Hot-melt Extrusion : Pharmaceutical Applications · Hot-melt Extrusion Pharmaceutical Applications Editor Dennis Douroumis ADVANCES IN PHARMACEUTICAL TECHNOLOGY Hot-melt Extrusion

Hot-meltExtrusionPharmaceutical ApplicationsEditor

Dennis Douroumis

ADVANCES IN PHARMACEUTICAL TECHNOLOGY

Hot-m

elt ExtrusionPharm

aceutical Applications

Dennis Douroumis

University of Greenwich, UK

Hot-melt extrusion (HME) is a 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 a 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. Editor

Douroum

is

Hot-meltExtrusionPharmaceutical Applications

ADVANCES IN PHARMACEUTICAL TECHNOLOGY

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Hot-melt Extrusion:Pharmaceutical Applications

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Hot-melt Extrusion:Pharmaceutical

Applications

Edited by

DENNIS DOUROUMIS

School of Science, University of Greenwich, UK

A John Wiley & Sons, Ltd., Publication

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This edition first published 2012© 2012 John Wiley & Sons Ltd.

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Dedication

As you set out for Ithacahope your road is a long one,

full of adventure, full of discovery.Laistrygonians, Cyclops,

angry Poseidon – don’t be afraid of them:you’ll never find things like that on your wayas long as you keep your thoughts raised high,

as long as a rare excitementstirs your spirit and your body.

ITHACA (Konstantinos Kavafis, 1911)

This book is dedicated to my wonderful wife Eleni-Angeliki and my lovelyson George-Alexander and daughter Eugenia-Erene. I thank them for their

continuous support and patience.

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Contents

List of Contributors xvPreface xvii

1. Single-screw Extrusion: Principles 1Keith Luker

1.1 Introduction 11.2 Ideal Compounding 21.3 Basics of the Single-screw Extruder 3

1.3.1 Screw Feed Section 51.3.2 Screw Compressor Section 91.3.3 Screw Metering Section 111.3.4 Mixers 111.3.5 Limitations of Conventional Single-screw Mixers 13

1.4 SSE Elongational Mixers 131.5 Summary 20

References 21

2. Twin-screw Extruders for Pharmaceutical Hot-melt Extrusion:Technology, Techniques and Practices 23Dirk Leister, Tom Geilen and Thobias Geissler

2.1 Introduction 232.2 Extruder Types and Working Principle 242.3 Individual Parts of a TSE 25

2.3.1 Drive Unit 252.3.2 Screws 252.3.3 Screw Elements 272.3.4 Distributive Flow Elements 282.3.5 Discharge Feed Screw 282.3.6 Barrel 29

2.4 Downstreaming 302.5 Individual Processing Sections of the TSE 31

2.5.1 Feeding Section 322.5.2 Conveying/Melting Section 322.5.3 Mixing Section 332.5.4 Venting Section 33

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2.5.5 Extrusion Section 332.6 Feeding of Solids 342.7 TSE Operating Parameters 34

2.7.1 Filling Level 362.7.2 Screw Speed 362.7.3 Feed Rate 372.7.4 Residence Time Distribution 372.7.5 Effect of Screw Speed and Feed Rate on Melt Temperature 39

2.8 Setting up an HME Process using QbD Principles 402.8.1 Understanding Knowledge Space 402.8.2 Defining Design Space 402.8.3 Determining Control Space 41

2.9 Summary 42References 42

3. Hot-melt Extrusion Developments in the Pharmaceutical Industry 43Ana Almeida, Bart Claeys, Jean Paul Remon and Chris Vervaet

3.1 Introduction 433.2 Advantages of HME as Drug Delivery Technology 443.3 Formulations used for HME Applications 45

3.3.1 Active Pharmaceutical Ingredient 463.3.2 Solid Dispersions 483.3.3 Bioavailability Improvement 493.3.4 Controlled Delivery Systems 513.3.5 Plasticizers 53

3.4 Characterization of Extrudates 553.4.1 Thermal Analysis 553.4.2 Atomic Force Microscopy 563.4.3 Residence Time 573.4.4 Spectroscopic Techniques 573.4.5 X-ray Diffraction (XRD) 583.4.6 Microscopy 583.4.7 Drug Release 58

3.5 Hot-melt Extruded Dosage Forms 583.5.1 Oral Drug Delivery 593.5.2 Films 613.5.3 Vaginal Rings and Implants 61

3.6 A View to the Future 63References 64

4. Solubility Parameters for Prediction of Drug/Polymer Miscibilityin Hot-melt Extruded Formulations 71Andreas Gryczke

4.1 Introduction 714.2 Solid Dispersions 72

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4.3 Basic Assumptions for the Drug–polymer MiscibilityPrediction 77

