted in different release windows of the drug. (Reprinted with permission from Zhao et al. 2022)

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Additionally, cellulose derivatives are also often used in combination with other, difficult-to-feed pharmaceutical polymers to enable processing in the FDM apparatus. For example, Vo et al. (2020) combined polyvinyl pyrrolidone vinyl acetate (Kollidon VA64) with HPC to enable printing of a cinnarizine-loaded floating tablet (Vo et al., 2020). Than et al. (2022) could successfully print Soluplus and Eudragit polymers when combined with HPC (Than et al., 2022).

2.3.1.2 Ethylene Vinyl Acetates Ethylene vinyl acetates are copolymers of ethylene and vinyl acetate monomers, where the content of vinyl acetate monomers (1–40%) mainly determines the chemical and physical characteristics of the resulting polymer (Schneider et al., 2017). This is especially important for FDM 3D-printing, as it has been shown that EVA grades with a high VA content are too flexible for successful printing (Samaro et al., 2021; Genina et al., 2016). EVAs are biocompatible and non-water soluble hence making them ideal polymeric carriers for the development of sustained release dosage forms like implants (Schneider et al., 2017). 2.3.1.3 Kollicoat IR Kollicoat IR is a co-polymer of polyethylene glycol and polyvinyl alcohol which is freely soluble in water. As a result, produced dosage forms display an immediate release behaviour (Kolter et al., 2012). The feedstock can easily be printed and successful printing with solid loads of up to 40% has been reported (Samaro et al., 2020). 2.3.1.4 Polycaprolactone Polycaprolactone is a biocompatible and biodegradable polyester which is commonly used in 3D-printing. It is easily printable and has been used in many studies in combination with drugs like indomethacin or theophylline (Viidik et al., 2021) or with polymers like poly(lactic acid) (Fu et al., 2018). Drug release occurs via diffusion, making it a suitable carrier for sustained release applications like intrauterine devices as can be seen in Fig. 2.10 (Holländer et al., 2016). Fig. 2.10 Intrauterine devices constructed via FDM 3D-printing of indomethacin-loaded polycaprolactone filaments. (Reprinted with permission from Holländer et al. 2016)

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Fig. 2.11 Illustration of different tablet shapes created either from polyethylene oxide (MW 100,000) in formulations PEO15 and PEO15-P or from HPMC with added PEG (MW 8000) in formulations HPMC15, HPMC35 and HPCM50. (Reprinted with permission under the open access CC BY 4.0 license from Tidau et al. 2019)

2.3.1.5 Polyethylene Oxide Polyethylene oxide (PEO) is a linear polymer made from ethylene oxide monomers. Low molecular weight PEOs (.20%) requiring plasticizers to enable processing (Nukala et al., 2019a; Macedo et al., 2020). Moreover, the filament is hygroscopic and susceptible to moisture uptake, which renders the filament more flexible (Macedo et al., 2020). PVA is commercially available as a filament with a consistent diameter. Drug loading is therefore often achieved utilizing passive diffusion as reported for example by Ayyoubi et al. (2021) who impregnated PVA filament with a nifedipine-ethanol solution prior to printing mini tablets (Ayyoubi et al., 2021). 2.3.1.10 Polyvinyl Pyrrolidone Polyvinyl pyrrolidone (povidone) represents a class of water soluble polymers consisting of linked vinylpyrrolidone monomers. As these polymers are freely water soluble, they are designed for immediate release dosage forms. Co-polymers of povidone and vinyl acetate (e.g. Kollidon VA64) have also been used in 3D-printing. The vinyl acetate moiety is water insoluble, but the ratio of monomers still enables free dissolution of the resulting co-polymer (Kolter et al., 2012). Both povidone and its co-polymer are rather brittle with limited feedability, hence requiring the addition of plasticizers (Kollamaram et al., 2018) or blending with other polymers (Shi et al., 2021). Moreover, the hygroscopicity of these

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formulations necessitates correct storage to avoid stability issues of the resulting filaments (Henry et al., 2021b).

2.3.1.11 Soluplus Soluplus is a polyvinylcaprolactam –polyvinyl acetate– polyethylene glycol copolymer. Due to its amphiphilic behaviour, it is capable of solubilizing poorly soluble drugs to increase their bioavailability while displaying an immediate release behaviour (Kolter et al., 2012). Soluplus is too brittle to enable direct printing and requires the addition of a plasticizer (Melocchi et al., 2016).

2.3.2

Active Pharmaceutical Ingredient

The active pharmaceutical ingredient (API) drives the choice of carrier polymer and process conditions since shear and thermal degradation should be avoided. HME and FDM are both anhydrous production processes, avoiding hydrolytic degradation pathways of the API (Crowley et al., 2007). Thermo-sensitive drugs might however be challenging to process via HME and/or FDM 3D-printing, as was shown by Wei et al. (2020) who noticed sublimation of carvedilol upon production of 3Dprinted tablets with polyvinyl alcohol (Wei et al., 2020). A careful selection of the polymeric carrier could however enable processing of thermo-sensitive drugs as was proven by Kempin et al. (2018) who could effectively utilize pantoprazole sodium at temperatures below 100 ◦C (Kempin et al., 2018). The API might be dissolved, dispersed as undissolved particles or a combination of both within the carrier matrix depending on the chemical, thermal and physical properties of both the drug and the carrier. The created system greatly influences the stability and processability of the resulting formulation. In general, a dispersion could be favorable due to its superior stability, while a solution system could enhance the bioavailability of the drug. The Hansen solubility parameters are a way to predict drug–polymer miscibility and hence which system will be generated (Kolter et al., 2012). Solanki et al. (2018) for example have prepared an amorphous solid dispersion (ASD) of the poorly soluble haloperidol for processing via 3Dprinting, this resulted in complete drug release at higher pH (Solanki et al., 2018). In another study, Chaudhari et al. (2021) have made amorphous quercetin-PVP filaments to produce skin patches with improved solubility (Chaudhari et al., 2021). The presence of crystalline drugs in the feedstock filament might hamper printability. First of all, the presence of crystalline particles within the carrier might interfere with the mechanical properties of the blend and hence the compatibility with the printers’ feeding gears. Both an increase and a decrease of the feedability have been mentioned based on drug content (Palekar et al., 2022; Samaro et al., 2020). Secondly, crystalline drugs might alter the rheological properties of the melt. Than et al. (2022) found that a higher theophylline content drastically increased the viscosity of the formulation, requiring a higher process temperature since the drug was not dissolved within the polymeric carrier and acted as a crystalline filler (Than et al., 2022). Thirdly, large clusters of crystalline material might block

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Fig. 2.12 Surface morphology of TPU filaments containing 0, 20 or 60% of unmilled (a) or milled (b) methformin hydrochloride, illustrating the necessity to control drug particle size. (Reprinted with permission from Verstraete et al. 2018)

the nozzle of the printer, especially if the clusters are larger than the nozzle opening. This phenomenon was noted with pantoprazole sodium agglomerates in a variety of filaments produced via ram extrusion, again emphasizing the importance of manufacturing a properly mixed filament (Kempin et al., 2018). Next, high contents of a crystalline drug have also been reported to negatively impact surface morphology, which might also induce filament feeding issues. Case studies have been reported about drug crystals on the surface of the filament which accumulated in the nozzle and caused degradation (Tidau et al., 2019). Milling of the crystalline drug has been shown to (partly) overcome these issues as can be seen in Fig. 2.12 (Verstraete et al., 2018). Lastly, the presence of crystalline API in a semi-crystalline polymer might affect the crystallization kinetics of the polymer, resulting in an altered solidification behaviour and a different visual quality of the dosage form. For example, Samaro et al. (2020) found the presence of metoprolol tartrate in polycaprolactone accelerated solidification, improving the quality of the resulting tablet (Samaro et al., 2020). An API might also act as a plasticizer by improving the flexibility of the polymer chains, hence decreasing the glass transition or/and melt temperature and viscosity profile of the melt. For example, Elbadawi et al. (2020) discovered that ciprofloxacine reduced the complete viscosity-over-shear profile of polycaprolactone (Elbadawi et al., 2020), Gottschalk et al. (2022) showed that ketoconazole lowered the viscosity of polyvinyl alcohol (Gottschalk et al., 2022), Sadia et al. (2018) identified enalapril maleate as a plasticizer for Eudragit EPO (Sadia et al., 2018) and Henry et al. (2021a) showed the melt point depression of ibuprofen on polycaprolactone as illustrated in Fig. 2.13 (Henry et al., 2021a).

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Fig. 2.13 Plasticizing effect of ibuprofen as illustrated by melting point depression of polycaprolactone. (Reprinted with permission from Henry et al. 2021a)

2.3.3

Processing Aids

Processing aids are excipients added to the polymer–drug formulation to improve printability. Different classes can be distinguished: plasticizers, dissolution modifiers, inert fillers and specialty excipients.

2.3.3.1 Plasticizer Plasticizers are a class of materials increasing the free volume and mobility of the polymer chains, which is noted by a decrease of the glass transition temperature (Tg). As a result, extrusion can be performed at lower temperatures which might be beneficial to avoid degradation of the API (Parulski et al., 2021). Moreover, plasticizers will also influence the mechanical properties of the filament and have been reported to increase the elasticity (Oladeji et al., 2022). Hence the concentration of plasticizer should be optimized to avoid hyper flexibility and feeding issues of the filament. Unfortunately, plasticizers have been associated with a lower stability of the end-product as described by for example Kempin et al. (2018) who noticed filament deformations when storing polyvinyl pyrrolidone filaments containing higher plasticizer fractions (20% triethyl citrate) (Kempin et al., 2018). Wei et al. (2020) noticed that the presence of sorbitol initiated rapid recrystallization of the drug in polyvinyl alcohol filaments (Wei et al., 2020). A variety of plasticizers have been investigated and successfully applied like glycerin (Lima et al., 2022), PEG (Oladeji et al., 2022), triethylcitrate (Kempin

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et al., 2018; Zhao et al., 2022; Sadia et al., 2018), dibutyl sebacate (Oladeji et al., 2022), sorbitol (Wei et al., 2020), stearic acid (Giri et al., 2020), d-alpha tocopherol PEG 1000 succinate (Ilyés et al., 2019) and mannitol (Kollamaram et al., 2018; Windolf et al., 2022). Water was investigated as a temporary plasticizer, successfully enabling extrusion of polyvinyl alcohol at lower temperatures. A drawback of this approach is however the potential for hydrolytic degradation (Pereira et al., 2019).

2.3.3.2 Dissolution Modifier Immediate release formulations are obtained by the addition of disintegrants, which accelerate the disintegration process of the 3D-printed tablet by means of swelling and consequent wicking of the liquid into the tablet. Common disintegrants that have been successfully tested in FMD 3D-printing are starch (Ehtezazi et al., 2018), sodium starch glycolate (Than and Titapiwatanakun, 2021; Ehtezazi et al., 2018), microcrystalline cellulose (Than et al., 2022), crospovidone (Than et al., 2022), low substituted HPC (Than et al., 2022) and croscarmellose sodium (Than et al., 2022; Ehtezazi et al., 2018). However, the addition of these disintegrants did not always effectively accelerate the dissolution process (Henry et al., 2021b; Sadia et al., 2018). Other materials might be added to create channels within the matrix upon dissolution, hence altering the drug diffusion rate. Examples are PEG (Elbadawi et al., 2020), chitosan (Yang et al., 2022) or mannitol (Omari et al., 2022). It must be noted that some constituents might serve both as a plasticizer and as a pore former in a certain formulation. This dual action of for example mannitol has been exploited by Kollamaram et al. (2018) by plasticizing povidone while simultaneously increasing the release rate of ramipril (Kollamaram et al., 2018). The addition of surfactants to improve wettability was also successfully tested. For example, sodium lauryl sulfate accelerated the dissolution kinetics of paracetamol (Ehtezazi et al., 2018) and Tween 80 enhanced the hydrophilicity of printed vaginal rings, hence enabling controlled progesterone release as can be seen in Fig. 2.14 (Fu et al., 2018). 2.3.3.3 Inert Filler Inert fillers have been added to formulations for either flow stabilization or feedability optimization. In terms of flow stabilization, the addition of fillers was reported to decrease die swell (Barnes, 2003), although discrepancies were reported in terms of filler type. Lamellar particles like talc were reported to generate flow stabilization, while glass beads and fibers were reported to generate flow instabilities (Baldi et al., 2014). Talc for example has been reported to decrease layer deformation of the printed object as can be seen in Fig. 2.15 (Oladeji et al., 2022) and enable rapid solidification (Okwuosa et al., 2016), while tribasic calcium phosphate allowed consistent melt flow (Sadia et al., 2016, 2018). In terms of feedability optimization, the addition of fillers increased the stiffness of extruded filaments. Oladeji et al. (2022) have added talc to a formulation containing HPMCAS to enable feeding. It must be noted that the dynamic viscosity of polymeric systems in combination with a filler was generally higher, which could influence processing temperature (Than et al., 2022).

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Fig. 2.14 Effect of adding a wetting agent (Tween 80) and a pore-former (PEG) on the dissolution profile of progesterone-loaded 3D-printed vaginal rings consisting of a poly(lactic acid)/polycaprolactone mixture (8:2). (Reprinted with permission from Fu et al. 2018)

Fig. 2.15 Surface morphology analysis using SEM images. Addition of talc (F5) to HPMCAS decreased layer deformation, even at higher plasticizer (PEG) concentration. (Reprinted with permission from Oladeji et al. 2022)

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2.3.3.4 Glidant Glidants might be added to facilitate the hot-melt extrusion process of poorly flowing powders. Examples are fumed silica (Windolf et al., 2022) or magnesium stearate (Ayyoubi et al., 2021). 2.3.3.5 Specialty Excipient The addition of lubricating liquids with a high boiling point like castor oil or oleic acid was effective to prevent filament from sticking to the nozzle wall. The lubricant was not incorporated into the filament itself but was added by passage through a lubricating station (Okwuosa et al., 2017). Certain substituents might be added in very specific cases to enhance the stability of the drug in the dosage form. The addition of magnesium carbonate, for example, provided an alkaline environment to avoid degradation and stabilize ACE inhibitors (Kollamaram et al., 2018). Titanium dioxide can be added to the formulation to ensure UV protection (Pereira et al., 2019).

2.4

Characterization Techniques

The printed pharmaceutical dosage forms are often investigated using traditional characterization techniques for oral pharmaceutical dosage forms as mentioned in the relevant monographs of the pharmacopoeia: friability (Nukala et al., 2019b,a), diametral hardness tests (Zhang et al., 2019; Henry et al., 2021c), disintegration time (Omari et al., 2022; Ehtezazi et al., 2018; Nukala et al., 2019a), dissolution testing (Kempin et al., 2018; Giri et al., 2020; Wei et al., 2020), weight and weight variability, dimension analysis (Henry et al., 2021b,c; Zhao et al., 2022) and drug content (Giri et al., 2020; Palekar et al., 2022; Wei et al., 2020; Zhao et al., 2022). However, printed dosage forms differ from traditional, compacted ones due to the inherent layer-by-layer production technique. Hence additional, innovative characterization techniques e.g. hardness, topography or solid state might be appropriate and have been developed.

2.4.1

Mechanical Resilience

In terms of mechanical resilience of the dosage form, it must be stated that FDM 3D-printed products always display directional anisotropy due to the layer-bylayer printing mechanism (Henry et al., 2021c). While the hardness of tablets manufactured via conventional direct compression mainly depends on the applied pressure, the hardness of FDM 3D-printed tablets is more dependent on material properties of the carrier, designed tablet structure and printing method (Zhao et al., 2022). As a result, an in-depth mechanical analysis of the constructed dosage form is more informative. Tests described in the literature include for example vertical hardness testing (Henry et al., 2021c; Zhao et al., 2022), Brinell hardness testing (Henry et al., 2021c) or the Brazilian test (Tidau et al., 2019). Figure 2.16

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Fig. 2.16 Application of different mechanical tests (Brinell, diametral and vertical strengths) on a variety of FDM 3D-printed dosage forms. The horizontal line at 1.7 MPa represents the industrial standard for minimal tensile strength. (Reprinted with permission under the open access CC BY 4.0 license from Henry et al. 2021c)

represents a comparison of different mechanical tests executed on printed tablets. Specific mechanical tests might be relevant for other dosage forms like suture retention tests for cardiovascular prostheses (Domínguez-Robles et al., 2022) and folding endurance tests for skin patches (Chaudhari et al., 2021) or buccal films (Eleftheriadis et al., 2020) (Fig. 2.17).

2.4.2

Topography

The surface of produced dosage forms is often rougher than traditional compacts since the product is constructed freestanding. The resulting morphology might thus present an interesting quality attribute. Techniques like scanning electron microscopy (Giri et al., 2020; Ehtezazi et al., 2018) or 3D-surface metrology microscopy (Domínguez-Robles et al., 2022) might enable detailed visualization of the topography. Figure 2.18 represents a series of cross-sections and surfaces of printed tubular grafts analysed through SEM. A higher drug loading was associated with a rougher surface (Domínguez-Robles et al., 2022).

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Fig. 2.17 SEM images of the surface and cross-section of 3D-printed TPU-based tubular grafts with different concentrations of dipyridamole (DIP). Higher concentrations of DIP are associated with rougher surfaces. (Reprinted with permission under the open access CC BY 4.0 license from Domínguez-Robles et al. 2022)

Fig. 2.18 Pore structure analysis of 3D-printed dosage forms from PLA (a–c) or PVA (d–f) utilizing X.μCT. Subfigures b and e represent the pore length distribution (color map), while c and f represent a y-z cross-section of the structure. (Reprinted with permission under the open access CC BY 4.0 license from Markl et al. 2017)

2.4.3

Solid State and Degradation

FDM 3D-printing is a thermal technique which might influence the solid state of the API or initiate degradation. Solid state analysis using crystallinity assessment based on for example wide angle X-ray diffraction (XRD) (Ilyés et al., 2019; Ehtezazi

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et al., 2018), infrared spectroscopy (Ehtezazi et al., 2018) or nuclear magnetic resonance (Kollamaram et al., 2018) might be interesting. Thermo-analytical methods like differential scanning calorimetry (Giri et al., 2020; Ilyés et al., 2019) or thermogravimetric analysis (Eleftheriadis et al., 2020; Domínguez-Robles et al., 2022) can also help to investigate crystallinity, polymorphism, interactions between drug and polymer and susceptibility towards degradation. API degradation through FDM 3D-printing could be investigated by characterization of the degradation pathways and resulting degradants utilizing high-pressure liquid chromatography (Ilyés et al., 2019) or mass spectroscopy (Ehtezazi et al., 2018).

2.4.4

Stability

Intermolecular bonds and interactions between constituents of the 3D-printed end product might indicate altered stability of the dosage form or dissolution of the drug within the polymeric carrier. Information of these bonds can be retrieved utilizing for example Fourier transform infrared spectroscopy (FT-IR) (Zhao et al., 2022; Omari et al., 2022). The tendency for moisture absorption (determined via for example Karl Fischer titration (Henry et al., 2021b) or dynamic vapour sorption (Cerda et al., 2020)) can also be critical to evaluate the stability of the printed product.

2.4.5

Porosity

The microstructure or pore architecture of a dosage form often drives its performance in terms of dissolution kinetics or mechanical resilience (Markl et al., 2018). In terms of microstructure, FDM 3D-printing is a unique production technique as it enables the design of a tablets’ microstructure almost independent from its outer dimensions (Henry et al., 2021c). Porosity determination and pore structure characterization hence become a vital quality characteristic of printed dosage forms. The most widely used technique to characterize total porosity is helium pycnometry (Henry et al., 2021b,c). More innovative techniques capable of additionally investigating pore structure include terahertz pulsed imaging (Markl et al., 2017) and X.μCT (Markl et al., 2017; Sadia et al., 2018).

2.4.6

Dissolution Behaviour

Dissolution behaviour is one of the most critical performance characteristics of a dosage form and is influenced by the microstructure and wettability of the dosage form. Microstructure determination of printed dosage forms has been discussed in the previous section. Wettability can be investigated using contact angle measurements (Joseph et al., 2021). In-depth real-time analysis of the dissolution

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behaviour of printed dosage forms can be performed utilizing optical coherence tomography (OCT) (Stewart et al., 2020) or time-lapsed X-ray micro-computed tomography (X.μCT) (Gioumouxouzis et al., 2017).

2.4.7

Distribution Homogeneity

Distribution homogeneity of the drug can be investigated using for example near infrared (NIR) chemical imaging (Samaro et al., 2021), Raman mapping (Okwuosa et al., 2017; Goyanes et al., 2015) or fluorescence microscopy (Kempin et al., 2017). Especially for multi-layered tablets, visualization of the individual, separated layers containing different drugs could be interesting. This approach also enables solid state analysis (Goyanes et al., 2015).

2.4.8

Specific Requirements

Dosage forms for applications other than oral intake might require unique properties. For example, implants are often tested to ensure bio-compatibility and cell viability (Domínguez-Robles et al., 2022; Eleftheriadis et al., 2020). Dosage forms developed specifically for bacterial treatment need testing to ensure antimicrobial efficacy (Domínguez-Robles et al., 2022). Mucoadhesive formulations are tested for their mucoadhesive properties utilizing mechanical tests (Eleftheriadis et al., 2020). Skin patches need sufficient folding endurance and a pH compatible with the skin (Chaudhari et al., 2021). Paediatric formulations might require additional testing to confirm taste masking of drugs (Scoutaris et al., 2018). The flexibility of 3D-printing could enable production of dosage forms onsite. Certain drugs might however display photosensitivity, requiring the need for appropriate packaging to ensure stability of the drug product (Henry et al., 2021b; Azizo˘glu and Özer, 2020). Moreover, certain drug products might require sterilization or aseptic production prior to application for example wound dressings (Oliveira et al., 2021) (Fig. 2.19).

2.5

Pharmaceutical Applications

The flexibility inherent to the 3D-printing technique allows the production of a wide variety of dosage forms targeting specific applications and containing a multitude of drugs as can be seen in Fig. 2.19. Moreover, FDM 3D-printing can not only be used to construct the dosage form but could also aid in the detection of falsified medicines by printing binary digits on the surface of printed dosage forms (Windolf et al., 2022). Some examples of FMD 3D-printed drug products are enlisted below.

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Fig. 2.19 An overview of different classes of 3D-printed dosage forms with their administration routes. (Reprinted with permission from Gioumouxouzis et al. 2019)

2.5.1

Oral Solid Dosage Forms

Oral solid dosage forms remain the most popular treatment strategy, which is reflected in the number of studies exploiting FDM for oral therapy (Fig. 2.20).

2.5.1.1 Multi-drug Therapies The concept of a polypill containing multiple drugs, each in their own personalized dose, was often investigated as it could increase patient compliance. For example,

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Fig. 2.20 A detailed overview of orally administered dosage forms. (Reprinted with permission from Gioumouxouzis et al. 2019)

Wei et al. (2020) constructed tablets containing carvedilol and haloperidol in a polyvinyl alcohol matrix. Pereira et al. (2019) constructed a multi-layered tablet containing up to 4 different drugs for cardiovascular treatment (Pereira et al., 2019). Other innovative tablet designs include for example a two-compartment dosage form, the DuoCaplet, which represents a smaller caplet containing paracetamol within a larger one containing caffeine. The idea is to enable the production of a controlled release tablet where the encapsulated drug is released after a certain lag time needed to dissolve the outer layer (Goyanes et al., 2015).

2.5.1.2 Paediatric Dosage Forms Due to the flexibility in size and shape, FDM 3D-printing proves to be exceptionally suited for the production of paediatric medicines. Scoutaris et al. (2018) have developed drug-loaded sweet-like chewable tablets (“Starmix”) utilizing indomethacinloaded HPMCAS filaments (Scoutaris et al., 2018).

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2.5.1.3 Targeting Specific Release The flexibility of 3D-printing allows the exploitation of different tablet designs to target a specific drug release profile, optimally suited for the proposed treatment strategy. Investigated modifications of the tablet include the construction of a specific porosity level, pore structure, surface area or polymeric composition. Porosity In comparison to direct compression, porosity and tablet dimensions are not correlated, as indicated by studies which reported the construction and characterization of tablets with identical size but varying porosity (Kempin et al., 2018; Henry et al., 2021c). This enables the production of dosage forms with a wide variety of release rates. For example, Henry et al. (2021) constructed dosage forms with an infill level varying from 20% to 90%. This altered the time needed to dissolve 63.2% of the API from 60 to 176 min (Henry et al., 2021c). Another study noted a decline in percentage of itraconazole released after 45 min from 96.9% to 80.9% when the infill was decreased from 67.2% to 39.9% (Jamroz et al., 2020). Moreover, the porosity of FDM 3D-printed products can be freely chosen which enables the production of hollow products. As a result, some studies have focused on the development of gastro-retentive floating tablets (GRFTs) to enhance the bioavailability of certain drugs. Giri et al. (2020), for example, developed a GRFT consisting of theophylline and hydroxypropyl cellulose (Giri et al., 2020). Zhao et al. (2022) prepared floating tablets containing a drug-loaded core and hollow air cell for the sustained release of venlafaxine (Zhao et al., 2022). Vo et al. (2020) developed floating tablets utilizing hydroxypropyl cellulose and vinylpyrrolidone vinyl acetate containing cinnarizine (Vo et al., 2020). Chai et al. (2017) have developed a floating tablet containing hydroxypropyl cellulose to increase the bioavailability of domperidone (Chai et al., 2017). Pore Structure Next to the degree of porosity, the pore structure can also be tailored utilizing different infill patterns. An example is given by Nukala et al. (2019a), who compared two infill patterns (hexagonal and diamond) and their effect on the mechanical strength and dissolution kinetics. They found significant differences between the patterns, even when the same level of infill was used (Nukala et al., 2019a). Surface Area Another way to control the dissolution behaviour is tailoring the surface area of the tablet. Viidik et al. (2021) designed tablets with an outer honeycomb lattice to increase the outer surface area and enhance the drug dissolution rate of theophylline (Viidik et al., 2021). In another study, Prasad et al. (2019) have developed circular and rectangular tablets with varying surface area to investigate the effect on dissolution (Prasad et al., 2019). Adaptations of the standard tablet design to achieve a certain release behaviour are easily made by modification of the digital design.

