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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Advances in Pharmaceutical Technology
- Sprache: Englisch
3D Printing of Pharmaceutical and Drug Delivery Devices 3D Printing of Pharmaceutical and Drug Delivery Devices Discover the latest, fast-developing technology to help move towards more cost-effective, small-batch, decentralized manufacturing of personalized systems 3D printing has revolutionized manufacturing. Its precision and flexibility have enabled the large-scale production of materials and devices too complex for conventional industrial manufacturing. This has been particularly revolutionary in the field of pharmaceutical production, where 3D printing is being integrated into the manufacture of both drugs and drug delivery devices. It has never been more important for industry professionals to understand this form of production. 3D Printing of Pharmaceuticals and Drug Delivery Devices: Progress from Bench to Bedside offers a comprehensive overview of 3D printing technology and its pharmaceutical applications. It introduces readers to a world in which bespoke drug delivery systems developed for specific users or conditions is rapidly becoming a reality. Its detailed coverage of strategies and industrial processes incorporates the latest research and real-world experience of production. 3D Printing of Pharmaceuticals and Drug Delivery Devices: Progress from Bench to Bedside readers will also find: * A multi-disciplinary authorial team of industry leaders * Discussion of common technical and regulatory barriers and their possible solutions * Far-ranging discussion of pharmaceutical applications across all sectors 3D Printing of Pharmaceuticals and Drug Delivery Devices: Progress from Bench to Bedside is essential reading for pharmaceutical industry professionals and researchers looking to occupy the leading edge.
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Veröffentlichungsjahr: 2024
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ADVANCES IN PHARMACEUTICAL TECHNOLOGY
A Wiley Book Series
Series Editors:
Dennis Douroumis, University of Greenwich, UKAlfred Fahr, Friedrich–Schiller University of Jena, GermanyJűrgen Siepmann, University of Lille, FranceMartin Snowden, University of Greenwich, UKVladimir Torchilin, Northeastern University, USA
Titles in the Series
Hot-Melt Extrusion: Pharmaceutical ApplicationsEdited by Dionysios Douroumis
Drug Delivery Strategies for Poorly Water-Soluble DrugsEdited by Dionysios Douroumis and Alfred Fahr
Computational Pharmaceutics: Application of Molecular Modeling in Drug DeliveryEdited by Defang Ouyang and Sean C. Smith
Pulmonary Drug Delivery: Advances and ChallengesEdited by Ali Nokhodchi and Gary P. Martin
Novel Delivery Systems for Transdermal and Intradermal Drug DeliveryEdited by Ryan Donnelly and Raj Singh
Drug Delivery Systems for Tuberculosis Prevention and TreatmentEdited by Anthony J. Hickey
Continuous Manufacturing of PharmaceuticalsEdited by Peter Kleinebudde, Johannes Khinast, and Jukka Rantanen
Pharmaceutical Quality by DesignEdited by Walkiria S. Schlindwein and Mark Gibson
In Vitro Drug Release Testing of Special Dosage FormsEdited by Nikoletta Fotaki and Sandra Klein
Characterization of Pharmaceutical Nano- and MicrosystemsEdited by Leena Peltonen
Biopharmaceutics: From Fundamentals to Industrial PracticeEdited by Hannah Batchelor
3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to BedsideEdited by Dimitrios A. Lamprou, Dennis Douroumis, and Sheng Qi
Forthcoming Titles:
Process Analytics for PharmaceuticalsEdited by Jukka Rantanen, Clare Strachan and Thomas De Beer
Mucosal Drug DeliveryEdited by Rene Holm
3D Printing of Pharmaceutical and Drug Delivery Devices
Progress from Bench to Bedside
Edited by
DIMITRIOS A. LAMPROU
Queen’s University BelfastLiburn Road, Belfast, United Kingdom
DENNIS DOUROUMIS
School of Science, University of GreenwichMedway Campus, Central AvenueChatham Maritime, United kingdom
SHENG QI
University of East AngliaNorwich Research Park, United Kingdom
This edition first published 2024
© 2024 John Wiley & Sons Ltd.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
The right of Dimitrios A. Lamprou, Dennis Douroumis, and Sheng Qi to be identified as the authors of this work / the editorial material in this work has been asserted in accordance with law.
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Hardback ISBN: 9781119835974; ePub ISBN: 9781119835981; ePDF ISBN: 9781119835998; oBook ISBN: 9781119836001
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“There is nothing impossible to those who dare -
- Alexander the Great”
Contents
Cover
Series Page
Title Page
Copyright Page
Dedication
About the Editors
List of Contributors
Series Preface
Preface
1 Materials for 3D Printing
1.1 Introduction
1.2 Material Processability Considerations for Pharmaceutical 3DP
1.2.1 Thermal Extrusion-Based 3D Printing
1.2.1.1 Thermal Considerations
1.2.1.2 Solubility Enhancement
1.2.1.3 Mechanical Considerations
1.2.2 Semi-Solid Extrusion 3DP
1.2.2.1 Rheological Considerations
1.2.2.2 Example Applications
1.2.3 Powder Bed Fusion 3D Printing
1.2.3.1 Powder Flowability Considerations
1.2.3.2 Powder Packing Density Considerations
1.2.3.3 Powder Energy Absorbance Considerations
1.2.4 Stereolithography 3D Printing
1.3 Classification of Common Materials Used in Pharmaceutical 3DP
1.3.1 Alcohol Derived Polymers
1.3.2 Eudragits
1.3.3 Other Polymers
1.3.4 Graft Polymers
1.3.5 Photocrosslinkable
1.3.6 Natural Materials
1.3.7 Lipid Materials
1.4 Conclusions and Future Perspectives
References
2 The Use of Microstructure Design and 3D Printing for Tailored Drug Release
2.1 Introduction
2.2 3D-Printing Technologies
2.3 3D Design for Drug-Loaded Device
2.3.1 CAD Design-Based Design
2.3.2 Computational Software-Based Design
2.3.3 3D-Printing Parameter-Based Design
2.3.4 Polypills and Complex Designs
2.4 3D Designs Influence Drug Release
2.4.1 Controlling Drug Release
2.4.2 Modifying Drug Release
2.5 Challenges and Perspective
References
3 3D Printing of Oral Solid Dosage Forms Using Selective Laser Sintering
3.1 Introduction
