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Preface xiii
List of Abbreviations xv
1 Basic Principles of Preformulation Studies 1
1.1 Introduction 1
1.2 Assay design 2
1.2.1 Assay development 3
1.3 Concentrations 5
1.3.1 Units of concentration 5
1.4 UV spectrophotometry 9
1.4.1 Method development for UV assays 11
1.5 Thin-layer chromatography (TLC) 14
1.5.1 TLC method development 15
1.5.2 High-performance TLC 17
1.6 High-performance liquid chromatography 19
1.6.1 Normal- and reverse-phase HPLC 20
1.6.2 HPLC method development 21
1.7 Differential scanning calorimetry 22
1.7.1 Interpreting DSC data 23
1.7.2 Modulated-temperature DSC 27
1.7.3 DSC method development 30
1.8 Dynamic vapour sorption 32
1.8.1 DVS method development 32
1.9 Summary 33
References 33
Answer to study question 34
Additional study questions 35
2 Ionisation Constants 36
2.1 Introduction 36
2.2 Ionisation 36
2.2.1 Percent ionisation 42
2.3 Buffers 44
2.4 Determination of pKa 44
2.4.1 Determination of pKa by potentiometric titration 45
2.4.2 Determination of pKa in nonaqueous solvents 45
2.4.3 Other factors affecting measurement of pKa 47
2.5 Summary 48
References 48
Answers to study questions 49
Additional self-study questions and answers 50
3 Partition Affinity 52
3.1 Introduction 52
3.2 Partitioning 52
3.2.1 Effect of partitioning 54
3.2.2 Determination of log P 55
3.2.3 Effect of salt formation on partitioning 62
3.3 Summary 63
References 63
Answers to study questions 64
4 Solubility 65
4.1 Introduction 65
4.2 Intrinsic solubility 67
4.2.1 Ideal solubility 69
4.2.2 Solubility as a function of temperature 73
4.2.3 Solubility and physical form 74
4.2.4 Measurement of intrinsic solubility 77
4.2.5 Calculation of pKa from solubility data 83
4.3 Summary 83
References 84
Answer to study question 84
Additional self-study questions and answers 84
5 Dissolution 86
5.1 Introduction 86
5.2 Models of dissolution 86
5.3 Dissolution testing 87
5.3.1 Intrinsic dissolution rate (IDR) 92
5.3.2 IDR as a function of pH 93
5.3.3 IDR and the common ion effect 94
5.4 Summary 96
References 96
6 Salt Selection 98
6.1 Introduction 98
6.2 Salt formation 99
6.2.1 Selection of a salt-forming acid or base 104
6.2.2 Salt screening 108
6.3 Salt solubility 110
6.3.1 Solubility of basic salts 111
6.3.2 Solubility of acidic salts 112
6.3.3 The importance of pHmax 114
6.4 Dissolution of salts 117
6.4.1 Modification of pHm 120
6.5 Partitioning of salts 121
6.6 Summary 123
References 124
Answers to study questions 126
7 Physical Form I – Crystalline Materials 127
7.1 Introduction 127
7.2 Crystal formation 127
7.2.1 Crystal formation from the melt 128
7.2.2 Crystal growth from solution 129
7.3 Crystal structure 130
7.4 Polymorphism 131
7.4.1 Thermodynamics of polymorphism 133
7.4.2 Physicochemical properties of polymorphs 137
7.5 Pseudopolymorphism 139
7.6 Polymorph screening 141
7.7 Characterisation of physical form 141
7.7.1 Characterisation of polymorphs 142
7.7.2 Characterisation of pseudopolymorphs 149
7.8 Summary 152
References 152
Answers to study questions 153
8 Physical Form II – Amorphous Materials 156
8.1 Introduction 156
8.2 Formation of amorphous materials 156
8.3 Ageing of amorphous materials 160
8.4 Characterisation of amorphous materials 162
8.4.1 Measurement of ageing 164
8.5 Processing and formation of amorphous material 168
8.5.1 Spray-drying 168
8.5.2 Freeze-drying 168
8.5.3 Quench-cooling 169
8.5.4 Milling 170
8.5.5 Compaction 171
8.6 Amorphous content quantification 171
8.6.1 Calibration standards 172
8.6.2 DSC for amorphous content quantification 173
8.6.3 DVS for amorphous content quantification 175
8.7 Summary 177
References 178
Answers to study questions 179
9 Stability Assessment 181
9.1 Introduction 181
9.2 Degradation mechanisms 183
9.2.1 Hydrolysis 185
9.2.2 Solvolysis 187
9.2.3 Oxidation 188
9.2.4 Photolysis 190
9.3 Reaction kinetics 191
9.3.1 Solution-phase kinetics 191
9.3.2 Zero-order reactions 192
9.3.3 First-order kinetics 193
9.3.4 Second-order reactions 194
9.3.5 Solid-state kinetics 195
9.4 The temperature dependence of reaction kinetics 198
9.5 Stress testing 203
9.5.1 Stress testing in solution 203
9.5.2 Stress testing in the solid-state 204
9.5.3 Drug–excipient compatibility testing 205
9.6 Summary 208
References 208
Answers to study questions 209
10 Particle Properties 211
10.1 Introduction 211
10.2 Microscopy 211
10.2.1 Light microscopy 212
10.2.2 Hot-stage microscopy 213
10.2.3 Electron microscopy 214
10.2.4 Atomic force microscopy 214
10.3 Particle shape 215
10.3.1 Habit 215
10.3.2 Particle sizing 219
10.3.3 Particle size distributions 222
10.4 Summary 227
References 227
Answer to study question 227
11 Powder Properties 228
11.1 Introduction 228
11.2 Powder flow and consolidation 228
11.2.1 Carr’s index 230
11.2.2 Hausner ratio 232
11.2.3 Angle of repose 232
11.2.4 Mohr diagrams 235
11.3 Compaction properties 240
11.3.1 Compaction simulators 242
11.4 Summary 243
References 243
Answers to study questions 243
Index 247
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