Hot-Melt Extrusion Pharmaceutical Applications Advances in Pharmaceutical Technology Series

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

1.3.1 Screw Feed Section 5

1.3.2 Screw Compressor Section 9

1.3.3 Screw Metering Section 11

1.3.4 Mixers 11

1.3.5 Limitations of Conventional Single-screw Mixers 13

1.4 SSE Elongational Mixers 13

1.5 Summary 20

References 21

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

2.3.1 Drive Unit 25

2.3.2 Screws 25

2.3.3 Screw Elements 27

2.3.4 Distributive Flow Elements 28

2.3.5 Discharge Feed Screw 28

2.3.6 Barrel 29

2.4 Downstreaming 30

2.5 Individual Processing Sections of the TSE 31

2.5.1 Feeding Section 32

2.5.2 Conveying/Melting Section 32

2.5.3 Mixing Section 33

2.5.4 Venting Section 33

2.5.5 Extrusion Section 33

2.6 Feeding of Solids 34

2.7 TSE Operating Parameters 34

2.7.1 Filling Level 36

2.7.2 Screw Speed 36

2.7.3 Feed Rate 37

2.7.4 Residence Time Distribution 37

2.7.5 Effect of Screw Speed and Feed Rate on Melt Temperature 39

2.8 Setting up an HME Process using QbD Principles 40

2.8.1 Understanding Knowledge Space 40

2.8.2 Defining Design Space 40

2.8.3 Determining Control Space 41

2.9 Summary 42

References 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

3.3.1 Active Pharmaceutical Ingredient 46

3.3.2 Solid Dispersions 48

3.3.3 Bioavailability Improvement 49

3.3.4 Controlled Delivery Systems 51

3.3.5 Plasticizers 53

3.4 Characterization of Extrudates 55

3.4.1 Thermal Analysis 55

3.4.2 Atomic Force Microscopy 56

3.4.3 Residence Time 57

3.4.4 Spectroscopic Techniques 57

3.4.5 X-ray Diffraction (XRD) 58

3.4.6 Microscopy 58

3.4.7 Drug Release 58

3.5 Hot-melt Extruded Dosage Forms 58

3.5.1 Oral Drug Delivery 59

3.5.2 Films 61

3.5.3 Vaginal Rings and Implants 61

3.6 A View to the Future 63

References 64

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

References 90

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

References 108

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

6.2.1 Chemical Structure and Molecular Weight 116

6.2.2 Glass Transition Temperature 119

6.2.3 Plasticizers 120

6.2.4 Thermostability 121

6.2.5 Viscosity 122

6.2.6 Specific Heat Capacity 124

6.2.7 Hygroscopicity 126

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

6.5.1 Controlled Release 135

6.5.2 Time-controlled-release Dosage Forms 136

6.5.3 pH-dependent Release 138

6.5.4 Taste Masking 139

6.6 Summary 140

References 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

7.6.1 Ethylcellulose 151

7.6.2 Combinations of Excipients 151

7.6.3 Solubilization 155

7.6.4 Film 159

7.6.5 Unique Dosage Forms 163

7.6.6 Abuse Resistance 163

7.6.7 Controlled Release 164

7.6.8 Solubility Parameters 166

7.7 Milling of EC, HPMC and PEO Extrudate 168

References 170

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

8.2.1 Structure 180

8.2.2 Modes of Drug Transport and Kinetics 180

8.2.3 Factors Affecting Drug Absorption 181

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

References 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

9.2.1 Taste Perception in Humans and Organization of Peripheral System 203

9.2.2 Transduction of Taste Signals 205

9.3 Taste Sensing Systems (Electronic Tongues) for Pharmaceutical Dosage Forms 206

9.3.1 Alpha MOS Electronic Tongue: Instrumentation and Operational Principles 206

9.3.2 Taste Analysis 208

9.3.3 Taste Masking Efficiency Testing 209

9.3.4 Advantages of E-tongue Taste Analysis 211

9.4 Hot-melt Extrusion: An Effective Means of Taste Masking 212

9.4.1 Taste Masking via Polymer Extrusion 212

9.4.2 Taste Masking via Solid Lipid Extrusion 216

9.5 Summary 219

References 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

10.2.1 Oral Immediate Release 225

10.2.2 Oral Controlled Release 232

10.2.3 Implants 233

10.3 Conclusion 234

References 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

11.4.1 Melt Temperature 242

11.4.2 Barrel Temperature 243

11.4.3 Cooling Temperature 243

11.4.4 Holding Pressure 243

11.4.5 Holding Time 243

11.4.6 Back Pressure 244

11.4.7 Injection Speed 244

11.4.8 Cooling Time/Cycle Time 244

11.5 Example: Comparison of Extruded and Injection-molded Material 245

11.6 Development of Products for Injection Molding 246

11.6.1 Excipients 246

11.6.2 Stability 248

11.6.3 Process Development 248

11.7 Properties of Injection-molded Materials 251

11.7.1 Egalet^® Technology 251

11.7.2 Controlling Physical State by Means of Hot-melt Extrusion and Injection Molding 253

11.7.3 Anti-tamper Properties of Injection-molded Tablets 254

11.8 Concluding Remarks 257

References 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

12.2.1 Particulate Solids Handling (PSH) 263

12.2.2 Melting 263

12.2.3 Devolatilization 264

12.2.4 Pumping and Pressurization 265

12.3 Dispersive and Distributive Mixing 265

12.4 HME Processes: Cases I and II 265

12.4.1 Case I 266

12.4.2 Case II 268

12.5 Dissolution of Drug Particulates in Polymeric Melt 270

12.5.1 Process Variables 270

12.5.2 Equipment Variables 273

12.5.3 Material Variables 275

12.6 Case Study: Acetaminophen and Poly(ethylene oxide) 278

12.7 Determination of Solubility of APAP in PEO 280

References 282

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

13.2.1 Scale-up: Batch Size 287

13.2.2 Scale-up: Feed Rate 288

13.2.3 Scale-up: Extruder Diameter 290

13.3 Volumetric Scale-up 290

13.3.1 Volumetric Scale-up: Length/Diameter (L/D) 292

13.3.2 Volumetric Scale-up: Diameter Ratio 292

13.3.3 Volumetric Scale-up: Screw Design 294

13.4 Power Scale-up 296

13.5 Heat Transfer Scale-up 298

13.6 Die Scale-up 299

13.7 Conclusion 299

References 300

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

14.5.1 Issues with HME in preparing Drug-eluting Devices 308

14.6 Devices and Implants 310

14.6.1 Anatomical Device Locations 310

14.6.2 Simple Devices 310

14.6.3 Non-medicated Prolonged Tissue Contact Devices 312

14.6.4 Medicated (Drug-eluting) Prolonged Tissue Contact Devices 313

14.7 Release Kinetics 318

14.7.1 Mechanisms of API Release 318

14.7.2 Example In Vitro Drug Elution Profiles 319

14.8 Conclusions 321

References 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

References 331

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

Dennis DouroumisUniversity of Greenwich, UK