Hot-Melt Extrusion

Dennis Douroumis University of Greenwich, UK

• List of Contributors xvPreface xvii1. Single-screw Extrusion: Principles 1Keith Luker1.1 Introduction 11.2 Ideal Compounding 21.3 Basics of the Single-screw Extruder 31.3.1 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 131.4 SSE Elongational Mixers 131.5 Summary 20References 212. Twin-screw Extruders for Pharmaceutical Hot-melt Extrusion: Technology, Techniques and Practices 23Dirk Leister, Tom Geilen and Thobias Geissler2.1 Introduction 232.2 Extruder Types and Working Principle 242.3 Individual Parts of a TSE 252.3.1 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 292.4 Downstreaming 302.5 Individual Processing Sections of the TSE 312.5.1 Feeding Section 322.5.2 Conveying/Melting Section 322.5.3 Mixing Section 332.5.4 Venting Section 332.5.5 Extrusion Section 332.6 Feeding of Solids 342.7 TSE Operating Parameters 342.7.1 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 392.8 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 412.9 Summary 42References 423. Hot-melt Extrusion Developments in the Pharmaceutical Industry 43Ana Almeida, Bart Claeys, Jean Paul Remon and Chris Vervaet3.1 Introduction 433.2 Advantages of HME as Drug Delivery Technology 443.3 Formulations used for HME Applications 453.3.1 Active Pharmaceutical Ingredient 463.3.2 Solid Dispersions 483.3.3 Bioavailability Improvement 493.3.4 Controlled Delivery Systems 513.3.5 Plasticizers 533.4 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 583.5 Hot-melt Extruded Dosage Forms 583.5.1 Oral Drug Delivery 593.5.2 Films 613.5.3 Vaginal Rings and Implants 613.6 A View to the Future 63References 644. Solubility Parameters for Prediction of Drug/Polymer Miscibility in Hot-melt Extruded Formulations 71Andreas Gryczke4.1 Introduction 714.2 Solid Dispersions 724.3 Basic Assumptions for the Drug–polymer Miscibility Prediction 774.4 Solubility and the Flory–Huggins Theory 784.5 Miscibility Estimation of Drug and Monomers 834.6 Summary 89References 905. The Influence of Plasticizers in Hot-melt Extrusion 93Geert Verreck5.1 Introduction 935.2 Traditional Plasticizers 945.3 Non-traditional Plasticizers 955.4 Specialty Plasticizers 1045.5 Conclusions 107References 1086. Applications of Poly(meth)acrylate Polymers in Melt Extrusion 113Kathrin Nollenberger and Jessica Albers6.1 Introduction 1136.2 Polymer Characteristics 1166.2.1 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 1266.3 Melt Extrusion of Poly(methacrylates) to Design Pharmaceutical Oral Dosage Forms 1286.4 Solubility Enhancement 1286.5 Bioavailability Enhancement of BCS Class IV Drugs 1326.5.1 Controlled Release 1356.5.2 Time-controlled-release Dosage Forms 1366.5.3 pH-dependent Release 1386.5.4 Taste Masking 1396.6 Summary 140References 1407. Hot-melt Extrusion of Ethylcellulose, Hypromellose and Polyethylene Oxide 145Mark Hall and Michael Read7.1 Introduction 1457.2 Background 1467.3 Thermal Properties 1477.4 Processing Aids/Additives 1477.5 Unconventional Processing Aids: Drugs, Blends 1497.6 Case Studies 1517.6.1 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 1667.7 Milling of EC, HPMC and PEO Extrudate 168References 1708. Bioadhesion Properties of Polymeric Films Produced by Hot-melt Extrusion 177Joshua Boateng and Dennis Douroumis8.1 Introduction 1778.2 Anatomy of the Oral Cavity and Modes of Drug Transport 1808.2.1 Structure 1808.2.2 Modes of Drug Transport and Kinetics 1808.2.3 Factors Affecting Drug Absorption 1818.3 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 194References 1949. Taste