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Fig. 2.21 Radiator-like oral solid dosage forms with varying inter-plate spacing to boost and control drug release. (Reprinted with permission from Isreb et al. 2019)

Sadia et al. (2018) incorporated channels in the tablet to promote dissolution kinetics by increasing the tablets’ surface area (Sadia et al., 2018). Solid and channeled minitablets have been prepared by Ayyoubi et al. (2021) to tailor the release of nifedipine (Ayyoubi et al., 2021). Radiator-shaped tablets utilizing polyethylene oxides with varying inter-plate spacing were produced to boost and tailor the release profile of theophylline, as can be seen in Fig. 2.21 (Isreb et al., 2019). Tidau et al. (2019) investigated the release from cylinders, rings and balls loaded with theophylline (Tidau et al., 2019).

Polymeric Composition Modifying the ratios between the components in a formulation or changing the additives could also be employed to obtain a specific release pattern. Tan et al. (2020) developed a dosing platform containing theophylline with a polymeric composition of hydroxypropyl cellulose, Eudragit RL PO and polyethylene glycol. They stated that different sustained release properties could be achieved when the ratio of these polymers was varied (Tan et al., 2020). Another approach to tailor dissolution behaviour was discussed by Shi et al. (2021) as they developed a dosing platform containing ibuprofen (20%), ethyl cellulose (60%) and a release modifier (20%). The release modifier was either poly(vinyl alcohol), Soluplus, PEG 6000, Eudragit RSPO, Eudragit RLPO, HPMC, Kollidon 17 PF, Kollidon 30 or Kollidon VA64. The nature of the release modifier influenced the dissolution kinetics of the model drug, hence controlling the zero-order release behaviour (Shi et al., 2021).

2.5.1.4 Amorphous Solid Dispersion Poorly soluble drug molecules are troublesome to formulate as they often display poor bioavailability. Transforming the formulation to an amorphous system, molecularly dispersed within its polymeric carrier could provide a solution. Hot-melt extrusion and consequent FDM 3D-printing will provide the necessary energy to overcome the crystal lattice energy of the drug (Kolter et al., 2012). This mechanism was exploited by Omari et al. (2022), who produced immediate release tablets of loratadine, a poorly soluble compound that was solubilized in hydroxypropyl cellulose (Omari et al., 2022). Parulski et al. (2022) could also produce stable (up to 52 weeks) amorphous dispersions of itraconazole, a poor soluble compound, in

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Fig. 2.22 Various designs of mini floating polypills for Parkinson’s disease. (Reprinted with permission under the open access CC BY 4.0 license from Windolf et al. 2022)

a Kollidon VA64-HPMC matrix. The produced tablets showed a highly improved dissolution rate (Parulski et al., 2022).

2.5.1.5 Complex Oral Dosage Forms The unlimited versatility of FDM 3D-printing can be used to construct a wide variety of complex dosage forms. An example is the polypill developed by Windolf et al. (2022) as can be seen in Fig. 2.22. The floating pill contained levodopa, benserazide and pramipexole for the treatment of Parkinson’s disease, addressing both prolongation of levodopa absorption and personalization of the treatment since the drugs possess a narrow therapeutic range (Windolf et al., 2022). Another example was the construction of abuse deterrent egg-shaped tablets (“egglets”) from PVA by Nukala et al. (2019b), which could prevent snorting and injection abuse (Nukala et al., 2019b). Zhang et al. (2022) developed combi-pills of tranexamic acid and indomethacin by coupling semi-solid syringe extrusion with FDM to achieve both an immediate and a sustained-release profile with the same pill (Zhang et al., 2022). 2.5.1.6 Print and Fill Technology Certain oral dosage forms are produced using the “print and fill” technology (Cailleaux et al., 2021). An outer, hollow shell is printed using a commercially available or self-made filament. During or after the printing process, it is filled with a drug or other substance. For example, Markl et al. (2017) constructed hollow compartmental tablets of polyvinyl alcohol. Halfway through, the printing process was stopped to enable manual filling with carbamazepine powder or selfnanoemulsifying liquids. After this filling step, the printing process was resumed (Markl et al., 2017). Linares et al. (2019) developed an automated sequence combining FDM 3D-printing and injection volume filling to produce “Printfills” as can be seen in Fig. 2.23. A porous structure is printed utilizing PLA, after which the process is automatically stopped and the structure filled with a drug-loaded ink consisting of a theophylline-loaded hydro-alcoholic gel (1% HPMC gel: ethanol in a 25:75 ratio). Consequently, printing is resumed and a pH sensitive polymer dispersion injected into the top layer (Linares et al., 2019). Stopping the process mid-print could however cause anomalies in the printed structure as was noted by X.μCT analysis (Markl et al., 2017). A solution could be to only fill the print after its production is finished, as was demonstrated by Maroni

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Fig. 2.23 An illustration of how injection volume filling (IVF) and FDM 3D-printing can be combined to create printfills (a). First, a porous structure is printed (b) which is automatically filled with a drug-loaded ink (c). Next, 3 additional layers are printed on top of the drug-loaded structure. Finally, the top layer is injected with a pH-sensitive polymeric dispersion to allow colontargeting (d) and the final printfill is obtained (e). (Reprinted with permission from Linares et al. 2019)

et al. (2017). They printed two hollow halves and joint structure. The hollow halves were manually filled with acetaminophen or dye-containing Kollicoat powder. Subsequently, the halves were manually assembled by means of the joint structure in between. This joint structure enables the two hollow parts to form a closed device but additionally also serves as separation between the two chambers. The produced capsular devices hence contained different compartments which could possess other thicknesses or compositions to produce two-pulse release patterns. Additionally, this device could contain different APIs or formulations (Maroni et al., 2017). Another example is provided by Okwuosa et al. (2018) who printed polymethacrylate shells which were filled with a theophylline solution or dipyridamole suspension in a single print step (Okwuosa et al., 2018). The print and fill technology can also be used to build additional functionalities into the dosage forms as demonstrated by Palekar et al. (2022) who developed aversion liquid-filled capsules (“3D-RECAL”). A capsule shell consisting of metformin-loaded polyvinyl alcohol was printed and manually filled with aversion liquid. The aversion liquid consists of pigment and starch in an oil base and its presence within the capsule did not interfere with drug release. However, this dark and viscous aversion liquid is released from the shell upon attempted solvent extraction or manipulation, engulfing the drug particles and forming swollen and non-snortable particles (Palekar et al., 2022).

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Transdermal and Transmucosal Films

FDM 3D-printing has also been used to produce transdermal and transmucosal films, as an alternative to the traditional oral treatment. Investigated dosage forms include fast-dissolving oral films, mucoadhesive buccal formulations, skin patches or microneedle patches.

2.5.2.1 Fast-Dissolving Oral Film Fast-dissolving oral films (FDFs) could improve customer acceptance by fast dissolution in the mouth without the need for water. Ehtezazi et al. (2018) demonstrated its potential by printing single- and multi-layered FDFs containing both tastemasking and drug layers (Ehtezazi et al., 2018). 2.5.2.2 Buccal Film Mucoadhesive buccal films could achieve local and systemic delivery while avoiding passage through the gastro-intestinal tract and the first-pass effect. Eleftheriadis et al. (2020), for example, have prepared mucoadhesive films using hydroxypropyl methylcellulose loaded with ketoprofen, for the local treatment of inflammation associated with periodontitis. A back layer of ethyl cellulose was created to ensure unidirectional release (Eleftheriadis et al., 2020). Elkanayati et al. (2022) have printed immediate-release buccal films consisting of xylitol and adipic acid in a polyethylene oxide carrier to treat xerostomia or dry mouth (Elkanayati et al., 2022). 2.5.2.3 Skin Patch Skin patches could be an interesting alternative to oral treatment for drugs displaying bitter taste, poor solubility and/or instability in the gastro-intestinal tract (Oliveira et al., 2021). Chaudhari et al. (2021) have 3D-printed skin patches for transdermal delivery from polyvinyl pyrrolidone containing amorphous quercetin to increase its bioavailability. The patch contained an impermeable back layer of Eudragit RS PO (Chaudhari et al., 2021). Another example is montelukast, a drug suffering from extensive first-pass metabolism resulting in limited bioavailability. Azizo˘glu and Özer (2020) have developed 3D-printed transdermal patches for skin delivery of montelukast, aiming to increase its bioavailability (Azizo˘glu and Özer, 2020). Alternatively, skin patches could be tailored in size and composition based on the region of interest and necessary treatment. Anatomically adaptable wound dressings containing the antimicrobial metals silver, copper and zinc were produced by Muwaffak et al. (2017) after 3D-scanning of the region of interest (Muwaffak et al., 2017). Another study reported the use of composite materials from PLA and lignin which were utilized to produce meshes with antioxidant properties for wound treatment (Domínguez-Robles et al., 2019). Goyanes et al. (2016) have developed anti-acne drug-loaded patches for topical delivery of salicylic acid utilizing 3Dscanning to construct a 3D-model based on the physical characteristics of a volunteer. Both polylactic acid and polycaprolactone were investigated as printing matrices (Goyanes et al., 2016).

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Fig. 2.24 Microneedle patches for galantamine delivery at x24 magnification (a), x200 magnification (b) and x335 magnification (c). (Reprinted with permission from Antonara et al. 2022)

2.5.2.4 Microneedle Patch Microneedle patches contain small needles usually of a height below 1000 .μm. They have been investigated for transdermal delivery of drugs to improve patient compliance, reach constant systemic drug levels and reduce dosing frequency. The needles will disrupt the stratum corneum, hence allowing diffusion of the drug directly into the deeper skin layers and consequently the blood circulation. Antonara et al. (2022), for example, printed polylactic acid microneedle scaffolds, after which these were infused with a galantamine solution (Fig. 2.24) (Antonara et al., 2022). Wireless controlled devices for wound delivery of vascular endothelial growth factor have been reported by Derakhshandeh et al. (2020), who produced polymeric miniaturized needle arrays utilizing a desktop FDM printer. These arrays were consequently loaded with the drug and placed into a programmable smart bandage (Derakhshandeh et al., 2020).

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Implants

Implants might be preferred over oral formulations since they deliver the drug at a specific site, hence potentially lowering the systemic concentration. As a result, side effects are reduced and patient compliance increased. 3D-printing could enable the production of tailored implants, with a shape modified to the needs of the patient (Domsta and Seidlitz, 2021). Kempin et al. (2017) have demonstrated the use of different polymers to create implants loaded with quinine. They obtained excellent drug homogeneity within the constructed implants whereby the drug release rate depended on the polymer or drug loading (Kempin et al., 2017).

2.5.3.1 Antiplatelet Therapy Antiplatelet vascular grafts containing dipyridamole have been prepared using thermoplastic polyurethane. The grafts showed effective antiplatelet activity and could provide sustained release for 30 days. Double-layered tubular grafts containing additional rifampicin with antimicrobial activity have also been prepared (Domínguez-Robles et al., 2022). 2.5.3.2 Anticonception Intrauterine devices and subcutaneous rods with sustained release were produced using indomethacin as model drug in ethylene vinyl acetate carriers (Genina et al., 2016) or polycaprolactone (Holländer et al., 2016). Vaginal rings with personalized shapes (O-, Y- or M-shaped) for controlled progesterone release have been produced by Fu et al. (2018) as can be seen in Fig. 2.25 (Fu et al., 2018). Urethra pessaries with personalized geometry to fit the anatomy of an individual vaginal cavity were produced by Spoerk et al. (2021), utilizing a novel polyester-based elastomer. The mechanical properties could be changed based on the patient requirements by adapting the in-silico model (Spoerk et al., 2021). A biodegradable projectile made from polylactic acid containing progesterone for contraception of wild life without the need to restrain the animal was constructed by Long et al. (2018). 2.5.3.3 Scaffold Sustained release scaffolds containing ibuprofen were prepared by Yang et al. (2022) utilizing polycaprolactone. The addition of chitosan acted as a plasticizer and induced the formation of channels within the implant, hence controlling diffusion rate (Yang et al., 2022). Polycaprolactone scaffolds with gold nanoparticles immobilized on their surface using plasma polymerization have been produced for tissue regeneration by Joseph et al. (2021). 2.5.3.4 Biodegradability Most implants are constructed utilizing non-biodegradable polymers, hence necessitating surgical removal after completion of the therapy. Stewart et al. (2020) have

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Fig. 2.25 CAD files (a–c) and 3D-printed (d–f) vaginal rings for progesterone release with tailored “O”, “Y” and “M” shapes. A cross-section is depicted in figure J. Reprinted with permission from Fu et al. (2018)

developed different sizes of a biodegradable implant from either PVA or PLA after which the implants were filled directly with a powdered model drug, ibuprofen. They also investigated the effect of implant coating on the release characteristics (Stewart et al., 2020).

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Challenges and Future Perspectives

Fused deposition modeling in pharmaceuticals could be a technique exploited in Industry 5.0, a new industrial revolution anticipating to merge human creativity and industrial accuracy to enable mass personalization. Smart additive manufacturing (SAM) is one of the keystones of Industry 5.0 due to its potential for sustainable and cost-effective production. Applications of SAM and more specifically FDM in healthcare could be prescription of personalized doses, manufacturing of personalized implants, assistive technology, smart medical education or disaster management. However, before these techniques can be exploited to provide decentralized manufacturing, the production life cycle will have to be digitized and innovated. Development of cloud manufacturing platforms could enable access control and intellectual property protection for designers, while the actual manufacturing occurs at a decentralized production site. Since fused deposition modeling is a digitized, computer-based technique, a high level of security in data storage and handling is required to guard patient privacy. Authentication, integrity of stakeholders, restricted access control and auditability of these digital processes could mitigate this risk. Additionally, decentralized production requires optimized supply chain management, which could be achieved by for example predictive analytics anticipating disruptions (Kumar et al., 2022). Understanding and controlling all production process variables from digital design to printed product is vital prior to implementation in healthcare. At the moment, most pharmaceutical research focuses on the use of non-GMP desktop printers from various brands in combination with different slicer programs like Cura, Makerware or PrusaSlicer. These programs convert stereolithography files to g-code, a sequence of instructions utilized by the printer. The conversion itself might vary between different programs, utilizing a different user interface, model settings and algorithms. Next to the program itself, different printer brands also introduce variability. Changes in nozzle length, feed mechanism or filament diameter tolerance for example might influence processability and jeopardize standardized results (Cailleaux et al., 2021; Henry et al., 2021a). Another critical aspect related to the design of a GMP printer is the importance of cleanability. In pharmaceutical research, different cleaning protocols utilizing high temperatures, brass brushes, immersion in solvents or flushing with cleaning polymers like cellulose-based derivatives have been investigated (Henry et al., 2021a; Melocchi et al., 2016). An acceptable medical printer should have easily cleanable parts, should be made from pharmaceutical grade material to avoid leachables in the drug product and should be in cleanroom (Trenfield et al., 2018). Application of the printing technique in healthcare however necessitates the use of biocompatible starting material (Awad et al., 2018) and the development of pharmaceutical-class printers including the use of inert contact parts, easily cleanable and enabling pharmaceutical process validation checks (Crowley et al., 2007). At the moment, only a limited number of materials are suitable for pharmaceutical FDM 3D-printing due to constraints in terms of mechanical, thermal

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and rheological behaviour. These limitations might lengthen the research and development phase of printed dosage forms and hamper their clinical translation. Adaptations of existing equipment, invention of new feeding approaches or development of new feedstock material could facilitate tapping into its full potential (Abdelhamid et al., 2022; Henry et al., 2021a) In 2015, the first 3D-printed product received FDA approval. The product, called Spiritam, was developed by Aprecia Pharmaceuticals using the ZipDose technology with powder 3D-printing. It was an orodispersible tablet loaded with levetiracetam for the treatment of epilepsy. Despite this earlier approval, there are unfortunately no regulatory guidelines available yet for 3D-printed drug products. Development of universal guidelines implies a strenuous task due to the variety of 3D-printing techniques and personalization of its products. Individual efficiency and risk assessment for each developed product might be required, which could hamper fast implementation in healthcare. Moreover, ambiguity exists about whether or not 3D-printing classifies as production or compounding technique, which will greatly affect regulatory requirements (Auriemma et al., 2022). Another aspect to keep in mind is the fact that the production rate of FDM 3Dprinting is rather slow in comparison with traditional manufacturing techniques, making the technique unsuitable for mass production. Flexible, batch-wise production remains one of the strengths of FDM 3D-printing (Parulski et al., 2021). Hence, it is anticipated that 3D-printing will not entirely replace traditional manufacturing but act as a complementary production technique, suitable for specific cases where personalization is highly desirable.

2.7

Conclusion

In the recent years, fused deposition modeling 3D-printing has become a popular technology in the field of pharmaceutical research. While the process itself seems simple, its implementation in pharmaceutical production is challenging. The mechanical properties and viscoelastic behaviour of the feedstock material dictate its processability with the FDM printer, limiting the portfolio of applicable pharmaceutical materials. Addition of processing aids or blending of polymers might strengthen the filament or lower its viscosity, hence resulting in new, printable formulations. The development of screening tools like tensile tests or small amplitude oscillatory shear tests might enable a structured investigation of complex formulations, while avoiding costly and time-consuming trial-and-error approaches. Alternatively, melt printing techniques utilizing alternative feedstock materials (e.g. pellets, powders) are also under development. Once a printable formulation has been developed, personalization of the drug product by designing a tailored dosage form and incorporating a specific drug (load) becomes decisive. Both in-silico model parameters and process settings should be optimized to obtain a qualitative end-product with acceptable mechanical properties and the required drug release profile. A variety of traditional and novel

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characterization techniques have been explored for 3D-printed drug products to ensure that quality is built-in into the process. The potential of FDM 3D-printing has been confirmed by numerous research groups through development and characterization of miscellaneous innovative dosage forms like oral tablets, transdermal films or implants. Nonetheless, before this technique can be fully implemented to produce personalized dosage forms on-site, the efficiency and reliability of 3D printers should be improved. Gradual optimization of the production process and expansion of the proficiency for printing by researchers might enable this technique to truly revolutionize pharmaceutical manufacturing.

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3

Stereolithography (SLA) in Pharmaceuticals Prashanth Ravi and Parimal Patel

Abstract

Commercial stereolithography (SLA) 3D printing has been around for over three decades. However, only recently the technology has been employed in pharmaceuticals to 3D print pills and devices for drug delivery, aided in part by the miniaturization of this technology. Compared to other 3D printing technologies based on powder or filament-based feedstock, SLA offers superior surface finish, accuracy, and material versatility. This chapter covers the major advancements in SLA 3D printing of pharmaceuticals and provides insight into the origin of SLA 3D printing and the current subcategories within this technology, the important governing process parameters, various applications in pharmaceuticals from peer-reviewed literature, and challenges that must be addressed to bring the technology closer to the clinic. Using SLA, rigid pills loaded with drugs such as paracetamol, caffeine, naproxen, chloramphenicol, prednisolone, aspirin, and berberine have been successfully 3D printed. In addition, soft devices for drug release have also been 3D printed. However, unexpected reactions have been reported in the literature which emphasize the cautionary aspect of 3D printing pharmaceuticals using SLA and the need for further meticulous research. Additionally, the regulatory hurdles including a general lack of quality control processes need to be addressed to bring this technology into the clinic. The throughput of SLA 3D printing for pharmaceuticals, like other 3D printing technologies, is substantially lower compared

P. Ravi () Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA e-mail: [email protected]; [email protected] P. Patel Department of Mechanical & Aerospace Engineering, University of Texas at Arlington, Arlington, TX, USA © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals, https://doi.org/10.1007/978-981-99-2404-2_3

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to conventional industrial fabrication processes. Further, post-processing steps such as support structure removal and post-curing are needed to achieve the desired end-use characteristics. However, a novel technique of volumetric 3D printing of pharmaceuticals holds promise to address some of these limitations, but the technology is still in the nascent stage and technical challenges such as dimensional accuracy and material compatibility still need to be addressed. SLA 3D printing of pharmaceuticals is a new and active area of research with potential to impact clinical practice in the future as critical roadblocks are addressed. Keywords

3D printing · Pharmaceuticals · Drug delivery · Stereolithography · Medical 3D printing · Vat photopolymerization

3.1

Introduction

Additive Manufacturing (AM) or three-dimensional (3D) printing technologies have transformed manufacturing across industries such as automotive, aerospace, healthcare, consumer products, and construction since their invention in the 1980s (Campbell et al. 2012). Historically, subtractive manufacturing was one of the primary methods of manufacturing wherein a large block of material was gradually chipped away using different techniques to achieve the desired shape. In AM or 3D printing, this paradigm is totally upended by instead gradually adding material layer-by-layer to form the intended object (Ravi et al. 2017). This empowers the user to fabricate complex objects including organic shapes such as those found in anatomical models utilized in pre-surgical planning in a relatively short period of time which would traditionally not be possible to manufacture or would require complex and often expensive tooling (Ravi et al. 2022a). However, it is important to note that there are varying degrees of post-processing needed subsequent to the printing operation to achieve the desired part characteristics based on the technology used. Within 3D printing, there are 7 distinct technologies as per the ASTM: Material Extrusion (MEX), Vat Photopolymerization (VP), Material Jetting (MJT), Binder Jetting (BJT), Powder Bed Fusion (PBF), Sheet Lamination (SL), and Directed Energy Deposition (DED) (Alexander et al. 2021). Each of these technologies has its own governing physics, process parameters, and usable material(s). Although the term “3D printing” has become mainstream because of its conciseness and parallel to the “2D” or paper-based inkjet printing, it really does not do justice in capturing the essence of the technology when compared to the term “Additive Manufacturing.” This is because the set of 7 AM technologies can be employed to actually fabricate physical parts having functional properties suited to real-world applications. Collectively, the 7 AM technologies enable the manufacture of complex objects using polymers, metals, composites, and ceramics. Although polymeric 3D printing was where the technology arose, metal 3D printing is seeing the highest growth recently in part due to the usage of the technology to manufacture

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high profile components such as the General Electric (GE) Aviation Leading Edge Aviation Propulsion (LEAP) engine nozzles, and an entire space shuttle engine for a National Aeronautics and Space Administration (NASA) project. The ability of 3D printing to manufacture complex shapes and customize both internal and external geometries translates well into medicine. Within healthcare, 3D printing is transforming medicine via the fabrication of patient-specific anatomic models, anatomic guides, implants with optimized internal architecture, and other devices (Mitsouras et al. 2015). The ability to personalize devices improves patient outcomes compared to using one size fits all devices. Traditional pharmaceutical manufacturing is generally time consuming, labor intensive, costly, rigid, and cumbersome, although once setup it can be used to manufacture huge volumes of tablets and other drug-loaded excipients. Three-dimensional printing technology offers the potential to address several of the shortcomings in traditional pharmaceutical manufacturing, although it is challenging to achieve high volume production using the current throughout of 3D printing technologies. In the last decade, researchers have begun exploring the fabrication of drug-loaded excipients using 3D printing technologies primarily owing to the ability to personalize dosages, customize external shapes as well as internal geometries, tailor the constituent materials, and reduce operational costs, among other characteristics. However, to date there is only 1 United States (US) Food & Drug Administration (FDA) approved 3D printed drug that was developed by Aprecia Pharmaceuticals and cleared in 2015 (Ravi 2020), although startup companies such as FabRx are making promising progress using their Printlets™ technology for fabricating oral dosage forms. One of the reasons for this is the lack of tight quality control processes in 3D printed pharmaceuticals compared to traditional manufacturing. The part-to-part variability in properties can be relatively quite high when fabricated using 3D printing compared to when fabricated using traditional manufacturing. Large well-controlled studies are needed to ascertain whether the part-to-part variability within the pharmaceutical domain is acceptable considering the advantages offered by 3D printing technologies. Since 2016, researchers have increasingly begun studying VP (stereolithography —SLA) 3D printing for pharmaceutical research. The SLA/VP 3D printing technology is widely different in terms of the feedstock material, process parameters, and end-use properties compared to conventional tablet manufacturing using power compression. This chapter will cover the major advancements in SLA/VP 3D printing of pharmaceuticals. A historical context of the development of SLA 3D printing over nearly 50 years will be provided in the beginning which will include the major subcategories within SLA/VP 3D printing along with certain benefits offered by this technology. This will be followed by a discussion of the important process parameters and considerations governing this technology. Next, a comprehensive summary of the major research works in the field over the last 6– 7 years will be discussed and summarized in tabular form. Recent works with high future potential will be highlighted. This will be followed by a discussion of the roadblocks preventing rapid progress and clinical translation of this technology with some final concluding remarks. The overarching goal of this chapter is to provide an overview of the state of SLA/VP 3D printing research in the pharmaceutical domain.

