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<p>List of Contributors xv</p> <p>Preface xvii</p> <p><b>1. Single-screw Extrusion: Principles 1<br /></b><i>Keith Luker</i></p> <p>1.1 Introduction 1</p> <p>1.2 Ideal Compounding 2</p> <p>1.3 Basics of the Single-screw Extruder 3</p> <p>1.3.1 Screw Feed Section 5</p> <p>1.3.2 Screw Compressor Section 9</p> <p>1.3.3 Screw Metering Section 11</p> <p>1.3.4 Mixers 11</p> <p>1.3.5 Limitations of Conventional Single-screw Mixers 13</p> <p>1.4 SSE Elongational Mixers 13</p> <p>1.5 Summary 20</p> <p>References 21</p> <p><b>2. Twin-screw Extruders for Pharmaceutical Hot-melt Extrusion: Technology, Techniques and Practices 23<br /></b><i>Dirk Leister, Tom Geilen and Thobias Geissler</i></p> <p>2.1 Introduction 23</p> <p>2.2 Extruder Types and Working Principle 24</p> <p>2.3 Individual Parts of a TSE 25</p> <p>2.3.1 Drive Unit 25</p> <p>2.3.2 Screws 25</p> <p>2.3.3 Screw Elements 27</p> <p>2.3.4 Distributive Flow Elements 28</p> <p>2.3.5 Discharge Feed Screw 28</p> <p>2.3.6 Barrel 29</p> <p>2.4 Downstreaming 30</p> <p>2.5 Individual Processing Sections of the TSE 31</p> <p>2.5.1 Feeding Section 32</p> <p>2.5.2 Conveying/Melting Section 32</p> <p>2.5.3 Mixing Section 33</p> <p>2.5.4 Venting Section 33</p> <p>2.5.5 Extrusion Section 33</p> <p>2.6 Feeding of Solids 34</p> <p>2.7 TSE Operating Parameters 34</p> <p>2.7.1 Filling Level 36</p> <p>2.7.2 Screw Speed 36</p> <p>2.7.3 Feed Rate 37</p> <p>2.7.4 Residence Time Distribution 37</p> <p>2.7.5 Effect of Screw Speed and Feed Rate on Melt Temperature 39</p> <p>2.8 Setting up an HME Process using QbD Principles 40</p> <p>2.8.1 Understanding Knowledge Space 40</p> <p>2.8.2 Defining Design Space 40</p> <p>2.8.3 Determining Control Space 41</p> <p>2.9 Summary 42</p> <p>References 42</p> <p><b>3. Hot-melt Extrusion Developments in the Pharmaceutical Industry 43<br /></b><i>Ana Almeida, Bart Claeys, Jean Paul Remon and Chris Vervaet</i></p> <p>3.1 Introduction 43</p> <p>3.2 Advantages of HME as Drug Delivery Technology 44</p> <p>3.3 Formulations used for HME Applications 45</p> <p>3.3.1 Active Pharmaceutical Ingredient 46</p> <p>3.3.2 Solid Dispersions 48</p> <p>3.3.3 Bioavailability Improvement 49</p> <p>3.3.4 Controlled Delivery Systems 51</p> <p>3.3.5 Plasticizers 53</p> <p>3.4 Characterization of Extrudates 55</p> <p>3.4.1 Thermal Analysis 55</p> <p>3.4.2 Atomic Force Microscopy 56</p> <p>3.4.3 Residence Time 57</p> <p>3.4.4 Spectroscopic Techniques 57</p> <p>3.4.5 X-ray Diffraction (XRD) 58</p> <p>3.4.6 Microscopy 58</p> <p>3.4.7 Drug Release 58</p> <p>3.5 Hot-melt Extruded Dosage Forms 58</p> <p>3.5.1 Oral Drug Delivery 59</p> <p>3.5.2 Films 61</p> <p>3.5.3 Vaginal Rings and Implants 61</p> <p>3.6 A View to the Future 63</p> <p>References 64</p> <p><b>4. Solubility Parameters for Prediction of Drug/Polymer Miscibility in Hot-melt Extruded Formulations 71<br /></b><i>Andreas Gryczke</i></p> <p>4.1 Introduction 71</p> <p>4.2 Solid Dispersions 72</p> <p>4.3 