Essentials of Pharmaceutical Preformulation

Essentials of Pharmaceutical Preformulation is a study guide which describes the basic principles of pharmaceutical physicochemical characterisation. Successful preformulation requires knowledge of fundamental molecular concepts (solubility, ionisation, partitioning, hygroscopicity and stability) and macroscopic properties (physical form, such as the crystalline and amorphous states, hydrates, solvates and co-crystals and powder properties), familiarity with the techniques used to measure them and appreciation of their effect on product performance, recognising that often there is a position of compromise to be reached between product stability and bioavailability.

This text introduces the basic concepts and discusses their wider implication for pharmaceutical development, with reference to many case examples of current drugs and drug products. Special attention is given to the principles and best-practice of the analytical techniques that underpin preformulation (UV spectrophotometry, TLC, DSC, XRPD and HPLC). The material is presented in the typical order that would be followed when developing a medicine and maps onto the indicative pharmacy syllabus of the Royal Pharmaceutical Society of Great Britain

Undergraduate-level pharmacy students and R&D / analytical scientists working in the pharmaceutical sector (with or without a pharmaceutical background) will find this text easy to follow with relevant pharmaceutical examples.

• Essential study guide for pharmacy and pharmaceutical science students
• Covers the pharmaceutical preformulation components of the Royal Pharmaceutical Society of Great Britain?s indicative syllabus
• Easy to follow text highlighted with relevant pharmaceutical examples
• Self-assessment assignments in a variety of formats
• Written by authors with both academic and industrial experience
• Companion website with further information to maximise learning

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

Companion website

This book is accompanied by a companion website at: ttp://www.wiley.com/go/gaisford/essentials

Visit the website for:

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• Multiple choice questions

Dr Simon Gaisford from the University of London. Dr. Gaisford is a senior lecturer in Pharmaceutics. His research interests include: Thermal analysis, isothermal calorimetry, differential scanning calorimetry (DSC), solution calorimetry, titration calorimetry (ITC), dynamic mechanical analysis (DMA), thermal ink-jetting, polymorphism, amorphous content quantification, inhalation, oral fast-dissolving films, personalised-dose medicines

Mark Saunders was awarded his first degree in Biological and Medicinal Chemistry from the University of Exeter and his PhD from the London School of Pharmacy under the supervision of Professors Kevin Taylor and Duncan Craig. His PhD programme was sponsored by GlaxoSmithKline and involved the design and characterisation of novel injectable lipid-based carrier vehicles for the treatment of Cystic Fibrosis.
After finishing his PhD, Mark consulted for the London based legal firm SJ Berwin, providing independant laboratory services in support of a successful major patent litigation trial on Paxil (Paroxetine Hydrochloride). After this, Mark was appointed Physical Scientist at a London based Contract Research Organisation (CRO), where he oversaw the growth and development of the company through to a commercial sell in 2007.
After spending 5 years in the Research and Development support arm of the company and having set up both the Physical Properties and Screening laboratories, Mark moved into Strategic Development where he directly lead the successful set up of a Japanese Business Development office in Tokyo. After 2 years in this position and havng seen the company grow significantly, Mark moved from this role and was involved in the commercial set up of Kuecept Ltd, of which he is a co-founder. Mark is also a member of UK and US Controlled Release Societies, Royal Society of Chemistry, Association of Pharmaceutical Scientists (APS), Internation Society of Aerosol Medicines, sits on the committee of the A