4.4 Solubility and the Flory–Huggins Theory 784.5 Miscibility Estimation of Drug and Monomers 834.6 Summary 89

References 90

5. The Influence of Plasticizers in Hot-melt Extrusion 93Geert Verreck

5.1 Introduction 935.2 Traditional Plasticizers 945.3 Non-traditional Plasticizers 955.4 Specialty Plasticizers 1045.5 Conclusions 107

References 108

6. Applications of Poly(meth)acrylate Polymers inMelt Extrusion 113Kathrin Nollenberger and Jessica Albers

6.1 Introduction 1136.2 Polymer Characteristics 116

6.2.1 Chemical Structure and Molecular Weight 1166.2.2 Glass Transition Temperature 1196.2.3 Plasticizers 1206.2.4 Thermostability 1216.2.5 Viscosity 1226.2.6 Specific Heat Capacity 1246.2.7 Hygroscopicity 126

6.3 Melt Extrusion of Poly(methacrylates) to Design PharmaceuticalOral Dosage Forms 128

6.4 Solubility Enhancement 1286.5 Bioavailability Enhancement of BCS Class IV Drugs 132

6.5.1 Controlled Release 1356.5.2 Time-controlled-release Dosage Forms 1366.5.3 pH-dependent Release 1386.5.4 Taste Masking 139


7. Hot-melt Extrusion of Ethylcellulose, Hypromellose andPolyethylene Oxide 145Mark Hall and Michael Read

7.1 Introduction 1457.2 Background 146

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7.3 Thermal Properties 1477.4 Processing Aids/Additives 1477.5 Unconventional Processing Aids: Drugs, Blends 1497.6 Case Studies 151

7.6.1 Ethylcellulose 1517.6.2 Combinations of Excipients 1517.6.3 Solubilization 1557.6.4 Film 1597.6.5 Unique Dosage Forms 1637.6.6 Abuse Resistance 1637.6.7 Controlled Release 1647.6.8 Solubility Parameters 166

7.7 Milling of EC, HPMC and PEO Extrudate 168References 170

8. Bioadhesion Properties of Polymeric Films Producedby Hot-melt Extrusion 177Joshua Boateng and Dennis Douroumis

8.1 Introduction 1778.2 Anatomy of the Oral Cavity and Modes of Drug Transport 180

8.2.1 Structure 1808.2.2 Modes of Drug Transport and Kinetics 1808.2.3 Factors Affecting Drug Absorption 181

8.3 Mucoadhesive Mechanisms 1828.4 Factors Affecting Mucoadhesion in the Oral Cavity 1838.5 Determination of Mucoadhesion and Mechanical Properties

of Films 1838.6 Bioadhesive Films Prepared by HME 1848.7 Summary 194

References 194

9. Taste Masking Using Hot-melt Extrusion 201Dennis Douroumis, Marion Bonnefille and Attila Aranyos

9.1 The Need and Challenges for Masking Bitter APIs 2019.2 Organization of the Taste System 203

9.2.1 Taste Perception in Humans and Organization ofPeripheral System 203

9.2.2 Transduction of Taste Signals 2059.3 Taste Sensing Systems (Electronic Tongues) for Pharmaceutical

Dosage Forms 2069.3.1 Alpha MOS Electronic Tongue: Instrumentation

and Operational Principles 2069.3.2 Taste Analysis 2089.3.3 Taste Masking Efficiency Testing 2099.3.4 Advantages of E-tongue Taste Analysis 211

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9.4 Hot-melt Extrusion: An Effective Means of Taste Masking 2129.4.1 Taste Masking via Polymer Extrusion 2129.4.2 Taste Masking via Solid Lipid Extrusion 216


10. Clinical and Preclinical Studies, Bioavailability andPharmacokinetics of Hot-melt Extruded Products 223Sandra Guns and Guy Van den Mooter

10.1 Introduction to Oral Absorption 22310.2 In Vivo Evaluation of Hot-melt Extruded Solid Dispersions 225

10.2.1 Oral Immediate Release 22510.2.2 Oral Controlled Release 23210.2.3 Implants 233

10.3 Conclusion 234References 234

11. Injection Molding and Hot-melt Extrusion Processing forPharmaceutical Materials 239Pernille Høyrup Hemmingsen and Martin Rex Olsen

