Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up Editor: Mohammed Maniruzzaman (C(%SM1THERS R A P R A A Smithers Group Company Shawbury, Shrewsbury, Shropshire, SY4 4NR, United Kingdom Telephone: +44 (0)1939 250383 Fax: +44 (0)1939 251118 http://www.polymer-books.com
CenB Preface Contents Contributors iii vii xv 1 Introduction to Hot-Melt Extrusion, Continuous Manufacturing: Scale-up via Hot-Melt Extrusion 1 1 Background 1 1.1 Introduction 1 1.1.1 Hot-Melt Extrusion Process Technology 2 1.1.2 Equipment 3 1.1.3 Benefits and Drawbacks to Hot-Melt Extrusion 4 1.1.4 Application of Hot-Melt Extrusion 5 1.1.5 Materials used in Hot-Melt Extrusion Processes 6 1.1.6 Development of Sustained-release Formulations 7 1.1.7 Marketed Products 7 1.2 Continuous Manufacturing 8 1.3 Scale-up via Hot-Melt Process 10 1.3.1 Case Study: Scale-up of a Hot-Melt Extrusion Process using Soluplus as Carrier 11 1.4 Conclusions 14 References 15 2 Hot-Melt Extrusion as Continuous Manufacturing Technique, Current Trends and Future Perspectives 19 2.1 Hot-Melt Extrusion as Continuous Manufacturing Technique 19 2.1.1 Hot-Melt Extrusion Equipment 21 2.1.2 Single-screw Extruder 24 vii
Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up 2.1.3 Twin-screw Extruders 24 2.1.4 Role of Glass Transition Temperature 26 2.1.5 Role of Mechanical Parameters 26 2.1.6 Use of Plasticisers or Surfactants 26 2.1.7 Challenges and Opportunities 26 2.2 Background Information on Batch Processing 27 2.2.1 Past and Future Trends of Continuous Manufacturing 28 2.2.2 Conventional Batch Process Design 29 2.2.3 Production Parameters 29 2.2.4 Production Parameters in Batch Processing 29 2.2.4.1 Active Pharmaceutical Ingredient(s) Manufacturing Site 29 2.2.4.2 Formulation Development 29 2.2.4.3 Industrial Scale-up 30 2.2.4.4 Regulatory Guidelines 30 2.2.5 Validation of Batch Processing 30 2.2.6 In-line Continuous Monitoring Techniques 30 2.3 Assimilation of Complete Quality-by-Design Models 35 2.3.1 Chief Modification in Procedural Expertise for Continuous Manufacturing 35 2.3.2 Process Parameters for Preformulation for Hot-Melt Extrusion 36 2.3.3 Implementation of a New Product Development Process 36 2.3.3.1 Modelling Simulation of Hot-Melt Extrusion Process 36 2.3.4 Flow Chart Model for Continuous Hot-Melt Extrusion based Pharmaceutical Manufacturing Process 39 2.3.5 Foremost Alteration in Structural Provisions for Quality and Technical Operations 41 2.3.6 Potential Benefits of Continuous Hot-Melt Extrusion Manufacturing 44 2.3.7 Regulatory Issues Related to Hot-Melt Extrusion 44
Contents 2.3.8 Process Analytical Technology Framework 45 2.4 Conclusion 46 References 47 3 Co-extrusion as a Novel Approach in Continuous Manufacturing Compliance 53 3 Background 53 3.1 Introduction 53 3.2 Applications of Co-extrusion via Hot-Melt Extrusion in Continuous Manufacturing 54 3.2.1 Problem Encountered During Co-extrusion 55 3.2.2 Variation of the Die Temperature 55 3.2.3 Swelling of the Die 55 3.2.4 Viscosity Matching 56 3.2.5 Adhesion 56 3.2.6 Inter diffusion 56 3.2.7 Delamination 57 3.3 Pharmaceutical Applications 57 3.3.1 Pharmaceutical Significance of the Co-extrusion Technique 57 3.4 Case Study 58 3.5 Conclusions 59 References 59 4 Solid-state Engineering of Drugs using Melt Extrusion in Continuous Process 63 4 Introduction 63 4.1 Dissolution Enhancement 63 4.1.1 Use of Novel Inorganic Excipients 63 4.1.2 Use of Polymers to Enhance Dissolutions of Poorly Water-soluble Active Pharmaceutical Ingredients 67 4.1.3 Continuous Co-crystallisation Engineering 68 4.1.4 Polymorphic Transformations via Hot-Melt Extrusion 69 ix
Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up 4.1.4.1 Polymorphic Transformation of Carbamazepine 70 4.1.4.2 Polymorphic Transformation of Artemisinin 70 References 71 5 Continuous Co-crystallisation of Poorly Soluble Active Pharmaceutical Ingredients to Enhance Dissolution 75 5.1 Introduction 75 5.2 Mechanism of Continuous Co-crystallisation by Twin-screw Extrusion 79 5.2.1 Eutectic-mediated Co-crystallisation 80 5.2.1.1 Ibuprofen-Nicotinamide Case 80 5.2.1.2 Carbamazepine-Saccharin Case 81 5.2.2 Solvent-assisted Co-crystallisation 85 5.2.3 Amorphous Phase-mediated Co-crystallisation 87 5.2.3.1 AMG 517-Sorbic Acid Case 87 5.3 Critical Parameters Influencing Continuous Co-crystallisation by Twin-screw Extrusion 89 5.3.1 Processing Temperature 89 5.3.2 Temperature-dependent Case 89 5.3.3 Temperature-independent Case 89 5.3.4 Screw Design 90 5.3.5 Screw Speed 90 5.3.6 Feed-rate 91 5.4 Case Study 91 5.4.1 Matrix-assisted Co-crystallisation of Carbamazepine-Nicotinamide System by Twin-screw Extrusion 91 5.4.2 Avoiding Thermal Degradation of Carbamazepine through In Situ Co-crystallising with Nicotinamide 92 5.5 Conclusions 93 References 93 x