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History and Principles of Stereolithography (SLA) 3D Printing

The idea of 3D printing evolved from the early 1970s when Pierre A. L. Ciraud described a method of application of layers of powdered material and their subsequent solidification through action of a high energy beam (Jamróz et al. 2018). Over the nearly 40 years of existence of 3D printing, several different technologies were developed, but they are primarily based on liquid solidification, powder solidification, and extrusion. The first significant work linked to modern SLA 3D printing emerged during the early 1970s when Dr. Hideo Kodama invented the modern layered approach foundational to 3D printing. In the late 1970s, Swainson presented a system for constructing 3D objects by two intersecting radiation beams (Huang et al. 2020). Commercial SLA or vat photopolymerization (VP) 3D printing is a liquid photopolymer-based technology invented in the 1980s (Hull 1986). The inventor Charles Hull was working with a company that used ultraviolet (UV) light to apply thin layers of plastic veneers on furniture, paper products, and tabletops. He then developed the idea of placing multiple layers of this material, one on top of each other, to build three-dimensional (3D) objects in almost any conceivable shape (Martinez et al. 2018a). In SLA 3D printing, a light source, typically a laser, is used to fabricate the 3D model layer-by-layer from a photopolymer reservoir. Traditionally, SLA 3D printing was confined to laser-based top-down industrial systems that were used for prototyping large components. However, progress across multiple technologies resulted in the miniaturization of SLA 3D printing to the desktop environment. The last decade has seen the rapid rise of bottom-up or inverted SLA 3D printing systems (Fig. 3.1), a key transformation enabling the

Fig. 3.1 Major types of inverted stereolithography 3D printing technology adapted with permission from (Pagac et al. 2021). Left: components of a typical SLA machine: (1) printed part, (2) liquid resin, (3) building platform, (4) UV laser source, (5) XY scanning mirror, (6) laser beam, (7) resin tank, (8) window, and (9) layer-by-layer elevation. Center: components of a typical DLP machine (only different components labeled): (4) light source, (5) digital projector, (6) light beams. Right: components of a typical CLIP machine (only different components labeled): (8) oxygenpermeable window, (9) dead zone, and (10) continuous elevation

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Fig. 3.2 Scheme of masked LCD-based VP 3D printing. Reproduced with permission from (O¨zóg et al. 2022)

miniaturization of the bulky and industrial SLA technology, aided in large part by the expiration of early key patents. This miniaturization is a key trait that makes this technology suitable for pharmaceutical 3D printing, since the pills/tablets/excipients 3D printed are relatively smaller compared to the large bulky components 3D printed for automotive, aerospace, or other prototyping applications. Some of these systems now incorporate digital light projection (DLP) sources or masked liquid crystal displays (LCD) backlit with light emitting diode (LED) arrays, which allow superior throughput compared to traditional laser-based scanning systems (Fig. 3.2). This superior throughout is achieved by exposing the entire layer at once in contrast to a raster-by-raster scan of the layer using a laser beam. Continuous liquid interface production (CLIP) was invented in 2015 and improves the post-layer fabrication peel operation in inverted SLA 3D printing (Tumbleston et al. 2015). A dead zone of liquid resin is created between the cured resin and oxygen-permeable membrane by exploiting the oxygen-based inhibition of free radical photopolymerization. Nexa3D invented the lubricant sublayer technology to substantially reduce the post-layer peel separation forces by incorporating a thin layer of lubricant (silicone oil) between the cured resin and bottom membrane (Zitelli et al. 2022). The post-layer peel separation (Fig. 3.3) is one of the fundamental limitations of inverted VP 3D printing technology limiting throughput of this powerful technology. It can consume up to 75% of the total print time, particularly with improvement in the intensity and efficiency of the LED array

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Fig. 3.3 (Left) Schematic of the post-layer peel separation process in inverted VP 3D printing. The current layer (green) adheres to the elastic membrane (red) at the bottom of the vat (resin container, walls in orange) after exposure to curing light radiation (not shown). The build platform (gray) is then gradually lifted up (gray arrow) to tense the elastic membrane (red) and separate the cured layer from the vat. After separation, the elastic membrane returns to normal position to allow resin (purple dashes) to flow back into the newly created void for fabricating the next layer. The process then repeats continuously until the part is 3D printed. (Right) The membrane tensional force (FM ) acts to detach the cured layer. The horizontal distance from the edge of the part to the vat walls is H, the vertical lift distance is L, the peel angle is θ and FS and FN are the shear and normal forces, respectively. Reproduced with permission from (Ravi et al. 2021a)

light sources and the recent transition to the monochromatic LCD masks that allow substantially higher transmission of light compared to the traditional color LCD screens. Digital light processing (DLP) and two photon polymerization (2PP) are also VP based 3D printing technologies (Xu et al. 2021a). DLP technology was invented by Texas Instruments (TI) and works by projecting an entire layer using an array of dynamic mirrors, whereas 2PP works by the sequential energizing of a resin voxel using two energetic photon pulses. The inverted SLA 3D printing technology necessitates the use of support scaffolding to anchor any floating model elements to the rest of the model and to deal with the peel separation forces (Awad et al. 2018). The printed model is in a green state that requires rinsing in a solvent to wash away uncured resin followed by post printing UV curing to fully set the crosslinking reactions that ultimately determine the mechanical properties of the final 3D printed object. The support scaffolding must be manually separated from the model in a meticulous manner to not damage any delicate features. Further, the post-processing must be factored into the picture before actually printing the model to ensure optimal orientation, support placement, and no suction cups. The liquid photopolymeric nature of materials affords superior versatility because the base photopolymer can be combined with a multitude of materials. For instance, resins can be created for diverse applications such as dental crowns, engineering prototypes, anatomic models, surgical guides, jewelry castings, flexible components, etc. and fabricated on the same desktop inverted SLA 3D printing system by having a modular system for swapping out the vat, build plate, and material cartridge. Furthermore, the accuracy and surface finish are among the

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best of any 3D printing technology available while the cost is substantially lower or on par compared to other 3D printing technologies (Awad et al. 2018). SLA has been demonstrated to produce models with less than 10-micron accuracy, whereas DLP can fabricate models with 30–100 micron accuracy (Martinez et al. 2018a). The accuracy is particularly important when fabricating drug-loaded tablets or other excipients that are relatively smaller in size to ensure correct drug dose delivery.

3.3

Stereolithography (SLA)/Vat Photopolymerization (VP) Materials

VP resins are developed using multiple components: liquid monomers, reactive diluents, flexibilizers, and stabilizers. When a photoinitiator undergoes impact by a UV light photon, it transforms into a reactive species and interacts with the liquid monomers to commence the radical chain polymerization reaction. The photoinitiator plays a key role in utilizing the electromagnetic energy of a particular wavelength of light and converting it into chemical energy. This reaction generates free radicals which propagate through the monomers and oligomers to create a polymer network. Many resins have been developed for VP but generally these are primarily composed of methacrylates or acrylic esters because they exhibit fast reaction rates, tunable mechanical properties, and stability. Although it is worthwhile to note that the resins can be highly brittle and prone to shrinkage during the radical chain polymerization reactions. When it comes to medical devices and the pharmaceutical industry, these resins must be biocompatible and digestible, hence the resin material is a critical parameter. Poly (ethylene glycol) diacrylate (PEGDA) monomer has been a regular choice to formulate resins by researchers and industry resin manufacturers due to its biocompatibility and degradability (Robles-Martinez et al. 2019; Martinez et al. 2018b). Generally, the photoinitiators are toxic to living organisms, hence it is crucial to keep the concentration to a minimal level, typically not more than 1 wt% in the overall formulations. Typical photoinitiators used are 2,4,6-trimethylbenzoyldiphenyl phosphine oxide (TPO) and bis-acylphosphine oxide (BAPO). Furthermore, the resin’s transparency impacts the scattering and attenuation of photons and its curing ability during printing. A clear acrylate resin, for instance, can allow more photons to penetrate deeper potentially leading to better cure compared to opaque resins. Certain dyes are added to the resin to make them opaque and impart color, and this can in turn increase light scattering and negatively impact the photon penetration into the resin therefore lowering the overall curing. Each subcategory of SLA 3D printing: SLA, DLP, 2PP, and CLIP, process these resins in slightly differing ways to create the actual 3D printed parts. It is evident that current choices for pharmaceutical resins are limited compared to the plethora of material choices available for conventional tablet manufacturing, and this challenge is one of the important barriers in the future that will determine success of the technology and penetration into the clinical space.

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Stereolithography (SLA)/Vat Photopolymerization (VP) Process Parameters

The printing process and process parameters can define the final mechanical properties and geometrical accuracies of printed parts. The laser/light power, LCD mask gray scale, resin temperature, laser scanning speed, and layer height are some important process parameters governing the quality and characteristics of the printed parts. While SLA can print up to 30 μm layers giving a high accuracy and smooth surface finish, it is relatively slow due to its laser scanning process. DLP printers can print 50–100 μm and print parts faster than SLA, while CLIP printers are 100 times faster than any other VP technologies potentially rendering them the best candidate for mass production. However, CLIP is known to struggle when 3D printing large solid models that generate huge amounts of polymerization related heat and require large volumes of resin to flow into the center for maintaining continuous fabrication. 2PP produces the highest resolution parts with as small as 100 nm features (Serbin et al. 2004), although the throughout is substantially lower. Other than speed and accuracy, each layer must peel from the transparent vat membrane, and this determines success or failure of parts printed using DLP, SLA, and masked SLA. The peel rate, governed by the lifting speed of the build plate, is positively correlated with the peel forces generated. In general, the lower the peel force the better the print quality and success rate. This is primarily why the optimal part orientation in SLA 3D printing reduces the largest as well as average cross-sectional area across layers. Polydimethylsiloxane (PDMS) and acrylic sheets, such as those manufacture from fluorinated ethylene polypropylene (FEP) and perfluoroalkoxy (PFA), are widely used as the transparent membrane at the bottom of the vat since they allow easy peel from the surface. However, drawbacks of these surfaces are that they permit passive oxygen diffusion, restricting the interfacial polymer cure, and are consumables that need frequent replacement which drive up the recurring cost of using this technology. The CLIP technology developed in 2015 promises to overcome the issue with an oxygen-permeable window at the print surface thereby integrating a persistent liquid interface allowing it to print continuously instead of in a layerby-layer fashion, but the results are excellent primarily when printing highly porous geometries and these results are not reproducible using large solid geometries. Last but not the least, one of the post-processing steps in VP printing involves rinsing the 3D printed parts using isopropyl alcohol (IPA) and post-curing with UV light to fully set the mechanical properties. Most commercial printer manufacturers provide washing and curing stations with meticulous instructions for use based on the type of resin being used to streamline the workflow from the digital model to the final physical 3D print.

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SLA in Pharmaceuticals

The dental and medical fields have widely adopted 3D printing to create patientspecific objects and even organs (Ravi et al. 2021a, 2022b; Trenfield et al. 2019). In the pharmaceutical domain, SLA 3D printing can offer the ability to rapidly fabricate dimensionally accurate drug-loaded excipients that are internally solid, cost-effective, and externally smooth (Deshmane et al. 2021). The integration of 3D printing with other innovative technologies into pharmaceuticals is predicted to give rise to a new digital pharmacy (Fig. 3.4). By incorporating non-invasive diagnostics or drug monitoring techniques, electronic prescriptions, and artificial intelligence (AI) technologies, 3D printing could provide a digital and decentralized platform for the fabrication of customized medicines in response to monitored output (SeoaneViaño et al. 2021). The entire process could be largely automated with minimal to no supervision once validated via extensive real-world testing across multiple sites. One of the principal benefits common to 3D printing technology is the ability to personalize medicine (Mathew et al. 2020; Elkasabgy et al. 2020). The ability to tailor the release profile and dosing of a 3D printed tablet simply by changing the geometries using computer-aided design (CAD) and the ability to incorporate drugs into injectable devices or mesh implants opens a wide range of possibilities. For instance, despite the numerous standard dosages available for drugs such as

Fig. 3.4 The virtuous cycle of personalized medicine in the future. With AI serving as the focal point, real-time monitoring can be used to customized dosages during the course of treatment using an in-house pharmaceutical 3D printer. Reproduced with permission from (Seoane-Viaño et al. 2021)

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levothyroxine, patients may still need to manually split pills on a daily/weekly basis to achieve the targeted dosing. This could potentially be addressed by 3D printing a personalized dosage of the medication for each patient. The fabrication of multidrug-loaded dosage forms to reduce pill burden and improve patient adherence becomes a possibility using the power of 3D printing technologies. Further, 3D printing enables the on-demand fabrication of drug products which is otherwise infeasible and expensive with conventional manufacturing (Seoane-Viaño et al. 2021). During supply chain shortages caused by the first COVID-19 surge, 3D printing was highly effective in providing much needed personal protective equipment (PPE) and ventilator parts to the healthcare community (Tino et al. 2020; Ravi et al. 2021b). The pharmaceutical SLA 3D printing domain is relatively new compared to fused deposition modeling (FDM), and there is a huge scope for further development (Brambilla et al. 2021; Ravi and Shiakolas 2021; Patel et al. 2022; Patel et al. 2018). Although 3D printing confers several advantages, it currently cannot compete with industrial mass production and is limited to the production of small batches of medicine due to the low throughput compared to traditional mass manufacturing techniques (Trenfield et al. 2018). However, 3D printing allows the fabrication of complex geometries that are impossible to manufacture using conventional methods (Patel 2018). The future of 3D printing will require the integration of real-time quality control processes to ensure product safety and efficacy, both of which are key aspects in determining the initial foray of 3D printed drugs into the clinic (Trenfield et al. 2019). One of the first studies to report SLA 3D printing of oral modified-release dosage forms was reported by Wang et al. (2016). Poly(ethylene glycol) diacrylate (PEGDA) monomer with diphenyl phosphine oxide (DPPO) photoinitiator was combined with 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) as model drugs on a Formlabs Form 1+ 3D printer. The geometry fabricated was a torus (Fig. 3.5) with 11 mm diameter, 4 mm height, and a central hole of 3 mm Fig. 3.5 Torus-shaped drug-loaded tablets with 11 mm diameter and 4 mm height 3D printed using a Form1+ 3D printer. Tablets are loaded with (a) paracetamol and (b) 4-ASA and contain varying ratios of PEGDA/PEG300. Reproduced with permission from (Wang et al. 2016)

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diameter. Compared to solid geometries, the torus allows for higher surface area and hence superior drug release performance. SLA 3D printing is traditionally restricted to fabricating objects using a single material per printing operation because the vat can only contain a single resin at one time. Fixed dosage combination (FDC) products containing at least two different active pharmaceutical ingredients are especially attractive for poly-medicated patients given that adherence is enhanced and pill burden is reduced (Fernández-García et al. 2020). However, the combination of multiple drugs within the same pill can bring a multitude of physicochemical and pharmacodynamic interactions. Researchers in the pharmaceutical domain have devised techniques to allow the fabrication of pills with different material formulations. Curti et al. modified a Formlabs Form 2 3D printer to 3D print with up to 12 different materials (Fig. 3.6), reducing the volume of minimum resin required for printing by 20-fold (Curti et al. 2021). This innovative setup allowed the high throughput screening of 156 photopolymer formulations which improved the turnaround time by 91.7% and cost by 95%. This is important given the relatively high cost of synthesizing even modest volumes of pharmaceutical grade photopolymer formulations. The fabrication of a single excipient with 6 different drug-loaded materials (polypill) (Xu et al. 2020) was performed using a Formlabs Form 1+ 3D printer with the OpenFL version of PreForm and manual swapping of the vat by pausing the print job. The 6 drugs included paracetamol, caffeine, naproxen, chloramphenicol, prednisolone, and aspirin (Fig. 3.7). A different research group fabricated a polyprintlet with 4 different hypertensive drugs (Xu et al. 2020). The 4 hypertensive drugs included irbesartan, atenolol, hydrochlorothiazide, and amlodipine (Fig. 3.8). An unexpected Michael addition between the diacrylate group of the photoreactive monomer and the primary amine group of amlodipine was confirmed

Fig. 3.6 (a) The original Form 2 SLA 3D printer and (b) the novel setup which allows testing with up to 12 different photopolymer formulations, simultaneously. Reproduced from (Curti et al. 2021)

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Fig. 3.7 A polypill with 6 different drug-loaded regions in cylindrical and ring geometries. Reproduced from (Robles-Martinez et al. 2019)

Fig. 3.8 Scanning electron microscope cross-sectional image of the polyprintlet loaded with (top to bottom) amlodipine, atenolol, irbesartan, and hydrochlorothiazide. Reproduced with permission from (Xu et al. 2020)

in the hypertensive drug-loaded polyprintlet using FTIR and NMR spectroscopy. This intriguing finding highlights the importance of carefully selecting photocurable resins for the manufacture of drug-loaded oral dosage forms. The compatibility of photocurable resins and drugs should be ensured via rigorous studies to avoid such unwanted chemical reactions that could potentially have a detrimental effect on the patient (Seoane-Viaño et al. 2021). Tablets with multiple drugs may improve patient compliance because of the reduced pill burden and may yield superior clinical outcomes for the patients. For instance, patients with end-stage renal disease undergoing dialysis often have other comorbidities such as diabetes or hypertension and can be required to take multiple pills throughout the day which can reduce compliance, thereby negatively affecting patient outcomes. Karakurt et al. encapsulated ascorbic acid in a poly(ethylene glycol) dimethacrylate-based polymer network with riboflavin as a photoinitiator and 3D printed co-axial annulus with 4-circle and honeycomb pattern geometries with surface area to volume ratios of 0.6–1.83 using an Anycubic Photon 3D printer

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(Karakurt et al. 2020). The fluorinated ethylene polypropylene (FEP) membrane separating the liquid photopolymer from the LCD masking screen was replaced with a 2 mm thick glass due to sticking and ripping of hydrogel on the FEP. Krobabic et al. used a Wanhao Duplicator 7 DLP 3D printer for fabricating cylindrical tablets that were 8 mm diameter and 2 mm thick using atomoxetine hydrochloride (ATH) photoreactive suspensions. PEGDA 700 and poly(ethylene glycol) PEG 400 (base polymers), DPPO (photoinitiator) and atomoxetine hydrochloride (active ingredient) photoreactive suspensions were used. The print time was 11–13 min for 5 tablets which highlights the much lower throughput compared to industrial manufacturing. Stanojevic et al. applied artificial neural network (ANN) with DLP 3D printing to tailor ATH release from immediate to prolonged by varying the drug loading and tablet thickness (Stanojevi´c et al. 2020). The ANN model was developed to predict the ATH release rate. The model drug was ATH because it is employed in a range of doses within children with attention-deficit hyperactivity disorder (ADHD) making it a fitting candidate for personalized therapy. In their research, PEGDA (52.4–63.7% w/w) with PEG400 (17.5–21.2% w/w), water (10% w/w), DPPO photoinitiator (0.10% w/w), and ATH (5–20% w/w) was used as resin on a Wanhao Duplicator 8 DLP 3D printer with Chitubox software, a communitybased slicing software. A summary of the SLA-based 3D printers utilized and pharmaceutical research and the drug excipients printed are provided in Tables 3.1 and 3.2. In addition to primarily rigid pills and excipients, elastic devices loaded with lidocaine hydrochloride (Fig. 3.9) were also fabricated for targeted bladder drug delivery (Xu et al. 2021b). Elastic resin was used to fabricate the bladder device, and lidocaine hydrochloride was mixed into the resin in 3 ratios—10%, 30%, and 50% w/w. Common drug compounds such as paracetamol, caffeine, naproxen, chloramphenicol, prednisolone, and aspirin have been successfully used to fabricate pills using SLA 3D printing. Additional compounds including 4-ASA, aspirin, ibuprofen, ascorbic acid, atenolol, hydrochlorothiazide, irbesartan, amlodipine, capsaicin, theophylline, and sulforhodamine B tablets have also been used to fabricate oral dosage forms using DLP or SLA 3D printing (Xu et al. 2021a). Frequently, PEGDA is used as the prepolymer with which other materials are mixed or into which the drug compound is loaded (Ravi et al. 2019). Relatively low-cost desktop SLA 3D printing systems such as the Formlabs Form1+, Form 2, Form 3/3B, the Anycubic Photon, the Wanhao Duplicator 7/8, etc. are most frequently used by researchers due to the vast user-base and online support from the communitybased sharing of knowledge related to 3D printing using these machines. Martinez et al. fabricated tablets with multiple geometries such as a cube, disc, pyramid, sphere, and torus using SLA 3D printing, and it was found that tablets with a constant surface area to volume ratio release drug at the same rate, whereas tablets with constant surface area but different volumes released drug at different rates (Martinez et al. 2018b). The group used PEGDA 700 as monomer, diphenyl(2,4,6trimethylbenzoyl) phosphine oxide (TPO) as photoinitiator, and paracetamol as model drug with a Formlabs Form 1+ 3D printer. To overcome very slow and incomplete drug release from tablets fabricated by DLP 3D printing, Krkobabic et

0.02

405

405

405

385

405 405

DLP

Mask SLA SLA

DLP

DLP DLP

Custom DLP printer Carbon3D M1 S1 CIP Prototype printer (Carbon)

40

405

DLP

Proprietary Proprietary 141 × 79 × 326 385 nm Unknown Unknown

CLIP CLIP

Slic3r Carbon printing software

Asiga Composer Creation Workshop Envision Labs Unknown

71.1 × 40 × 75 191 × 109 × 254

Unknown

FabRx

Unknown

Unknown

365

200

Photon Slicer

115 × 65 × 155 Unknown

Creation Workshop X Unknown

120 × 68 × 180 Unknown

Preform

145 × 145 × 175

DLP

30 30

Unknown

Unknown

30

0.25

Wanhao Duplicator 7 Custom DLP printer Anycubic Photon 3D Custom-hybrid SLA and inkjet printer Volumetric DLP printer Pico 2 HD Titan 1, Kudo 3D

405

Laser

Form 2

Wavelength Power (W) Build volume (nm) Power (W) (L × W × H; mm3 ) Software 405 0.1 125 × 125 × 165 Preform

Light source Laser

SLA 3D printer Form 1+

Johnson et al. (2016) Caudill et al. (2018), Bloomquist et al. (2018)

Lu et al. (2015)

Lim et al. (2021) Lim et al. (2017)

Rodríguez-Pombo et al. (2022)

Konasch et al. (2019)

Karakurt et al. (2020)

Kadry et al. (2019)

References Robles-Martinez et al. (2019), Martinez et al. (2018b, 2017); Wang et al. (2016); Tan and Ho (2019), Xu et al. (2020), Xenikakis et al. (2019) Xu et al. (2021b, 2021c), Pere et al. (2018), Economidou et al. (2019), Healy et al. (2019), Uddin et al. (2020), Sharma et al. (2022) Krkobabi´c et al. (2019), Madzarevic et al. (2019)

Table 3.1 Major resin 3D printers used in pharmaceutical research applications and their characteristics

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Paracetamol, acetylsalicylic acid, naproxen, chloramphenicol, caffeine prednisolone Paracetamol, aspirin

Paracetamol

Insulin

Active pharmaceutical ingredient Paracetamol 4-Aminosalicylic acid

Poly(caprolactone) Triol, (PCL Triol), Polyethylene glycol diacrylate (PEGda), diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide (TPO)

Dental SG resin Xylitol, Mannitol, Trehalose Polyethylene glycol diacrylate (PEGda), diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide (TPO) Polyethylene glycol diacrylate (PEGda), diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide (TPO)

Polymer and excipients Poly(ethylene glycol) diacrylate, Poly(ethylene glycol) 300, diphenyl(2,4,6trimethylbenzoyl) phosphine oxide

Tablets

Tablets

Tablets

Microneedle

Drug delivery Tablets

Table 3.2 Summary of SLA pharmaceutical 3D printing research

UV/Vis Spectrophotometry, FTIR, DSC, Drug release, SEM, Statistical analysis

Raman Spectroscopy, X-ray Powder Diffraction (XRPD), drug loading using HPLC, drug release, Swelling ratio

Characterization techniques Environmental scanning electron microscopy (ESEM), X-ray powder diffraction (XRPD), drug concentration using HPLC, Dissolution Scanning electron microscopy (SEM), Circular Dichroism (CD) analysis, Raman Analysis, MN penetration, HPLC SEM, drug loading using HPLC, drug release, surface area to volume ratio, swelling

Form 2

Form 1+

Form 1+

Form 2

3D printer Form 1+

(continued)

Healy et al. (2019)

Robles-Martinez et al. (2019)

Pere et al. (2018), Economidou et al. (2019) Martinez et al. (2018b)

References Wang et al. (2016)

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Elastic resin from Formlabs

PEGDA, PEG400, DPPO, Nacl, Mannitol

Paracetamol

Tablets

Drug delivery device loaded with drug

PEGDA, riboflavin, triethanolamine Hydrogel tablets

SEM, NMR, UV–vis spectrophotometry, Diffusion apparatus DSC, XRPD, micro-CT, SEM, drug, HPLC, dissolution apparatus, mechanical testing, hemolysis assessment, statistical analysis Drug loading using UV/VIS, tensile strength, drug release, kinetic modeling and drug dissolution, particle size, SEM, DSC, FTIR

Hydrochlorothiazide, PEGDA, TPO, Tablets/printlets SEM, XRPD, DSC, HPLC, FTIR, PEG300 Nuclear magnetic resonance (NMR) spectroscopy, dissolution apparatus

Characterization techniques Dynamic light scattering, chromatography, calipers, friability, hardness, FTIR, swelling, SEM PEGDA, PEG, Riboflavin Tablets UV–Vis spectroscopy, dissolution apparatus, DSC, Artificial neural net, kinetic models of drug release PEGDA, PEGDMA, Tablets/printlts FTIR, SEM, hardness, swelling ratio, 2-Hydroxy-4 -(2-hydroxyethoxy)-2water content, drug content, methylpropiophenone dissolution apparatus,

Polymer and excipients Drug delivery PEGDA, polyethylene oxide (PEO), Tablets TPO

Lidocaine hydrochloride

Irbesartan, atenolol, hydrochlorothiazide and amlodipine Ascorbic acid

Theophylline

Ibuprofen

Active pharmaceutical ingredient Berberine

Table 3.2 (continued)

References Sharma et al. (2022)

Xu et al. (2021b)

Karakurt et al. (2020)

Xu et al. (2020)

Kadry et al. (2019)

Wanhao Duplicator Krkobabi´c et al. 7 (2019)

Form 2 SLA

Anycubic Photon 3D

Custom DLP ® printer with DLP ™ Discovery 4100 and Omnicure s2000 UV source Form 1+

Wanhao Duplicator Madzarevic et al. 7 (2019)