11.1 Introduction 23911.2 Hot-melt Extrusion in Brief 24011.3 Injection Molding 24111.4 Critical Parameters 242

11.4.1 Melt Temperature 24211.4.2 Barrel Temperature 24311.4.3 Cooling Temperature 24311.4.4 Holding Pressure 24311.4.5 Holding Time 24311.4.6 Back Pressure 24411.4.7 Injection Speed 24411.4.8 Cooling Time/Cycle Time 244

11.5 Example: Comparison of Extruded and Injection-molded Material 24511.6 Development of Products for Injection Molding 246

11.6.1 Excipients 24611.6.2 Stability 24811.6.3 Process Development 248

11.7 Properties of Injection-molded Materials 25111.7.1 Egalet R© Technology 25111.7.2 Controlling Physical State by Means of Hot-melt Extrusion

and Injection Molding 25311.7.3 Anti-tamper Properties of Injection-molded Tablets 254

11.8 Concluding Remarks 257References 257

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12. Laminar Dispersive and Distributive Mixing with Dissolutionand Applications to Hot-melt Extrusion 261Costas G. Gogos, Huiju Liu and Peng Wang

12.1 Introduction 26112.2 Elementary Steps in HME 263

12.2.1 Particulate Solids Handling (PSH) 26312.2.2 Melting 26312.2.3 Devolatilization 26412.2.4 Pumping and Pressurization 265

12.3 Dispersive and Distributive Mixing 26512.4 HME Processes: Cases I and II 265

12.4.1 Case I 26612.4.2 Case II 268

12.5 Dissolution of Drug Particulates in Polymeric Melt 27012.5.1 Process Variables 27012.5.2 Equipment Variables 27312.5.3 Material Variables 275

12.6 Case Study: Acetaminophen and Poly(ethylene oxide) 27812.7 Determination of Solubility of APAP in PEO 280

References 282

13. Technological Considerations Related to Scale-up of Hot-meltExtrusion Processes 285Adam Dreiblatt

13.1 Introduction 28513.2 Scale-up Terminology 287

13.2.1 Scale-up: Batch Size 28713.2.2 Scale-up: Feed Rate 28813.2.3 Scale-up: Extruder Diameter 290

13.3 Volumetric Scale-up 29013.3.1 Volumetric Scale-up: Length/Diameter (L/D) 29213.3.2 Volumetric Scale-up: Diameter Ratio 29213.3.3 Volumetric Scale-up: Screw Design 294

13.4 Power Scale-up 29613.5 Heat Transfer Scale-up 29813.6 Die Scale-up 29913.7 Conclusion 299

References 300

14. Devices and Implant Systems by Hot-melt Extrusion 301Andrew Loxley

14.1 Introduction 30114.2 HME in Device Development 30214.3 Hot-melt Extruder Types 303

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14.4 Comparison of HME Devices and Oral Dosage Forms 30514.5 HME Processes for Device Fabrication 306

14.5.1 Issues with HME in preparing Drug-eluting Devices 30814.6 Devices and Implants 310

14.6.1 Anatomical Device Locations 31014.6.2 Simple Devices 31014.6.3 Non-medicated Prolonged Tissue Contact Devices 31214.6.4 Medicated (Drug-eluting) Prolonged Tissue Contact Devices 313

14.7 Release Kinetics 31814.7.1 Mechanisms of API Release 31814.7.2 Example In Vitro Drug Elution Profiles 319

14.8 Conclusions 321References 321

15. Hot-melt Extrusion: An FDA Perspective on Productand Process Understanding 323Abhay Gupta and Mansoor A. Khan

15.1 Introduction 32315.2 Quality by Design 32515.3 Utilizing QbD for HME Process Understanding 328

References 331

16. Improved Process Understanding and Control of a Hot-meltExtrusion Process with Near-Infrared Spectroscopy 333Chris Heil and Jeffrey Hirsch

16.1 Vibrational Spectroscopy Introduction 33316.2 Near-infrared Method Development 33916.3 Near-infrared Probes and Fiber Optics 34416.4 NIR for Monitoring the Start-up of a HME Process 34716.5 NIR for Improved Process Understanding and Control 350

References 353

Index 355

Documents

Hot-melt Extrusion : Pharmaceutical Applications · Hot-melt Extrusion Pharmaceutical Applications Editor Dennis Douroumis ADVANCES IN PHARMACEUTICAL TECHNOLOGY Hot-melt Extrusion