3.2 Operational Principles of Selective Laser Sintering
3.2.1 Manufacturing Challenges for SLS
3.2.2 Laser Selection and Scanning Speed
3.2.3 Powder Material Parameters
3.2.4 Powder Bed and Recoater Parameters
3.3 3D-Printed Oral Dosages
3.4 Advantages of SLS
3.4.1 Printing Features
3.4.2 Control of Surface Properties
3.4.3 Printing of Complex Geometries
3.4.4 Using a Wide Range of Materials
3.4.5 Drug Loading and Dose Combinations
3.4.6 Personalised Dosage Forms
3.4.7 SLS Disadvantages
3.5 Conclusions
References
4 3D Printing for Medical Device Applications
4.1 Introduction
4.2 3D Printers
4.2.1 SLA
4.2.2 FFF
4.2.3 Selective Laser Sintering (SLS)
4.3 Biomaterials for 3D-Printed Medical Devices
4.3.1 Bioresorbable Polymers
4.3.1.1 Synthetic Bioresorbable Polymers
4.3.1.2 Natural Bioresorbable Polymers
4.3.2 Non-Bioresorbable Polymers
4.3.3 Smart Polymers
4.3.4 Metal and Ceramic
4.4 3D-Printed Personalised Medical Devices
4.4.1 Vascular Repair Devices
4.4.2 Splints
4.4.3 Nerve Guidance Conduits
4.4.4 Tissue Engineering
4.4.5 3D Printing in Dentistry
4.4.6 3D-Printed Orthopaedic Devices
4.5 Regulatory
4.6 Future Perspectives
References
5 3D Printed Implants for Long-Acting Drug Delivery
5.1 Introduction
5.2 Types of 3D-Printed Scaffolds
5.2.1 Implantable Scaffolds
5.2.1.1 Passive Implants
5.2.1.2 Active Implants
5.2.2 Injectable Scaffolds
5.2.3 Innovative 3D-Printed Scaffolds
5.3 Critical Parameters in Designing 3D-Printed Implantable Scaffolds
5.3.1 Structural Characteristics
5.3.1.1 Geometry of Implants
5.3.1.2 Porosity Properties and Pore Features
5.3.1.3 Surface Properties
5.3.2 Mechanical Properties
5.3.3 Biological and Physiological Parameters
5.3.3.1 Cellular Adhesion
5.3.3.2 Absorption and Degradation Rates
5.3.3.3 Biocompatibility Aspects
5.4 Critical Parameters in Selecting Materials for 3D-Printed Scaffolds
5.4.1 Materials Used in 3D-Printed Long-Acting Scaffolds
5.4.1.1 Natural Polymers
5.4.1.2 Synthetic Polymers
5.4.1.3 Ceramics and Metals
5.4.1.4 Composites
5.5 Manufacturing Techniques for Implantable Scaffolds
5.5.1 Hot-Melt Extrusion
5.5.2 Compression
5.5.3 Injection Moulding
5.5.4 Solvent Casting
5.5.5 3D Printing
5.5.6 Scale-Up in 3D-Printing Process for the Manufacturing of Scaffolds
5.6 Drug Release Mechanism of Long-Acting 3D-Printing Polymeric Implantable Systems
5.7 Outlining Regulatory Framework for 3D-Printed Implantable Scaffolds
5.7.1 Commercial Implantable Scaffolds
5.8 Conclusions
References
6 Wound Dressings by 3D Printing
6.1 Wound Healing Process
6.1.1 Haemostasis/Coagulation
6.1.2 Inflammation
6.1.3 Proliferation
6.1.4 Re-epithelisation/Remodelling
6.1.5 Wound Classification
6.1.6 Wound Dressings
6.1.7 3D Printing
6.1.8 3D-Printed Dressings
6.2 Case Studies
6.3 Summary/Conclusions
References
7 3D Printing of Hydrogels
7.1 Introduction
7.2 Applications of 3D-Printed Hydrogels
7.2.1 Tissue Engineering
7.2.2 Wound Healing
7.2.3 Drug Delivery
7.3 Types of Hydrogel Materials for 3D Printing
7.3.1 Natural Polymers
7.3.2 Synthetic Polymers
7.3.3 Natural-Synthetic Hybrid Polymers
7.3.4 Ionically Charged Polymers
7.3.5 Crosslinked Polymers
7.3.6 Method of Hydrogel Preparation
7.4 3D Printing Techniques for Hydrogels
7.4.1 Laser-Based 3D Printing
7.4.1.1 Stereolithography
7.4.1.2 Two-Photon Polymerisation
7.4.1.3 Laser-Induced Forward Transfer
7.4.2 Extrusion-Based Printing
7.4.3 Inkjet-Based Printing
7.5 Printability and Printing Parameters
7.5.1 Bioink Design
7.5.1.1 Materials Selection, Concentration and Viscosity
7.5.1.2 Rheological Properties
7.5.1.3 Shear-Thinning
7.5.1.4 Viscoelasticity and Yield Stress
7.5.1.5 Cell Encapsulation
7.5.2 Crosslinking Techniques
7.5.2.1 Thermal Crosslinking
7.5.2.2 Physical Ionic Crosslinking
7.5.2.3 Chemical Crosslinking
7.5.2.4 Photocrosslinking
7.5.3 3D Printing Parameters
7.5.3.1 Temperature
7.5.3.2 Pressure
7.5.3.3 Speed
7.6 Clinical Translation
7.6.1 Regulatory Considerations
7.6.2 Manufacturing Considerations
7.6.3 Limitations and Future Direction
7.7 Conclusions
References
8 Analytical Characterisation of 3D-Printed Medicines
8.1 Introduction
8.2 Preformulation
8.2.1 Thermal Analysis
8.2.2 X-Ray Powder Diffraction (XRPD)
8.2.3 Infrared Spectroscopy
8.2.4 Hot-Stage Microscopy (HSM)
8.2.5 Customizsd Sample Preparation for the Preformulation Protocol
8.3 In-Process Characterisations
8.3.1 Mechanical Analysis
8.3.2 Rheological Analysis
8.3.3 Drug Characterisation
8.4 Final Product
8.4.1 Morphological Analysis
8.4.2 X-Ray Computed Microtomography (XμCT)
8.4.3 Terahertz Pulsed Imaging (TPI)
8.4.4 Mercury Porosimetry
8.4.5 Helium Pycnometry
8.5 Conclusions
References
9 Adoption of 3D Printing in Pharmaceutical Industry
9.1 Partnering and Growing
9.2 Regulatory Strategy
9.2.1 Product Development
9.2.2 Manufacturing
9.3 Business Model
9.3.1 In-House Pipeline Products
9.3.2 Co-Development
9.4 Regulatory Strategy
9.5 Partnering and Growing
9.6 Business Model and Strategy
9.6.1 Closing Remarks
References
10 Clinical Benefits of 3D Printing in Healthcare
10.1 Introduction
10.2 3D Printing Technologies
10.2.1 Binder Jetting
10.2.2 Vat Photopolymerization
10.2.3 Powder Bed Fusion
10.2.4 Material Jetting
10.2.5 Material Extrusion
10.2.5.1 Fused Deposition Modelling
10.2.5.2 Semi-Solid Extrusion
10.2.5.3 Direct Powder Extrusion
10.3 Preclinical Applications of 3D Printing
10.3.1 Immediate and Modified Release Oral Printlets
10.3.2 3D-Printed Drug Delivery Devices for Other Routes of Administration
10.4 Clinical Applications of 3D Printing
10.4.1 Personalised Medications
10.4.2 Improved Acceptability and Medication Compliance
10.4.2.1 Paediatric Patients
10.4.2.2 Adult and Geriatric Patients
10.4.3 Mass Manufacturing
10.4.4 Decentralised On-Demand Fabrication
10.4.5 Veterinary Applications
10.5 Challenges, Regulatory View and Future Applications
10.6 Conclusion
References
11 Regulatory Aspects of 3D-Printed Medicinal Products
11.1 Introduction
11.2 Current Regulatory Framework
11.3 Quality Aspects of 3D-Printed Medicinal Products
11.4 3D-Printed Paediatric Medicinal Products
11.5 3D-Printed Systems With Tailored Release Profiles
11.6 Conclusions
Disclaimer
References
Index
End User License Agreement
List of Tables
CHAPTER 01
Table 1.1 Examples of polymers...