3D printer Form 2

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Microneedles Microneedles

PEGDA 575, PEGDA 700, PEG 300, LAP

PEGDA, vinyl pyrrolidone (VP), BAPO,

Commercial resin

Class I biocompatible resin

Paracetamol

AHP-3

Model dyes (no drug) Cisplatin

Microneedles

PEGDA, LAP,

Bovine serum albumin

Ibuprofen

Form 2

Form 1+

Custom-hybrid SLA and Inkjet printer Volumetric 3D printer with multiple projections Rheology, swelling ratio, cytotoxicity, Pico 2 HD from drug release, mechanical strength, Asiga skin penetration of MNs, in vitro cellular cytotoxicity, statistical analysis Compression test, skin penetration, in Form 1+ vitro permeation, SEM SEM, optical coherence tomography Form 2 (OCT), in vitro drug release, atomic absorption spectroscopic analysis, skin penetration, cytotoxicity, tumor development, in vivo antitumor efficacy

Drug loading, Swelling ratio, water content, DSC, dissolution apparatus Tensile strength, XRD, SEM, drug loading, dissolution, drug release kinetic profile, drug stability, statistical analysis Drug depots in Single and multiple deposition of ink, tablets diffusion of ink, DDS (drug delivery system) Printlets ESEM, DSC, XRPD, Micro-CT, FTIR, HPLC, Dissolution apparatus

Hydrogel tablets Tablets

PEGDA, PEG300, Riboflavin, TEOHA, DPPO PEGDA, PEG400, TPO

Ibuprofen

(continued)

Xenikakis et al. (2019) Uddin et al. (2020)

RodríguezPombo et al. (2022) Lim et al. (2021)

Konasch et al. (2019)

Martinez et al. (2017) Xu et al. (2021c)

3 Stereolithography (SLA) in Pharmaceuticals 113

Docetaxel, dexamethasoneacetate, Rhodamine B,

Bovine serum albumin

Rhodamine B, fluorescein

PEGDMA, poly(ethylene glycol) methyl ether methacrylate, di(ethylene glycol) methyl ether methacrylate (MP2MA), 2-hydroxyethyl methacrylate (HEMA), n-propyl methacrylate (PMA), polycaprolactone dimethacrylate (PCLDMA), TPO

Drug-loaded devices

Microneedles

Microneedles

Microneedles

Dacarbazine

Poly (ethylene fumarate) (PPF), diethyl fumarate (DEF), BAPO TMPTA, poly (ethylene glycol) dimethacrylate (PEGDMA 550), polycaprolactone trimethacrylate (PCL-tMa 1100), acrylic acid, TPO PEGDMA 350, TPO

Drug delivery Microneedles

Active pharmaceutical Polymer and excipients ingredient Diclofenac sodium 3DM Castable Resin

Table 3.2 (continued)

Microneedles coating and optimization, multi-protein microneedle patch coating, coating dissolution in vitro and ex vivo CLIP process and product characterization, SEM, DSC, In vitro drug release, drug loading, polymerization kinetics of resins, cell culture, Cytocompatibility of leachables and degradation products

Characterization techniques Test of fracture force, skin MN penetration, in vitro biocompatibility of resin, HPLC, data analysis NMR, viscosity, mechanical testing, in vitro drug release Biocompatibility, skin penetration,

S1 CLIP Prototype printer (Carbon)

S1 CLIP Prototype printer (Carbon)

Custom DLP printer Carbon 3D M1

3D printer Titan 1

Bloomquist et al. (2018)

Caudill et al. (2018)

Johnson et al. (2016)

Lu et al. (2015)

References Lim et al. (2017)

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Fig. 3.9 The hollow SLA 3D printed bladder device before (top left) and after (top right) filling with drug loading mixture; and the hollow device under stretching (bottom). Reproduced with permission from (Xu et al. 2021b)

al. investigated the effect of PEG 400, salt, and mannitol as hydrophilic excipients with paracetamol as the model drug, PEGDA as photopolymer, and DPPO as the photoinitiator (Krkobabi´c et al. 2019). They found that the addition of hydrophilic polymers increases drug release rate, while PEGDA had the greatest influence on tensile strength. Martinez et al. successfully 3D printed PEGDA hydrogels loaded with ibuprofen containing up to 30% w/w water and 10% w/w ibuprofen using a Formlabs Form 1+ SLA 3D printer (Martinez et al. 2017). The cylindrical pills 3D printed were 10.5 mm diameter and 3.5 mm tall. Dissolution profiles were found to be dependent on water content. The hydrogels 3D printed with riboflavin/triethanolamine as photoinitiator showed superior quality compared to when DPPO was used as initiator. However, the presence of hydrophilic excipients can impede printability and formability in SLA 3D printing. Xu et al. used PEGDA as monomer, TPO as photoinitiator, and ibuprofen as the model drug (Xu et al. 2021c). Tartrazine was used as photoabsorber due to its solubility and non-toxicity. A separate study by Pariskar et al. also used Tartrazine as photoabsorber to fabricate highly precise objects (Pariskar et al. 2022). Smaller pellets showed different release characteristics compared to larger pellets. Konasch et al. developed a hybrid SLA and inkjet-based printing process where a drug delivery system (DDS) was created using SLA whereas the drug depots were integrated into the DDS using inkjet printing (Konasch et al. 2019). For testing, PEGDA samples with integrated depots

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Fig. 3.10 PEGDA-based specimens with (a) single blue ink depot; (b) top and (c) angular view of specimen with 13 individual depots; and (d) side view of specimen with 2 different ink depots (blue and pink). Reproduced from (Konasch et al. 2019)

were fabricated and filled with blue and pink solutions (Fig. 3.10). Subsequently, bovine serum albumin as a model drug was placed inside a DDS. Januskaite et al. found the visual appearance of DLP printlets to be the most appealing (61.7%) to pediatric patients compared to printlets fabricated using selective laser sintering (21.2%), semi solid extrusion (11.7%), and FDM (5.4%) (Januskaite et al. 2020). The high surface quality of the printed parts is one of the biggest advantages of resin-based 3D printing (SLA/DLP). An artificial neural network (ANN) model was developed to predict atomoxetine (ATH) release rate, a drug used to treat attention-deficit hyperactivity disorder (ADHD), and the drug release rate was tailored by varying drug loading and tablet thickness. Tan et al. found that the addition of Alizarin dye to the photopolymer improved resolution through reduction of light scattering (Tan and Ho 2019). A fascinating recent development expected to revolutionize SLA in pharmaceuticals is the rapid volumetric 3D printing of paracetamol printlets. Rodriguez-Pombo et al. fabricated an entire torus-shaped tablet (Fig. 3.11) at once in 17 s from PEGDA-based resin formulation as opposed to the layer-by-layer fabrication of SLA 3D printing techniques that can take over 10 min (Rodríguez-Pombo et al. 2022). In the research, PEGDA was the crosslinking monomer, lithium phenyl2,4,6-trimethylbenzoylphosphinate (LAP) was the photoinitiator, paracetamol was the drug, and water or PEG 300 were included as diluents in varying concentrations to facilitate the drug release. The volumetric 3D printer was based on DLP composed of a digital mirror device (DMD), a 385 nm UV light source, and UV optical lenses (f = 210 mm). However, only optically clear resins are suitable with this technique at present because the photon depth of penetration into the photopolymer is limited in opaque resins. This is the reason why only small parts (less than 25 mm) can be 3D printed at present using the volumetric approach, although this maybe a minor issue given the generally small size of pharmaceutical pills. Furthermore, the pills still need to be rinsed in IPA and post-cured to fully establish the mechanical properties of the polymer, and these times are not included in the reported 17 s 3D printing time. However, the reduction of print speed to

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Fig. 3.11 Schematic showing the three orthogonal light beam projections (left, right, bottom) for achieving volumetric 3D printing of the torus-shaped pill without support structures in 17 s. Reproduced from (Rodríguez-Pombo et al. 2022)

17 s from the several minutes to hours frequently consumed to 3D print tablets still represents a significant improvement in the throughput. Another area of pharmaceutical research being affected by SLA 3D printing is microneedles (MN) for transdermal delivery because of the technology’s ability to print tiny features (1 × 1 mm cross section) with excellent resolution and accuracy. Economidou et al. successfully printed insulin-sugar coated arrays of spear and pyramid-shaped MNs which facilitated rapid low glucose level in mice, and 3D printed MNs were easy to operate than standard metal MNs (Pere et al. 2018; Economidou et al. 2019). While keeping in mind the biocompatibility of their resin, Lim et al. used a 7:3 ratio of vinyl pyrrolidone and PEGDA with AHP loading to formulate a resin and 3D print a personalized MN patch to demonstrate potential for transdermal delivery for wrinkle management (Lim et al. 2021). In vitro tests on human cadaver skin demonstrated the 3D printed resin’s ability to penetrate successfully while at the same time minimize cytotoxicity to human fibroblasts. Researchers have shown that MNs fabricated through SLA 3D printing are equivalent or sufficient in strength compared to metal MNs to puncture human skin for delivering dye and insulin-sugar (Xenikakis et al. 2019).

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Challenges and Future Potential

Although SLA 3D printing is a promising technology with demonstrated initial potential in the pharmaceutical domain, several challenges remain. Some of these challenges include the presence of unreacted monomers in the 3D printed pills, the occurrence of unexpected drug-photopolymer reactions in the pills, unintended temperature increase of the photopolymer in the curing region due to the exothermic nature of the process, the need for manual/semi-automatic optimization of the printing parameters for every formulation, and regulatory hurdles relating to the quality and safety of the 3D printed pharmaceuticals (Xu et al. 2021a). Regulatory challenges remain for 3D printing despite the US FDA issuing a technical guidance for manufacturing medical devices through additive manufacturing (Di Prima et al. 2016). The conventional manufacturing of drugs benefits from mass production, validation, and verification in batches, quality assurance methods, and already established procedures for submitting FDA new drug applications. It is unlikely that the same process and product validation protocols can be followed for the custom-made drugs using SLA technology which are tailored to a patient. The process variability in SLA 3D printing is one of the important variables that affect the repeatability of the printed tablets and other excipients. At present there are no guidelines available for 3D printed products for drug delivery which is an area of research currently benefitting from the advantages offered by SLA 3D printing. Despite existence of the Prescription Drug User Fee Act (PDUFA) in the US which allows biopharma companies to fast-track drug approval through a user fee (CDER 2018), the competitive environment for making drugs within the US and the broader North American continent does not push industry manufacturers to invest in new technology such as SLA 3D printing and come up with verification, validation, and quality assurance techniques which can then be adapted by the US FDA for testing and clearance of 3D printed drugs. Generating materials that are biocompatible, SLA-3D-printable, ready for production, compatible with multiple drugs, and applicable across age groups highlights one of the primary challenges facing SLA 3D printed medicines. It is highly unlikely that a single developed resin can serve as a universal filler material for SLA printed medicines, just like there are a plethora of material options available for biocompatible dental applications, anatomic surgical guides, anatomic models, and implants. However, the future potential of custom-made drugs can transform medicine, especially when creating drugs with controlled substances such as anti-depressants, or for medication to treat attention-deficit hyperactivity disorder (ADHD) for which the mass-manufactured drug options are not a great solution for different individuals across age groups. A key aspect to consider here is the ability to monitor the quality of SLA 3D printed drugs in real-time and achieve high quality analogous to the tight and wellestablished quality control processes in conventional pharmaceutical manufacturing. Furthermore, the 3D printed parts require meticulous support structure removal and other post-processing, the material can potentially lead to toxicity, and the mechanical properties tend to reduce with time (Awad et al. 2018). Additionally, SLA 3D

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printing cannot yet match industrial pharmaceutical manufacturing techniques in terms of the quality, repeatability, and throughput. As these challenges are gradually addressed, it is anticipated that SLA 3D printing could potentially begin to impact clinical practice, although its widespread adoption will require a huge attitudinal and vocational shift from pharmaceutical professionals. SLA has proven its initial utility in pharmaceutical research with many peer-reviewed reports demonstrating promising results. With further improvements in the technology and the materials the ability to fabricate yet more complicated drug-loaded constructs for additional diseases is to be expected.

3.7

Summary

SLA 3D printing of pharmaceuticals is a relatively new and burgeoning niche within the broader space of 3D printed pharmaceuticals and medical devices. Although the niche is in its nascent stage, there is an increasing number of papers appearing in the peer-reviewed literature. A simple PubMed search revealed 170 papers in the niche since 2010, with nearly 85% of these papers being published just in the last 5 years, showing the exponential growth of research activity in the area. However, the first focused original research paper was published only in 2016 (Wang et al. 2016). SLA 3D printing has been used to 3D print tablets containing a plethora of different drugs as well as to 3D print soft drug releasing devices. The high surface quality and accuracy of the technology offer key benefits for 3D printing pharmaceutical pills, although certain drawbacks such as lack of an extensive material library and tight quality control processes are hindering rapid progress. The recent advent of volumetric 3D printing promises the rapid fabrication of tablets, although key issues such as dimensional stability, material compatibility, and optimization of post-processing steps remain to be addressed.

References Alexander AE, Wake N, Chepelev L, Brantner P, Ryan J, Wang KC (2021) A guideline for 3D printing terminology in biomedical research utilizing ISO/ASTM standards. 3D Print Med 7:4– 9. https://doi.org/10.1186/s41205-021-00098-5 Awad A, Trenfield SJ, Goyanes A, Gaisford S, Basit AW (2018) Reshaping drug development using 3D printing. Drug Discov Today 23:1547–1555. https://doi.org/10.1016/j.drudis.2018.05.025 Bloomquist CJ, Mecham MB, Paradzinsky MD, Janusziewicz R, Warner SB, Luft JC, Mecham SJ, Wang AZ, DeSimone JM (2018) Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins. J Control Release 278:9–23. https://doi.org/10.1016/ j.jconrel.2018.03.026 Brambilla CRM, Okafor-muo OL, Hassanin H, Elshaer A (2021) 3dp printing of oral solid formulations: a systematic review. Pharmaceutics 13:1–25. https://doi.org/10.3390/ pharmaceutics13030358 Campbell I, Bourell D, Gibson I (2012) Additive manufacturing: rapid prototyping comes of age. Rapid Prototyp J 18:255–258. https://doi.org/10.1108/13552541211231563

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4

Selective Laser Sintering (SLS) in Pharmaceuticals Tukaram Karanwad, Srushti Lekurwale, and Subham Banerjee

Abstract

Rapidly developing and evolving rapid prototyping technologies and the emergence of 3D printable materials integrated with drug moieties have enormous potential in the customization of dosage forms required for patients. Feature-rich functionalities of solid dosage forms such as desired control over porous internal architecture, complex geometry, and wide varieties of possible shapes and size, which are very difficult to achieve with mass manufacturing, are now possible with Selective Laser Sintering (SLS) mediated rapid prototyping. SLS-mediated 3D printing technology is the powder bed fusion technology that provides control over the release pattern of the drug incorporated in the dosage form in terms of immediate or controlled as well as the sustained release of the drug. This can be easily achieved using appropriate matrix-forming agents from a wide range of processable polymers and fine-tuning of various process parameters. An added benefit of this powder bed fusion technology is that, it allows the fabrication of any solid oral dosage form in just a single step without use of any solvent, which turns this technique of rapid prototyping into green technology. Thus, the purpose of this chapter is to discuss basic fundaments of SLS, its potential pharmaceutical applications along with diverse processable materials, essential process parameters and their effect on SLS-mediated fabrication, setbacks for scale-up, regulatory consideration, and future aspects of SLS-mediated 3D printing in pharmaceuticals.

T. Karanwad · S. Lekurwale · S. Banerjee () Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals, https://doi.org/10.1007/978-981-99-2404-2_4

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Keywords

Selective laser sintering (SLS) · Additive manufacturing (AM) · Solid oral dosage forms (SODFs) · Pharmaceuticals

4.1

Introduction

Additive manufacturing (AM)/ 3D printing techniques have revolutionized various industries since their emergence in the 1980s. This rapid manufacturing technology was initially used globally with a wide range of applications in construction, automotive, and aerospace engineering (Alhnan et al. 2016; Shahrubudin et al. 2020). Later, researchers contributing to the biomedical and pharmaceutical fields were highly fascinated by the specific attributes of AM technology, which is the ability of personalization and customization, which has the ability to turn the biomedical and pharmaceutical industries toward personalized and highly precise healthcare products (Ventola 2014). Conventional pharmaceutical manufacturing of solid oral dosage forms (SODFs) has limitations in terms of time, cost, labor consumption, rigidity, and tediousness. However, the newly emerging field of AM has the potential to overcome these limitations, as it offers more flexibility in terms of the dose and geometry of the dosage form with desired drug release kinetics, which can fulfill the needs of patients on demand. These benefits parallel the provision of enhancing the safety and efficacy of the drug incorporated into the formulation (Warsi et al. 2018; Park et al. 2019). Currently, researcher are using 3D printing technology to fabricate pharmaceutical oral dosage forms and drug delivery devices for personalized medicine with different shapes, sizes, compositions, and release kinetics (Trenfield et al. 2018). Applications of 3D printing in pharmaceuticals globally attracted attention when the first pharmaceutical 3D printed product Spritam (levetiracetam) tablet based on ZipDose Technology was manufactured using binder jet platform technology by the USA based pharmaceutical company Aprecia Pharmaceuticals, which was approved by the Food and Drug Administration (FDA) in 2015 (Seoane-Viaño et al. 2021). Binder jetting is a powder-based technology in which a binder solution is deposited on a powder bed (Melnyk and Oyewumi 2021). However, other AM techniques have also been well explored in the pharmaceutical field, such as fused deposition modeling (FDM), where filaments are used as potential feedstock materials and work on the principle of extrusion (Mathew et al. 2020). Stereolithography (SLA), in which polymerization/solidification of photosensitive materials occurs selectively, is based on vat polymerization (Kafle et al. 2021). Selective laser sintering (SLS) is based on the principle of fusion of powder particles using laser-derived heat (Charoo et al. 2020; Awad et al. 2020a). Each technology has unique features and requires diverse feedstock materials, making it exceptional for numerous applications (Awad et al. 2021). These technologies are actively contributing to drug delivery applications and manufacturing of biomedical

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products, such as organs, tissues, artificial skin, and bone cartilage (Shahrubudin et al. 2020). SLS is more comparable to conventional tablet manufacturing by the powder press/compression phenomenon, as it also utilizes loose powder as a feedstock, and these powder particles are joined selectively at the end of the process, utilizing laser-derived heat to produce the desired 3D printed object (Lepowsky and Tasoglu 2018; Gioumouxouzis et al. 2019). The thermoplastic materials are required to sintered the 3D printed object. For consolidation or sintering of these thermoplastic polymers into a unique 3D printed object, SLS has different laser sources, such as carbon dioxide (CO2 ), fiber, diode, etc. (Kamsani et al. 2022). In SLS 3D printing technology, powder particles are fused together into a solid mass just before melting using a laser source, which is called sintering (Zhang et al. 2018). In the pharmaceutical field, researchers are exploring SLS technology of 3D printing for the fabrication of SODFs and other drug delivery devices through the sintering of drug-incorporated polymers. SLS 3D printing technology can fabricate complex structures without external support because in this powderbased technology, the unsintered powder acts as a support for the sintering of the object (Awad et al. 2021). Furthermore, the process parameters significantly affect the fabrication and features of 3D-printed objects (Awad et al. 2020a). These attributes provide opportunities for the use of SLS-based AM technology in the pharmaceutical field. This chapter focuses on the journey of SLS 3D printing technology in the pharmaceutical field, different SLS 3D printers explored for pharmaceutical dosage form fabrication, the principle of sintering, various challenges associated with the selection of materials and process parameters, setbacks of SLS in pharmaceuticals, and applications of SLS-mediated 3D printing technology in the pharmaceutical field with necessary and expected regulatory considerations.

4.2

History of SLS

In 1986, the first SLS 3D printer was invented by Dr. Carl Deckard and Dr. Joe Beaman at the University of Texas, Austin, USA (Juster 1994). The group decided to collaborate with Nova Automation (Fina et al. 2018a); as a result, Nova Automation became a DTM corporation in 1987 and manufactured SLS model 125. Subsequently, a production version of SLS technology, Sinterstation 2000, was introduced into the market in 1993 (Juster 1994). In 2001, Nanyang Technological University in Singapore developed a pharmaceutical application for SLS. During the same year, Leong et al. (2001) explored the possibility of fabrication of a porous polymeric matrix using SLS 3D printing technology at the first time, which could be used for drug delivery applications. The aim of this study was to fabricate porous matrices by controlling the porosity. In addition, laser power and scan speed were investigated to determine the resultant variations in drug penetration and pore morphology. Fine nylon powder was used as the matrix former, along with methylene blue as a model drug for the planned part

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build (cubical structures) process, using a Sinterstation SLS 3D printer. Mercury porosimetry was employed to ascertain the percentage porosity of the cubical parts. In vitro release demonstrated the accomplishment of a controlled release pattern of methylene blue through variation of selected SLS process parameters (Leong et al. 2001). Alterations in the design of drug delivery carriers and manipulation of the porosity of dense objects could help alter the characteristics of SODFs. The upcoming years have demanded variations in process parameters, which could help modulate drug delivery. Cheah et al. (2002) successfully fabricated cylindrical composite structures using the SLS platform technology for possible applications in drug delivery. The aim of this study was to design and build cylindrical structures with varying porosities, with a denser outer layer and a porous inner layer, which acted as a diffusion barrier layer and drug encapsulation center, respectively. Polyamide (PA) powder [Duraform™ (PA)] was used as a matrix former, and methylene blue was used as a model drug. The in vitro release demonstrated the ability of these composite structures to retard the model drug release in a simulated fluid (Cheah et al. 2002). Leong et al. (2006) successfully attempted to build porous microstructures that could be used as controlled drug delivery devices based on the aforementioned principle. They used couple of biodegradable polymers [Polycaprolactone (PCL) and poly (−L) lactic acid (PLLA)], and fabrication was done with the help of the Sinterstation 2500 SLS 3D printing system (Leong et al. 2006). In both studies, researchers investigated the effects of critical process parameters, such as laser power, laser scanning speed, and part bed temperature (print bed temperature) on printability (Cheah et al. 2002; Leong et al. 2006). After 2006, owing to the fact-based assumption that high-energy input in terms of lasers in SLS 3D printing technology may result in the degradation of drugs used during the fabrication of any dosage form using this technique, the role of SLS was restricted to tissue engineering scaffolds and other related biomedical applications. Thus, no single study has been conducted over an extended period of 10 years, related to the fabrication of drug-loaded SODFs. Fina et al. (2017) demonstrated the suitability of SLS-mediated fabrication of drug-loaded formulations (tablets), which they termed as printlets (Fina et al. 2017). All studies related to SLS-mediated fabrication of drug-loaded formulations using several pharmaceutical grade polymers are considered pharmaceutical applications of the SLS 3D printing platform. Since 2017, researchers have explored SLS AM technology in the field of pharmaceuticals. Thus, investigations by various researchers related to the pharmaceutical applications of SLS are summarized below in tabular format (Tables 4.1 and 4.2), along with a detailed explanation of the research outcomes obtained in each study.

