Hot-Melt Extrusion Pharmaceutical Applications

Hot-melt extrusion (HME) - melting a substance and forcing it through an orifice under controlled conditions to form a new material - is an emerging processing technology in the pharmaceutical industry for the preparation of various dosage forms and drug delivery systems, for example granules and sustained release tablets. 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#60;br /> 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.

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.

List of Contributors	p. xv
Preface	p. xvii
Single-screw Extrusion: Principles	p. 1
Introduction	p. 1
Ideal Compounding	p. 2
Basics of the Single-screw Extruder	p. 3
Screw Feed Section	p. 5
Screw Compressor Section	p. 9
Screw Metering Section	p. 11
Mixers	p. 11
Limitations of Conventional Single-screw Mixers	p. 13
SSE Elongational Mixers	p. 13
Summary	p. 20
References	p. 21
Twin-screw Extruders for Pharmaceutical Hot-melt Extrusion: Technology, Techniques and Practices	p. 23
Introduction	p. 23
Extruder Types and Working Principle	p. 24
Individual Parts of a TSE	p. 25
Drive Unit	p. 25
Screws	p. 25
Screw Elements	p. 27
Distributive Flow Elements	p. 28
Discharge Feed Screw	p. 28
Barrel	p. 29
Downstreaming	p. 30
Individual Processing Sections of the TSE	p. 31
Feeding Section	p. 32
Conveying/Melting Section	p. 32
Mixing Section	p. 33
Venting Section	p. 33
Extrusion Section	p. 33
Feeding of Solids	p. 34
TSE Operating Parameters	p. 34
Filling Level	p. 36
Screw Speed	p. 36
Feed Rate	p. 37
Residence Time Distribution	p. 37
Effect of Screw Speed and Feed Rate on Melt Temperature	p. 39
Setting up an HME Process using QbD Principles	p. 40
Understanding Knowledge Space	p. 40
Denning Design Space	p. 40
Determining Control Space	p. 41
Summary	p. 42
References	p. 42
Hot-melt Extrusion Developments in the Pharmaceutical Industry	p. 43
Introduction	p. 43
Advantages of HME as Drug Delivery Technology	p. 44
Formulations used for HME Applications	p. 45
Active Pharmaceutical Ingredient	p. 46
Solid Dispersions	p. 48
Bioavailability Improvement	p. 49
Controlled Delivery Systems	p. 51
Plasticizers	p. 53
Characterization of Extrudates	p. 55
Thermal Analysis	p. 55
Atomic Force Microscopy	p. 56
Residence Time	p. 57
Spectroscopic Techniques	p. 57
X-ray Diffraction (XRD)	p. 58
Microscopy	p. 58
Drug Release	p. 58
Hot-melt Extruded Dosage Forms	p. 58
Oral Drag Delivery	p. 59
Films	p. 61
Vaginal Rings and Implants	p. 61
A View to the Future	p. 63
References	p. 64
Solubility Parameters for Prediction of Drug/Polymer Miscibility in Hot-melt Extruded Formulations	p. 71
Introduction	p. 71
Solid Dispersions	p. 72
Basic Assumptions for the Drug-polymer Miscibility Prediction	p. 77
Solubility and the Flory-Huggins Theory	p. 78
Miscibility Estimation of Drug and Monomers	p. 83
Summary	p. 89
References	p. 90
The Influence of Plasticizers in Hot-melt Extrusion	p. 93
Introduction	p. 93
Traditional Plasticizers	p. 94
Non-traditional Plasticizers	p. 95
Specialty Plasticizers	p. 104
Conclusions	p. 107
References	p. 108
Applications of Poly(meth)acrylate Polymers in Melt Extrusion	p. 113
Introduction	p. 113
Polymer Characteristics	p. 116
Chemical Structure and Molecular Weight	p. 116
Glass Transition Temperature	p. 119
Plasticizers	p. 120
Thermostability	p. 121
Viscosity	p. 122
Specific Heat Capacity	p. 124
Hygroscopicity	p. 126
Melt Extrusion of Poly(methacrylates) to Design Pharmaceutical Oral Dosage Forms	p. 128
Solubility Enhancement	p. 128
Bioavailability Enhancement of BCS Class IV Drugs	p. 132
Controlled Release	p. 135
Time-controlled-release Dosage Forms	p. 136
pH-dependent Release	p. 138
Taste Masking	p. 139
Summary	p. 140
References	p. 140
Hot-melt Extrusion of Ethylcellulose, Hypromellose and Polyethylene Oxide	p. 145
Introduction	p. 145
Background	p. 146
Thermal Properties	p. 147
Processing Aids/Additives	p. 147
Unconventional Processing Aids: Drags, Blends	p. 149
Case Studies	p. 151
Ethylcellulose	p. 151
Combinations of Excipients	p. 151
Solubilization	p. 155
Film	p. 159
Unique Dosage Forms	p. 163
Abuse Resistance	p. 163
Controlled Release	p. 164
Solubility Parameters	p. 166
Milling of EC, HPMC and PEO Extrudate	p. 168
References	p. 170
Bioadhesion Properties of Polymeric Films Produced by Hot-melt Extrusion	p. 177
Introduction	p. 177
Anatomy of the Oral Cavity and Modes of Drug Transport	p. 180
Structure	p. 180
Modes of Drug Transport and Kinetics	p. 180
Factors Affecting Drug Absorption	p. 181
Mucoadhesive Mechanisms	p. 182
Factors Affecting Mucoadhesion in the Oral Cavity	p. 183
