Simon Gaisford UCL School of Pharmacy, University College London, London, UK

Transcription

1 Essentials of Pharmaceutical Preformulation Simon Gaisford UCL School of Pharmacy, University College London, London, UK Mark Saunders Kuecept Ltd, Potters Bar, Herts, UK WILEY-BLACKWELL A John Wiley &. Sons, Ltd., Publication

2 Contents Preface List of Abbreviatiofi s xiii xv 1 Basic Principles of preformulation Studies Introduction Assay design Assay develop^ent Concentrations Units of cohce n tration UV spectrophotometry Method dev el0prnent for UV assays Thin-layer chromatogfaphy (TLC) TLC method d^elop^ent High-perform^nce TLC High-performance liqu^ chromatography Normal- and f^erse-phase HPLC HPLC method d^velopment Differential scanning calo rimetry Interpreting psq data Modulated-te^Perature DSC DSC method d ev elop m ent Dynamic vapour sorption DVS method d e Velop m ent Summary 33 References 33 Answer to study qu est'on 34 Additional study ques^ons 35 2 Ionisation Const^nt s Introduction Ionisation Percent ionis^on 42

3 CONTENTS 2.3 Buffers Determination of pk a Determination of <pk a by Potentiometrie titration Determination of pk a in nonaqueous solvents Other factors affecting measurement of pk a Summary 48 References 48 Answers to study questions 49 Additional self-study questions and answers 50 3 Partition Affinity Introduction Partitioning Effect of partitioning Determination of log P Effect of salt formation on partitioning Summary 63 References 63 Answers to study questions 64 4 Solubility Introduction Intrinsic solubility Ideal solubility Solubility as a funetion of temperature Solubility and physical form Measurement of intrinsic solubility Calculation of pk a from solubility data Summary 83 References 84 Answer to study question 84 Additional self-study questions and answers 84 5 Dissolution Introduction Models of dissolution Dissolution testing Intrinsic dissolution rate (IDR) IDR as a funetion of ph IDR and the common ion effect Summary 96 References 96 Answers to study questions 97

4 CONTENTS ix 6 Salt Selection Introduction Salt formation Selection of a salt-forming acid or base Salt Screening Salt solubility Solubility of basic salts Solubility of acidic salts The importance of ph max Dissolution of salts Modification of ph m Partitioning of salts Summary 123 References 124 Answers to study questions Physical Form I - Crystalline Materials Introduction Crystal formation Crystal formation from the melt Crystal growth from Solution Crystal structure Polymorphism Thermodynamics of polymorphism Physicochemical properties of polymorphs Pseudopolymorphism Polymorph Screening Characterisation of physical form Characterisation of polymorphs Characterisation of pseudopolymorphs Summary 152 References 152 Answers to study questions Physical Form II - Amorphous Materials Introduction Formation of amorphous materials Ageing of amorphous materials Characterisation of amorphous materials Measurement of ageing Processing and formation of amorphous material Spray-drying Freeze-drying Quench-cooling 169

5 X CONTENTS Mitling i/u Compaction Amorphous content quantification Calibration Standards DSC for amorphous content quantification DVS for amorphous content quantification 8.7 Summary 177 References 178 Answers to study questions Stability Assessment Introduction Deqradation mechanisms 183 IOC Hydrolysis Solvolysis Oxidation Photolysis 1Q1 9.3 Reaction kinetics Solution-phase kinetics 1Q Zero-order reactions First-order kinetics Second-order reactions Solid-state kinetics The temperature dependence of reaction kinetics 9.5 Stress testing 2 3?D Stress testing in Solution Stress testing in the solid-state 20^ Drug-excipient compatibility testing?f)5 9.6 Summary 208 prjo References c Answers to study questions 2^9 10 Particle Properties Introduction Microscopy 2^ Light microscopy Hot-stage microscopy Electron microscopy 2^ Atomic force microscopy 10.3 Particle shape Habit Particle sizing Particle size distributions Summary 227 References 227 Answer to study question 227

6 CONTENTS xi 11 Powder Properties Introduction Powder flow and consolidation Carr's index Hausner ratio Angle of repose Mohr diagrams Compaction properties Compaction Simulators Summary 243 References 243 Answers to study questions 243 Index 247 Companion Website This book is accompanied by a companion Website at: Visit the Website for: Figures and tables from the book Multiple choice questions