Basic Assumptions for the Drug–polymer Miscibility Prediction 77</p> <p>4.4 Solubility and the Flory–Huggins Theory 78</p> <p>4.5 Miscibility Estimation of Drug and Monomers 83</p> <p>4.6 Summary 89</p> <p>References 90</p> <p><b>5. The Influence of Plasticizers in Hot-melt Extrusion 93<br /></b><i>Geert Verreck</i></p> <p>5.1 Introduction 93</p> <p>5.2 Traditional Plasticizers 94</p> <p>5.3 Non-traditional Plasticizers 95</p> <p>5.4 Specialty Plasticizers 104</p> <p>5.5 Conclusions 107</p> <p>References 108</p> <p><b>6. Applications of Poly(meth)acrylate Polymers in Melt Extrusion 113<br /></b><i>Kathrin Nollenberger and Jessica Albers</i></p> <p>6.1 Introduction 113</p> <p>6.2 Polymer Characteristics 116</p> <p>6.2.1 Chemical Structure and Molecular Weight 116</p> <p>6.2.2 Glass Transition Temperature 119</p> <p>6.2.3 Plasticizers 120</p> <p>6.2.4 Thermostability 121</p> <p>6.2.5 Viscosity 122</p> <p>6.2.6 Specific Heat Capacity 124</p> <p>6.2.7 Hygroscopicity 126</p> <p>6.3 Melt Extrusion of Poly(methacrylates) to Design Pharmaceutical Oral Dosage Forms 128</p> <p>6.4 Solubility Enhancement 128</p> <p>6.5 Bioavailability Enhancement of BCS Class IV Drugs 132</p> <p>6.5.1 Controlled Release 135</p> <p>6.5.2 Time-controlled-release Dosage Forms 136</p> <p>6.5.3 pH-dependent Release 138</p> <p>6.5.4 Taste Masking 139</p> <p>6.6 Summary 140</p> <p>References 140</p> <p><b>7. Hot-melt Extrusion of Ethylcellulose, Hypromellose and Polyethylene Oxide 145<br /></b><i>Mark Hall and Michael Read</i></p> <p>7.1 Introduction 145</p> <p>7.2 Background 146</p> <p>7.3 Thermal Properties 147</p> <p>7.4 Processing Aids/Additives 147</p> <p>7.5 Unconventional Processing Aids: Drugs, Blends 149</p> <p>7.6 Case Studies 151</p> <p>7.6.1 Ethylcellulose 151</p> <p>7.6.2 Combinations of Excipients 151</p> <p>7.6.3 Solubilization 155</p> <p>7.6.4 Film 159</p> <p>7.6.5 Unique Dosage Forms 163</p> <p>7.6.6 Abuse Resistance 163</p> <p>7.6.7 Controlled Release 164</p> <p>7.6.8 Solubility Parameters 166</p> <p>7.7 Milling of EC, HPMC and PEO Extrudate 168</p> <p>References 170</p> <p><b>8. Bioadhesion Properties of Polymeric Films Produced by Hot-melt Extrusion 177<br /></b><i>Joshua Boateng and Dennis Douroumis</i></p> <p>8.1 Introduction 177</p> <p>8.2 Anatomy of the Oral Cavity and Modes of Drug Transport 180</p> <p>8.2.1 Structure 180</p> <p>8.2.2 Modes of Drug Transport and Kinetics 180</p> <p>8.2.3 Factors Affecting Drug Absorption 181</p> <p>8.3 Mucoadhesive Mechanisms 182</p> <p>8.4 Factors Affecting Mucoadhesion in the Oral Cavity 183</p> <p>8.5 Determination of Mucoadhesion and Mechanical Properties of Films 183</p> <p>8.6 Bioadhesive Films Prepared by HME 184</p> <p>8.7 Summary 194</p> <p>References 194</p> <p><b>9. Taste Masking Using Hot-melt Extrusion 201<br /></b><i>Dennis Douroumis, Marion Bonnefille and Attila Aranyos</i></p> <p>9.1 The Need and Challenges for Masking Bitter APIs 201</p> <p>9.2 Organization of the Taste System 203</p> <p>9.2.1 Taste