Masking Using Hot-melt Extrusion 201Dennis Douroumis, Marion Bonnefille and Attila Aranyos9.1 The Need and Challenges for Masking Bitter APIs 2019.2 Organization of the Taste System 2039.2.1 Taste Perception in Humans and Organization of Peripheral System 2039.2.2 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 2119.4 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 2169.5 Summary 219References 21910. Clinical and Preclinical Studies, Bioavailability and Pharmacokinetics of Hot-melt Extruded Products 223Sandra Guns and Guy Van den Mooter10.1 Introduction to Oral Absorption 22310.2 In Vivo Evaluation of Hot-melt Extruded Solid Dispersions 22510.2.1 Oral Immediate Release 22510.2.2 Oral Controlled Release 23210.2.3 Implants 23310.3 Conclusion 234References 23411. Injection Molding and Hot-melt Extrusion Processing for Pharmaceutical Materials 239Pernille Høyrup Hemmingsen and Martin Rex Olsen11.1 Introduction 23911.2 Hot-melt Extrusion in Brief 24011.3 Injection Molding 24111.4 Critical Parameters 24211.4.1 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 24411.5 Example: Comparison of Extruded and Injection-molded Material 24511.6 Development of Products for Injection Molding 24611.6.1 Excipients 24611.6.2 Stability 24811.6.3 Process Development 24811.7 Properties of Injection-molded Materials 25111.7.1 Egalet® 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 25411.8 Concluding Remarks 257References 25712. Laminar Dispersive and Distributive Mixing with Dissolution and Applications to Hot-melt Extrusion 261Costas G. Gogos, Huiju Liu and Peng Wang12.1 Introduction 26112.2 Elementary Steps in HME 26312.2.1 Particulate Solids Handling (PSH) 26312.2.2 Melting 26312.2.3 Devolatilization 26412.2.4 Pumping and Pressurization 26512.3 Dispersive and Distributive Mixing 26512.4 HME Processes: Cases I and II 26512.4.1 Case I 26612.4.2 Case II 26812.5 Dissolution of Drug Particulates in Polymeric Melt 27012.5.1 Process Variables 27012.5.2 Equipment Variables 27312.5.3 Material Variables 27512.6 Case Study: Acetaminophen and Poly(ethylene oxide) 27812.7 Determination of Solubility of APAP in PEO 280References 28213. Technological Considerations Related to Scale-up of Hot-melt Extrusion Processes 285Adam Dreiblatt13.1 Introduction 28513.2 Scale-up Terminology 28713.2.1 Scale-up: Batch Size 28713.2.2 Scale-up: Feed Rate 28813.2.3 Scale-up: Extruder Diameter 29013.3 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 29413.4 Power Scale-up 29613.5 Heat Transfer Scale-up 29813.6 Die Scale-up 29913.7 Conclusion 299References 30014. Devices and Implant Systems by Hot-melt Extrusion 301Andrew Loxley14.1 Introduction 30114.2 HME in Device Development 30214.3 Hot-melt Extruder Types 30314.4 Comparison of HME Devices and Oral Dosage Forms 30514.5 HME Processes for Device Fabrication 30614.5.1 Issues with HME in preparing Drug-eluting Devices 30814.6 Devices and Implants 31014.6.1 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 31314.7 Release Kinetics 31814.7.1 Mechanisms of API Release 31814.7.2 Example In Vitro Drug Elution Profiles 31914.8 Conclusions 321References 32115. Hot-melt Extrusion: An FDA Perspective on Product and Process Understanding 323Abhay Gupta and Mansoor A. Khan15.1 Introduction 32315.2 Quality by Design 32515.3 Utilizing QbD for HME Process Understanding 328References 33116. Improved Process Understanding and Control of a Hot-melt Extrusion Process with Near-Infrared Spectroscopy 333Chris Heil and Jeffrey Hirsch16.1 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 350References 353Index 355