P1: TIX/XYZ P2: ABC JWST166-fm JWST166-Douroumis March 6, :11 Printer: Yet to come Trim: 244mm 168mm. Contents. List of Contributors

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1 List of Contributors Preface xv xvii 1. Single-screw Extrusion: Principles 1 Keith Luker 1.1 Introduction Ideal Compounding Basics of the Single-screw Extruder Screw Feed Section Screw Compressor Section Screw Metering Section Mixers Limitations of Conventional Single-screw Mixers SSE Elongational Mixers Summary 20 References Twin-screw Extruders for Pharmaceutical Hot-melt Extrusion: Technology, Techniques and Practices 23 Dirk Leister, Tom Geilen and Thobias Geissler 2.1 Introduction Extruder Types and Working Principle Individual Parts of a TSE Drive Unit Screws Screw Elements Distributive Flow Elements Discharge Feed Screw Barrel Downstreaming Individual Processing Sections of the TSE Feeding Section Conveying/Melting Section Mixing Section Venting Section 33 COPYRIGHTED MATERIAL

2 viii Extrusion Section Feeding of Solids TSE Operating Parameters Filling Level Screw Speed Feed Rate Residence Time Distribution Effect of Screw Speed and Feed Rate on Melt Temperature Setting up an HME Process using QbD Principles Understanding Knowledge Space Defining Design Space Determining Control Space Summary 42 References Hot-melt Extrusion Developments in the Pharmaceutical Industry 43 Ana Almeida, Bart Claeys, Jean Paul Remon and Chris Vervaet 3.1 Introduction Advantages of HME as Drug Delivery Technology Formulations used for HME Applications Active Pharmaceutical Ingredient Solid Dispersions Bioavailability Improvement Controlled Delivery Systems Plasticizers Characterization of Extrudates Thermal Analysis Atomic Force Microscopy Residence Time Spectroscopic Techniques X-ray Diffraction (XRD) Microscopy Drug Release Hot-melt Extruded Dosage Forms Oral Drug Delivery Films Vaginal Rings and Implants A View to the Future 63 References Solubility Parameters for Prediction of Drug/Polymer Miscibility in Hot-melt Extruded Formulations 71 Andreas Gryczke 4.1 Introduction Solid Dispersions 72

3 ix 4.3 Basic Assumptions for the Drug polymer Miscibility Prediction Solubility and the Flory Huggins Theory Miscibility Estimation of Drug and Monomers Summary 89 References The Influence of Plasticizers in Hot-melt Extrusion 93 Geert Verreck 5.1 Introduction Traditional Plasticizers Non-traditional Plasticizers Specialty Plasticizers Conclusions 107 References Applications of Poly(meth)acrylate Polymers in Melt Extrusion 113 Kathrin Nollenberger and Jessica Albers 6.1 Introduction Polymer Characteristics Chemical Structure and Molecular Weight Glass Transition Temperature Plasticizers Thermostability Viscosity Specific Heat Capacity Hygroscopicity Melt Extrusion of Poly(methacrylates) to Design Pharmaceutical Oral Dosage Forms Solubility Enhancement Bioavailability Enhancement of BCS Class IV Drugs Controlled Release Time-controlled-release Dosage Forms ph-dependent Release Taste Masking Summary 140 References Hot-melt Extrusion of Ethylcellulose, Hypromellose and Polyethylene Oxide 145 Mark Hall and Michael Read 7.1 Introduction Background 146