Croscarmellose sodium, Kollicoat ® IR, Candurin NXT Ruby Red Kollidon VA 64, ® Candurin Gold Sheen, Magnesium aluminometasilicate, Silicon dioxide Normal maize starch

Isoniazid, Acepromazine

–

Indomethacin

Eudragit L100-55, ® Candurin Gold Sheen

Polymers and excipients Kollidon SR, ® Candurin Gold Sheen

Theophylline Anhydrous USP

Active pharmaceutical ingredients Acetaminophen

3D printed structures

Amorphous Solid Dispersions (ASDs) pellet

Printlets

Tablets

SODFs Tablets

Table 4.1 Various applications of SLS 3D printing in SODFs

Dissolution apparatus, Rheometer, Nuclear Magnetic Resonance (NMR), DSC, XRD, SEM

Characterization techniques Polarized Light Microscopy (PLM), Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction (PXRD), Wide-Angle X-ray Scattering (WAXS), Hot Stage Microscopy (HSM), Scanning Electron Microscopy (SEM), X-ray Micro-Computed Tomography (Micro-CT), Reverse Phase High-Performance Liquid Chromatography (RP-HPLC), USP- II Near-infrared spectroscopy, DSC, Thermogravimetric Analysis (TGA), PXRD, Digital Caliper, TBH 200, SEM, Micro-CT, UV-visible spectrophotometer Hardness tester, USP-II, SEM, Micro-CT, PXRD, DSC, Fourier Transform Infrared Spectroscopy (FT-IR), RP-HPLC, Ultra Performance Liquid Chromatography-Mass Spectrometer (UPLC-MS) DSC, PXRD, Micro-CT, Terahertz Time-domain Spectroscopy (THz-TDS)

(Santitewagun et al. 2022)

(Khuroo et al. 2022)

Trenfield et al. (2022a)

References (Giri and Maniruzzaman 2023)

(continued)

This version of the (Shahbazi et Sintratec Kit features al. 2022) a 2.3-watt blue diode laser (λ-445 nm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

Printers This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm))

4 Selective Laser Sintering (SLS) in Pharmaceuticals 129

Crospovidone, HPMC, Vivapharm E3, Mannitol ® Parteck M 200, Candurin Gold Sheen, Kollidon VA 64 Fine, Crospovidone NF, AEROSIL 200

Irbesartan

Tablets

PEG 4000, PEG 600, PEG 8000, PEG 10000, Eudragit EPO, Hydroxypropyl Methylcellulose (HPMC), Low-substituted Hydroxypropyl Cellulose (L-HPC), Carboxymethyl starch sodium, Croscarmellose sodium, Lactose, Tartrazine lake. Kollicoat IR, IR-absorbing dye Printlets (Tablets)

Indomethacin, Berberine hydrochloride

–

Poly(ethylene) oxide, Ethyl cellulose, Eudragit L 100–55, ® Candurin Gold Sheen

Caffeine, Ibuprofen

Hardness tester, Mercury Intrusion Porosimeter (MIP), SEM, FT-IR, DSC, DT apparatus, UV-Vis Spectrophotometer

DSC, FT-IR

Characterization techniques SEM, DSC, FT-IR, Hardness tester, USP-III, USP- IV, UV-Vis Spectrophotometer Multiparticulate Diffuse Reflectance Infrared Fourier units Transform Spectroscopy (DRIFT), PXRD, HPLC, Helium pycnometer Single and Surface tension and Melt rheology, multilayer ultraviolet (UV) absorption of printlets powders, Dissolution apparatus, UV-Vis Spectrophotometer

Active pharmaceutical Polymers and excipients SODFs ingredients Metronidazole Polyamide 12 (PA12), Sodium Printlets chloride

Table 4.1 (continued)

This version of Sinterit Lisa, features an IR/Red diode laser (5 W) (λ-808 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

Printers This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) Homogenized spot melting (HSM) printer Blue diode (λ-450 nm)

(Madžarevi´c et al. 2021)

(Lekurwale et al. 2022)

(Wei et al. 2022)

(Vasiljevi´c et al. 2022)

References (Kulinowski et al. 2022)

130 T. Karanwad et al.

Indomethacin

Indomethacin

Nifedipine

Paracetamol

Ibuprofen, Ibuprofen sodium

Itraconazole

Kollidon VA 64, ® Candurin Gold Sheen, Magnesium aluminometasilicate, Silicon dioxide

Kollidon VA 64, ® Candurin gold sheen, Sodium phosphate monobasic, Sodium hydroxide, Sodium chloride Kollidon VA 64, ® Candurin Gold Sheen

Hydroxypropyl cellulose (HPC)-SSL, HPC-SL, ® HPC-L, Candurin Gold sheen Kollidon VA 64, Succinic acid, Tartaric acid, Fumaric acid, Maleic acid, Malic acid Charcoal

Printlet (Tablet)

Printlet (Tablet)

Printlet (Tablet)

DSC, SEM, HSM, PXRD, DVS, USP-II, WAXS, Zetasizer nano ZS Hot melt extrusion (HME), Dino Lite Microscopy, PLM, SEM, Texture analyser (TA-XT2), XPRD, mDSC, FT-IR, Raman Mapping, HPLC, USP-II

UV-Vis Spectrophotometer, HPLC-MS, HPLC-UV/Vis mDSC, PXRD, VWR digital caliper

Morphologi G3s System, SEM, Micro-CT, PXRD, USP-II

DSC, FT-IR, PXRD, Thermo- gravimetric analysis (TGA), USP-II, UHPLC

SODFs

Printlet

XRPD, Near Infrared Spectroscopy (NIR), Raman spectroscopy, HPLC,

Printlets/discs

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

This version of Sharebot SnowWhite features a CO2 laser (14 Watt) (λ-10.6 μm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

(continued)

Thakkar et al. (2021c)

Thakkar et al. (2021a)

Thakkar et al. (2021b)

Kulinowski et al. (2021)

Gueche et al. (2021c)

Trenfield et al. (2022b)

4 Selective Laser Sintering (SLS) in Pharmaceuticals 131

Polyvinyl alcohol, Eudragit EPO, Eudragit RLPO, Polyethylene glycol, Carboxy methyl sodium, Ethyl cellulose, Hydroxypropyl methylcellulose, Kollicoat MAE 100P, Stearic acid Kollicoat IR, SuperTab 14 SD, ® Candurin NXT Ruby Red, Talc

Indomethacin, Tinidazole, Nifedipine, Astragalus polysaccharide, Metoprolol tartrate, Diclofenac sodium, Paracetamol, Ibuprofen

Lopinavir

Kollidon VA 64, Kollidon VA 64 (Fine), Duraform PA12

Polymer and excipients Kollidon VA 64

Paracetamol, Paracetamol Fine

Active pharmaceutical ingredients Paracetamol

Table 4.1 (continued)

ASDs Printlet (Tablet)

Multilayered Printlets

SODFs

SODFs SODFs

HPLC, USP-II, SEM, Micro-CT, FT-IR, DSC, XRD

XRD, DSC, USP-II, UV-Visible Spectrophotometer

SEM, Laser granulometry, FT-IR, DSC, XRPD, Size exclusion chromatography (SEC)

Characterization techniques XPRD, SEM, Sotax DT 150, FT-IR, UHPLC

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

Printers This version of Sharebot SnowWhite features a CO2 laser (14 W) (λ-10.6 μm) This version of Sharebot SnowWhite features a CO2 laser (14 W) (λ-10.6 μm) 3500, Jinke Trading, blue diode laser (λ-450 nm)

Hamed et al. (2021)

Yang et al. (2021)

Gueche et al. (2021d)

References Gueche et al. (2021a)

132 T. Karanwad et al.

ODTs

β-Cyclodextrin Cavamax W7, ® Kollidon VA 64, Candurin Gold Sheen, Mannitol (Parteck Delta)

Kollidon VA 64, Microcrystalline cellulose, Aluminum lake, Super Tab 14SD, Food Blue No. 1, Iron oxide, Sodium hydroxide and Monobasic potassium phosphate

Ondansetron Hydrochloride USP

Clindamycin palmitate hydrochloride

Printlet (Tablet)

Orodispersible Printlet (ODTs) (Tablet)

Polyprintlets

ASDs Printlet (Tablet)

Kollidon VA 64 ® Candurin Gold Sheen

Copovidone, Kollidon VA 64, FujiSil (Colloidal Silicon Dioxide), ® Candurin Gold Sheen, Monohydrate and dihydrate Sodium phosphate salts Polyethylene oxide (PEO) 100,000, ® Candurin Gold Sheen

Paracetamol

Amlodipine and Lisinopril dihydrate

Ritonavir

HPLC, USP-II, SEM, Micro-CT, FT-IR, DSC, XRD, Tablet hardness tester, Erweka friabilator USP-II, SEM, DSC, XRD, Micro-CT, FT-IR, NIR, HPLC

Reflectance NIR spectrometer, HPLC, XRD, TGA, Tablet hardness tester, Erweka friability tester Tablet hardness tester (TBH 200), SEM, USP-II

DSC, HME, WAXS, FT-IR, Silid-state Nuclear Magnetic Resonance (ssNMR), HPLC

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

(continued)

Mohamed et al. (2020)

Allahham et al. (2020)

Awad et al. (2020b)

Trenfield et al. (2020)

Davis Jr et al. (2021)

4 Selective Laser Sintering (SLS) in Pharmaceuticals 133

Eudragit RL, Eudragit L100-55, HPMC Vivapharm E5, ® Candurin Gold Sheen Kollidon VA 64, HPMC Vivapharm E5.

Paracetamol

Paracetamol

Paracetamol Ibuprofen

Kollidon VA 64, ® Candurin NXT Ruby Red, SuperTab 14 SD, Monobasic Potassium phosphate, Potassium hydroxide Kollicoat IR, Ethyl cellulose N7

Polymers and excipients Kollicoat IR, ® Candurin Gold Sheen

Diclofenac sodium

Active pharmaceutical ingredients –

Table 4.1 (continued)

Printlet (Tablet)

Printlet (Tablet)

Miniprintlet/Dual Miniprintlets

Printlet (Tablet)

SODFs Printlet (Tablet)

Digital caliper, Tablet hardness tester 200, SEM, Micro-CT, HPLC

DSC, TGA XRD, SEM, HPLC, UV-visible spectroscopy Near-infrared spectroscopy HPLC, Raman spectroscopy and mapping, XRPD

USP-II, UV-visible spectroscopy, FT-IR, SEM, Micro-CT, XRD

Characterization techniques Visual preference survey

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

Printers This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm) This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

Fina et al. (2018c)

Trenfield et al. (2018)

Awad et al. (2019)

Ali et al. (2019)

References Januskaite et al. (2020)

134 T. Karanwad et al.

Kollicoat IR, Eudragit RL, Eudragit L100-55, ® Candurin Gold Sheen. Polycaprolactone

Polycaprolactone

Polycaprolactone

Progesterone

Fluorouracil

Progesterone

Paracetamol

Multi-reservoir drug delivery system

Printlet (Tablet)

Tablet

Printlet (Tablet)

SEM, IR, UV-visible spectroscopy

IR and NIR Spectroscopy SEM, DSC, UV-visible spectroscopy

IR, DSC, SEM, XRD, Texture analyzer (TA), UV-visible spectroscopy, Dissolution apparatus

DSC, P-XRD, Digital caliper, SEM, Micro-CT, Tablet hardness tester, HPLC, USP-II This version of SLS printers features a CO2 laser (9 W) (λ-10.6 μm) This version of SLS printers features a CO2 laser (9 W) (λ-10.6 μm) This version of SLS printers features a CO2 laser (9 W) (λ-10.6 μm)

This version of the Sintratec Kit features a 2.3-watt blue diode laser (λ-445 nm)

Salmoria et al. (2012)

Salmoria et al. (2017a)

Salmoria et al. (2017b)

Fina et al. (2017)

4 Selective Laser Sintering (SLS) in Pharmaceuticals 135

Polymers and Excipients Polyethylene

Polyethylene

Polycaprolactone

Active pharmaceutical ingredients Progesterone, Fluorouracil

Fluorouracil

Ibuprofen

Implant

Waffles for implantable drug delivery

Drug delivery system Intrauterine device (IUD)

Table 4.2 Applications of SLS 3D printing in implantable drug delivery

XRD, SEM, TA, DMA, UV-Visible spectroscopy, Dissolution apparatus

IR, NIR, DSC, SEM, Texture analyzer (TA), UV-visible spectroscopy, Dissolution apparatus

Characterization techniques IR, DSC, SEM, Dynamic Mechanical analysis (DMA), HPLC, Dissolution apparatus

Printer This version of SLS printers features a CO2 laser (9 W) (λ-10.6 μm) This version of SLS printers features a CO2 laser (9 W) (λ-10.6 μm) This version of SLS printers features a CO2 laser (9 W) (λ-10.6 μm)

Salmoria et al. (2016)

Salmoria et al. (2017c)

Reference Salmoria et al. (2018)

136 T. Karanwad et al.

4 Selective Laser Sintering (SLS) in Pharmaceuticals

4.3

137

SLS Technologies

The enlisted (Table 4.3) and depicted (Fig. 4.1) SLS technologies from different manufacturing companies have varied laser power, laser wavelength, laser source, build volumes, and software which were explored for pharmaceutical applications. Among the aforementioned SLS 3D printers, only three laser sources were used for sintering the pharmaceutical SODFs. The results (Fig. 4.2.) depicted the percentage of exploration of SLS 3D printers based on the laser source used.

4.4

Working Principle of SLS

SLS 3D printer has generally composed of different parts, such as (1) powder reservoir/feed bed, storage tank for the thermoplastic polymer materials (feedstock), which holds the feeded powder material and provides a fresh powder layer to print bed for further sintering process; (2) build plate/print bed, a platform for the sintering of feedstock material to convert it into desired 3D structures layerby-layer; (3) a laser source, responsible for the sintering of powder materials; (4) galvano mirrors, provide directions to the laser beam for proper projection on the print bed; (5) a recoater, a roller that helps to spread fresh powder from the powder reservoir/feed bed to print bed with a constant layer thickness of each powder layer; and (6) an overflow bin, collecting chamber or tank for unsintered powder material (Awad et al. 2020a). Various parts of SLS 3D printer and it’s working principle are summarized in Fig. 4.3. The SLS 3D printing technique works in a stepwise process as follows:(1) Preheating/warm-up phase, which includes heating of the powder reservoir/feed bed to activate the feedstock to the processing temperature; (2) build phase, which is further divided into three operational sub-steps: (a) powder recoating, build plate/print bed lowers by the selected layer thickness followed by spreading of the powder layer of a particular thickness from the feed bed to the print bed with the help of a recoater. Excess powder material enters the overflow bin; (b) Energy input, laser beam guided by galvano mirrors is applied to the powder material available on the print bed and holds the powder material at the printing temperature; (c) consolidation, powder material present on a print bed is exposed to laser and consolidated to build the part on the print bed. The second step is repeated until the entire structure is fabricated or sintered. (3) The cooldown phase, unsintered powder material on both the feed and print beds was bought at room temperature along with the sintered object (Sivadas et al. 2021). Finally, the sintered objects were isolated, and loosely packed (unsintered) powder material present on the surface of the sintered object was removed manually using a brush or compressed air.

SLS 3D Printers Sintratec Kit 3500, Jinke Trading Sharebot SnowWhite Sinterstation 2500 Sinterit Lisa Formlabs Fuse 1 Natural Robotics VIT SLS Red Rock 3D

Laser type Diode (blue) Diode (blue) CO2 CO2 Diode (red) Fiber CO2 Diode (blue)

Laser wavelength (μm) 0.445 0.450 10.6 10.6 0.808 1.066 10.6 0.450

Laser power (W) 2.3 0.05–3.5 14 25–100 5 10 40 5

Table 4.3 List of SLS 3D printers explored for pharmaceutical applications Build volume (L × W × H) 110 × 110 × 110 N/A 100 × 100 × 100 N/A 150 × 200 × 160 165 × 165 × 300 250 × 250 × 300 180 × 180 × 180

Software Sintratec central N/A Slic3r SLS system Sinterit studio PreForm Web based (local) N/A

References Sintratec (2022) Yang et al. (2021) Sharebot (2022) 3D Systems (2022) Sinterit (2022) Formlabs (2022) Natubots (2022) Redrocksls (2022)

138 T. Karanwad et al.

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139

Fig. 4.1 Images of commercially available SLS printers (Sintratec 2022; Sharebot 2022; 3D Systems 2022; Sinterit 2022; Formlabs 2022; Natubots 2022; Redrocksls 2022)

Blue diode laser Red diode laser CO2 laser 18.2% 3%

78.8% Fig. 4.2 Demonstrates the percentage exploration of SLS 3D printers based on laser source used (Up to 2022)

Post-printing processing, such as polishing, coating, or surface finishing, generally enhances the mechanical strength and aesthetic value of a printed object (Charoo et al. 2020).

4.5

Advantages of SLS over other AM and Conventional Manufacturing (CM) Technologies

SLS could be superior to other 3D printing technologies, owing to its advantages over other 3D printing and CM technologies. It eliminates any pre-treatment stage

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Fig. 4.3 Principle of SLS

of raw materials (e.g., preparation of filaments in FDM or granulation in the case of tablet compression) and provides printlets in one step. SLS is a solventfree technique that is mainly applicable to drugs that are at risk of degradation due to hydrolysis and is safer because it reduces the risk of solvent toxicity; therefore, it could be a green technology. SLS can be used to sinter objects with a higher resolution owing to the precision of the laser. SLS offers a wide range of transformable materials such as plastics, polymers, ceramics, alloys, and metals, which are stable at high temperatures and laser exposure. The feedstock in the SLS batch could be processed and recycled to reduce waste generation. Additional excipients are not required in SLS (compared to the conventional method), which reduces toxicity and production costs. SLS helps to fabricate objects with the desired porosity and internal architecture; therefore, control over drug release can be achieved as per the required application. SLS fabricated an object by partial melting or sintering of the powder material, without using a solvent as a binding agent. SLS technology is more suitable for scale-up and mass production in industry than other 3D printing technologies. These are the reasons why SLS can be considered the most advanced, one of the latest, effective, and green technologies proposed for the fabrication of pharmaceutical SODFs (Allahham et al. 2020; Fina et al. 2018b; Awad et al. 2019; Riza et al. 2020).

4.6

Selection of Process Parameters for SLS

The process parameters involved in SLS must be identified to fabricate an SLSprinted dosage form with desired qualities. The energy density (ED) (J/mm3 ) is the amount of energy transmission per unit volume in the SLS, which determines the

4 Selective Laser Sintering (SLS) in Pharmaceuticals

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Fig. 4.4 Process parameters related to the SLS 3D printing technology

degree of sintering of an object. Four parameters influence this critical parameter: laser power (LP), scanning speed (SS), layer thickness (LT) (Brown et al. 2018), and hatch spacing (HS) (Dadbakhsh et al. 2016). The correlation between these parameters can be explained using the following equation (Gueche et al. 2021a): ED =

LP SS × H S × LT

These printing variables can strongly influence the properties of a sintered component, such as the porosity, mechanical strength, density, hardness, and surface roughness. Controlling porosity provides control over the release pattern. Thus, researchers are utilizing these process parameters, which are tunable in various SLS 3D printers, to obtain the desired characteristics of sintered 3D objects (Okafor-Muo et al. 2020). The following process parameters strongly affect the features of the object as mentioned above (Fig. 4.4).

4.6.1

Preheating and Printing Temperature

The preheating temperature plays a vital role in the sinterability of the material as well as the consolidation and accuracy of the printed object. The preheating effect modulates the preheating temperature in terms of the nature of the polymer. In case of amorphous polymers, the preheating temperature should be near the glass transition temperature, but less than the glass transition temperature. In case of a crystalline polymer, the preheating temperature should be near the onset melting temperature of the polymer but less than the melting temperature. If the preheating temperature exceeds the glass transition temperature and melting temperature, the flow of powder from the feed bed to the print bed could be improper owing to the loss in the mobility of particles, finally generating a caking and bonding effect of the powder in the feed bed (Shi et al. 2021). The printing temperature indicates two different temperatures: a) the feed bed temperature and b) the print bed temperature. The feed bed temperature was defined as the temperature of the powder-holding tank. This temperature aids in

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the preheating of the powder, which ultimately reduces the amount of laser energy required for sintering, the thermal gradient between the sintered and unsintered materials, and the thermal expansion of the feedstock caused by the laser to improve the sintering process (Goodridge et al. 2012). The print bed temperature refers to the surface temperature, which is the superficial temperature of the powder present on the build platform/print bed (Awad et al. 2020a). Both feed bed and print bed temperatures are crucial for proper sintering (Funkhouser et al. 2020). The previously sintered layer can experience curling if a more significant temperature difference is present between the scanned and newly spread layers (Goodridge et al. 2012). Thermoplastic powder polymers, which are either crystalline or amorphous, are used as raw materials. Optimum and different printing temperatures are required for sintering both types of polymers. For amorphous polymers, the required temperature is slightly above the glass transition temperature (Tg ). For crystalline polymers, the required temperature is slightly lower than the melting temperature (Tm ) (e.g., 3– 4 ◦ C) (Goodridge et al. 2012). For mixtures and semi-crystalline materials, the required temperature is close to the glass transition temperature (Tg ) calculated using the simple fox equation (Fina et al. 2018a). 1 W2 W1 + = Tg1 Tg2 Tg W1 and W2 are the weight fractions of the respective polymers, and Tg1 and Tg2 are the glass transition temperatures of the individual polymers.

4.6.2

Laser Power

The SLS instrument comprised of different parts, of which, the laser is the most crucial part of the printer. Diverse SLS printer models have various types of lasers, such as Nd: YAG, CO2 , CO, fiber, and diodes. These various types of lasers have different wavelengths and powers. An optimum laser wavelength is required for sintering diverse materials owing to their optical characteristics. For example, thermoplastic materials are sintered superiorly in the presence of high wavelength (Awad et al. 2020a; Awad et al. 2021). According to the applications and materials, an optimized laser power and scanning speed are essential (Leong et al. 2006). However, numerous materials cannot absorb laser energy because of their laserabsorbing capacity of a particular material at a particular wavelength. In this case, an external laser-absorbing agent is required (Awad et al. 2020a; Awad et al. 2021), as discussed in detail in Sect. 8.2. The effect of laser power on the strength of the object was not as significant as that of the hatch spacing and scan speed. However, it affects the porosity of an object (Brown et al. 2018). In addition, the dimensional accuracy of sintered parts depends on the optimal laser power (Hou et al. 2021). As the laser power employed for the SLS-mediated fabrication increases, the porosity of the printed object decreases.

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This phenomenon can also be confirmed by X-ray micro-computed topography (micro-CT) analysis (Fina et al. 2018a), as well as by observing the increased fusion of particles in scanning electron microscopy (SEM) analysis of objects printed at various laser powers (Cheah et al. 2002; Leong et al. 2006). An increase in laser power improves printing efficiency, but decreases printing accuracy (Yang et al. 2021). The porosity of sintered objects is strongly correlated with drug release. Thus, Yang et al. (2021) employed a lower laser power (1.0 W) for the SLSmediated fabrication of immediate release formulations and higher laser power (1.75 W and 3.15 W) for sustained-release formulations (Yang et al. 2021).

4.6.3

Laser Scanning Speed

The scanning speed of the laser indicates the rate at which the laser beam bombarded the powder surface directly. The laser power is not tunable in some SLS printer models; hence, adjustment of the laser scanning speed is the best choice for optimization of the laser energy employed for sintering. The laserscanning speed is directly correlated with the porosity and printing time of the printed object. When the laser scanning speed is lowered, the interaction of the laser with the powder material present on the build plate/print bed increases, thereby reducing the porosity of the sintered object owing to the increased SLS-mediated consolidation/densification and longer printing time, and vice versa (Cheah et al. 2002; Leong et al. 2006; Thakkar et al. 2021a). Fina et al. (2018) observed that printlets sintered at higher scan speeds received less energy input than those sintered at lower scan speeds. Thus, they were less heavy and less dense because of the smaller number of necks formed. In addition, it was observed that they had less mechanical strength in terms of the breaking force and higher % open porosity. The drug release rate increases as the scanning speed increases (Fina et al. 2018c). Hamed et al. (2021) compared SODFs printed at various laser scanning speeds in terms of printing time, amorphization achieved, voids, and dissolution rate. Printlets fabricated at higher scan speeds required less printing time and showed less amorphization, more voids, and an increased drug dissolution rate than printlets fabricated at a lower scanning speed (Hamed et al. 2021). The optimal scanning speed helps maintain the dimensional accuracy and processing efficiency for the completion of object fabrication (Hou et al. 2021).

4.6.4

Hatch Spacing

The hatch spacing, also known as the line offset, is the distance between two consecutive scanning vectors. Therefore, a short hatch spacing resulted in better energy transfer (Gueche et al. 2021b). This improved energy transfer increases the sintering and printing quality; however, it also increases printing time. The distance between two vectors is lengthier, which lowers the quality of printing, affects the features of the printed object, and reduces printing time. The hatch spacing is too

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large, which means that an object cannot sinter and has low mechanical strength. Therefore, an optimum hatch spacing is required to sinter the desired object (Awad et al. 2020a). Davis et al. (2021) studied the effect of hatch spacing on the fabrication of an ASDs. Based on experimental trials, it was concluded that if the hatch spacing is too large, the object cannot be printed, and the ASDs cannot be fabricated (Davis Jr et al. 2021). There is a great deal of importance in the hatch distance, which is related to parameters such as the porosity and surface roughness. An imperfect bond forms between the individual paths when the hatch distance is greater than the path width. When the hatch distance equals the path width, an imperfect melt pool is created in a similar manner (Halama et al. 2022).

4.6.5

Layer Thickness

The layer thickness is essential for sintering of 3D printed objects via SLS. The layer thickness refers to the thickness of the fresh powder layer spread on the print bed from the feed chamber/feed bed using a recoater. The Z-axis of the printer was lowered according to the layer thickness, and the recoater rolled out the powder from the feed bed chamber to the print bed. The layer thickness also affects the printlet resolution. The layer is thinner, which means that the resolution of the printed object is high; however, this also increases fabrication time. A thicker layer results in lower resolution of the printed object, which decreases the printing time. An optimum layer thickness is required for sintering a desired object (Awad et al. 2020a). This geometric deviation is known as the “staircase effect” and is associated with the thickness of the powder layer and appears on the side walls of the built parts. During the building process, the thickness of the layers determines the resolution of the sidewall surface. Thinner layers result in a higher level of surface quality but also prolong the manufacturing process (Kozak and Zakrzewski 2018).

4.7

Powder Properties Crucial for Printability in SLS

4.7.1

Particle Size and Shape

The particle shape and size plays vital role in the sintering of printed objects. An optimum particle morphology is required to achieve sintering of the desired object. Smaller particles hamper flow owing to electrostatic forces and form clusters. Larger particles entail additional energy to sinter and have low mechanical strength owing to their larger vacant spaces (Awad et al. 2020a). There has been research conducted by Dadbakhsh et al. (2016) on the effect of particle size and shape on the processability of SLS and the mechanical properties of TPO elastomers. Based on the experimental results, it was concluded that smaller particles require a higher temperature for consolidation than coarser particles, resulting in a denser

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object. However, the DSC profiles were the same for both coarse and fine particles (Dadbakhsh et al. 2016). The irregular particle shapes hinder the flowability, which means unequal distribution of the laser energy, and hence, uneven sintering of the desired object. The particles should have a spherical shape and an acceptable particle size distribution (58–180 μm) for a homogenous energy distribution and sintering (Awad et al. 2020a).

4.7.2

Flow Properties

Hausner’s ratio is the ratio of the tap and bulk densities of the powders and determines the flowability of the powder material. Determination of the flowability of the powder used as SLS feedstock material is essential to avoid spreadability issues of feedstock during layer formation with the help of a moving recoater. Powders with a Hausner’s ratio should typically be less than 1.25 to provide the high flowability required for SLS (Schmid et al. 2013).

4.8

Material Selection for the SLS

4.8.1

Thermoplastic Polymers

In general, thermoplastic polymers are used to consolidate 3D-printed objects using SLS in the pharmaceutical field. Researchers initially explored amorphous polymers, such as polycarbonates, for SLS-mediated part building, which resulted in a high resolution and dimensional accuracy of the printlet with respect to the provided computer-aided design (CAD). However, the drawbacks of polycarbonate printlets are their low mechanical strength and robustness of the builded part (Awad et al. 2020a). Semi-crystalline engineering polymers, such as PA, are considered the best-suited polymers for SLS-mediated manufacturing in the engineering industry because of their unique properties, such as optimum processability, good mechanical strength, and thermal stability. In addition, PA can consolidate high-density objects (Salmoria et al. 2011); owing to these properties, different SLS manufacturing companies provide this polymer with a 3D printer. For various pharmaceutical applications, researchers have explored numerous thermoplastic polymers such as PCL (Leong et al. 2006; Salmoria et al. 2016, 2017a), PLLA, high-density polyethylene (HDPE), polylactic acid (PLA), polymethylmethacrylate (PMMA), polyurethane, poly(ether ether ketone) (PEEK), and polyvinyl alcohol (PVA) (Awad et al. 2020a). Currently, researchers are exploring different pharmaceutical grade polymers for their application as matrix formers in the SODFs as listed in Table 4.1.