Perception in Humans and Organization of Peripheral System 203</p> <p>9.2.2 Transduction of Taste Signals 205</p> <p>9.3 Taste Sensing Systems (Electronic Tongues) for Pharmaceutical Dosage Forms 206</p> <p>9.3.1 Alpha MOS Electronic Tongue: Instrumentation and Operational Principles 206</p> <p>9.3.2 Taste Analysis 208</p> <p>9.3.3 Taste Masking Efficiency Testing 209</p> <p>9.3.4 Advantages of E-tongue Taste Analysis 211</p> <p>9.4 Hot-melt Extrusion: An Effective Means of Taste Masking 212</p> <p>9.4.1 Taste Masking via Polymer Extrusion 212</p> <p>9.4.2 Taste Masking via Solid Lipid Extrusion 216</p> <p>9.5 Summary 219</p> <p>References 219</p> <p><b>10. Clinical and Preclinical Studies, Bioavailability and Pharmacokinetics of Hot-melt Extruded Products 223<br /></b><i>Sandra Guns and Guy Van den Mooter</i></p> <p>10.1 Introduction to Oral Absorption 223</p> <p>10.2 In Vivo Evaluation of Hot-melt Extruded Solid Dispersions 225</p> <p>10.2.1 Oral Immediate Release 225</p> <p>10.2.2 Oral Controlled Release 232</p> <p>10.2.3 Implants 233</p> <p>10.3 Conclusion 234</p> <p>References 234</p> <p><b>11. Injection Molding and Hot-melt Extrusion Processing for Pharmaceutical Materials 239<br /></b><i>Pernille Høyrup Hemmingsen and Martin Rex Olsen</i></p> <p>11.1 Introduction 239</p> <p>11.2 Hot-melt Extrusion in Brief 240</p> <p>11.3 Injection Molding 241</p> <p>11.4 Critical Parameters 242</p> <p>11.4.1 Melt Temperature 242</p> <p>11.4.2 Barrel Temperature 243</p> <p>11.4.3 Cooling Temperature 243</p> <p>11.4.4 Holding Pressure 243</p> <p>11.4.5 Holding Time 243</p> <p>11.4.6 Back Pressure 244</p> <p>11.4.7 Injection Speed 244</p> <p>11.4.8 Cooling Time/Cycle Time 244</p> <p>11.5 Example: Comparison of Extruded and Injection-molded Material 245</p> <p>11.6 Development of Products for Injection Molding 246</p> <p>11.6.1 Excipients 246</p> <p>11.6.2 Stability 248</p> <p>11.6.3 Process Development 248</p> <p>11.7 Properties of Injection-molded Materials 251</p> <p>11.7.1 Egalet^® Technology 251</p> <p>11.7.2 Controlling Physical State by Means of Hot-melt Extrusion and Injection Molding 253</p> <p>11.7.3 Anti-tamper Properties of Injection-molded Tablets 254</p> <p>11.8 Concluding Remarks 257</p> <p>References 257</p> <p><b>12. Laminar Dispersive and Distributive Mixing with Dissolution and Applications to Hot-melt Extrusion 261<br /></b><i>Costas G. Gogos, Huiju Liu and Peng Wang</i></p> <p>12.1 Introduction 261</p> <p>12.2 Elementary Steps in HME 263</p> <p>12.2.1 Particulate Solids Handling (PSH) 263</p> <p>12.2.2 Melting 263</p> <p>12.2.3 Devolatilization 264</p> <p>12.2.4 Pumping and Pressurization 265</p> <p>12.3 Dispersive and Distributive Mixing 265</p> <p>12.4 HME Processes: Cases I and II 265</p> <p>12.4.1 Case I 266</p> <p>12.4.2 Case II 268</p> <p>12.5 Dissolution of Drug Particulates in Polymeric Melt 270</p> <p>12.5.1 Process Variables 270</p> <p>12.5.2 Equipment Variables 273</p> <p>12.5.3 Material Variables 275</p> <p>12.6 Case Study: