Hot-Melt ExtrusionPharmaceutical Applications
Hot-melt extrusion (HME) - melting a substance and forcing it through an orifice under controlled conditions to form a new material - is an emerging processing technology in the pharmaceutical industry for the preparation of various dosage forms and drug delivery systems, for example granules and sustained release tablets. Hot-Melt Extrusion: Pharmaceutical Applications covers the main instrumentation, operation principles and theoretical background of HME. It then focuses on HME drug delivery systems, dosage forms and clinical studies (including pharmacokinetics and bioavailability) of HME products. Finally, the book includes some recent and novel HME applications, scale -up considerations and regulatory issues. Topics covered include: principles and die design of single screw extrusion twin screw extrusion techniques and practices in the laboratory and on production scale HME developments for the pharmaceutical industry solubility parameters for prediction of drug/polymer miscibility in HME formulations the influence of plasticizers in HME applications of polymethacrylate polymers in HME HME of ethylcellulose, hypromellose, and polyethylene oxide bioadhesion properties of polymeric films produced by HME taste masking using HME clinical studies, bioavailability and pharmacokinetics of HME products injection moulding and HME processing for pharmaceutical materials laminar dispersive & distributive mixing with dissolution and applications to HME technological considerations related to scale-up of HME processes devices and implant systems by HME an FDA perspective on HME product and process understanding improved process understanding and control of an HME process with near-infrared spectroscopy Hot-Melt Extrusion: Pharmaceutical Applications is an essential multidisciplinary guide to the emerging pharmaceutical uses of this processing technology for researchers in academia and industry working in drug formulation and delivery, pharmaceutical engineering and processing, and polymers and materials science. This is the first book from our brand new series Advances in Pharmaceutical Technology. Find out more about the series here.
List of Contributors xv Preface xvii 1. Single-screw Extrusion: Principles 1 Keith Luker 1.1 Introduction 1 1.2 Ideal Compounding 2 1.3 Basics of the Single-screw Extruder 3 1.4 SSE Elongational Mixers 13 1.5 Summary 20 2. Twin-screw Extruders for Pharmaceutical Hot-melt Extrusion: Technology, Techniques and Practices 23 Dirk Leister, Tom Geilen and Thobias Geissler 2.1 Introduction 23 2.2 Extruder Types and Working Principle 24 2.3 Individual Parts of a TSE 25 2.4 Downstreaming 30 2.5 Individual Processing Sections of the TSE 31 2.6 Feeding of Solids 34 2.7 TSE Operating Parameters 34 2.8 Setting up an HME Process using QbD Principles 40 2.9 Summary 42 3. Hot-melt Extrusion Developments in the Pharmaceutical Industry 43 Ana Almeida, Bart Claeys, Jean Paul Remon and Chris Vervaet 3.1 Introduction 43 3.2 Advantages of HME as Drug Delivery Technology 44 3.3 Formulations used for HME Applications 45 3.4 Characterization of Extrudates 55 3.5 Hot-melt Extruded Dosage Forms 58 3.6 A View to the Future 63 4. Solubility Parameters for Prediction of Drug/Polymer Miscibility in Hot-melt Extruded Formulations 71 Andreas Gryczke 4.1 Introduction 71 4.2 Solid Dispersions 72 4.3 Basic Assumptions for the Drug–polymer Miscibility Prediction 77 4.4 Solubility and the Flory–Huggins Theory 78 4.5 Miscibility Estimation of Drug and Monomers 83 4.6 Summary 89 5. The Influence of Plasticizers in Hot-melt Extrusion 93 Geert Verreck 5.1 Introduction 93 5.2 Traditional Plasticizers 94 5.3 Non-traditional Plasticizers 95 5.4 Specialty Plasticizers 104 5.5 Conclusions 107 6. Applications of Poly(meth)acrylate Polymers in Melt Extrusion 113 Kathrin Nollenberger and Jessica Albers 6.1 Introduction 113 6.2 Polymer Characteristics 116 6.3 Melt Extrusion of Poly(methacrylates) to Design Pharmaceutical Oral Dosage Forms 128 6.4 Solubility Enhancement 128 6.5 Bioavailability Enhancement of BCS Class IV Drugs 132 6.6 Summary 140 7. Hot-melt Extrusion of Ethylcellulose, Hypromellose and Polyethylene Oxide 145 Mark Hall and Michael Read 7.1 Introduction 145 7.2 Background 146 7.3 Thermal Properties 147 7.4 Processing Aids/Additives 147 7.5 Unconventional Processing Aids: Drugs, Blends 149 7.6 Case Studies 151 7.7 Milling of EC, HPMC and PEO Extrudate 168 8. Bioadhesion Properties of Polymeric Films Produced by Hot-melt Extrusion 177 Joshua Boateng and Dennis Douroumis 8.1 Introduction 177 8.2 Anatomy of the Oral Cavity and Modes of Drug Transport 180 8.3 Mucoadhesive Mechanisms 182 8.4 Factors Affecting Mucoadhesion in the Oral Cavity 183 8.5 Determination of Mucoadhesion and Mechanical Properties of Films 183 8.6 Bioadhesive Films Prepared by HME 184 8.7 Summary 194 9. Taste Masking Using Hot-melt Extrusion 201 Dennis