Table 1.2 Examples of solid...
Table 1.3 Example materials...
Table 1.4 Example materials...
Table 1.5 Additional functional...
CHAPTER 02
Table 2.1 Deposition-based...
CHAPTER 04
Table 4.1 Examples of commercial...
Table 4.2 Non-bioresorbable...
CHAPTER 05
Table 5.1 Categories of...
Table 5.2 Advantages and...
Table 5.3 Advantages and...
Table 5.4 Commercial...
Table 5.5 Drug release...
CHAPTER 06
Table 6.1 Summary of the...
Table 6.2 Summary of 3D-printed...
CHAPTER 11
Table 11.1 Commonly employed...
List of Illustrations
CHAPTER 01
Figure 1.1 (a) The temperature...
Figure 1.2 Drug delivery...
Figure 1.3 Visualisation...
Figure 1.4 Process of...
CHAPTER 02
Figure 2.1 3D printing for...
Figure 2.2 The general class...
Figure 2.3 The critical steps...
Figure 2.4 Different methods...
Figure 2.5 Computational...
Figure 2.7 (a) The appearances...
Figure 2.6 (a) Sample cross-section...
Figure 2.8 Various types...
CHAPTER 03
Figure 3.1 Historic...
Figure 3.2 Typical...
Figure 3.3 Diagram...
Figure 3.4 Ishikawa...
Figure 3.5 Flow function...
Figure 3.6 Kollidon and...
Figure 3.7 Paracetamol...
Figure 3.8 Printed minipellets...
Figure 3.9 (a) Printed KVA64...
Figure 3.10 The example of...
Figure 3.11 (a) Images of...
Figure 3.12 Effect of laser...
CHAPTER 04
Scheme 4.1 Evolution of...
Scheme 4.2 Typical synthetic...
CHAPTER 05
Figure 5.1 Classification...
Figure 5.2 Mechanisms of...
Figure 5.3 Critical attributes...
Figure 5.4 Illustration...
Figure 5.5 Illustration...
Figure 5.6 Illustration...
Figure 5.7 Illustration...
Figure 5.8 Biological evaluation...
CHAPTER 06
Figure 6.1 Differences in...
Figure 6.2 Summary of the...
Figure 6.3 Classification...
Figure 6.4 Schematic illustration...
Figure 6.5 (a) Schematic...
Figure 6.6 Confocal images...
Figure 6.7 3D-printed...
Figure 6.8 3D scan model...
Figure 6.9 Process scheme...
CHAPTER 07
Figure 7.1 Schematic of...
Figure 7.2 The three main...
Figure 7.3 Hydrogel ink...
Figure 7.4 Filament formation...
CHAPTER 08
Figure 8.1 3D-printing...
Figure 8.2 Schematic illustration...
Figure 8.3 Hypothetical...
Figure 8.4 Hypothetical...
Figure 8.5 Hypothetical...
Figure 8.6 Schematic illustration...
Figure 8.7 Hypothetical FTIR...
Figure 8.8 Schematic illustration...
Figure 8.9 Schematic illustration...
Figure 8.10 Hypothetical stress-strain...
Figure 8.11 Hypothetical graphical...
Figure 8.12 Hypothetical graphical...
Figure 8.13 Hypothetical graphical...
Figure 8.14 Hypothetical graphical...
Figure 8.15 Schematic illustration...
Figure 8.16 Schematic illustration...
Figure 8.17 (A) Hypothetical...
Figure 8.18 Hypothetical (A)...
CHAPTER 09
Figure 9.1 Illustration of the...
CHAPTER 10
Figure 10.1 Pharmaceutical...
Figure 10.2 (A) Schematic...
Figure 10.3 (A) Images and...
Figure 10.4 (A) (Left) 3D...
Figure 10.5 (A) SSE 3D-printed...
Figure 10.6 Images of (A)...
Figure 10.7 (A) Image of chewable...
Figure 10.8 Design and preparation...
Figure 10.9 (A) Outline of the...
Figure 10.10 (A) Images of Printlets...
Figure 10.11 Images of (A) SLS...
Figure 10.12 The virtual cycle...
CHAPTER 11
Figure 11.1 Fishbone diagram...
Figure 11.2 Selecting a polymer...
Guide
Cover
Series Page
Title Page
Copyright Page
Dedication
Table of Contents
About the Editors
List of Contributors
Series Preface
Preface
Begin Reading
Index
End User License Agreement
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About the Editors
Dimitrios A. Lamprou
Dimitrios A. Lamprou is Full Professor (Chair) of Biofabrication and Advanced Manufacturing at Queen’s University Belfast. Dimitrios has been recognized as world leader in 3D Printing and has also been named in the Stanford University’s of World’s Top 2% Scientists. He is currently the author of over 150 peer-reviewed publications and of over 350 conference abstracts, and has given over 150 Invited Talks to institutions and conferences across the world. His research and academic leadership have been recognized in a range of awards, including the Royal Pharmaceutical Society of Great Britain Science Award and the Scottish Universities Life Sciences Alliance Leaders Scheme Award.
Dennis Douroumis
Dr. Dennis Douroumis is a professor in Pharmaceutical Technology and Process Engineering at the University of Greenwich, UK
His research activities focus on emerging technologies including: (a) 3D printing technologies for pharmaceutical dosage forms or novel medical devices (microneedles, bioresorbable scaffolds), (b) Continuous manufacturing processes for the development of medicinal products, and (c) Nanomaterial synthesis and surface modification for cancer treatment.
Dennis has established several national and international collaborations with world-class colleagues/researchers including industrial funded projects and several EU/UK grants. He received the prestigious award of Eminent Fellowship of the Academy of Pharmaceutical Sciences for the excellence in the pharmaceutical sciences over a prolonged period with an emphasis on advocacy and leadership. He has also received an award for his “Outstanding Scientific Contribution” in Pharmaceutical Processes and invited to deliver the Award Lecture, sponsored by AstraZeneca.
Sheng Qi
Sheng Qi is Professor of Pharmaceutical Material Science and Technology at the School of Pharmacy of the University of East Anglia (UEA). She runs a dynamic research group with most projects co-created and developed with relevant industrial partners/collaborators to address real-world clinically unmet needs. Sheng has great interests in material science and processing, and passion in innovation. By working closely with industrial partners as well as cross-discipline collaborators, her research has contributed to product development and innovations in many industrial sectors, from pharmaceutical, medical device to food, cosmetic, agri-tech and sustainable packaging. Within the field of pharmaceutical 3D printing, her efforts focus on the development of a fundamental understanding on how to adapt industrial 3D printing methods to safely process pharmaceutical materials and manufacture pharmaceutical products. She founded and leads the UEA Health and Social partner (UEAHSCP) Point of Care 3D Printing Research Group. The research group create the network for academic scientists to work closely with clinicians, pharmacists, and patients in Norfolk and Suffolk to identify and develop efficient and cost-effective uses of 3D printing in acute hospital environments for improving patient care.
