Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up

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Amelia Charity Atkinson
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1 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) Fax: +44 (0)

2 CenB Preface Contents Contributors iii vii xv 1 Introduction to Hot-Melt Extrusion, Continuous Manufacturing: Scale-up via Hot-Melt Extrusion 1 1 Background Introduction Hot-Melt Extrusion Process Technology Equipment Benefits and Drawbacks to Hot-Melt Extrusion Application of Hot-Melt Extrusion Materials used in Hot-Melt Extrusion Processes Development of Sustained-release Formulations Marketed Products Continuous Manufacturing Scale-up via Hot-Melt Process Case Study: Scale-up of a Hot-Melt Extrusion Process using Soluplus as Carrier Conclusions 14 References 15 2 Hot-Melt Extrusion as Continuous Manufacturing Technique, Current Trends and Future Perspectives Hot-Melt Extrusion as Continuous Manufacturing Technique Hot-Melt Extrusion Equipment Single-screw Extruder 24 vii

3 Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up Twin-screw Extruders Role of Glass Transition Temperature Role of Mechanical Parameters Use of Plasticisers or Surfactants Challenges and Opportunities Background Information on Batch Processing Past and Future Trends of Continuous Manufacturing Conventional Batch Process Design Production Parameters Production Parameters in Batch Processing Active Pharmaceutical Ingredient(s) Manufacturing Site Formulation Development Industrial Scale-up Regulatory Guidelines Validation of Batch Processing In-line Continuous Monitoring Techniques Assimilation of Complete Quality-by-Design Models Chief Modification in Procedural Expertise for Continuous Manufacturing Process Parameters for Preformulation for Hot-Melt Extrusion Implementation of a New Product Development Process Modelling Simulation of Hot-Melt Extrusion Process Flow Chart Model for Continuous Hot-Melt Extrusion based Pharmaceutical Manufacturing Process Foremost Alteration in Structural Provisions for Quality and Technical Operations Potential Benefits of Continuous Hot-Melt Extrusion Manufacturing Regulatory Issues Related to Hot-Melt Extrusion 44

4 Contents Process Analytical Technology Framework Conclusion 46 References 47 3 Co-extrusion as a Novel Approach in Continuous Manufacturing Compliance 53 3 Background Introduction Applications of Co-extrusion via Hot-Melt Extrusion in Continuous Manufacturing Problem Encountered During Co-extrusion Variation of the Die Temperature Swelling of the Die Viscosity Matching Adhesion Inter diffusion Delamination Pharmaceutical Applications Pharmaceutical Significance of the Co-extrusion Technique Case Study Conclusions 59 References 59 4 Solid-state Engineering of Drugs using Melt Extrusion in Continuous Process 63 4 Introduction Dissolution Enhancement Use of Novel Inorganic Excipients Use of Polymers to Enhance Dissolutions of Poorly Water-soluble Active Pharmaceutical Ingredients Continuous Co-crystallisation Engineering Polymorphic Transformations via Hot-Melt Extrusion 69 ix

5 Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up Polymorphic Transformation of Carbamazepine Polymorphic Transformation of Artemisinin 70 References 71 5 Continuous Co-crystallisation of Poorly Soluble Active Pharmaceutical Ingredients to Enhance Dissolution Introduction Mechanism of Continuous Co-crystallisation by Twin-screw Extrusion Eutectic-mediated Co-crystallisation Ibuprofen-Nicotinamide Case Carbamazepine-Saccharin Case Solvent-assisted Co-crystallisation Amorphous Phase-mediated Co-crystallisation AMG 517-Sorbic Acid Case Critical Parameters Influencing Continuous Co-crystallisation by Twin-screw Extrusion Processing Temperature Temperature-dependent Case Temperature-independent Case Screw Design Screw Speed Feed-rate Case Study Matrix-assisted Co-crystallisation of Carbamazepine-Nicotinamide System by Twin-screw Extrusion Avoiding Thermal Degradation of Carbamazepine through In Situ Co-crystallising with Nicotinamide Conclusions 93 References 93 x

6 Contents 6 Taste Masking of Bitter Active Pharmaceutical Ingredients for the Development of Paediatric Medicines via Continuous Hot-Melt Extrusion Processing 97 6 Introduction Hot-Melt Extrusion as an Active Taste Masking Technique Taste Masking via Continuous Hot-Melt Extrusion Process Polymers as Suitable Carriers for Taste Masking Use of Lipids as Carriers for Taste Masking in Hot-Melt Extrusion Continuous Manufacturing of Oral Films via Hot-Melt Extrusion Case Study: Taste Masking of Bitter Active Pharmaceutical Ingredients via Continuous Hot-Melt Extrusion Processing Materials In Vivo Taste Masking Evaluation In Vitro Taste Masking Evaluation: Astree e-tongue Sample Preparation for Astree e-tongue Results and Discussion In Vivo/In Vitro Taste Evaluations Ill 6.5 Conclusions 115 References Continuous Manufacturing of Pharmaceutical Products via Melt Extrusion: A Case Study Introduction 121 Case Study Materials and Method Materials Preparation of Formulation Blends and Continuous Hot-Melt Extrusion Processing Scanning Electron Microscopy/Energy Dispersive X-ray Analysis 123 XI

7 Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up Thermal Analysis Powder X-ray Diffraction In Vitro Drug Release Studies Analysis of Drug Release Mechanism Results and Discussion Continuous Manufacturing of Pellets via Hot-Melt Extrusion Advanced Surface Analysis Thermal Analysis Amorphicity Analysis In Vitro Dissolution Studies Analysis of Release Mechanism Conclusions 135 References Novel Pharmaceutical Formulations Using Hot-Melt Extrusion Processing as a Continuous Manufacturing Technique Introduction Materials and Methods Materials Hot-Melt Extrusion Processing Differential Scanning Calorimetry Analysis Hot Stage Microscopy Analysis X-ray Powder Diffraction In Vitro Drug Release Studies High-performance Liquid Chromatography Analysis Results and Discussion Hot-Melt Extrusion Processing Thermal Analysis X-ray Powder Diffraction Analysis In Vitro Dissolution Studies Conclusions 146 References 147 xii

8 Contents 9 Continuous Polymorphic Transformations Study via Hot-Melt Extrusion Process Background Polymorphism Case Study: Polymorphic Transformation of Paracetamol Experimental Methods Theoretical Calculation Continuous Hot-Melt Extrusion Process and In-line Monitoring Thermal Analysis Results and Discussion Continuous Extrusion Process and Theoretical Consideration Physicochemical Characterisation of the Polymorphic Transformation during Hot-Melt Extrusion In-line Near-infrared Spectroscopy Monitoring Conclusions 165 References 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 Introduction The Advantages of Hot-Melt Extrusion Examples of Problems Solved Thanks to Hot-Melt Extrusion From Micro-scale to Industrial-scale Viscosity of the Three Samples at Different Temperatures Viscosity at Various Temperatures Hot-Melt Extrusion as a Standard Technology for the Pharmaceutical Industry Innovations 175 xni

9 Practical Guide to Hot-Melt Extrusion: Continuous Manufacturing and Scale-up 10.5 Conclusions 179 References Continuous Manufacturing via Hot-Melt Extrusion and Scale-up: Regulatory Aspects Introduction Continuous Manufacturing and Hot-Melt Extrusion Processing Technology Aspects of the Controls/Parameters in Hot-Melt Extrusion Processing Continuous Manufacturing via Hot-Melt Extrusion Continuous Manufacturing Process over Batch Process Scale-up Methodologies Regulatory Aspects Summary 193 References 193 Abbreviations 197 Index 201 xiv

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