Acetaminophen and Poly(ethylene oxide) 278</p> <p>12.7 Determination of Solubility of APAP in PEO 280</p> <p>References 282</p> <p><b>13. Technological Considerations Related to Scale-up of Hot-melt Extrusion Processes 285<br /></b><i>Adam Dreiblatt</i></p> <p>13.1 Introduction 285</p> <p>13.2 Scale-up Terminology 287</p> <p>13.2.1 Scale-up: Batch Size 287</p> <p>13.2.2 Scale-up: Feed Rate 288</p> <p>13.2.3 Scale-up: Extruder Diameter 290</p> <p>13.3 Volumetric Scale-up 290</p> <p>13.3.1 Volumetric Scale-up: Length/Diameter (L/D) 292</p> <p>13.3.2 Volumetric Scale-up: Diameter Ratio 292</p> <p>13.3.3 Volumetric Scale-up: Screw Design 294</p> <p>13.4 Power Scale-up 296</p> <p>13.5 Heat Transfer Scale-up 298</p> <p>13.6 Die Scale-up 299</p> <p>13.7 Conclusion 299</p> <p>References 300</p> <p><b>14. Devices and Implant Systems by Hot-melt Extrusion 301<br /></b><i>Andrew Loxley</i></p> <p>14.1 Introduction 301</p> <p>14.2 HME in Device Development 302</p> <p>14.3 Hot-melt Extruder Types 303</p> <p>14.4 Comparison of HME Devices and Oral Dosage Forms 305</p> <p>14.5 HME Processes for Device Fabrication 306</p> <p>14.5.1 Issues with HME in preparing Drug-eluting Devices 308</p> <p>14.6 Devices and Implants 310</p> <p>14.6.1 Anatomical Device Locations 310</p> <p>14.6.2 Simple Devices 310</p> <p>14.6.3 Non-medicated Prolonged Tissue Contact Devices 312</p> <p>14.6.4 Medicated (Drug-eluting) Prolonged Tissue Contact Devices 313</p> <p>14.7 Release Kinetics 318</p> <p>14.7.1 Mechanisms of API Release 318</p> <p>14.7.2 Example In Vitro Drug Elution Profiles 319</p> <p>14.8 Conclusions 321</p> <p>References 321</p> <p><b>15. Hot-melt Extrusion: An FDA Perspective on Product and Process Understanding 323<br /></b><i>Abhay Gupta and Mansoor A. Khan</i></p> <p>15.1 Introduction 323</p> <p>15.2 Quality by Design 325</p> <p>15.3 Utilizing QbD for HME Process Understanding 328</p> <p>References 331</p> <p><b>16. Improved Process Understanding and Control of a Hot-melt Extrusion Process with Near-Infrared Spectroscopy 333<br /></b><i>Chris Heil and Jeffrey Hirsch</i></p> <p>16.1 Vibrational Spectroscopy Introduction 333</p> <p>16.2 Near-infrared Method Development 339</p> <p>16.3 Near-infrared Probes and Fiber Optics 344</p> <p>16.4 NIR for Monitoring the Start-up of a HME Process 347</p> <p>16.5 NIR for Improved Process Understanding and Control 350</p> <p>References 353</p> <p>Index 355</p>

<p><b>Dennis Douroumis</b> <i>University of Greenwich, UK</i>

<p><b>ADVANCES IN PHARMACEUTICAL TECHNOLOGY</b> <p><b>Hot-melt Extrusion</b><br> Pharmaceutical Applications <p>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. <p><b><i>Hot-melt Extrusion: Pharmaceutical Applications</i></b> 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. <p>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. <p><b><i>Hot-melt Extrusion: Pharmaceutical Applications</i></b> 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.

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