Determination of Mucoadhesion and Mechanical Properties of Films	p. 183
Bioadhesive Films Prepared by HME	p. 184
Summary	p. 194
References	p. 194
Taste Masking Using Hot-melt Extrusion	p. 201
The Need and Challenges for Masking Bitter APIs	p. 201
Organization of the Taste System	p. 203
Taste Perception in Humans and Organization of Peripheral System	p. 203
Transduction of Taste Signals	p. 205
Taste Sensing Systems (Electronic Tongues) for Pharmaceutical Dosage Forms	p. 206
Alpha MOS Electronic Tongue: Instrumentation and Operational Principles	p. 206
Taste Analysis	p. 208
Taste Masking Efficiency Testing	p. 209
Advantages of E-tongue Taste Analysis	p. 211
Hot-melt Extrusion: An Effective Means of Taste Masking	p. 212
Taste Masking via Polymer Extrusion	p. 212
Taste Masking via Solid Lipid Extrusion	p. 216
Summary	p. 219
References	p. 219
Clinical and Preclinical Studies, Bioavailability and Pharmacokinetics of Hot-melt Extruded Products	p. 223
Introduction to Oral Absorption	p. 223
In Vivo Evaluation of Hot-melt Extruded Solid Dispersions	p. 225
Oral Immediate Release	p. 225
Oral Controlled Release	p. 232
Implants	p. 233
Conclusion	p. 234
References	p. 234
Injection Molding and Hot-melt Extrusion Processing for Pharmaceutical Materials	p. 239
Introduction	p. 239
Hot-melt Extrusion in Brief	p. 240
Injection Molding	p. 241
Critical Parameters	p. 242
Melt Temperature	p. 242
Barrel Temperature	p. 243
Cooling Temperature	p. 243
Holding Pressure	p. 243
Holding Time	p. 243
Back Pressure	p. 244
Injection Speed	p. 244
Cooling Time/Cycle Time	p. 244
Example: Comparison of Extruded and Injection-molded Material	p. 245
Development of Products for Injection Molding	p. 246
Excipients	p. 246
Stability	p. 248
Process Development	p. 248
Properties of Injection-molded Materials	p. 251
Egalet® Technology	p. 251
Controlling Physical State by Means of Hot-melt Extrusion and Injection Molding	p. 253
Anti-tamper Properties of Injection-molded Tablets	p. 254
Concluding Remarks	p. 257
References	p. 257
Laminar Dispersive and Distributive Mixing with Dissolution and Applications to Hot-melt Extrusion	p. 261
Introduction	p. 261
Elementary Steps in HME	p. 263
Paniculate Solids Handling (PSH)	p. 263
Melting	p. 263
Devolatilization	p. 264
Pumping and Pressurization	p. 265
Dispersive and Distributive Mixing	p. 265
HME Processes: Cases I and II	p. 265
Case I	p. 266
Case II	p. 268
Dissolution of Drug Particulates in Polymeric Melt	p. 270
Process Variables	p. 270
Equipment Variables	p. 273
Material Variables	p. 275
Case Study: Acetaminophen and Poly(ethylene oxide)	p. 278
Determination of Solubility of APAP in PEO	p. 280
References	p. 282
Technological Considerations Related to Scale-up of Hot-melt Extrusion Processes	p. 285
Introduction	p. 285
Scale-up Terminology	p. 287
Scale-up: Batch Size	p. 287
Scale-up: Feed Rate	p. 288
Scale-up: Extruder Diameter	p. 290
Volumetric Scale-up	p. 290
Volumetric Scale-up: Length/Diameter (L/D)	p. 292
Volumetric Scale-up: Diameter Ratio	p. 292
Volumetric Scale-up: Screw Design	p. 294
Power Scale-up	p. 296
Heat Transfer Scale-up	p. 298
Die Scale-up	p. 299
Conclusion	p. 299
References	p. 300
Devices and Implant Systems by Hot-melt Extrusion	p. 301
Introduction	p. 301
HME in Device Development	p. 302
Hot-melt Extruder Types	p. 303
Comparison of HME Devices and Oral Dosage Forms	p. 305
HME Processes for Device Fabrication	p. 306
Issues with HME in preparing Drug-eluting Devices	p. 308
Devices and Implants	p. 310
Anatomical Device Locations	p. 310
Simple Devices	p. 310
Non-medicated Prolonged Tissue Contact Devices	p. 312
Medicated (Drug-eluting) Prolonged Tissue Contact Devices	p. 313
Release Kinetics	p. 318
Mechanisms of API Release	p. 318
Example In Vitro Drug Elution Profiles	p. 319
Conclusions	p. 321
References	p. 321
Hot-melt Extrusion: An FDA Perspective on Product and Process Understanding	p. 323
Introduction	p. 323
Quality by Design	p. 325
Utilizing QbD for HME Process Understanding	p. 328
References	p. 331
Improved Process Understanding and Control of a Hot-melt Extrusion Process with Near-Infrared Spectroscopy	p. 333
Vibrational Spectroscopy Introduction	p. 333
Near-infrared Method Development	p. 339
Near-infrared Probes and Fiber Optics	p. 344
NTR for Monitoring the Start-up of a HME Process	p. 347
NIR for Improved Process Understanding and Control	p. 350
References	p. 353
Index	p. 355
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Hot-Melt Extrusion Pharmaceutical Applications

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