List of Contributors
Sune Andersen, Research & Development Department, Janssen, Beerse, Belgium
Atheer Awad, UCL School of Pharmacy, University College London, London, UK and Department of Clinical, Pharmaceutical and Biological Sciences, University of Hertfordshire, Hatfield, UK
Abdul Basit, UCL School of Pharmacy, University College London, London, UK and FABRX Ltd., Henwood House, Henwood Ashford, Kent, UK and FABRX Artificial Intelligence, Carrete ra de Escairón, Currelos (O Saviñao), Spain
Fotios Baxevanis, Medicines & Healthcare Products Regulatory Agency, London, UK
Peter Belton, School of Chemistry, University of East Anglia, Norwich, UK
Richard Bibb, School of Design & Creative Arts, Loughborough University, Loughborough, UK
Joshua Boateng, School of Science, Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK
Cecile Boudot, Evonik Corporation, Birmingham, Alabama, US
Sam Boulton, Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK
Yahya E. Choonara, Wits Advanced Drug Delivery Platform Research Unit, School of Therapeutic Sciences, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg, South Africa
Marcilio Cunha-Filho, Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences, University of Brasilia, Brasília, Brazil
Mahokh Dadsetan, Evonik Corporation, Birmingham, Alabama, US
Aikaterini Dedeloudi, School of Pharmacy, Queen’s University Belfast, Belfast, UK
Dennis Douroumis, Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK and Delta Pharmaceutics Ltd., Kent, UK
Andrea Engel, Evonik Corporation, Birmingham, Alabama, US
Atabak Tabriz Ghanizadeh, Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK and Delta Pharmaceutics Ltd., Kent, UK
Andy Gleadall, School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, UK
Alvaro Goyanes, UCL School of Pharmacy, University College London, London, UK, FABRX Ltd., Henwood House, Henwood Ashford, Kent, UK, FABRX Artificial Intelligence, Carrete ra de Escairón, Currelos (O Saviñao), Spain and Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, iMATUS and Health Research Institute of Santiago de Compostela, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
Peyton Hopson, Advanced Engineering and Technology Department, Johnson & Johnson, Jacksonville, Florida, US
Scott Jones, Evonik Corporation, Birmingham, Alabama, US
Thomas Kipping, Life Science, Process Solutions and Formulation Materials, Merck Life Science KGaA, Darmstadt, Germany
Theresia Kuntz, Evonik Operations GmbH, Kirschenallee, Darmstadt, Germany
Hannah Kuofie, Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK
Dimitripos A. Lamprou, School of Pharmacy, Queen’s University Belfast, Belfast, UK
Ana Luiza Lima, Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences, University of Brasilia, Brasília, Brazil
Maria Malamatari, Medicines & Healthcare Products Regulatory Agency, London, UK
Thomas McDonagh, School of Pharmacy, University of East Anglia, Norwich, UK
Sheng Qi, School of Pharmacy, University of East Anglia, Norwich, UK
Poornima Ramburrun, Wits Advanced Drug Delivery Platform Research Unit, School of Therapeutic Sciences, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg, South Africa
Lívia L. Sá-Barreto, Faculty of Ceilandia, University of Brasilia (UnB), Brasília, Brazil
James Scoble, Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK
Iria Seosne-Viaño, UCL School of Pharmacy, University College London, London, UK and Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Paraquasil Group (GI-2109), Faculty of Pharmacy, iMATUS and Health Research Institute of Santiago de Compostela, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
John Tipton, Evonik Corporation, Birmingham, Alabama, US
Bernanbe Tucker, Evonik Corporation, Birmingham, Alabama, US
Ka-Wai Wan, Medicines & Healthcare Products Regulatory Agency, London, UK
Joey Yan, School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, UK
Bin Zhang, School of Pharmacy, University of East Anglia, Norwich, UK
Jian-Feng Zhang, Evonik Corporation, Birmingham, Alabama, US
Advances in Pharmaceutical Technology: Series Preface
The series Advances in Pharmaceutical Technology covers the principles, methods and technologies that the pharmaceutical industry uses to turn a candidate molecule or new chemical entity into a final drug form and hence a new medicine. The series will explore means of optimizing the therapeutic performance of a drug molecule by designing and manufacturing the best and most innovative of new formulations. The processes associated with the testing of new drugs, the key steps involved in the clinical trials process and the most recent approaches utilized in the manufacture of new medicinal products will all be reported. The focus of the series will very much be on new and emerging technologies and the latest methods used in the drug development process.
The topics covered by the series include the following:
Formulation: The manufacture of tablets in all forms (caplets, dispersible, fast‐melting) will be described, as will capsules, suppositories, solutions, suspensions and emulsions, aerosols and sprays, injections, powders, ointments and creams, sustained release and the latest transdermal products. The developments in engineering associated with fluid, powder and solids handling, solubility enhancement, colloidal systems including the stability of emulsions and suspensions will also be reported within the series. The influence of formulation design on the bioavailability of a drug will be discussed and the importance of formulation with respect to the development of an optimal final new medicinal product will be clearly illustrated.
Drug Delivery: The use of various excipients and their role in drug delivery will be reviewed. Amongst the topics to be reported and discussed will be a critical appraisal of the current range of modified‐release dosage forms currently in use and also those under development. The design and mechanism(s) of controlled release systems including macromolecular drug delivery, microparticulate controlled drug delivery, the delivery of biopharmaceuticals, delivery vehicles created for gastrointestinal tract targeted delivery, transdermal delivery and systems designed specifically for drug delivery to the lung will all be reviewed and critically appraised. Further site‐specific systems used for the delivery of drugs across the blood–brain barrier including dendrimers, hydrogels and new innovative biomaterials will be reported.
Manufacturing: The key elements of the manufacturing steps involved in the production of new medicines will be explored in this series. The importance of crystallisation; batch and continuous processing, seeding; and mixing including a description of the key engineering principles relevant to the manufacture of new medicines will all be reviewed and reported. The fundamental processes of quality control including good laboratory practice, good manufacturing practice, Quality by Design, the Deming Cycle, Regulatory requirements and the design of appropriate robust statistical sampling procedures for the control of raw materials will all be an integral part of this book series.
An evaluation of the current analytical methods used to determine drug stability, the quantitative identification of impurities, contaminants and adulterants in pharmaceutical materials will be described as will the production of therapeutic bio‐macromolecules, bacteria, viruses, yeasts, moulds, prions and toxins through chemical synthesis and emerging synthetic/molecular biology techniques. The importance of packaging including the compatibility of materials in contact with drug products and their barrier properties will also be explored.
Advances in Pharmaceutical Technology is intended as a comprehensive one‐stop shop for those interested in the development and manufacture of new medicines. The series will appeal to those working in the pharmaceutical and related industries, both large and small, and will also be valuable to those who are studying and learning about the drug development process and the translation of those drugs into new life saving and life enriching medicines.
Dennis DouroumisAlfred FahrJűrgen SiepmannMartin SnowdenVladimir Torchilin
Preface
Over the last 10 years the science and technological advances of three-dimensional (3D) printing (3DP) have significantly evolved. The first 3D printer was developed in early 80s by Chuck Hull, who used a technology called stereolithography (SLA) patented in 1988 by 3D Systems. Since then, we have witnessed a technological transformation where a wide range of 3DP technologies have found applications in several sectors including, art, automotive, aerospace, pharmaceutical, biomedical sciences, tissue engineering and regenerative medicine, among other sectors.
