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 medicinesMark 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 APS Materials Science Focus Group and has co-authored over 20 peer reviewed papers and 2 book chapters on preformulation.

• Preface xiiiList of Abbreviations xv1 Basic Principles of Preformulation Studies 11.1 Introduction 11.2 Assay design 21.2.1 Assay development 31.3 Concentrations 51.3.1 Units of concentration 51.4 UV spectrophotometry 91.4.1 Method development for UV assays 111.5 Thin-layer chromatography (TLC) 141.5.1 TLC method development 151.5.2 High-performance TLC 171.6 High-performance liquid chromatography 191.6.1 Normal- and reverse-phase HPLC 201.6.2 HPLC method development 211.7 Differential scanning calorimetry 221.7.1 Interpreting DSC data 231.7.2 Modulated-temperature DSC 271.7.3 DSC method development 301.8 Dynamic vapour sorption 321.8.1 DVS method development 321.9 Summary 33References 33Answer to study question 34Additional study questions 352 Ionisation Constants 362.1 Introduction 362.2 Ionisation 362.2.1 Percent ionisation 422.3 Buffers 442.4 Determination of pKa 442.4.1 Determination of pKa by potentiometric titration 452.4.2 Determination of pKa in nonaqueous solvents 452.4.3 Other factors affecting measurement of pKa 472.5 Summary 48References 48Answers to study questions 49Additional self-study questions and answers 503 Partition Affinity 523.1 Introduction 523.2 Partitioning 523.2.1 Effect of partitioning 543.2.2 Determination of log P 553.2.3 Effect of salt formation on partitioning 623.3 Summary 63References 63Answers to study questions 644 Solubility 654.1 Introduction 654.2 Intrinsic solubility 674.2.1 Ideal solubility 694.2.2 Solubility as a function of temperature 734.2.3 Solubility and physical form 744.2.4 Measurement of intrinsic solubility 774.2.5 Calculation of pKa from solubility data 834.3 Summary 83References 84Answer to study question 84Additional self-study questions and answers 845 Dissolution 865.1 Introduction 865.2 Models of dissolution 865.3 Dissolution testing 875.3.1 Intrinsic dissolution rate (IDR) 925.3.2 IDR as a function of pH 935.3.3 IDR and the common ion effect 945.4 Summary 96References 966 Salt Selection 986.1 Introduction 986.2 Salt formation 996.2.1 Selection of a salt-forming acid or base 1046.2.2 Salt screening 1086.3 Salt solubility 1106.3.1 Solubility of basic salts 1116.3.2 Solubility of acidic salts 1126.3.3 The importance of pHmax 1146.4 Dissolution of salts 1176.4.1 Modification of pHm 1206.5 Partitioning of salts 1216.6 Summary 123References 124Answers to study questions 1267 Physical Form I – Crystalline Materials 1277.1 Introduction 1277.2 Crystal formation 1277.2.1 Crystal formation from the melt 1287.2.2 Crystal growth from solution 1297.3 Crystal structure 1307.4 Polymorphism 1317.4.1 Thermodynamics of polymorphism 1337.4.2 Physicochemical properties of polymorphs 1377.5 Pseudopolymorphism 1397.6 Polymorph screening 1417.7 Characterisation of physical form 1417.7.1 Characterisation of polymorphs 1427.7.2 Characterisation of pseudopolymorphs 1497.8 Summary 152References 152Answers to study questions 1538 Physical Form II – Amorphous Materials 1568.1 Introduction 1568.2 Formation of amorphous materials 1568.3 Ageing of amorphous materials 1608.4 Characterisation of amorphous materials 1628.4.1 Measurement of ageing 1648.5 Processing and formation of amorphous material 1688.5.1 Spray-drying 1688.5.2 Freeze-drying 1688.5.3 Quench-cooling 1698.5.4 Milling 1708.5.5 Compaction 1718.6 Amorphous content quantification 1718.6.1 Calibration standards 1728.6.2 DSC for amorphous content quantification 1738.6.3 DVS for amorphous content quantification 1758.7 Summary 177References 178Answers to study questions 1799 Stability Assessment 1819.1 Introduction 1819.2 Degradation mechanisms 1839.2.1 Hydrolysis 1859.2.2 Solvolysis 1879.2.3 Oxidation 1889.2.4 Photolysis 1909.3 Reaction kinetics 1919.3.1 Solution-phase kinetics 1919.3.2 Zero-order reactions 1929.3.3 First-order kinetics 1939.3.4 Second-order reactions 1949.3.5 Solid-state kinetics 1959.4 The temperature dependence of reaction kinetics 1989.5 Stress testing 2039.5.1 Stress testing in solution 2039.5.2 Stress testing in the solid-state 2049.5.3 Drug–excipient compatibility testing 2059.6 Summary 208References 208Answers to study questions 20910 Particle Properties 21110.1 Introduction 21110.2 Microscopy 21110.2.1 Light microscopy 21210.2.2 Hot-stage microscopy 21310.2.3 Electron microscopy 21410.2.4 Atomic force microscopy 21410.3 Particle shape 21510.3.1 Habit 21510.3.2 Particle sizing 21910.3.3 Particle size distributions 22210.4 Summary 227References 227Answer to study question 22711 Powder Properties 22811.1 Introduction 22811.2 Powder flow and consolidation 22811.2.1 Carr’s index 23011.2.2 Hausner ratio 23211.2.3 Angle of repose 23211.2.4 Mohr diagrams 23511.3 Compaction properties 24011.3.1 Compaction simulators 24211.4 Summary 243References 243Answers to study questions 243Index 247Companion websiteThis book is accompanied by a companion website at: ttp://www.wiley.com/go/gaisford/essentialsVisit the website for:• Figures and tables from the book• Multiple choice questions