4 x 7.3 Thermal Properties Processing Aids/Additives Unconventional Processing Aids: Drugs, Blends Case Studies Ethylcellulose Combinations of Excipients Solubilization Film Unique Dosage Forms Abuse Resistance Controlled Release Solubility Parameters Milling of EC, HPMC and PEO Extrudate 168 References Bioadhesion Properties of Polymeric Films Produced by Hot-melt Extrusion 177 Joshua Boateng and Dennis Douroumis 8.1 Introduction Anatomy of the Oral Cavity and Modes of Drug Transport Structure Modes of Drug Transport and Kinetics Factors Affecting Drug Absorption Mucoadhesive Mechanisms Factors Affecting Mucoadhesion in the Oral Cavity Determination of Mucoadhesion and Mechanical Properties of Films Bioadhesive Films Prepared by HME Summary 194 References Taste Masking Using Hot-melt Extrusion 201 Dennis Douroumis, Marion Bonnefille and Attila Aranyos 9.1 The Need and Challenges for Masking Bitter APIs Organization of the Taste System Taste Perception in Humans and Organization of Peripheral System Transduction of Taste Signals Taste Sensing Systems (Electronic Tongues) for Pharmaceutical Dosage Forms Alpha MOS Electronic Tongue: Instrumentation and Operational Principles Taste Analysis Taste Masking Efficiency Testing Advantages of E-tongue Taste Analysis 211

5 xi 9.4 Hot-melt Extrusion: An Effective Means of Taste Masking Taste Masking via Polymer Extrusion Taste Masking via Solid Lipid Extrusion Summary 219 References 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 In Vivo Evaluation of Hot-melt Extruded Solid Dispersions Oral Immediate Release Oral Controlled Release Implants Conclusion 234 References Injection Molding and Hot-melt Extrusion Processing for Pharmaceutical Materials 239 Pernille Høyrup Hemmingsen and Martin Rex Olsen 11.1 Introduction Hot-melt Extrusion in Brief Injection Molding Critical Parameters Melt Temperature Barrel Temperature Cooling Temperature Holding Pressure Holding Time Back Pressure Injection Speed Cooling Time/Cycle Time Example: Comparison of Extruded and Injection-molded Material Development of Products for Injection Molding Excipients Stability Process Development Properties of Injection-molded Materials Egalet R Technology Controlling Physical State by Means of Hot-melt Extrusion and Injection Molding Anti-tamper Properties of Injection-molded Tablets Concluding Remarks 257 References 257

6 xii 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 Elementary Steps in HME Particulate Solids Handling (PSH) Melting Devolatilization Pumping and Pressurization Dispersive and Distributive Mixing HME Processes: Cases I and II Case I Case II Dissolution of Drug Particulates in Polymeric Melt Process Variables Equipment Variables Material Variables Case Study: Acetaminophen and Poly(ethylene oxide) Determination of Solubility of APAP in PEO 280 References Technological Considerations Related to Scale-up of Hot-melt Extrusion Processes 285 Adam Dreiblatt 13.1 Introduction Scale-up Terminology Scale-up: Batch Size Scale-up: Feed Rate Scale-up: Extruder Diameter Volumetric Scale-up Volumetric Scale-up: Length/Diameter (L/D) Volumetric Scale-up: Diameter Ratio Volumetric Scale-up: Screw Design Power Scale-up Heat Transfer Scale-up Die Scale-up Conclusion 299 References Devices and Implant Systems by Hot-melt Extrusion 301 Andrew Loxley 14.1 Introduction HME in Device Development Hot-melt Extruder Types 303

7 xiii 14.4 Comparison of HME Devices and Oral Dosage Forms HME Processes for Device Fabrication Issues with HME in preparing Drug-eluting Devices Devices and Implants Anatomical Device Locations Simple Devices Non-medicated Prolonged Tissue Contact Devices Medicated (Drug-eluting) Prolonged Tissue Contact Devices Release Kinetics Mechanisms of API Release Example In Vitro Drug Elution Profiles Conclusions 321 References Hot-melt Extrusion: An FDA Perspective on Product and Process Understanding 323 Abhay Gupta and Mansoor A. Khan 15.1 Introduction Quality by Design Utilizing QbD for HME Process Understanding 328 References 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 Near-infrared Method Development Near-infrared Probes and Fiber Optics NIR for Monitoring the Start-up of a HME Process NIR for Improved Process Understanding and Control 350 References 353 Index 355

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