After first approval of Spritam (Apreicia Pharmaceuticals) in 2015 by the US Food and Drug Administration (FDA), 3DP technologies have attracted considerable interest among academia and industry. All three Editors are actively involved in the development of pharmaceutical dosage forms using a variety of 3DP technologies and particularly in personalised medicines, medical devices or implants, which used to edit this very important new book in this developed area. The main aim was to gather the collective experience of eminent scientists in the field to present recent trends and advances that will be of use to experienced researchers, educators or students who are actively involved in 3DPg.
It is anticipated that 3DP will revolutionise the pharmaceutical sector in the manufacturing of small batches or preclinical evaluation of new formulations, due to its unique advantages for customised dosage from in terms of dose strength, size, shape and release rates. Therefore, pharmaceutical industry will enter a new era moving to personalised dosage forms moving from the “one-size-fits-all” approach. In the near future medicines will be manufactured at the point of care (e.g., hospitals, pharmacies) to meet patient needs and improve clinical outcomes. Moreover, 3DP technologies offer a new business model through the transition from a manufacturer-centric to a consumer-centric logic and decentralised supply chain. Hence, it will offer better efficiency due to the low inventory and operating cost, less waste and print on demand personalised medicines with increased patients’ access. However, the landscape in printing pharmaceuticals is not clear yet and there is a pressing need for greater flexibility both in manufacturing and regulatory matters.
The first Chapter provides an overview of key processing properties and critical attributes of materials used in a range of 3DP technologies. Excellent understanding of material properties is crucial for the development of designs with specific features but also for the selection of the appropriate printing technologies. The second chapter introduces additional 3DP technologies discussing challenges and perspectives. In addition, it covers a range of critical aspects from the computer-aided design (CAD) to the control of printing parameters and how those can be tuned to control drug release of printed dosage forms.
The third chapter introduces one of the upcoming printing methods in pharmaceutics, Selective Laser Sintering (SLS), as an emerging printing technology for the development of pharmaceutical dosage form, varying from small to large batch manufacturing or personalised dosage forms. It describes critical material properties and process parameters though a number of case studies.
Chapters 4 and 5, provide a comprehensive overview of 3DP technologies use for the fabrication of personalised medical devices and implantable drug delivery systems. The structural characteristics, such as geometry, porosity, surface properties and mechanical properties including biological aspects are among the elements someone should consider for the design of medical devices. The selection of appropriate polymers and 3DP technology, are presented in detail for a range of application such as tissue engineering, dentistry and orthopaedics. Regulatory matters related to medical devices are also discussed, briefly.
Chapters 6 and 7 are dedicated to the printing of hydrogels in various fields including wound healing, tissue engineering and drug delivery purposes. The consideration and selection of suitable materials depending on the 3DP technology are presented in detail along with limitations and future directions.
Chapter 8 presents a range of analytical techniques that are used for pre-formulation studies and particularly for the selection of materials prior to 3DP followed by advanced technologies introduced for structural characterization of the end product. In this chapter, the reader will be informed about the features and expected outcomes of analytical techniques.
The last three chapters provide the landscape on 3DP technologies for pharmaceutical product manufacturing including existing commercial applications and business models. This includes decentralised manufacturing and collaborative partnerships for the commercialization of marketed products. Emphasis is given on clinical challenges for the development of customised paediatric, geriatric or even veterinary dosages forms. Finally, a widespread overview of the existing regulatory framework and guidance for 3D printed medicinal products particularly in United Kingdom (UK) and European Union (EU) is introduced. Quality aspects embracing Quality by Design (QbD), process analytical technology (PAT) tools, and excipients safety for additive manufacturing (AM) are also discussed.
Prof. Dimitrios Lamprou (Queen’s Belfast University)Prof. Dennis Douroumis (University of Greenwich)Prof. Sheng Qi (East Anglia University)
1 Materials for 3D Printing
Thomas McDonagh, Bin Zhang and Sheng Qi
School of Pharmacy, University of East Anglia, Norwich, UK
1.1 Introduction
Three-dimensional printing (3DP), also known as Additive Manufacturing (AM), has emerged as an exciting technology for the manufacture of pharmaceutical products for personalised patient treatment. The interindividual variability of the human population is a constant challenge when striving for effective drug delivery because patients come in different shapes, sizes, ages, genetics, and necessities and so require medication personalised to their needs for the most effective outcomes [1, 2]. 3DP has been shown to be a flexible technique that can be used to manufacture drug delivery devices (DDDs) for a wide array of applications such as tablets, implants, microneedles, and suppositories [3–5]. In addition, compared to conventional large-scale production techniques such as tablet pressing, 3DP is much more flexible with the potential to simplify supply chains and accelerate development cycles. Such traits make 3DP an ideal candidate technology to produce on-demand personalised medicines and in turn improve patient quality of life. However, there are still several challenges hindering its adoption. Limited availability of biocompatible materials, the incompatibility of the active pharmaceutical ingredient) (API), and/or polymer with the printing conditions, and regulatory hurdles present a significant challenge when designing 3DP pharmaceutical products. This is highlighted by the presence of just one 3DP pharmaceutical product currently on the market as of 2023, Spritam® [6].
Material choice is a fundamental consideration when designing a pharmaceutical dosage form. All drug products are comprised of an API (the bioactive component) and inactive functional excipients which facilitate the release of the API to the target location in the body. With the advance of 3D-printing medicine, API carrier materials have an increasingly important role in not only protecting the API in a convenient printable package and disguising unpalatable ingredients but also in facilitating complex release profiles. Several 3D-printing techniques are applicable for manufacturing DDD: Thermal Extrusion-based deposition systems (TE); Semi-solid extrusion (SSE); Stereolithography (SLA); and Powder Bed fusion (PBF). Successful printing of pharmaceuticals requires consideration of the nature of the 3D-printing process. Each technique has its own benefits and limitations in terms of material compatibility, print quality, and scalability and so must be considered as a whole when designing a new DDD. The objective of this chapter is to first discuss each printing technique, exploring the key material characteristics and processing parameters that influence both printability and drug delivery performance. Subsequently, the materials which have shown suitability for 3DP manufacture of DDD will be discussed with a focus on the key material attributes relevant for printing and drug release properties.
1.2 Material Processability Considerations for Pharmaceutical 3DP
1.2.1 Thermal Extrusion-Based 3D Printing
Thermal extrusion (TE)-based 3D printing is a popular solvent free 3DP technique for printing thermoplastic polymer and API formulations. In TE printing, thermal energy is applied to a print head to melt material, enabling extrusion through a nozzle onto a build plate. Thermoplastic polymers are used because they are composed of long linear chains, held together by weak attraction forces. When subjected to high temperatures in the print head, they soften or melt to enable extrusion before solidifying upon cooling. The nozzle and/or build plate are controlled by linear actuators that enable precise deposition into a pre-defined geometry in a layer-by-layer fashion according to a 3D digital model. Good print resolution is achievable with resolutions typically between 100 μm and 400 μm [7, 8], depending on the diameter of nozzle used. A benefit of TE printing is the minimal post processing requirements. Printed parts are full strength immediately after printing and unlike other 3DP techniques, no washing or drying steps are required. Furthermore, release rates of TE drug products are highly tuneable by varying printing software parameters such as infill density [9]. Due to the mechanical stability of TE drug products, this technique appears to be more suitable for controlled or sustained release applications [10, 11], although immediate release pharmaceutical products have also been explored [12].
