Contents Preface... iii Contents...vii Contributors...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 viii
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 Interdiffusion... 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... 111 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 xiii
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