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Laser Absorbing Agent

The source of the thermal energy utilized for sintering is the laser, the feedstock used for sintering must have a laser light-absorbing capacity. PA resin generally shows high laser absorption ability; thus, there is no need for any specific laserabsorbing agent when PA is used as feedstock for SLS-mediated sintering. In case of pharmaceutical grade thermoplastic polymers, a laser-absorbing agent is required to absorb the laser and radiate the heat generated in the feedstock material (Charoo et al. 2020). For SLS 3D printers containing a blue diode laser source (445 nm ® wavelength), Candurin has been successfully employed by various researchers ® to enhance laser absorption. Candurin is a metallic colorant and is available in ® two forms: Candurin Gold Sheen (3%) (Trenfield et al. 2018; Awad et al. 2020a; Fina et al. 2017; Allahham et al. 2020; Thakkar et al. 2021a; Trenfield et al. 2020) ® and Candurin NXT Ruby Red (Hamed et al. 2021; Khuroo et al. 2022; Ali et al. 2019) used for SLS-mediated 3D printing using various pharmaceutical grade thermoplastic polymers. ® In addition to Candurin many other laser-absorbing agents have been used as aids in SLS-mediated sintering. A 1.16% w/w Food Blue No.1 aluminum lake and 0.16% w/w iron oxide were successfully used as laser-absorbing agents for a 3D printer comprising a blue diode laser (Mohamed et al. 2020). Yang et al. (2021) studied the effects of various photoabsorbers on the SLS printability. Different pigments (brilliant blue, cocaine, and tartrazine) and lakes (cocaine and tartrazine) were mixed at a constant concentration (0.2% w/w) with RL powder, and the SLS printability was compared in terms of surface smoothness and mechanical strength. Tartrazine lake was found to be the optimal photoabsorber for RL powder. In continuation of this study, researchers have also analyzed the effect of various concentrations of tartrazine lakes on RL powder. They considered H and Ho as indicators of printing accuracy and energy conversion efficiency, respectively. As the tartrazine lake concentration increased from 0.2% to 0.4%, the printing efficiency increased, but a simultaneous decrease in printing accuracy was observed owing to over sintering. This study was performed using an SLS 3D printer with a blue diode laser (Yang et al. 2021). Kulinowski et al. (2021) fabricated highdose paracetamol tablets using powdered charcoal (5%w/w) as a laser-absorbing agent, and the SLS 3D printer used had a blue diode laser (Kulinowski et al. 2021). Subsequently, Lekurwale et al. (2022) sintered 3D printlets using an SLS 3D printer equipped with an IR/red diode laser. A novel IR-absorbing agent was combined with Kollicoat IR, which is a thermoplastic polymer, at various concentrations. The material was sintered at a dye concentration of 1.25%w/w after attempts to sinter the feedstock into suitable printlets at lower dye concentrations (0%, 0.04%, and 0.6%) (Lekurwale et al. 2022).

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Pharmaceutical Applications of SLS

Salmoria et al. (2012) determined the effect of the concentration gradient used during the manufacturing of the diffusion-based drug delivery profile of an SLSmediated drug delivery device (DDD). Two reservoir-type DDD have been developed using PCL. Two types of controlled drug-release devices were designed: the first with a reservoir wall made up of only PCL polymer, and the other with polycaprolactone and 15% progesterone. The drug release kinetics for both reservoirs were zero-order, showing linear release over time. This study confirmed that it is possible to construct a reservoir-type DDD based on the principle of functional gradient for controlled drug release (Salmoria et al. 2012). In 2017, for the first time in the pharmaceutical field, Fina et al. (2017) fabricated the oral drug-loaded product using two thermoplastic pharmaceutical grade excipients: Kollicoat IR and Eudragit L100–55. At three different concentrations (5%, 20%, and 35%), paracetamol as a model drug was incorporated into the six different printed formulations (Fig. 4.5). Authors have analyzed the drug release pattern of the formulation and verified the adaptability of the SLS 3D printer in the pharmaceutical field. Kollicoat IR showed a pH-independent release pattern, whereas Eudragit L100–55 showed a pH-dependent release pattern. Additionally, the study concluded that SLS-based AM technology could be useful in the pharmaceutical field (Fina et al. 2017).

Fig. 4.5 Printlets shown the percentage of paracetamol combination with the respective polymers at upper row, starting from left to right 1) Paracetamol (5%) with Kollicoat IR, 2) Paracetamol (20%) with Kollicoat IR, 3) Paracetamol (35%) with Kollicoat IR, at lower row, starting from left to right (1) Paracetamol (5%) with Eudragit L100-55, (2) Paracetamol (20%) with Eudragit L100-55, (3) Paracetamol (35%) with Eudragit L100-55. Adapted with permission from (Fina et al. 2017)

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Salmoria et al. (2017) prepared an implantable tablet containing PCL/fluorouracil (FU) using the SLS 3D printing technology. As a result of variation in laser power, mechanical strength and drug release pattern were varied. This study found that when the laser power (3 W to 7 W) was increased, all sintered formulations showed better coalescence with a higher degree of sintering, owing to greater neck formation. In addition, they observed that the initial burst release of the drug (FU) may be due to its aqueous solubility, followed by controlled release. This phenomenon is beneficial for treating cancer owing to bursts, followed by the accumulation of FU drug molecules at the tumor site (Salmoria et al. 2017a). In the upcoming year, Fina et al. (2018) fabricated cylindrical and gyroid lattices and structured printlets using SLS 3D printing technology with four different pharmaceutical grade thermoplastic polymers: Eudragit L100–55, polyethylene glycol, Eudragit RL, and ethyl cellulose N7 (Fig. 4.6). This study aimed to check the applicability of SLS 3D printing technology for the prototyping of different structures and to check the release of the drug from different polymers owing to the change in the design, while keeping the composition fixed. This study also altered the laser scanning speed, which is an important process parameter in SLS 3D printing. Based on the variation in the process parameters, they observed variation in the porosity of the printlets, which directly affected the drug release pattern of the structured printlets. This phenomenon occurred because of the varied interaction time between the powder particles and the laser. The in vitro dissolution resulted in

Fig. 4.6 Images represented that (a) cylindrical printlets with different polymers such as polyethylene oxide (PEO), Eudragit L100 (EUD L), ethyl cellulose (EC), and Eudragit RL (EUD RL), and (b) cylindrical printlets with different polymers such as polyethylene oxide (PEO), Eudragit L100 (EUD L), ethyl cellulose (EC), and Eudragit RL (EUD RL), Adapted with permission from (Fina et al. 2018b)

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the release of the drug from the fabricated gyroid lattice-structured printlets using the four different polymers, which was faster than the cylindrical printlets owing to the increase in the surface area of the gyroid lattice in the dissolution media. Another vital observation of this study was the successful fabrication of the designed structures owing to the precision and accuracy of the laser (Fina et al. 2018b). The same author’s team (2018) investigated the applicability of an SLS 3D printer for prototyping ODTs. In this study, thermoplastic pharmaceutical excipients, such as Kollidon VA 64 and HPMC Vivapharm E5 were used with paracetamol as a model drug. Using observations from a previous study, the authors varied the laser scanning speed for sintering ODTs. The results showed that when the laser scanning speed was increased, the open and closed porosities increased, resulting the increased release of the drug from the printlets for all six formulations. They observed that the disintegration time of sintered printlets using Kollidon VA 64 with the highest laser scanning speed (300 mm/s) was 4 s. Hence, the SLS 3D printer is feasible for fabricating ODTs by varying the process parameters (Fina et al. 2018c). To explore the feasibility of SLS 3D printing in pharmaceutical fabrication, Trenfield et al. (2018) prepared different printlets with different shapes and a high drug loading of up to 40% w/w (Fig. 4.7). These printlets were assessed using non-destructive analytical tools such as process analytical techniques, Raman confocal microscopy, and portable NIR spectroscopy. In this study, up to 40% w/w paracetamol was loaded into the printlets, and the pharmaceutical grade thermoplastic polymer Eudragit L100-55 was used as the polymer matrix. The

Fig. 4.7 Represents the different shape of dosage forms with the maximum 40% drug loading. Adapted with permission from (Trenfield et al. 2018)

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results were corroborated using sophisticated destructive analytical tools, such as PXRD and HPLC analyses. Hence, this study concluded that a non-destructive analytical tool could be used to expedite the characterization of 3D printed SODFs (Trenfield et al. 2018). To continue this study, the same research group (2020) prepared polyprintlets containing two different drugs, amlodipine and lisinopril, at various therapeutic concentrations. Subsequently, the drug content was evaluated using a non-destructive portable NIR spectrometer. The first calibration curve was plotted using pure 1–5% w/w amlodipine and pure 2–10% w/w lisinopril; the regression values were found to be (R2 = 0.997, 0.991), after which the accuracy and specificity were calculated to be within the acceptable range. Finally, the results obtained for drug content via HPLC and NIR spectroscopy were compared, and no significant difference was observed in the drug content. The study concluded that the non-destructive tool could analyze the contents of two drugs in 3D printed SODFs (Trenfield et al. 2020). SLS 3D printing technology was extensively explored in 2019 and 2020, with additional advantages. Awad et al. (2019) prepared miniprintlets and dual miniprintlets with diameters of 1 and 2 mm, respectively, with a modified release. In this study, they used two pharmaceutical grade polymers: (1) Kollicoat IR was used as an immediate-release polymer and (2) Ethyl cellulose was used as a sustainedrelease polymer. These miniprintlets and the dual miniprintlets exhibited controlled drug release. The SEM images of the miniprintlets and dual miniprintlets show the sintering morphology with a single polymer and dual polymers (Fig. 4.8) (Awad et al. 2019). Process variables are the vital components of each technology. This affects printlet quality and its different characteristics. Ali et al. (2019) studied the effects of the process parameters on the quality of prototypes (printlets). The authors used the Box-Behnken response surface methodology to assess the effect of the process parameters on printlet quality. Laser scanning speed, printing chamber/print bed temperature, and lactose monohydrate concentration were selected as the process variables. The hardness, dissolution, disintegration, and weight variation were used to assess the quality of the printlets. Based on this study, they found that the variation in process parameters was affected on the characteristics of the printlets (Ali et al. 2019). Mohamed et al. (2020) conducted a similar study using a Box-Behnken design. The authors found that the process variable affected the quality of the printlets (Mohamed et al. 2020). In the upcoming year, Allaham et al. (2020) prepared an SLS-mediated 3D printed ODTs containing an ondansetron-cyclodextrin complex. The complex was first prepared, and mannitol was added as a diluent. The fabricated ondansetron ODTs was compared with the same ondansetron-containing marketed ODTs formulation. Both formulations disintegrated within approximately 15 s, and 90% drug release was observed after 300 s. This might be owing to the maximum open and closed pore formation in both formulations, which was assessed by using the micro-CT (Fig. 4.9). Based on these results, the authors concluded that SLSmediated 3D printing technology was feasible for fabricating ODTs formulations, which were similar to the marketed ODTs formulation. An additional role of SLS 3D printing is to customize the dose according to patient needs (Allahham et al. 2020).

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Fig. 4.8 SEM images of the (a) miniprintlets and (b) dual miniprintlets, blue region indicates the Kollicoat IR region, and yellow region indicates the ethyl cellulose region (Awad et al. 2019)

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Fig. 4.9 X-ray micro-CT images of the formulation I and formulation II (Allahham et al. 2020)

For the first time in pharmaceuticals, ODTs formulations with Braille and Moon patterns were sintered using SLS-mediated 3D printing technology (Fig. 4.10) for a patient with visual impairment by Awad et al. (2020) The purpose of the formulation was for the braille and moon patterns on the surface of ODTs to be readable to blind patients. The sintered ODTs formulations disintegrated within 5 s. Despite this immediate release, ODTs exhibit optimal mechanical strength (Awad et al. 2020b). Since 2021, the SLS AM technology has been widely explored in the pharmaceutical field. In the same year, Dravis et al. (2021) prepared ASDs printlets using SLS 3D printing technology which is a single-step process. In this study, ritonavir was used as the model drug, and copovidone was used as the ideal polymer. The author attempted to develop a formulation with different ratios of ritonavir and copovidone and varied process parameters. The main aim of this study was to evaluate the impact of the process parameters with an optimum range for the successful preparation of ASD formulations. Based on this study, they concluded that the selected parameters played a vital role in the preparation of ASDs in ritonavir-containing SODFs. Deviations from the optimized parameters led to batch failure. In addition, they reported that ASDs augmented the 21-fold increase in solubility. Finally, SLS 3D printing technology was feasible for formulating ASDs of ritonavir-copovidone, with a drastic increase in drug release (Davis Jr et al. 2021). Hamed et al. (2021) formulated an ASDs for lopinavir using an SLS-mediated AM technology. The purpose of this investigation was to compute the crystalline fraction of lopinavir using the XRPD-chemometric model and to prepare an efficacious ASDs. In this study, 25–50% lopinavir concentration was used with

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Fig. 4.10 SLS-mediated 3D printlets with different shapes having the moon and braille pattern on the surface (Awad et al. 2020b)

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a variation in the laser scanning speed of 75–100 mm/s. A chemometric model was developed using principal component analysis (PCA) and partial least squares (PLS). These results indicated that the drug percentage was not affected by the crystallinity of lopinavir, but the laser scanning speed affected the crystallinity of the drug. The authors also mentioned that SLS 3D printing technology has an advantage over HME for the preparation of ASDs, owing to the single-step process (Hamed et al. 2021). Pharmaceutical grade excipients and drugs have not been extensively explored for the preparation of SODFs using SLS-mediated rapid prototyping technology. Based on this, Yang et al. (2021) selected different frequently used pharmaceutical grade excipients and drugs and assessed their printability. In addition, the authors investigated the release behavior of selected immediate and sustained-release polymers. The study showed that yellow-colored drugs could be printed because the drugs were able to absorb the 450 nm wavelength of the laser. However, the white-colored drugs were unable to absorb the 450 nm wavelength of the laser. Additional colored dyes were tested for the printing of white-colored drugs via mixing with each other; however, tartrazine dye could absorb the laser at the optimum concentration. Finally, all drugs showed printability with the different pharmaceutical grade polymers with varied ratios. In addition, the effects of the polymer, drug, and process parameters were assessed, resulting in a collective effect on printability and release patterns (Yang et al. 2021). Gueche et al. (2021) sintered the SODFs of paracetamol and Kollidon VA 64 using a CO2 laser. The CO2 laser has a 10.6 μm wavelength, which is the highest power laser among all the SLS-mediated printers used for the sintering of SODFs. The authors assessed the feasibility of using a CO2 laser for sintering the SODFs. Two grades of polymer (Kollidon VA 64 and Kollidon VA 64 fine), and two grades of drug (paracetamol and paracetamol fine) were used to sinter SODFs. The sintered SODFs were compared with Duraform PA12, a polymer frequently used for sintering various prototypes. In the pharmaceutical field, the authors successfully fabricated SODFs with pharmaceutical grade polymers, without adding a laser-absorbing material. In addition, the results indicated that the drug was not degraded despite the higher laser power, as confirmed by the UHPLC analysis. Hence, CO2 laserembedded printer is also feasible for sinter SODFs using the process parameters, which provide customization of the dosage forms according to patient needs. In addition, thermosensitive drugs may be degraded owing to high laser power, which needs to be confirmed using analytical tools (Gueche et al. 2021d). To continue the above study, the same team (2021) evaluated the effects of process parameters using the QbD approach. In this study, four vital process parameters were selected such as the scan speed, heating temperature, layer thickness, and laser power. The obtained results indicated that the optimum heating temperature is important for the sinterability of solid oral forms, owing to the curling effect of the sintered layers, which arises due to an undesired heating temperature range. In addition, the authors found that the remaining three parameters were critical and ultimately affected the sinterability of the formulation and the curling of the sintered layer (Gueche et al. 2021a). The foremost concern in the pharmaceutical field is that more than 40% of the drugs face solubility related issues. Thakkar et al. (2021) prepared

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Fig. 4.11 HME based granules embedded, sintered 3D printlets. Adopted with permission from (Thakkar et al. 2021c)

granules using HME to enhance the solubility of indomethacin, a poorly soluble drug. The prepared granules were analyzed using a UV-visible reflectance probe for continuous assessment of the amorphous form of the drug. Then the granules were mixed with the pharmaceutical grade thermoplastic polymer Kollidon VA 64. The blend was subjected to fabrication of the printlets via SLS-mediated 3D printing technology, which resulted in successful sintering of the 3D printlets (Fig. 4.11). The three prepared components (granules, blends, and sintered printlets) were characterized using conventional evaluation techniques and advanced solid-state characterization tools. The results indicated that the flow properties of the blend increased owing to the preparation of the granules, which improved the sinterability of the printlets. In addition, the drug was converted into an amorphous form owing to granulation; hence, the solubility of the drug was enhanced (Thakkar et al. 2021c). The process parameters significantly affect the sintering and quality of the printlets. Thakkar et al. (2021) assessed the effects of the drug particle size and laser speed on the sintering of ASDs printlets using SLS 3D printing. They used an indomethacin crystalline drug with a particle size of more than 50 μm and HME-extruded granules of indomethacin with a particle size of less than 5 μm. The prepared physical mixture of the drug and the polymer matrix was sintered at various scan speeds (50, 75, and 100 mm/s). Characterization was performed using an analytical tools, and amorphization of the drug was assessed at various process parameter variations. The authors found that indomethacin particle size and scan speed had a significant effect on the sintering of ASDs (Thakkar et al. 2021a). The laser of a particular wavelength and temperature used in the SLS process might result in the degradation of photosensitive drugs. Thakkar et al. (2021) studied the impact of the process parameters and composition of the formulation on the quality of sintered 3D printlets and assessed solid-state changes and degradation of the drug. Nifedipine was selected as the model drug, ® and Kollidon VA 64 was selected as the thermoplastic polymer with Candurin

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Fig. 4.12 Ferromagnetic nanoparticle embedded, SLS-mediated 3D printlets with the variation of the Laser scanning speed and hatch spacing (Zhang et al. 2023)

Gold Sheen, a laser-absorbing material. A preliminary study suggested that the laser speed, laser-absorbing material concentration, and surface temperature were independent variables. The Box-Behnken design has resulted in the assessment impact of the surface temperature on degradation, crystallinity, and solid-state transformation (Thakkar et al. 2021b). Zhang et al. (2021) fabricated carbonyl iron (ferromagnetic nanoparticles)-embedded SLS-mediated 3D printlets (Fig. 4.12). In this novel experiment, isoniazid was used as a model drug, Kollidon VA 64 as ® the polymer, Candurin gold sheen as the photoabsorbing material, and carbonyl iron was mixed to accelerate the consolidation of the printlets and release of the drug. Ferromagnetic nanoparticle may play three important roles. This will help in sintering owing to its laser absorption ability, accelerate drug release in the presence of a magnetic field from the printlet, and fulfill the daily requirements of iron. Subsequently, the process parameters were varied to optimize the process. In conclusion, the incorporation of ferromagnetic nanoparticles improved the sintering and release rates of the drug (Zhang et al. 2021). Kulinowski et al. (2021) sintered high-dose-loaded printlets using an SLS 3D printing platform. Paracetamol (95%) was used as the model drug, and charcoal (5%) was used as the laser-absorbing material. The results showed that a large

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number of drug-containing printlets could be fabricated with a modified release profile via process parameter variations (Kulinowski et al. 2021). The combination of material properties and process parameters played a crucial role in the sintering of the SODFs and drug release pattern. Gueche et al. (2021) sintered a solid dosage form using dicarboxylic acids and copovidone. Dicarboxylic acid was used as the plasticizer to minimize the printing temperature. Ibuprofen acid and ibuprofen sodium salt were used to assess the plasticizing effects of different drugs. The plasticizing effect was analyzed using DSC, which is a promising thermal analysis tool. The authors found that dicarboxylic acid improved the plasticizing effect, which reduced the heating temperature required for the fabrication of solid oral forms of Kollidon VA 64 and model drugs (Gueche et al. 2021c). Madžarevi’c et al. (2021) applied the decision tree model as a data-mining tool to assess the effect of energy density and various formulation factors on the SLS-mediated printability of irbesartan tablets. Authors obtained 80% accuracy from a decision tree model to determine the correlation between formulation factors, energy density, and SLS printability. It was found that the amount of crospovidone and energy density applied during printing mostly affected the SLS printability. Energy density had a positive effect on the weight and disintegration time of the printed tablets. DSC confirmed that the amorphization of irbesartan was achieved during printing. The authors reported that laser scanning speed and energy density mostly affected the physical characterization of tablets and had negligible effect on drug release (Madžarevi´c et al. 2021). Later, Trenfield et al. (2022) successfully explored SLS as a single-step process for producing ASDs using the BCS class II drug itraconazole (20% w/w) along with various grades of HPC, such as HPC-SSL, HPC-SL, and HPC-L. In this study, researchers initially analyzed the conversion of the drug into an amorphous form using the XRPD technique, followed by non-destructive evaluation of the amorphous solid content in the itraconazole-loaded formulation both qualitatively and quantitatively using process analytical technology (PAT), including Raman and NIR spectroscopy. A comparison of sinterability between the grades of the HPC polymer used was performed based on bulk characterization (Trenfield et al. 2022b). Khuroo et al. (2022) studied the significance of formulation and SLS-related process parameters on rapidly dissolving isoniazid printlets through detailed analysis of their physicochemical properties, stability, and pharmacokinetics of fabricated printlets. As a result of this investigation, laser scanning speed was found to be the process parameter that mostly affected the weight, breaking force, and disintegration time of printlets. The oral bioavailability of these SLS-mediated 3D printlets was identical to that of compressed tablets (Fig. 4.13) (Khuroo et al. 2022). Kulinowski et al. (2022) observed that pharmaceutical grade polymers explored as matrix former for SLS 3D printed SODFs encountered practical issues like poor mechanical strength. They used carbon-stained PA12 to fabricate composite printlets with a high dose of metronidazole of up to 80–90% (therapeutic dose of 600 mg). These printlets had hardness values above 40 N, which is comparable to those of conventionally compressed tablets. In addition, the effects of laser scanning speed and osmotic agent on drug release were reported, and dissolution was found to be improved

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Fig. 4.13 Pharmacokinetic profiles of the printlets and compressed tablets in rabbits. Adopted with permission from (Khuroo et al. 2022)

by the addition of an osmotic agent. Using PA12 for the fabrication of high-dose composite printlets resulted in good mechanical strength of the printlets, along with a porous internal structure, which can be successfully used for the treatment of H. pylori infection. Thus, this study highlighted the possible use of materials dedicated to SLS 3D printing for drug delivery applications, along with the need to search for other appropriate materials (Kulinowski et al. 2022). Wei et al. (2022) used a customized 3D printer with a beam homogenizer, which allowed homogenized spot melting of the powder bed material. It melted the complete powder layer at a once, helping reducing the surface temperature gradient of the powder bed. Authors reported the use of crystalline polymer (40% PEG 8000) having a low Tg , required flow, and heat conducting properties in molten state as solid binders for formation of sustained-release tablets of indomethacin. In addition, SLS-mediated printing of berberine hydrochloride was achieved using various release modifiers, such as: CMS-Na, L-HPC, CCMC-Na, and lactose (Wei et al. 2022). Shahbazi et al. (2022) performed an interesting study on the molecular behavior and kinetic evaluation of normal maize starch molecules at the printer temperature used for the extrusion and powder bed fusion (SLS)-based 3D printing. SLS offers typical crosslinking or branching behavior to starch, along with increased molecular size and viscoelastic properties. However, it reduced the digestive extent of starch. For molecular level characterization, analytical tools such as SEC,

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NMR, DSC, and XRD were employed during the study (Shahbazi et al. 2022). Santitewagun et al. (2022) reported the applicability of THz-TDS for the evaluation of solid state of SLS-mediated ASDs of indomethacin. The authors also compared the traditional methods of solid-state characterization, such as DSC and PXRD, with THz-TDS. THz-TDS was found to be applicable to the stability prediction of ASD (Santitewagun et al. 2022). Vasiljevi’c et al. (2022) employed the SLS technique for the formation of multiparticulate units using model drugs, caffeine, and ibuprofen as well as different polymers, including poly(ethylene)oxide, ethyl cellulose, and methacrylic acidethyl acrylate copolymer. The incorporation of polymers was found to notably affect the properties of multiparticulate units (Vasiljevi´c et al. 2022). Giri et al. (2023) demonstrated the suitability of SLS technology for the fabrication of sustained-release tablets, utilizing Kollidon SR as a sustained-release polymer and acetaminophen as a model drug. Tablets containing 10% drug, 85% polymer, and 5% laser-absorbing dye showed approximately 90% of the drug release over 12 h, as opposed to a burst release from the free drug and physical mixture of drug and polymer before sintering (Fig. 4.14). DSC, XRD, WAXD, and PLM confirmed the amorphization of acetaminophen during sintering (Fig. 4.15a). HSM was used to better understand the fusion of particles during the sintering process at different temperatures; it represents the simulated conditions of the sintering process at a particular temperature (Fig. 4.15b) (Giri and Maniruzzaman 2023). The era of the SLS 3D printing in pharmaceutical is increasing day by day

Fig. 4.14 Dissolution profiles of the free acetaminophen (ACH), physical mixture (PM), and the 3D-printed tablet (left); schematic illustration of drug release phenomenon from a matrix-based system containing Kollidon SR as a matrix-forming agent (right). Adapted with permission from (Giri and Maniruzzaman 2023)

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®

Fig. 4.15 (a) PLM microscope images of acetaminophen (ACH), Kollidon SR (KSR), Candurin , physical mixture (PM), and the 3D-printed powered tablet. Birefringence is indicated by white arrows. (b) Hot-state microscopy images of acetaminophen (ACH), Kollidon SR (KSR), and physical mixture (PM) at 50 ◦ C, 140 ◦ C, and 170 ◦ C. Adapted with permission from (Giri and Maniruzzaman 2023)

due to the feasibility and intense applicability of the SLS 3D printing technology. However, there is a need to understand the setbacks for the scale-up of SLS 3D printing technology. The implementation of regulatory norms for the acceleration of SLS 3D printing technology in the pharmaceutical field is required.