Most current TE 3DP technologies are not compatible with the direct printing of raw powder materials. Direct TE of powders presents challenges in terms of feeding (poor flowability), homogenous mixing, and degassing (trapped air between powder particles) [13]. As such, a prior hot-melt extrusion (HME) step is commonly used to sufficiently mix reagents and process them into a more attractive feedstock for printing. In HME, heat and mechanical shear is used to mix reagents producing a homogenous melt which can be extruded into uniform filaments. Most pharmaceutical polymers require a temperature of at least 15 °C to 60 °C above their glass transition (Tg) to be sufficiently molten for processing [14]. Filaments can be printed using the widespread, low-cost technology fused deposition modelling (FDM) or can be pelletised into granules for use with direct granule TE.
1.2.1.1 Thermal Considerations
The first material processability consideration for TE 3DP concerns the thermal processing. Thermal processing presents a challenge when working with pharmaceutical formulations because some API and polymers are thermolable and will begin to degrade at high temperatures, reducing the efficacy of the pharmaceutical product. Additionally, formulation viscosity is intrinsically linked to temperature. High temperatures increase the kinetics of a formulation, reducing its apparent viscosity [15]. Therefore, successful TE operates within a temperature window that sufficiently reduces the viscosity of the polymer melt (above Tmin) to enable good mixing and extrusion, whilst maintaining the API stability (below the thermal degradation temperature). To ensure solubility of API in the polymer melt, a third boundary temperature is often introduced, called the solubility line (Tc) [16]. This theoretical design space is shown in Figure 1.1. The design space can be seen to shrink for high drug load formulations due to the increased Tc required to solubilise the API. Additionally, increased residence time in the HME can be used to increase API dissolution but also increases the likelihood of thermal degradation. These same design constraints are also applicable when printing. Lower than optimal printing temperatures increase formulation viscosity that can cause nozzle blockages and low bond strength between printed layers [17] and high temperatures can result in further API degradation and poor print quality.
Figure 1.1 (a) The temperature–composition phase diagram of the hot-melt extrusion process. The temperature design space falls below the thermal degradation temperature and, depending on composition, above the solubility line or polymer’s minimum processing temperature Tmin. Product phase behaviour is governed by the solubility line (formulation Tc) and formulation glass transition Tg. (b) Hot-melt extrusion process operating design space diagram. Three processing regimes (melting, dissolution, and suspension) can be delineated by temperature and kinetic considerations. (Source: Reproduced from [18] with permission from Elsevier 2018.)
Whilst some sensitive API may appear to be incompatible with TE due to low thermal degradation temperatures (Tdeg), strategies exist to reduce the thermal load on formulations enabling printing at lower temperatures. By using these techniques, a wide variety of polymers and API has been successfully printed, with drug loadings from 5% to 60% w/w shown to be feasible [19]. The first technique involves carefully selecting polymers and excipients which are extrudable at low temperatures. This generally involves use of plasticisers which act as a lubricant between segments of polymer chains, thus increasing the materials flexibility and softness. Kollamaram et al. succeeded in printing Ramipril and 4-aminosalicylic acid (4-ASA) loaded tablets using a PVP PVP-VA copolymer system plasticised with PEG 1500 [20]. Ramipril is transformed into the impurity diketopiperazine upon exposure to temperatures higher than its melting point (109 °C) and 4-ASA begins to degrade at 130 °C. Filaments loaded with 3% drug were obtained by HME at 70 °C and tablets were printed at 90 °C. HPLC analysis confirmed that both drugs were stable with no signs of degradation, demonstrating how the careful selection of polymer and plasticiser can enable the printing of thermolabile API at low temperatures. Another technique involves avoiding the thermal and mechanical stress induced during HME altogether by using filament impregnation. The filament impregnation technique was first reported in 2014 [21], where API was loaded into the filament post HME by soaking in a saturated alcoholic drug solution. Whilst several authors have reported on the impregnation technique for DDD applications, drug loading is very low (<3% w/w) [22–24], limiting its use to drugs with therapeutic effects at low dose [25]. Additionally, whilst the impregnation method does avoid the thermal stress induced during HME, the API still has to pass through the heated print head. Goyanes et al. used this method to load 4-ASA into commercially produced Polyvinyl alcohol (PVA) filaments by soaking in a saturated ethanolic drug solution for 24 hours before printing [26]. After printing at 210 °C, the already limited drug loading was reduced by approximately half to 0.12% w/w, indicating that even though residence time in the print head is short (a few seconds) it is sufficient for significant degradation of thermolabile drugs.
1.2.1.2 Solubility Enhancement
One area in which thermal extrusion 3DP coupled with HME has shown great promise is in enhancing the bioavailability of poorly soluble API, opening the door to a host of molecules previously considered unviable as drugs [27]. More than 40% of new chemical entities produced during drug discovery exhibit poor solubility characteristics, greatly limiting their therapeutic effectiveness [28]. API can exist either as a solid suspension or be partially or fully dissolved in the polymer matrix. This crystallinity is highly influence by processing conditions (Figure 1.1). It is desirable that API remain in the amorphous form in DDD so that the dissolution, dispersion, or erosion of the tablets mediate the drug release rather than the solubility of the crystalline drugs. The intense mixing and heating imposed by the rotating screws in HME can cause the API molecules to dissolve in the molten polymer, transforming the crystalline drug into a more uniform, amorphous dispersion. With the drug in an amorphous form, no energy is required to break the drug crystal lattice. For this reason, relative to the crystalline form, the amorphous form of many poorly water-soluble drugs can achieve substantially higher apparent solubility and markedly faster dissolution [29]. For successful results, polymer and functional excipients should be carefully chosen to maximise API solubility. Polymer-API miscibility can be predicated using the Hansen solubility parameter [30]. For poorly miscible formulations, the drug may crystallise out during storage, resulting in physical stability issues and variability in drug release. Sometimes crystallisation inhibitors are added to formulations which can help slow this process [31].
1.2.1.3 Mechanical Considerations
In the case of FDM printing, filament strength and flexibility are a further processing consideration. For successful FDM printing, filaments must possess good mechanical strength and flexibility to endure the FDM feeding mechanism. This is a significant challenge for DDD applications because most pharmaceutical grade polymers lack such attributes, being either too brittle so that the filaments break in the motor gear or too soft so that they cannot be pushed by the drive gear, thus hindering printing [32, 33]. Recent efforts have been focused on using rheology, filament mechanical screening, and machine learning to identify useful parameters that can be used as predictive tools in pharmaceutical development [34–37]. Xu et al. found toughness to be an effective predictive parameter of filament printability using a simple stiffness test [38]. After screening over 30 in-house manufactured filaments, they found stiffness values greater than 80 g/mm2 % to be a good indicator of filament printability. When modifying formulations to improve processability, it is important to consider the effects additional excipients will have on the function of the drug product. It is common to incorporate large quantities of additives and plasticisers into the formulation which often do not add any functionality to the main drug delivery and absorption functions, leading to the design of complex formulations with increased weight and increased potential for the adverse stability of the pharmaceutical product. Recently emerging TE techniques, termed direct powder/granule deposition TE, have focused on bypassing the need for filament forming. Using this technique, the HME extrusion and printing steps are effectively combined in a single step printing process. This not only simplifies DDD manufacture but can also be used to print formulations that would not be suitable for forming filaments. Goyanes et al. used a direct single-screw powder extruder (FabRx, UK) to prepare sustained release itraconazole printlets (3D-printed tablets) [39]. McDonagh et al. used a similar granule fed 3DP technology, Arburg Plastic Freeforming (APF), to explore the printability of non-FDM printable formulations [40]. Eudragit E PO, a very brittle polymer loaded with paracetamol, was successfully printed into immediate release tablets without the use of plasticisers. The simplified manufacturing process and more versatile material feed mechanism make direct powder/pellet thermal extrusion an exciting 3DP technology for the future. Table 1.1 summaries the typical polymers used in thermal extrusion 3D printing of solid dosage forms, which are used widely beyond the example studies listed here.
