Hot–Melt Extrusion: Pharmaceutical Applications

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.

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.