4.10

Setbacks for Scale-Up of SLS-Mediated Rapid Prototyping

SLS is a powder bed fusion technology that has limitations in terms of the fabrication of SODFs, such as the thermal stability of the drug, post-processing, recycling, need for system development, and defects (Fig. 4.16) that need to be discussed in detail for a better understanding in subsequent sections.

4.10.1 Thermal Stability of Drug In SLS-mediated sintering, a laser is used as a thermal energy source to partially melt the powder material, forming a melt pool, followed by particle fusion to give

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Fig. 4.16 Setbacks for the scale-up of SLS-mediated rapid prototyping

rise to a 3D object. The utilization of thermal energy in the form of a laser limits the pharmaceutical applications of SLS for the fabrication of drug delivery systems for thermally stable drugs. Owing to the higher energy of CO2 , the laser can degrade drugs more often than the low-energy beam of a blue diode laser. However, it should also be considered that the most prevalent SLS printers with a CO2 laser beam as the heat source provides a facility to modulate the laser power being traced. Owing to the limitations of thermal stability, materials, such as proteins, enzymes, and hormones, cannot be processed using SLS (Charoo et al. 2020; Gueche et al. 2021b).

4.10.2 Post-Processing The surface of the part fabricated using SLS has a powdery appearance and rough surface finish because of the presence of a non-sintered powder material on the surface. Awad et al. (2019) observed particles on the surface of Kollicoat IR miniprintlets using SEM analysis (Awad et al. 2019). Trenfield et al. (2022) used SLS as a single-step procedure for drug amorphization but still observed the presence of some crystalline drugs during Raman spectroscopic inspection. This was owing to the incomplete clearance of the unsintered powder from the surface of the 3D-printed discs. Thus, to prevent dissolution irregularities and to maintain a uniform solid state and aesthetic value of the dosage form, post-processing of the fabricated parts must be performed using compressed air or manual brushing (Trenfield et al. 2022b).

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4.10.3 Recycling Generally, only 5–15% of the total feedstock used undergoes sintering if SLS’s pharmaceutical applications of SLS are considered. The remaining 85–95% powder material remained unsintered. Economically and ecologically, it is necessary to reuse the previously processed powdered materials for subsequent sintering. However, this unsintered powder undergoes specific physical and chemical changes, including thermal degradation, enhanced viscosity due to increased molecular weight, changes in the size and shape of particles due to their interaction with the laser and high-temperature exposure followed by cooling. The reuse of processed materials can affect the mechanical strength of the finished product. Thus, it is recommended to add 30% virgin powder material to the unsintered powder material and reuse it in further batches (Charoo et al. 2020; Gueche et al. 2021b). Gueche et al. (2021) studied the potential plasticizing effect of dicarboxylic acids (fumaric, succinic, malic, maleic, and tartaric acids) on the reduction in the optimal heating temperature of the polymer powder during SLS, which can reduce the thermal degradation of the powder and active drug constituents (Gueche et al. 2021c).

4.10.4 Need of System Development (a) In process control/online control. There is no diagnostic system for controlling the size and shape of melt pools in the present systems. By controlling the overhangs and thin features online, the final printed part ensures a high accuracy and repeatability. The incorporation of on-line/in-line control systems in SLS reduces wastage of time and raw materials. (b) Multiple laser sources in one system. No single laser source can process a wide variety of feedstock materials; therefore, it would be beneficial if various types of laser sources are present in a single system for a wide processing range. (c) Fabrication time. To make SLS competitive with conventional processes, production speed must be improved. This can be accomplished through parallel scanning using multiple beams. (d) Standardization. Objects printed using different SLS 3D printers exhibit different appearance and properties. Thus, printers, processes, materials, and post-processing should be standardized to form proper regulations before commercialization of the SLS in pharmaceutical applications (Kumar 2014).

4.10.5 Defects Geometric and dimensional defects, surface quality, microstructure, and mechanical properties are among the most common defects in printlets printed using the SLS-mediated 3D printing technology. SLS process parameters and material characteristics generally influence the defect specifications (Charoo et al. 2020).

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The literature extensively discusses shrinkage as one of the fundamental reasons for dimensional inaccuracy, which results in poor laser sintering performance. Benedetti et al. (2019) studied the shrinkage behavior of semi-crystalline polymers (PEKK and PA12) with objects printed using SLS 3D printing technology. They reported that powder bulk density, crystallization, and thermal retraction are the main material characteristics that affect shrinkage. The PA12 parts were mostly distorted by crystallization, accounting for 60% of the overall shrinkage. In PEKK parts with heights less than 10 mm, an upskin and downskin effect is evident, which is responsible for the expansion (Benedetti et al. 2019).

4.11

Regulatory Attentions for the SLS

As we have discussed in the above sections, SLS-3D printing technology has numerous applications in the pharmaceutical field. Owing to the broad applicability in the pharmaceuticals, researchers successfully had sintered the SODFs with varied release pattern and shape for different kind of patients, while considering their requirements. Based on the observations of the studies, there is high percentage of chances to scale-up the fabrication of sintered dosage forms from the laboratory to industry. In addition, there is an unconditional requirement is that the wellestablished regulatory consideration from the different regulatory bodies. Imperative amendment in the FDA guidelines for the 3D printed SODFs will expedite the tech transfer, in similar way of implementation FDA guidelines for the additive manufacturing of the medical devices in 2017 (Gueche et al. 2021b). Fabrication of SODFs according to the needs of the patient is possible by adjusting the process parameters provided by the SLS-3D printing technology within a broad window. Utilizing these process parameters researchers had fabricated the different types of formulations such as ODTS, immediate-release tablets, sustainedrelease tablets, polyprintlets, miniprintlets, and dual miniprintlets, by using various pharmaceutical grade polymers and other excipients (Fina et al. 2017; Awad et al. 2019; Fina et al. 2018c; Giri and Maniruzzaman 2023). Subsequently, the quality by design method was utilized to optimize the effect of the process parameters on the quality of the SODFs (Gueche et al. 2021a; Ali et al. 2019; Mohamed et al. 2020). Ultimately, these process parameters affect the characteristics of the sintered designs. In addition, different SLS 3D printers have different resolution of printing, reservoir dimensions, types of recoater, slicers, and software’s associated. As discussed in Sect. 11.4, there is a need to standardize printer and process parameters. In addition, the laser is the heat source in SLS. To control this additional heat source, it is necessary to evaluate the drug, excipients, final blend, and formulation using advanced analytical techniques such as DSC, TGA, and HSM. The feasibility of SLS as a one-step process for changing crystalline API into amorphous forms has been investigated. Because of this, PXRD analysis of the aforementioned samples is required for the inspection of solid-state forms for regulatory consideration. Trenfield et al. 2022 combined PAT with near-infrared and Raman spectroscopies

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to determine the solid-state (amorphous content) of itraconazole in an SLSmediated solid oral formulation. Consequently, the aforementioned techniques can be considered for solid-state analysis of SLS-mediated prototypes (Trenfield et al. 2022b). Using an SLS 3D printer, fabrication is a wholly automated process that takes place in a contained setting. Printing temperature, laser power, laser-scanning speed, layer thickness hatch spacing, etc. are all process parameters that affect how quickly or slowly an object can be fabricated using SLS. Therefore, it is important to create on-line/in-line quality control tools in order to assess the ongoing printing process and investigate product quality all at once. A more precise and repeatable end result can be achieved through the incorporation of these rules into online quality analysis (Gueche et al. 2021b; Kumar 2014). In 2020, Trenfield et al. reported the successful use of a handheld near-infrared spectrophotometer for the non-destructive dose analysis of SLS-manufactured polypills containing amlodipine and lisinopril. In addition, for the first time, they reported a non-destructive quality analysis of the same polypills using a real-time release (RTR) study (Trenfield et al. 2020). In 2018, Trenfield et al. (2018) reported the use of PAT as a point-and-shoot method for non-destructive dose verification of paracetamol in printlets fabricated using SLS. This approach involves the use of near-infrared spectroscopy and Raman confocal microscopy for non-destructive quality analysis to facilitate the integration of SLS in the healthcare sector. Therefore, these techniques can be arranged as online/in-line quality control tools to save time and waste raw materials (Trenfield et al. 2018). The porosity of the matrix is important to control the release of incorporated API. Thus, porosity is an essential criterion for evaluating the printed formulations. Various researchers have reported the use of SEM for qualitative evaluation and micro-CT for quantitative evaluation of matrix porosity (Giri and Maniruzzaman 2023; Santitewagun et al. 2022). These analytical techniques should be considered when framing the regulatory considerations for SLS-mediated SODFs. SLS requires various laser-absorbing agents to improve the sinterability of the unsinterable pharmaceutical grade excipients/feedstock materials. The laser-absorbing agents used should be generally recognized as safe (GRAS) certified, which will ultimately reduce the risk of toxicity. The SLS-mediated fabrication also requires GMP to prevent reproducibility related issues. Reuse and recycling procedures for used feedstock should be fixed and well-regulated to achieve uniform manufacturing.

4.12

Conclusion

SLS 3D printing technology is gaining importance for the preparation of SODFs and other drug delivery devices. Experimental studies have shown that SLS 3D printing has numerous applications in drug delivery. SODFs with tunable release behaviors can be fabricated using different thermoplastic polymers and varying process parameters. For example, orodispersible, immediate, controlled, and sustained release as well as ASDs.

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Different SLS 3D printers with unique laser sources of various wavelengths are commercially available. Each laser source and its characteristics significantly affect the sinterability of the different thermoplastic polymers. Some of these SLS 3D printers have been explored in the pharmaceutical field. Since 2017, the graph of SLS in the pharmaceutical field has been growing unexceptionally because of the feasibility of process parameters and materialrelated parameter variations, which ultimately helps to modify dosage forms according to patient needs. In addition, researchers have discovered drawbacks of SLS-based AM technology. Overcoming these drawbacks will become a significant challenge for researchers in coming years. Technology transfer from the lab to industry will benefit from these regulatory considerations. Furthermore, it may offer stability for the industrial fabrication of SODFs.

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Semi-Solid Extrusion (SSE) in Pharmaceuticals Nadine Lysyk Funk, Júlia Leão, Thayse Viana de Oliveira, and Ruy Carlos Ruver Beck

Abstract

Semi-solid extrusion (SSE) is an extrusion-based 3D printing technique, widely employed in food printing and bioprinting. In pharmaceutics, SSE is becoming the most explored technique to obtain solid dosage forms with specific characteristics, such as chewable, fast-dissolving or gastro-floating tablets, polypills, oral and topical films, and rectal suppositories, among others. The advantages of SSE include a low work temperature, with less risk of drug instability, and the availability of a broad range of excipients (e.g., natural or synthetic polymers, lipids and food additives) as feedstock materials to obtain gels or pastes in the 3D printing process. However, the properties of the dosage forms can be impacted by formulation-related factors, like the semi-solid rheological behaviour, the size of the dispersed materials, and the geometrical shape of the dosage form, as well as the parameters of the printing process, such as printing speed, infill pattern and number of layers. Due to this versatility, SSE has become a powerful tool to produce innovative dosage forms with clinical relevance for specific groups, including paediatric, geriatric and veterinary populations, as personalised medicines. Keywords

Additive manufacturing · Drug delivery · Hydrogels · Nanomedicine · Polymeric blend · Printing parameters

N. L. Funk · J. Leão · T. V. de Oliveira · R. C. R. Beck () Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil e-mail: [email protected]; [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals, https://doi.org/10.1007/978-981-99-2404-2_5

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Introduction

Material extrusion techniques, including fused deposition modelling (FDM) and semi-solid extrusion (SSE), have been the most explored 3D printing technologies in pharmaceutical development in the past few years (dos Santos et al. 2021). Since the first report on the development of drug dosage forms using the SSE technique (Khaled et al. 2014), many authors have studied its advantages to produce personalised medicines, affording an increase in scientific publications involving its use in the manufacture of drug dosage forms by 3D printing. SSE is a 3D printing technique that utilises semi-solid formulations as feedstock material. Formulations are placed inside a syringe, usually disposable, and extruded through a nozzle that can vary in diameter, according to the formulation or printing requirements. Mechanisms of extrusion can include pneumatic, mechanical or solenoid extrusion (Fig. 5.1). Following the application of pressure to the syringe plunger, the material is deposited on the printer table in a layer-by-layer manner until the desired dosage form size and geometry are complete. After printing, a solidification step is required to maintain the structure, justifying why water-based formulations are the most explored form so far (Seoane-Viaño et al. 2021a). One of the most important advantages of SSE is the possibility of working at room temperature, making it possible to use this 3D printing technique for thermolabile active substances. On the other hand, some printers allow the temperature in the printer table and head to be varied within a specific range. Another benefit that is easily observed in the pharmaceutical field is the simplicity of the process of adding the active substance to the material to be printed, as it can be directly added to the base gel, cream or paste, together with the excipients. This process makes it easy to customise the drug dose and/or its release profile (Firth et al. 2018). Although SSE appears to be an easy technique in terms of the ink formulation and printing process, some critical aspects have an impact on the quality of the printed material. Regarding the ink formulation, its rheological and textural characterisation plays a crucial role in the success of the printing process. The greatest challenge while developing a gel or paste for SSE is finding the right viscosity for printing. Less viscous feedstocks make it difficult to control the flow through the nozzle, while a higher viscosity may result in the nozzle clogging or having inadequate flow (Rahimnejad et al. 2021), as depicted in Fig. 5.1. Compared to other techniques, like FDM, SSE prints at low resolution, mainly because of the characteristics of the printed material. Also, a drying step is usually needed after the printing process, which can lead to shrinking, deformation and even to a loss of shape of the final product. Despite the limitations mentioned above, SSE has been widely explored in the pharmaceutical field due to its versatility (Vithani et al. 2019a; Karalia et al. 2021). In this scenario, a great variety of drug delivery systems manufactured by SSE 3D printing have been reported in the literature, such as polypills (Haring et al. 2018), chewable tablets (Goyanes et al. 2019; Karavasili et al. 2020), oral and topical films (Wang et al. 2020; Elbadawi et al. 2021), fast-dissolving or gastro-floating tablets

Fig. 5.1 Schematic illustration of the semi-solid extrusion 3D printing technique (left side), the critical parameters related to the extrusion process (extrusion mechanisms, parameters and nozzle diameter), and types of feedstock materials

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(Falcone et al. 2021) and rectal suppositories (Seoane-Viaño et al. 2021b), among others. These reports reinforce the versatility of the technique to develop different types of dosage forms for specific groups, as personalised medicines. New findings and perspectives can be observed due to the increased number of scientific reports about the 3D printing of pharmaceuticals embracing the SSE technique in the past few years. Thus, this chapter will describe and discuss the main critical parameters of the SSE printing process in pharmaceutics, such as the feedstock materials, the printing ink properties and the printing process. At the end, a broad view will be presented about the application of the SSE technique in the development of pharmaceuticals.

5.2

Feedstock Materials

The main difference among the different extrusion-based 3D printing techniques is the type of feedstock employed. Due to its easier process requirements, the SSE technique enables the use of semi-solid materials that are directly extruded through a nozzle to form the desirable dosage form. Semi-solids are formulations obtained by the dispersion or solubilisation of one excipient or blend of excipients in an appropriate solvent to reach a suitable viscosity. Examples include creams, ointments, pastes and gels, among others (European Pharmacopoeia 10.0 2019). Gels are preferred in the 3D printing of pharmaceuticals and are the most explored semi-solid so far, due to the high amount of water present in their formulation, which rapidly evaporates after deposition on the printer table, guaranteeing that the dosage form structure is maintained. Reports on the 3D printing of pharmaceuticals describe the use of natural, semi-synthetic and synthetic polymers (individually or blended), food additives and lipid-based formulations to produce 3D printed dosage forms by SSE for administration by different routes (Table 5.1). The main excipient must be chosen according to its rheological properties and the release profile intended for the printed dosage form and must be generally recognised as safe (GRAS), guaranteeing the biocompatibility of the formulation. Depending on the nature of the polymer, crosslinking reactions can be employed before or after printing to improve the mechanical strength of the feedstock or the printed product. Crosslinking methods include chemical (e.g., photo and thermal crosslinking), physical (e.g., addition of multivalent cations) or enzymatic crosslinking (GhavamiNejad et al. 2020). These external stimulations promote changes in the sol-gel state of the polymers, enabling researchers to control some properties, such as the viscosity of the feedstock (Fan et al. 2022). These approaches are interesting not only to adjust and improve the printability of the ink formulations, but also to achieve a desirable drug release profile. Regarding the drug release profiles, the development of immediate drug release 3D printed dosage forms by SSE has explored the use of different polymers, including hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), ® polyvinylpyrrolidone (PVP), Gelucire 48/16 and poly(vinyl alcohol)-polyethylene

Polymeric blends

Synthetic and semi-synthetic

Gastric-floating systems Mucoadhesive buccal films Scaffold for diabetic wound treatment Gummy for paediatric patients

Ofloxacin Propranolol hydrochloride Satureja cuneifolia extract Lamotrigine

HPMC K100M:HPMC E5:Sodium alginate (15:15:10) Gelatin:PVP (1:1 w/w) and Gelatin:PVA (1:1 w/w) Sodium alginate:PEG (5:1 w/w)

Gelatin:HPMC (at different w/w ratio)

Fast-disintegrating tablets Orodispersible films for veterinary use Orodispersible printlets for paediatric use Wound dressing

Redispersible 3D printed oral solid forms

Main application Gastro-retentive dosage form Hydrogel dressing

Lidocaine

Hydrochlorothiazide

Drug Ricobendazole Lidocaine hydrochloride and levofloxacin Resveratrol and curcumin co-encapsulated in nanocapsules Phenytoin sodium Prednisolone

Chitosan:Pectin (1:4 v/v)

PVP 30 K

HPMC HPC

CMC

Main ink formulation material Natural Sodium alginate Chitosan methacrylate

(continued)

Tagami et al. (2021)

Ilhan et al. (2020)

Jovanovic et al. (2021)

Fang et al. (2022)

Díaz-Torres et al. (2021) Long et al. (2019)

Panraksa et al. (2022) Sjöholm et al. (2020)

de Oliveira et al. (2022)

Reference Falcone et al. (2022) Teoh et al. (2021)

Table 5.1 Feedstock material employed in the development of pharmaceutical dosage forms by the SSE 3D printing technique, drugs loaded in the formulation and its main application

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Tacrolimus Dapagliflozin propanediol monohydrate

Gelucire 44/14:Coconut oil (4:1)

Liquid phase—Caproyl 90:Octanoic acid:PEG 400 (2:2:1) Solid phase—Poloxamer 188:PEG 6000 (1:1)

Self-nanoemulsifying tablet

Suppository

Main application Paediatric-friendly dosage form Child-friendly dosage form Paediatric dosage form

Seoane-Viaño et al. (2020) Algahtani et al. (2021)

Karavasili et al. (2022) Lafeber et al. (2021)

Reference Karavasili et al. (2020)

CMC Carboxymethyl cellulose, HPMC Hydroxypropyl methylcellulose, HPC Hydroxypropyl cellulose, PVP 30 K Polyvinyl pyrrolidone 30 K, PVP Polyvinyl pyrrolidone, PVA Poly(vinyl alcohol), PEG Polyethylene glycol

®

Paracetamol and ibuprofen Furosemide and sildenafil

Cereal ® Gelucire 48/16

Lipid-based formulation

Drug Paracetamol and ibuprofen

Main ink formulation material Food additive Bitter chocolate

Table 5.1 (continued)

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glycol (PVA-PEG) graft copolymers (Kolicoat IR) (Funk et al. 2022). Whenever a faster drug release is preferred, the addition of disintegrants to formulations, such as croscarmellose sodium (Conceição et al. 2019) and sodium starch glycolate (Khaled et al. 2015a), has also been reported as a suitable approach. It is also possible to attain controlled drug release behaviours using the SSE technique, comprising different release mechanisms depending on the feedstock material. One of the most explored polymers to afford controlled release profiles by SSE is HPMC (Khaled et al. 2014; Wen et al. 2019; El Aita et al. 2020), with its increased concentration generally delaying drug release from the 3D printed form (Cui et al. 2019; Cheng et al. 2020). Along with the rational choice of the polymer, the SSE technique allows some parameters of the printing process that can tailor the drug release from the 3D printed dosage forms to be changed, according to the requested treatment of a specific patient or group of patients. Changes in geometry, infill percentage, layer thickness, and width and height of the dosage form have been explored as a strategy to achieve immediate or controlled drug release formulations. In the following subsections, the most described classes of feedstock material used to produce 3D printed dosage forms by SSE will be discussed individually.

5.2.1

Semi-Synthetic and Synthetic Polymers

Currently, semi-synthetic and synthetic polymers have been extensively utilised as feedstock material for SSE 3D printing, mostly cellulosic polymers like HPMC, carboxymethyl cellulose (CMC) and HPC. Most of these cellulosic polymers are commercially available with different substitution degrees and molecular weights, and these modifications impact on their physicochemical properties (Zamboulis et al. 2022). Different grades and concentrations of HPMC have been explored to produce diverse dosage forms, such as mucoadhesive oral films (Tagami et al. 2019), ophthalmological patches (Tagami et al. 2022), tablets (Cui et al. 2019; Panraksa et al. 2022), and gastro-floating tablets (Li et al. 2018), showing different release profiles, depending on the concentration of HPMC. In addition, the higher the molecular weight and viscosity of the HPMC, the slower the drug release. Regarding the mechanism of drug release, hydrophobic drugs are usually released by gel erosion, and hydrophilic drugs through diffusion from the gel layer formed by the HPMC (Funk et al. 2022). CMC has also been recently reported in the development of orodispersible films (O’Reilly et al. 2021), mucoadhesive films (Schmidt et al. 2022) and tablets (de Oliveira et al. 2022). Most research involving CMC is based on its use in 3D bioprinting (Rahman and Quodbach 2021). One of the advantages of its use as a feedstock material for SSE 3D printing is its capacity to form hydrogels with an elastic solid behaviour at low concentration, which favours shape recovery after the printing step (Rahman and Quodbach 2021).

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Other synthetic and semi-synthetic polymers have also been described as the main formulation material for SSE 3D printed dosage forms, usually formulated as blends, which will be described next in this chapter. PVA-PEG graft copolymer and PVA have been reported for the development of SSE 3D printed tablets (El Aita et al. 2019; Dores et al. 2020), whereas PVP was reported for the manufacture of gelatin-based mucoadhesive films (Jovanovic et al. 2021). As mentioned earlier in this chapter, crosslinking reactions can be employed before, during or after printing. For some synthetic and semi-synthetic polymers, pH and temperature are employed as parameters to change the sol-gel state of the materials, promoting reticulation of the polymeric chains and changing a solution to a semi-solid, which can be useful in a SSE 3D printing process. The stimuli-responsiveness of some polymers can also be employed to improve the printability of feedstocks during printing. Temperature changes in the printer head and table can promote a proper flow and structure rigidity, for example (Herrada-Manchón et al. 2020). Photocrosslinking can be employed during and after printing, to guarantee reticulation of the polymeric chains and decrease the time needed for the printed material to dry (Hollander et al. 2018). Additionally, immersing the printed material in acidic or basic solutions is usually reported as a post-printing treatment in bioprinting to ensure the structural integrity of the object (Sadeghianmaryan et al. 2020). Examples of stimuli-responsive polymers include carbomers, such as Carbopol, which form a solution in water and rapidly acquire viscosity when agents such as NaOH are added to increase the formulation pH (Zidan et al. 2019; Alayoubi et al. 2022). Although less explored in the development of 3D printed dosage forms, thermosensitive feedstocks have already been reported in bioprinting (Rahimnejad et al. 2022) and food development (Liu et al. 2018), comprising the use of polymers such as gelatin, collagen, methylcellulose and poloxamers.

5.2.2

Natural Polymers

Polymers with natural origin are commonly used as excipients in pharmaceuticals because of their safety, biocompatibility and biodegradability, which are desirable characteristics for the development of dosage forms by SSE. These polymers have mainly been applied in wound dressing tissue engineering and artificial skin development by SSE 3D printing (Zamboulis et al. 2022). In pharmaceutics, sodium alginate (Falcone et al. 2021; Falcone et al. 2022), chitosan (Teoh et al. 2021), pectin (Goyanes et al. 2019) and polymeric blends with natural polymers (Long et al. 2019; Herrada-Manchón et al. 2020) have been reported as semi-solid ink components for the manufacture of 3D printed drug delivery systems. Chitosan is a natural polymer extracted from the exoskeletons of crabs and shrimps and has mucoadhesive properties, attributed to its positive charges due to the presence of amino groups in its structure, which can be interesting for the development of mucoadhesive formulations (Whyte et al. 2019). This polymer undergoes the sol-gel transition by physical gelling through pH variation, as its

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swelling occurs at acidic pH due to protonated amino groups and the appearance of repulsions between the polymer chains, increasing the viscosity of the gel (Irimia et al. 2018). Chitosan hydrogels have been explored for the topical delivery of lidocaine and levofloxacin from anaesthetic wound dressings (Teoh et al. 2021) and as a blend with pectin for lidocaine delivery (Long et al. 2019). Another natural polymer explored in the SSE technique is sodium alginate, a copolymer formed by blocks of mannuronic (M) and glucuronic (G) acid, at different proportions and arranged in a consecutive or alternate manner that impacts directly on its physicochemical properties. The higher the M block content, the higher the viscosity, while a higher content of G blocks results in greater gelling properties (Łabowska et al. 2021). An increase of the mechanical properties of alginate hydrogels can be reached by physical crosslinking, notably with Ca2+ . A better definition of the printed dosage form can be achieved by increasing the concentration of this crosslinker. Falcone and coworkers explored the ionotropic gelation of alginate in the development of SSE 3D printed floating drug delivery systems containing propranolol hydrochloride (Falcone et al. 2021) and ricobendazole (Falcone et al. 2022).