Table 1.1 Examples of polymers used in thermal extrusion 3D printing of pharmaceuticals.
Polymer
Drug
Printer
Application
Polyvinyl Alcohol
(PVA)
Budesonide
MakerBot Replicator 2X Desktop
Controlled release tablets [
41
]
Hydroxypropyl Methylcellulose (HPMC)
Ibuprofen
MakerBot Replicator 2X Desktop
Controlled release tablets [
42
]
Polycaprolactone (PCL)
Ibuprofen
Prusa i3 Mk3S
Controlled release tablets [
9
]
Eudragit
®
E
Paracetamol
Arburg Plastic Freeformer
Immediate release tablets [
40
]
Polyurethanes
Dapivirine
Arburg Plastic Freeformer
Controlled release vaginal rings [
43
]
Hydroxypropylcellulose
Itraconazole
FabRx M3DIMAKER™
Sustained release printlets [
39
]
Ethylene Vinyl Acetate (EVA)
Indomethacin
MakerBot Replicator 2X Desktop
Intrauterine implant [
44
]
PLA, PVA, HPMC, HPMCAS, Kollicoat
®
IR, PEG, Triethyl Citrate
Paracetamol
MakerBot Replicator 2X Desktop
Two pulse, oral drug delivery [
45
]
PVA, Sorbitol
Lisinopril Dihydrate, Indapamide, Rosuvastatin Calcium and Amlodipine Besylate
MakerBot Replicator 2X Desktop
Polypill [
46
]
1.2.2 Semi-Solid Extrusion 3DP
Semi-solid extrusion (SSE), also known as pressure-assisted micro syringe (PAM), is a 3DP technique used to print pastes, hydrogels, and other viscous polymer systems. The working principle of SSE is similar to thermal extrusion 3DP in the sense that viscous formulations are extruded through a nozzle to form a 3D structure according to a designed geometry. However, SSE relies on use of a solvent rather than high temperature to obtain the rheological properties to enable extrusion. This allows for much milder printing conditions that enable processing of many biocompatible materials. Khaled et al. state that if a polymer can be processed into powder form, it can be printed using PAM [47]. Room temperature printing is hugely beneficial when working with thermo-sensitive API [4]. However, solvent use also presents challenges in terms of toxicity, API stability, and print quality because a drying step is required post printing that can result in significant shrinkage. SSE printing has shown promise for developing drug eluting tablets [48] and soft scaffolds for tissue engineering [49] and is currently used on the market for printing personalised gummy vitamins [50]. Very high drug loadings up to 96% have been shown to be feasible [51]. Print quality is typically not as good as FDM- and SLA-based printing methods, with resolutions around 200 μm to 400 μm being common [52, 53]. However, high precision drug delivery systems have been shown to be possible with some clever post processing. Wu et al. manufactured microneedles patches for glucose delivery using SSE (Figure 1.2d) [54]. Pillar structures were first extruded using a sodium alginate-based paste. Subsequently, the pillars were stretched using a glass cover slide and crosslinked by spraying with a Ca2+ solution, producing conical microneedles with tip diameters of 24.5 μm.
Figure 1.2 Drug delivery devices manufactured using PAM 3DP. (a) Five-in-one dose Polypill [58]. (b) Floating sustained-release printlets with different fill densities [59]. (c) Chewable isoleucine printlets prepared in different sizes, flavours, and colours [60]. (d) 3D-printed microneedle patch [54]. (e) From left to right: 25, 50, 100, and 200 mm2 drug loaded films [61]. (Source: Reproduced with permission from [54, 58–61], Elsevier.)
1.2.2.1 Rheological Considerations
The materials extruded during SSE printing should be in a semi-solid form, also referred to as a gel or paste. These are formed by mixing polymer(s), functional excipient(s), and the drug with an appropriate solvent at a ratio that results in a paste suitable for printing. As a nozzle-based extrusion technology, optimal pastes should have suitable viscosity, yield stress under shear, compression, and viscoelastic elastic properties [55] to enable continuous printing without blockage. These rheological parameters must also be configured to the geometry of the nozzle in the print head. Depending on nozzle configuration, a wide range of paste viscosities from 30 mPa.s to >6 × 107 mPa.s have been reported to be extrudable [56]. Of particular concern to the SSE 3D printing method is the polymer’s response to being extruded, how well it is able to adhere to previously printed layers, and its ability to hold the weight of subsequent layers [57]. Shear thinning characteristics are desirable because the viscosity of the paste can be significantly reduced when a high shear rate is exerted during printing. Shear thinning properties influence not only the capability to be pushed through a narrow nozzle at a given temperature but also the ability to regain structure and shape after deposition.
1.2.2.2 Example Applications
First used to produce polypills and tablets, this technology has rapidly evolved to manufacture other types of dosage forms and medical devices. Example applications explored in the literature are chewable tablets, orodispersible films, rectal suppositories, and implantable patches [4]. Some of these applications are shown in Figure 1.2 and Table 1.2. SSE printing has been shown to be a versatile 3DP modality capable of printing a wide range of dosage forms suitable for a variety of release profiles from immediate release tablets to sustained release implants.
Table 1.2 Examples of solid dosage forms and devices produced by SSE 3DP.
