Essentials of Pharmaceutical Preformulation

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

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 31.3 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

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