5.2.3

Polymeric Blends

Although there are many types of polymers, they are not always suitable for the formulation of printable feedstocks (or printing ink). For example, polymers may present high elasticity or break tendencies, which makes their deposition on the printing table difficult, or adhesion properties that hamper the system flowability. Blends of polymers with distinct properties are therefore being explored to achieve a successful printing ink by tailoring its consistency or flowability, or aiming to reach a specific drug release profile from the 3D printed dosage forms. To improve the texture and consistency of the semi-solid after extrusion, Sjöholm et al. (2020) produced polymeric blends using polyethylene oxide and hydroxypropyl cellulose EXF or hydroxypropyl cellulose LF. According to the authors, a proper texture needs to be smooth and uniform, not too viscous and not too fluid (Sjöholm et al. 2020). Similarly, corn starch, xanthan gum, carrageenan and gelatin (Herrada-Manchón et al. 2020), gelatin and PVP or PVA (Jovanovic et al. 2021), and gelatin and HPMC (Tagami et al. 2021) are examples of polymeric blends used to improve the printability and flow properties of hydrogels, to reach a defined rheological behaviour that prevents the collapse of the structure, but is also not too viscous to clog the nozzle. Polymeric blends are explored not only to improve the physical characteristics of the hydrogel, but also to modify the drug release rate from the 3D printed dosage form, as reported for the use of blends composed of hydroxypropyl methylcellulose K100 M (HPMC K4100) or E5 (HPMC E5), sodium alginate, microcrystalline cellulose and lactose (Fang et al. 2022), where the influence of the percentage of each polymer was evaluated on the drug release rate. The higher the ratio of HPMC K4100, the lower the drug release rate. On the other hand, the presence of sodium

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alginate in the blend did not influence the drug release from the tablets. However, the use of polymer blends may also be focused on improving the pharmaceutical effect of the dosage form per se. In the development of a diabetic wound dressing, Ilhan et al. (2020) prepared sodium alginate and PEG hydrogels based on the compatibility of the resulting 3D printed film with the skin. These two polymers have high biocompatibility, low toxicity and were also chosen due to their ability to accelerate the healing process by promoting tissue regeneration.

5.2.4

Food Additives

SSE has also been explored in the alliance between medicines and food. Adherence to treatment is very important for the success of pharmacological therapy, but it is quite variable among the paediatric population, depending on the characteristics of the drug, such as palatability and organoleptic properties (taste, colour, smell and texture, among others). In this sense, studies have shown promising results when printing food containing drugs (Zajicek et al. 2013). As an example, cereal and chocolate were reported as alternative feedstocks to develop 3D printed paediatricfriendly dosage forms with improved acceptance and to facilitate the administration of paracetamol and ibuprofen to children. Cereal-based 3D printed dosage forms have been developed, to be administered during breakfast in association with milk. Dissolution studies were performed mimicking the gastric and intestinal environments, in fasted state and fed state, in the presence of high-fat or low-fat milk. Results showed that paracetamol dissolution was not affected by the presence of milk, resulting in a total drug release in less than 75 min. Meanwhile, ibuprofen (a more hydrophobic drug) displayed a slower release in comparison to paracetamol; however, the ibuprofen dissolution rate increased with a high-fat content milk (drug release of 64% in low-fat milk and 81% in highfat milk after 240 min) (Karavasili et al. 2022). An alternative approach was presented by developing cartoon-shaped 3D printed dosage forms using bitter chocolate and corn syrup as feedstock materials. Both hydrophilic (paracetamol) and hydrophobic (ibuprofen) drugs were molecularly dispersed into the chocolate-based formulations and showed a pH-dependent drug release when evaluated in simulated salivary (pH 7.0) and gastric (pH 2.0) fluids. Complete paracetamol release was observed after 2 h at pH 2.0, while a slower ibuprofen release was observed in the same medium (16.98 ± 4.68%) (Karavasili et al. 2020). As previously mentioned, food additives are an interesting choice when paediatric appeal is required. Their alliance with SSE 3D printing shows some advantages, mainly because of the possibility of dose adjustment according to the patient’s characteristics, to improve palatability and to make the pharmacotherapy more attractive. However, these approaches should be considered carefully, as this alliance of drugs and food may impair the rational use of medicines or could incite drug intoxication in children.

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Lipids

Lipid-based drug delivery systems are of particular interest in the development of 3D printed pharmaceuticals due to their potential to solubilise poorly soluble drugs and improve their bioavailability, with or without the use of a specific temperature. These systems involve natural or synthetic oils and surfactants, alone or combined, and are divided into four classes: type I, oil solutions; type II, self-emulsifying drug delivery systems; type III, microemulsifying/nanoemulsifying drug delivery systems; and type IV, blends with a higher proportion of hydrophilic surfactants and cosolvents, and a lower proportion of oils (Pouton 2000; Vithani et al. 2019b). Only a few reports are available in the literature regarding the use of lipid-based SSE feedstocks in the development of formulations for oral (Vithani et al. 2019a; Lafeber et al. 2021; Johannesson et al. 2021) and rectal (Seoane-Viaño et al. 2020; Seoane-Viaño et al. 2021b) administration. Overall, these studies demonstrate the feasibility of achieving an adequate viscosity of feedstocks using blends of lipid ® excipients such as Gelucire (PEG 32 mono and diesters of stearic and palmitic ® acid), coconut and soybean oils, and Kolliphor (copolymer of ethylene oxide and propylene oxide), among others. The blends reported were able to improve the solubility of poorly soluble drugs and resulted in different drug release profiles from pharmaceutical dosage forms.

5.3

Printing Ink Properties

The development of feedstocks with suitable properties for SSE 3D printing can be considered challenging. As previously discussed, excipients of different natures can be used to obtain printable semi-solids as printing inks for a SSE 3D printing process. However, the unique properties given by the intrinsic characteristics of the excipients used to formulate the feedstock materials, as much as their blends and the different printer setups available on the market, make it difficult to establish the properties required by a formulation for its optimal 3D printing performance. Many efforts have been made to find the optimal properties of gels and pastes so that they perform well during the 3D printing process, but a final conclusion and understanding have yet to be established. Up to now, rheological evaluation and texture analysis are the most discussed characterisation tests in this sense, providing information that can help researchers to predict the behaviour of semi-solid formulations during and after the printing process. In addition, they can supply data such as minimum strength to initiate flow, viscoelastic behaviour, shape recovery, gelation kinetics of thermosensitive hydrogels, extrudability and cohesiveness, among others (Rahimnejad et al. 2021; Zidan et al. 2019). The viscosity of the printing inks has a direct impact on the resolution of the printed object. The flow of the material is more difficult to control in less viscous formulations, often presenting variations between the physical properties designed

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in the printer software and the real properties of the 3D printed structure, such as filament width, infill percentage and geometry. Moreover, the lack of consistency hampers the printing of a first strong solid layer to support the subsequent layers, reducing the resolution of the printed product. On the contrary, formulations that are too viscous may result in nozzle clogging or non-homogeneous extrusion, which influences the properties of the object and the 3D printing reproducibility. In this case, the deposition of subsequent layers will be more difficult due to the presence of holes in the structure. Additionally, both circumstances will have a direct impact on the drug content and drug release from the 3D printed dosage forms (Rahimnejad et al. 2021; Decante et al. 2021). In general, SSE formulations exhibit non-Newtonian flow behaviour and a shearthinning characteristic, meaning that a decrease in viscosity is observed with increased stress (Mohammed et al. 2021). Moreover, viscoelastic feedstocks are preferred as they present a balance between an uncontrolled flow (due to a lower viscous modulus, G) and the need for a high force to initiate flow (higher elastic modulus, G ), which indicates formulations with a clogging tendency (Zidan et al. 2019). Ideally, the elasticity (G ) takes over during rest or low stress, and a higher G is observed with increasing stress (Fig. 5.2). This crossover point of elastic and viscous moduli reveals the yield point where the fluid starts to flow and behave

Fig. 5.2 Elastic modulus (G ) and viscous modulus (G) variation during extrusion process. After a force is applied to the syringe, polymer chains align facilitating flow (G > G ). During rest, before and after printing, elasticity takes over (G < G ) to guarantee structure maintenance

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more like a liquid. Once the stress is stopped and the formulation is deposited at the printer table, the viscosity is expected to return as close to the original values as possible (thixotropy), in order to guarantee structure maintenance during layer deposition, and printing accuracy (Mohammed et al. 2021). Mechanical evaluation has also been an important characterisation tool to evaluate the semi-solid properties of the printing ink. The texture analyser (TA) is a versatile piece of equipment that allows the use of different probes to mimic diverse process conditions, through extrusion, compression, adhesion, and tensile tests, for example. Regarding the 3D printing of pharmaceuticals, the TA can be applied to measure the consistency, hardness, springiness, cohesiveness and extrudability of feedstocks. These properties can report information about the force needed to extrudate a gel through the printing nozzle (extrudability); shape recovery after extrusion (hardness, resilience); the extrudate swelling phenomenon of feedstocks after extrusion through the nozzle (springiness), which impacts on printing accuracy; and the adhesive force between the inner particles of semi-solids (cohesiveness), and between the semi-solid and the syringe wall (adhesiveness); among others (Anukiruthika et al. 2020). Despite the important contributions of the TA (Schmidt et al. 2022; de Oliveira et al. 2022; Zidan et al. 2019), this characterisation technique has been little explored in the SSE of pharmaceuticals so far, with most efforts being in the field of food development. In addition to formulation development, there is also the potential to explore the TA in the characterisation of the final printed dosage form, regarding properties such as elasticity, hardness, adhesion to skin or mucosae, gumminess (which correlates hardness and cohesiveness) and chewiness (related to elastic resistance) (Stable Microsystems 2022). To enhance the rheological and textural properties of feedstocks, studies have explored the use of polymer blends and their particular characteristics, such as their stimuli-responsiveness. The use of thermosensitive pastes can be a strategy to improve the printability of semi-solids, as some SSE printers provide the option of adjusting the temperature (5 ◦ C to 40 ◦ C, for example) in the printer head and table. In this way, it is possible to adjust the flowability of a paste by controlling the temperature in the printer head, while changes in the table temperature can guarantee structure maintenance due to a faster recovery in the viscosity (Yang et al. 2020; Rahimnejad et al. 2022). Although some semi-solids present a suitable consistency for printing, a postprinting treatment can be required to assure structure rigidity. Therefore, the use of chemical crosslinkers have been described, especially in bioprinting. In this procedure, the feedstock can either be printed inside a crosslinking solution, immersed after being printed or photocrosslinked. However, this step can be challenging in the development of drug delivery systems, as drug release may occur once the matrix is immersed in an aqueous medium. Also, the photocrosslinking of polymers may form toxic subproducts, whereas the use of a UV source can degrade the drug, reducing the efficacy of the treatment or forming toxic degradation products. As a post-process step is usually required to obtain the final product, other treatments can be used to avoid the risk of degradation of the raw materials or

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drugs. Drying processes have been used to guarantee evaporation of the solvent present in the gel or paste (printing ink). Generally, the printed material is submitted to drying for 24 h (Sjöholm and Sandler 2019) to 48 h (Schmidt et al. 2022) at room temperature, until a constant weight is reached. However, higher temperatures have been also used in this post-treatment step (Khaled et al. 2018; Karavasili et al. 2022) and a vacuum dryer has even been used (El Aita et al. 2019; Zidan et al. 2019). The drying time can vary, depending on the material used, and this process can also interfere with the product’s final shape, leading to shrinking or deformation due to solvent loss (El Aita et al. 2019; Seoane-Viaño et al. 2021a). Moreover, higher temperatures can form bubbles, colour changes and uneven and fragile dosage forms (Sjöholm et al. 2020; Falcone et al. 2021). As discussed above, broad possibilities are given by the use of different characterisation techniques to evaluate the properties of feedstocks and shorten the path to reach a printable semi-solid profile. However, along with the optimisation of the printing ink properties, there are other critical parameters related to the mechanical printing process that can directly affect the success and accuracy of the printed products, as will be discussed next.

5.4

Critical Parameters of the Printing Process

SSE involves the printing of a semi-solid material, which is added to a syringe and extruded through a nozzle, forming a filament that is deposited on the printer table, layer-by-layer, until the dosage form is complete, as explained previously. However, this process is not always as easy as it seems, and different process parameters can affect the properties and behaviour of the object, or more specifically, of the 3D printed dosage form. Initially, a 3D model is created using computer-aided design (CAD) software and converted into a .stl file, which is imported into slicing software. At this point, the 3D model will be sliced into layers, and all the printing parameters, such as infill density and pattern; shape and size; printing speed; layer height; number of layers and all the commands that the printer will perform, are generated through a G-code file that is finally imported to the printer software. It is important to understand how these software work because some may not allow changes to the printing route when there is more than one dosage form being printed at the same time, which may affect the weight distribution (Lafeber et al. 2021). This limitation happens because the printer head may pass over the structure being printing, deforming it or even depositing extra material on its structure, leading to mass variation and lower reproducibility. These variations are not appropriate for drug delivery, as they can result in drug content variation per dosage form. Therefore, it is important to know how changes to the 3D model and 3D printing process parameters may benefit the properties of the final dosage form, according to the original design. These software provide different types of infill patterns of the printed object, such as rectilinear (Sjöholm et al. 2020), grids (Hollander et al. 2018; O’Reilly

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et al. 2021) and concentric (Li et al. 2019; Falcone et al. 2022), among others. The ideal infill pattern is the one that most resembles the structure to be printed, which will guarantee a good structuring of the dosage form. The infill density can also be modified from 0 to 100%. The infill pattern usually interferes with the dissolution and disintegration time (Cui et al. 2019; El Aita et al. 2020). At a lower infill percentage, the dosage form will be leakier, which may generate a faster disintegration and dissolution time (Panraksa et al. 2022), while a higher infill percentage may delay this time. The number of layers, the external geometry (Khaled et al. 2018) and the excipients added to the feedstock material can also interfere with the disintegration and dissolution time. In addition, it should be highlighted that the infill percentage also has an influence on the drug content of the dosage form: the lower the infill percentage, the lower the drug content of the 3D printed dosage form. Once the 3D model and the printing parameters are settled, the next step is to choose the right nozzle diameter for the material to be printed, as this can affect the size and shape of the extruded filament and the printing accuracy (Gibson et al. 2015; Gilliespie et al. 2020; Bom et al. 2022). Nozzles with a high inner diameter, short length and conical shape (instead of a cylindrical shape) increase the extrudability of semi-solid inks (Cai et al. 2020), whereas those with a lower inner diameter provide a higher resolution of the printed object (Seoane-Viaño et al. 2021a). However, the smaller the inner diameter of the nozzle, the greater the chances of partial or full nozzle clogging. Partial nozzle clogging can lead to material dragging and the deposition of a smaller amount of material, leading to a failure in printing accuracy and reproducibility. Meanwhile, full nozzle clogging delays the printing process because it requires the nozzle to be cleaned, leading to material loss and the whole process needing to be restarted (Bom et al. 2022). The distance between the nozzle and the printer table can also interfere with the behaviour of the printing process. Some printer software execute this calibration automatically, while others require manual calibration, using the axes (X, Y and Z) of the printer software to adjust this distance. The ideal distance is the one where the filament can be easily extruded without deformation, providing a uniform deposition on the printer table. If this distance is too close, the flow may be partially or completely interrupted, resulting in a low printing accuracy. Meanwhile, if the distance is too far, the filament will not be able to deposit correctly on the printer table or could even get stuck in the nozzle tip, forming an agglomerate that can settle or be dragged over the printer table (Firth et al. 2018). Another critical parameter of the printing process is the travel speed of the printing head. A high travel speed may result in inconsistent deposition of the extruded material, whereas a slow travel speed may lead to a higher deposition of material than expected at the same printing position. The ideal speed should be optimised and is reached when the filament has enough time to adhere to the printing table with no failure or inconsistent deposition (Seoane-Viaño et al. 2021a). Regarding the printing pressure, the flow adjustment is carried out manually in some printers, which is not suitable since the pressure can vary significantly if no specific

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pressure value is used. Ideally, the printing pressure should be set on the printer’s software, to assure the same flow and working pressure for all samples. With all these process parameters optimised and set, the 3D printing of the pharmaceutical dosage form can begin. Ideally, the first printed layer should have no failure of filament deposition and no other imperfections, as it needs to be well structured to receive the subsequent layers, otherwise these subsequent layers may not deposit properly, causing deformation of the dosage form structure. Therefore, considering the most common problems discussed above, after the development of a printing ink with suitable rheological properties, optimisation of the printing process parameters is necessary, including choosing a nozzle with an adequate size to allow the filament to be properly extruded, adjusting the printing speed to ensure correct deposition of the filament and selecting an adequate distance from the printing table. The adjustment of all these parameters, among others discussed in this section, will ensure the deposition of a homogeneous first printing layer, which is essential to host the following layers and thus develop homogeneous pharmaceutical dosage forms according to the originally designed properties and performance.

5.5

Applications of Semi-Solid Extrusion (SSE) in Pharmaceutics

In recent years, SSE has been gaining visibility as an innovative approach for the development of pharmaceuticals. Applications of SSE 3D printing in the development of human and veterinary medicines have raised their manufacture to a customised level, making their translation into the clinic a real possibility (Fig. 5.3). One of the great advantages of this technique is the possibility of applying it to the manufacture of different dosage forms, to be administered by different routes, whose drug dose and drug release profile can be adjusted (Rahman and Quodbach 2021). In this section, the applications of SSE in the development and manufacture of medicines will be presented, including studies exploring dosage forms intended for oral administration, which is most reported for SSE, as well as topical and rectal routes. The first application of SSE in the manufacture of drug dosage forms was in 2014, when Khaled and colleagues produced bilayer tablets containing guaifenesin for oral administration. The first layer was composed of HPMC 2910, providing an immediate drug release, whereas the second layer was composed of HPMC 2208, affording a sustained release profile to the tablet. The printed forms showed mechanical and physical properties within the acceptable range, as defined by the United States Pharmacopeia (USP) (Khaled et al. 2014). This study opened new horizons in the development of customised medicines using SSE 3D printing. In the following years, novel studies were carried out to demonstrate the application of SSE in the development of oral dosage forms, whose manufacture increased in complexity. SSE was used to produce complex polypills, where several drugs could be printed in a single dosage form (Firth et al. 2018). Khaled et al.

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Fig. 5.3 Semi-solid extrusion technique in the pharmaceutical development of human and animal treatments, the main drug therapeutic classes employed and other applications. *ODS Orodispersible

(2015b) employed SSE to produce a polypill for the controlled release of captopril, nifedipine and glipizide (Fig. 5.4a). HMPC was used as the hydrophilic polymeric matrix, and captopril was incorporated at a porous osmotic compartment at the bottom of the tablet, while nifedipine and glipizide were individually placed inside an upper open compartment that allowed the sustained diffusion of the drugs. The authors demonstrated the feasibility of producing a tablet containing three drugs, located in separated compartments to avoid incompatibility issues and with different and defined release mechanisms (Khaled et al. 2015b).

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Fig. 5.4 (a) Polypill containing captopril in the bottom compartment, and nifedipine (hole I) and glipizide (hole II) individually located in the sustained release compartments (Khaled et al. 2015b); (b) Gastric-floating clarithromycin delivery system (Chen et al. 2021); (c) Chocolatebased formulations containing paracetamol and ibuprofen (Karavasili et al. 2020); (d) Ranitidine paediatric gummy formulations (Herrada-Manchón et al. 2020); (e) Oral mucoadhesive film containing triamcinolone acetonide-loaded mesoporous silica particles (Schmidt et al. 2022); (f) Tacrolimus suppositories (Seoane-Viaño et al. 2021b); (g) Gabapentin ChewTs for veterinary use (Sjöholm et al. 2022); (h) Redispersible 3D printed tablet containing resveratrol and curcumin coencapsulated in organic nanocarriers (de Oliveira et al. 2022). All the figures are reproduced with permission from Copyright Elsevier (please see the Acknowledgements section for details)

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More recently, Goh et al. (2021) produced SSE 3D printed polypills with multiple release profiles for the delivery of caffeine and vitamin B analogues. The polypill was developed with two compartments: the inner core for the sustained release of caffeine and the outer shell containing vitamin B analogues for immediate release. CraftBlends™ excipients for 3D printing were chosen to achieve different release profiles. Craft Blend R30M, containing disintegrants and binders, was the main component of the outer shell, meant to achieve total vitamin B dissolution in 30 min in simulated gastric fluid. Meanwhile, Craft Blend R4H excipients, composed of binders and gel forming agents, were used for the inner core, to achieve a sustained caffeine dissolution in 4 h in both acidic and basic pH. Continuing to explore the oral route, SSE has also been applied to the manufacture of gastro-floating tablets, which have a higher residence time in gastric fluid, with a sustained drug release and regular plasma concentrations (Li et al. 2018). These systems can be simply prepared by changing the infill percentage of the dosage forms (Li et al. 2018), using a more complex process with a coaxial SSE (Falcone et al. 2021) or by designing a core-shell floating systems (Chen et al. 2021). Li et al. (2018) demonstrated that a lower infill percentage (30 > 50 > 70%), generated a higher floating time (12 > 12 > 8 h) using a dipyridamole 3D printed gastro-floating tablet composed of HPMC K4M (15%), HPMC E15 (15%), microcrystalline cellulose (MCC) PH101 (30%) and PVP K30 (5%). The floating phenomena achieved in simulated gastric fluid could be mostly explained by differences in density and the greater access of air to the inner structure of the printed material. As an alternative approach, propranolol hydrochloride floating systems were developed using coaxial SSE. The polymer alginate (outer channel) and a mixture of the crosslinking agent (Ca2+ ) and the drug (inner channel) were added in two different syringes to produce a hollow filament as a result of the ionotropic gelation of the alginate during the printing process. The developed tablets were able to float for 5 h in an acidic medium containing 0.1 M HCl, and drug release was complete after 6 h (Falcone et al. 2021). A different strategy was proposed by Chen et al. (2021) to produce gastricfloating tablets using multi-nozzle SSE (Fig. 5.4b). They designed a low-density shell using a blend of HPMC K15M CR, Poloxamer 188 and PVP K30 containing the drug clarithromycin, and a floating core of ethylcellulose 20, carbomer 934P and CaCO2 . The micro airbag structure developed by 3D printing added to the interaction of carbomer and CaCO2 (generating CO2 when in contact with water) in the inner tablet structure, increasing the buoyancy of the dosage form, which showed a floating time of more than 10 h. Additionally, a high drug loading was achieved (74.5%), and the total release of clarithromycin was observed in 8 h in acetate buffer medium (pH 5.0). Another relevant application of SSE in the 3D printing of oral dosage forms involves the development of paediatric-friendly formulations (Karavasili et al. 2022, Fig. 5.4c. Chewable (Herrada-Manchón et al. 2020; Tagami et al. 2021) and orodispersible tablets (Díaz-Torres et al. 2021; Suárez-González et al. 2021), among others, have already been reported in the literature to improve patient compliance.

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Zhu et al. (2022) developed 3D printed gummy chewable tablets with a bear shape, a pink colour and an orange flavour. The formulation was mainly composed of gelatin, sodium carboxymethyl starch and carrageenan, and fitted immediate release specifications using the drug pharmacopoeial dissolution medium, with a total propranolol hydrochloride release in 15 min. The combination of gelatin and carrageenan resulted in formulations with good masticatory properties, which were improved by increasing the gelatin in the formulation. Finally, a taste analysis experiment was conducted in a randomised crossover, double-blind trial in healthy humans and the bitterness of the drug was successfully masked by the addition of bitterness inhibitors (γ-aminobutyric acid) and sucralose in the formulation. Using the same perspective, Herrada-Manchón et al. (2020) created SSE 3D printed gummies containing ranitidine hydrochloride and strawberry flavour (Fig. 5.4d). The gummies were printed with four different thermo-reversible inks, combining gelatin, carrageenan and xanthan gum as the main components, and varying the presence or absence of corn starch and ranitidine. The inks with starch in their composition were found to be more appropriate for the SSE 3D printing technique, providing good extrudability and faster restructuring after printing, and the 3D printed form was easily removed from the printing bed. Dissolution studies were performed according to the USP monograph for ranitidine tablets, using the gummies containing ranitidine with or without corn starch. The presence of corn starch resulted in a more extended-release of ranitidine, achieving 60% of drug dissolution in 45 minutes, while almost 100% of the drug was released after 15 minutes in the absence of corn starch, presenting an immediate release-like profile. Also focused on the development of paediatric formulations, hydrochlorothiazide orodispersible printlets with banana flavour were developed using PVP 30 K as the main polymeric matrix. The authors made modifications to the tablet infill and concluded that the disintegration specification of the European Pharmacopoeia for orodispersible tablets (100% in 180 s) could be achieved by reducing the infill percentage to 70%. Moreover, about 80% of the drug was released within 20 min in water, meeting FDA requirements for the developed dosage form (Díaz-Torres et al. 2021). As stated before, the development of dosage forms using SSE 3D printing goes beyond the oral route. A recent review showed that studies devoted to the development of topical dosage forms by SSE have been increasing in the last 3 years, describing the 3D printing of wound dressings, patches, films and scaffolds, for example (de Oliveira et al. 2021). Recent studies have reported the development of scaffolds containing a plant extract intended for the treatment of skin wounds (Ilhan et al. 2020) and the association of mesoporous silica nanoparticles in 3D printed films for application in oral mucosa lesions (Schmidt et al. 2022). Satureja cuneifolia extract was incorporated into SSE feedstock to produce scaffolds for diabetic wound treatment. This plant extract is already known for its antidiabetic, antioxidant, anticholesterolemic and antimicrobial properties (Jafari et al. 2016). A polymeric blend of sodium alginate and PEG was used to formulate the SSE feedstock, mainly due to its biocompatibility, hydrophilic nature, and its ability

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to provide a favourable environment for local cell proliferation. The porous structure of the 3D printed scaffold (