Polymer
Drug
Solvent
Printer
Application
HPMC
Poly(Acrylic Acid)
Guaifenesin
Water
Fab@Home, USA
Tablets [
57
]
Croscarmellose Sodium and Hydroxypropyl Cellulose (HPC)
Levetiracetam (96%)
10% ethanol solution
Desktop semi-solid 3D extrusion printer
Immediate release tablets [
51
]
HPMC
Cellulose Acetate
Nifedipine
Captopril
Glipizide
Hydro alcoholic
Acetone
DMSO
RegenHU, Switzerland
Polypill [
62
]
Cellulose Acetate, D-Mannitol, PEG 6000, Sodium
Starch Glycolate, and PVP
Pravastatin (20%), atenolol (30%), ramipril (15%), aspirin (28.62%), and hydrochlorothiazide (5.86%)
Acetone and dimethyl sulfoxide (DMSO)
RegenHU 3D printer
Polypill [
58
]
Sucrose, Pectin, and Maltodextrin
Isoleucine (14.4%)
Water
Adapted 3D printer (The Magic Candy Factory, UK)
Chewable printlets [
60
]
Mesoporous Silica Nanoparticles (Msn) and Bioactive Glass Coatings in a Porous β-TCP Bioceramic
Isoniazid (INH)/Rifampin (RFP)
Chloroform and dimethyl sulfoxide (DMSO)
3D-Bioplotter system, EnvisionTEC, Germany
Porous scaffold [
63
]
HPC and PVA
Warfarin (1.3%)
Ethanol and purified water
BioBots 1 (BioBot, USA) EXT 3D
Orodispersible film (ODF) [
61
]
Sodium Alginate and Hydroxyapatite
Insulin
Water
Allevi 2 bioprinter
Microneedle patches [
54
]
1.2.3 Powder Bed Fusion 3D Printing
Powder bed fusion (PBF) 3DP refers to 3D-printing technologies that use powder material as a feedstock. Many polymers and API are available as a powder, making PBF printing a versatile technique for drug delivery device manufacture. Two subset technologies are suitable for pharmaceutical applications: binder jetting (BJ) and selective laser sintering (SLS). Both technologies share the same principle of selectively binding powder in a layer-by-layer fashion to build up a 3D part. In BJ printing, powder binding is achieved by depositing a liquid binder that effectively glues adjacent particles together, whereas in SLS printing, a laser is used to partially melt and agglomerate selected particles. Subsequent layers are built up by spreading a fresh thin layer of powder on top of the bound layer and repeating the fusion process. Depending on the equipment used, different mechanisms exist for this powder spreading. The most common method is the use of a metallic blade, a roller, or a rake for generating a powder layer with a precise layer height. API is typically incorporated into the powder blend but can also be added to the liquid binder in BJ printing [64]. After printing, loose powder is removed and recycled, revealing the printed structure. Further drying or curing is often necessary to further strengthen the print. Compared to other 3DP techniques, print surface finish and resolution is poor due to the rough nature of the powder feedstock and prints are fairly porous due to the loose packing of powder. Whilst less suitable for high strength, load bearing applications, the fairly weak binding and porous nature of PBF solid dosage forms can be advantageous for immediate release applications that require rapid dissolution. Porous, hygroscopic structures can be easily penetrated and broken down by liquids, making PBF prints well suited for oral delivery applications. This feature is seen in the only currently Food and Drug Administration (FDA) approved 3D-printed pharmaceutical product, Spritam, which is manufactured using a proprietary BJ technology and undergoes rapid disintegration (~10 seconds) when taken with a sip of liquid [65].
Powder is an attractive feedstock for 3DP because pharmaceutical materials are already widely available in this form factor, so can be directly used in PBF techniques, simplifying the production process. The direct use means powder properties play a key role concerning both processing performance and part properties that require careful consideration for successful printing. Figure 1.3 shows some of the relationships between powder properties and bulk powder behaviour on in-process printing performance and final print properties. Of these properties, powder flowability, packing density, and energy absorbance are the key attributes that determine formulation printability.
Figure 1.3 Visualisation of the relationships between powder properties, bulk powder behaviour, powder performance in process, and finally, the manufactured part quality as elaborated by different research groups. (Source: Reproduced under the Creative Commons Attribution 4.0 International License [66].)
1.2.3.1 Powder Flowability Considerations
In PBF, good flow properties are required to ensure that a homogenous, thin layer of fresh powder is distributed during spreading at the start of each layer. Small particles (<20 μm), which are desirable for higher resolution printing, are particularly challenging to process due to their relatively large specific surface area that results in a high extent of adhesiveness to surfaces and other particles due to van der Waal interactions [67]. General methods of improving powder flowability are decreasing the width of the powder size distribution (PSD) [68, 69], increasing particle sphericity and smoothness [70], increasing particle size [71], decreasing moisture content [72], and addition of flow enhancers [73]. To enhance the particle morphology of the PBF feedstock, it can be pre-processed by grinding, milling, or spray drying [74, 75]. To obtain an even particle size distribution, it is recommended to sieve the feed powder prior to its use [76].
1.2.3.2 Powder Packing Density Considerations
The packing density of the powder feedstock has a strong influence on the final print density, surface roughness, and mechanical properties. A wide multimodal PSD is necessary to achieve a high powder bulk density, as the fine particles can fill the gaps between the larger ones. This is contradictory to the necessities for good powder flow and illustrates how contradictory the requirements for only one parameter can be with respect to different aspects of the PBF process. For high-strength applications such as bone tissue scaffolds, a high packing density is required to produce dense parts, whereas for pharmaceutical applications, low density prints are desirable to enhance tablet disintegration and drug release rates [77].
1.2.3.3 Powder Energy Absorbance Considerations
Powder energy absorbance describes the feedstocks’ ability to absorb energy and bind to adjacent particles during printing. For the case of BJ printing, the energy absorbance refers to the interaction of the powder with the binder fluid. Binder deposition and spread is dependent on the viscosity, surface tension, and density of the binder solution and the wettability and specific surface area of the powder material [78]. In SLS printing, the energy absorbance is the feedstocks’ capacity to absorb the wavelength of the laser used during printing. BJ has been shown to be effective for printing high-dose hydrophilic formulations for rapid disintegration [64, 79]. However, achieving good print quality can be a challenge when it comes to printing large doses of hydrophobic molecules which require water-based binders. Poor selection of a binder and powder bed properties may result in sliding of powder layers during printing and a decrease in the final product quality [80]. Formulating binders using a mixture of water and organic solvents can be used to overcome this but creates the problem of efficient removal of toxic solvent from the final formulation. In SLS printing, powder binding is dependent on the power and wavelength of the laser source, the laser energy absorptivity of the powder material, and the scanning speed [81, 82]. Increased laser power or decreased scanning speed increases powder particles exposure to the laser, increasing the level of sintering between particles. By tuning these parameters, part strength and porosity can be controlled which in turn mediate drug performance. For example, paracetamol loaded HPMC tablets have been printed at 100, 200, and 300 mm s−1 to achieve controlled drug release over 4, 3, and 2 hours, respectively [83]. Furthermore, scanning power and speed can be adjusted during a single print to create variable density dosage forms. This method was first used with biodegradable polymers by Leong et al. in 2006 [82]. The group printed PCL and poly(L-lactic acid) (PLLA) tablets with a denser outer region to act as a diffusion barrier and a more porous inner region to encapsulate the drug and achieve zero-order release. Additionally, it is important to consider the energy absorbance range of a powder feedstock. Typically, CO2 laser diodes emit energy in the visible light region. Since most pharmaceutical polymers are white in colour, minimal energy absorption will occur naturally. As such, pharmaceutical grade colourants can be incorporated into the powder feedstock to facilitate the absorption of energy. Due to the localised heating used in SLS printing, there are concerns about the degradation of API during printing. Several studies have reported minimal drug degradation using fairly stable API such as paracetamol [84], ibuprofen [85], and progesterone [86], but there is no evidence to suggest thermolabile API can be employed with this technique. Table 1.3 provides example formulas used in powder bed fusion 3D printing of pharmaceuticals and devices.
Table 1.3 Example materials used in powder bed fusion 3D printing of pharmaceutical solid dosage forms and devices.
Powder bed fusion type
Polymer
Binder ink
Drug
Printer
Application
Binder
Solvent
BJ
Maltitol, maltodextrin, PVP
PVP
Aqueous buffer
Captopril (in binder)
TheriForm process
Immediate release tablet [
64
]
Kollidon SR and HPMC
PVP, Tween 20, triethyl citrate
Water, Ethanol
Pseudoephedrine hydrochloride (in binder)
TheriForm process
Controlled release tablet [
79
]
Lactose, PVP, mannitol
PVP
Water, Ethanol
Paracetamol (in powder bed)
Fochif Mechatronics Technology (China)
Fast disintegrating tablet [
87
]