Douroumis, Marion Bonnefille and Attila Aranyos 9.1 The Need and Challenges for Masking Bitter APIs 201 9.2 Organization of the Taste System 203 9.3 Taste Sensing Systems (Electronic Tongues) for Pharmaceutical Dosage Forms 206 9.4 Hot-melt Extrusion: An Effective Means of Taste Masking 212 9.5 Summary 219 10. Clinical and Preclinical Studies, Bioavailability and Pharmacokinetics of Hot-melt Extruded Products 223 Sandra Guns and Guy Van den Mooter 10.1 Introduction to Oral Absorption 223 10.2 In Vivo Evaluation of Hot-melt Extruded Solid Dispersions 225 10.3 Conclusion 234 11. Injection Molding and Hot-melt Extrusion Processing for Pharmaceutical Materials 239 Pernille Høyrup Hemmingsen and Martin Rex Olsen 11.1 Introduction 239 11.2 Hot-melt Extrusion in Brief 240 11.3 Injection Molding 241 11.4 Critical Parameters 242 11.5 Example: Comparison of Extruded and Injection-molded Material 245 11.6 Development of Products for Injection Molding 246 11.7 Properties of Injection-molded Materials 251 11.8 Concluding Remarks 257 12. Laminar Dispersive and Distributive Mixing with Dissolution and Applications to Hot-melt Extrusion 261 Costas G. Gogos, Huiju Liu and Peng Wang 12.1 Introduction 261 12.2 Elementary Steps in HME 263 12.3 Dispersive and Distributive Mixing 265 12.4 HME Processes: Cases I and II 265 12.5 Dissolution of Drug Particulates in Polymeric Melt 270 12.6 Case Study: Acetaminophen and Poly(ethylene oxide) 278 12.7 Determination of Solubility of APAP in PEO 280 13. Technological Considerations Related to Scale-up of Hot-melt Extrusion Processes 285 Adam Dreiblatt 13.1 Introduction 285 13.2 Scale-up Terminology 287 13.3 Volumetric Scale-up 290 13.4 Power Scale-up 296 13.5 Heat Transfer Scale-up 298 13.6 Die Scale-up 299 13.7 Conclusion 299 14. Devices and Implant Systems by Hot-melt Extrusion 301 Andrew Loxley 14.1 Introduction 301 14.2 HME in Device Development 302 14.3 Hot-melt Extruder Types 303 14.4 Comparison of HME Devices and Oral Dosage Forms 305 14.5 HME Processes for Device Fabrication 306 14.6 Devices and Implants 310 14.7 Release Kinetics 318 14.8 Conclusions 321 15. Hot-melt Extrusion: An FDA Perspective on Product and Process Understanding 323 Abhay Gupta and Mansoor A. Khan 15.1 Introduction 323 15.2 Quality by Design 325 15.3 Utilizing QbD for HME Process Understanding 328 16. Improved Process Understanding and Control of a Hot-melt Extrusion Process with Near-Infrared Spectroscopy 333 Chris Heil and Jeffrey Hirsch 16.1 Vibrational Spectroscopy Introduction 333 16.2 Near-infrared Method Development 339 16.3 Near-infrared Probes and Fiber Optics 344 16.4 NIR for Monitoring the Start-up of a HME Process 347 16.5 NIR for Improved Process Understanding and Control 350 References 353 Index 355
Dr. Dionysios Douroumis, Senior Lecturer, School of Science, University of Greenwich, UK After completing his postgraduate studies Dr Douroumis worked as a postdoctoral fellow at the Friedrich – Schiller University of Jena in the Department of Pharmacy, and later as a Senior Scientist at Phoqus Pharmaceutical plc, tasked with the development of sustained/pulsatile release formulations, orally disintegrating tablets and taste masking of bitter drugs; some of these studies were in collaboration with Evonik GmbH in Darmstadt, Germany. He is currently Senior Lecture at the in the University of Greenwich School of Science where he coordinates the course for the MSc Pharmaceutical Science Programme (350 students per annum) and is also a tutor for undergraduate studies in Pharmaceutical Sciences.
Hot melt extrusion (HME) is relatively new process in the pharmaceutical industry, emerging as a processing technology for the preparation of various dosage forms and drug delivery systems. Hot-Melt Extrusion: Pharmaceutical Applications covers the main instrumentation, operation principles and theoretical background of HME with focus on HME drug delivery systems, dosage forms and clinical studies (including pharmacokinetics and bioavailability) of HME products. It also includes recent and novel HME applications, scale -up considerations and regulatory issues. This important new book presents a comprehensive study on the pharmaceutical applications of hot-melt extrusion, a field which until now has remained fragmented. By addressing basic operation principles and critical aspects of HME as well as cutting edge trends of extrusion based manufacturing technologies the reader is able to understand the effective processes needed to develop pharmaceutical products from lab scale to commercialization. Hot-Melt Extrusion: Pharmaceutical Applications is an essential multidisciplinary guide to the emerging pharmaceutical uses of this processing technology for researchers in academia and industry working in drug formulation and delivery, pharmaceutical engineering and processing, and polymers and materials science.
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