Contents 6 Taste Masking of Bitter Active Pharmaceutical Ingredients for the Development of Paediatric Medicines via Continuous Hot-Melt Extrusion Processing 97 6 Introduction 97 6.1 Hot-Melt Extrusion as an Active Taste Masking Technique 97 6.1.1 Taste Masking via Continuous Hot-Melt Extrusion Process 97 6.1.2 Polymers as Suitable Carriers for Taste Masking 99 6.1.3 Use of Lipids as Carriers for Taste Masking in Hot-Melt Extrusion 104 6.2 Continuous Manufacturing of Oral Films via Hot-Melt Extrusion 105 6.2.1 Case Study: Taste Masking of Bitter Active Pharmaceutical Ingredients via Continuous Hot-Melt Extrusion Processing 106 6.3 Materials 107 6.3.1 In Vivo Taste Masking Evaluation 107 6.3.2 In Vitro Taste Masking Evaluation: Astree e-tongue 107 6.3.3 Sample Preparation for Astree e-tongue 108 6.4 Results and Discussion 108 6.4.1 In Vivo/In Vitro Taste Evaluations Ill 6.5 Conclusions 115 References 115 7 Continuous Manufacturing of Pharmaceutical Products via Melt Extrusion: A Case Study 121 7 Introduction 121 Case Study 122 7.1 Materials and Method 122 7.1.1 Materials 122 7.1.2 Preparation of Formulation Blends and Continuous Hot-Melt Extrusion Processing 122 7.1.3 Scanning Electron Microscopy/Energy Dispersive X-ray Analysis 123 XI
Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up 7.1.4 Thermal Analysis 123 7.1.5 Powder X-ray Diffraction 124 7.1.6 In Vitro Drug Release Studies 124 7.1.7 Analysis of Drug Release Mechanism 124 7.2 Results and Discussion 126 7.2.1 Continuous Manufacturing of Pellets via Hot-Melt Extrusion 127 7.2.2 Advanced Surface Analysis 129 7.2.4 Thermal Analysis 130 7.2.5 Amorphicity Analysis 131 7.2.6 In Vitro Dissolution Studies 132 7.2.7 Analysis of Release Mechanism 133 7.3 Conclusions 135 References 136 8 Novel Pharmaceutical Formulations Using Hot-Melt Extrusion Processing as a Continuous Manufacturing Technique 139 8 Introduction 139 8.1 Materials and Methods 140 8.1.1 Materials 140 8.1.2 Hot-Melt Extrusion Processing 140 8.1.3 Differential Scanning Calorimetry Analysis 140 8.1.4 Hot Stage Microscopy Analysis 140 8.1.5 X-ray Powder Diffraction 141 8.1.6 In Vitro Drug Release Studies 141 8.1.7 High-performance Liquid Chromatography Analysis 141 8.2 Results and Discussion 142 8.2.1 Hot-Melt Extrusion Processing 142 8.2.2 Thermal Analysis 142 8.2.3 X-ray Powder Diffraction Analysis 144 8.2.4 In Vitro Dissolution Studies 145 8.3 Conclusions 146 References 147 xii
Contents 9 Continuous Polymorphic Transformations Study via Hot-Melt Extrusion Process 149 9 Background 149 9.1 Polymorphism 149 9.2 Case Study: Polymorphic Transformation of Paracetamol 150 9.2.1 Experimental Methods 151 9.2.2 Theoretical Calculation 151 9.2.3 Continuous Hot-Melt Extrusion Process and In-line Monitoring 152 9.2.4 Thermal Analysis 153 9.3 Results and Discussion 154 9.3.1 Continuous Extrusion Process and Theoretical Consideration 154 9.3.2 Physicochemical Characterisation of the Polymorphic Transformation during Hot-Melt Extrusion 156 9.3.3 In-line Near-infrared Spectroscopy Monitoring 163 9.4 Conclusions 165 References 165 10 From Pharma Adapted Extrusion Technology to Brand New Pharma Fitted Extrusion Design: The Concept of Micro-scale Vertical Extrusion and its' Impact in Terms of Scale-up Potential 169 10 Introduction 169 10.1 The Advantages of Hot-Melt Extrusion 170 10.1.1 Examples of Problems Solved Thanks to Hot-Melt Extrusion 170 10.2 From Micro-scale to Industrial-scale 171 10.2.1 Viscosity of the Three Samples at Different Temperatures 172 10.2.2 Viscosity at Various Temperatures 173 10.3 Hot-Melt Extrusion as a Standard Technology for the Pharmaceutical Industry 174 10.4 Innovations 175 xni
Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up 10.5 Conclusions 179 References 179 11 Continuous Manufacturing via Hot-Melt Extrusion and Scale-up: Regulatory Aspects 181 11 Introduction 181 11.1 Continuous Manufacturing and Hot-Melt Extrusion Processing Technology 181 11.2 Aspects of the Controls/Parameters in Hot-Melt Extrusion Processing 184 11.3 Continuous Manufacturing via Hot-Melt Extrusion 185 11.4 Continuous Manufacturing Process over Batch Process 187 11.5 Scale-up Methodologies 188 11.6 Regulatory Aspects 191 11.7 Summary 193 References 193 Abbreviations 197 Index 201 xiv