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

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

Chapter 1. Basic Principles of Preformulation Studies

1.1. Introduction

1.2. Assay design

1.2.1. Assay development

1.3. Concentrations

1.3.1. Units of concentration

1.4. UV spectrophotometry

1.4.1. Method development for UV assays

1.5. Thin-layer chromatography (TLC)

1.5.1. TLC method development

1.5.2. High-performance TLC

1.6. High-performance liquid chromatography

1.6.1. Normal and reverse phase HPLC

1.6.2. HPLC Method development

1.7. Differential scanning calorimetry

1.7.1. Interpreting DSC data

1.7.2. Modulated-temperature DSC

1.7.3. DSC Method development

1.8. Dynamic vapour sorption

1.8.1. DVS method development

1.9 Summary

Chapter 2. Ionisation constants

2.1. Introduction

2.2. Ionisation

2.3. Buffers

2.4. Determination of pKa

2.4.1. Determination of pKa by potentiometric titration

2.4.2. Determination of pKa in non-aqueous solvents

2.4.3. Other factors affecting measurement of pKa

2.5. Summary

Chapter 3. Partitioning affinity

3.1. Introduction

3.2. Partitioning

3.2.1. Effect of partitioning

3.2.2. Determination of log P

3.2.2.1. Shake-flask method

3.2.2.2. Chromatographic methods

3.2.3. Effect of salt formation on partitioning

3.3. Summary

Chapter 4. Solubility

4.1. Introduction

4.2 Intrinsic solubility

4.2.1. Ideal solubility

4.2.2. Solubility as a function of temperature

4.2.3. Solubility and physical form

4.2.4. Measurement of intrinsic solubility

4.2.5. Calculation of pKa from solubility data

4.4. Summary

Chapter 5. Dissolution

5.1. Introduction

5.2. Models of dissolution

5.2.1. Intrinsic dissolution rate (IDR)

5.2.2. IDR as a function of pH

5.2.3. IDR and the common ion effect

5.3. Summary

Chapter 6. Salt selection

6.1. Introduction

6.2. Salt formation

6.2.1. Selection of a salt-forming acid or base

6.2.2. Salt screening

6.3. Salt solubility

6.3.1. Solubility of basic salts

6.3.2. Solubility of acidic salts

6.3.3. The importance of pHmax

6.4. Dissolution of salts

6.4.1. Modification of pHm

6.5. Partitioning of salts

6.6. Summary

Chapter 7. Physical form I ? Crystalline materials

7.1. Introduction

7.2. Crystal formation

7.2.1 Crystal formation from the melt

7.2.2. Crystal growth from solution

7.3. Crystal structure

7.4. Polymorphism

7.4.1. Thermodynamics of polymorphism

7.4.2. Physicochemical properties of polymorphs

7.5. Pseudopolymorphism

7.6 Polymorph screening

7.7 Characterisation of physical form

7.7.1. Characterisation of polymorphs

7.7.2. Characterisation of pseudopolymorphs

7.8. Summary

Chapter 8. Physical form II ? Amorphous materials

8.1. Introduction

8.2. Formation of amorphous materials

8.3. Aging of amorphous materials

8.4. Characterisation of amorphous materials

8.4.1. Measurement of aging

8.5. Processing and formation of amorphous material

8.5.1. Spray-drying

8.5.2. Freeze-drying

8.5.3. Quench-cooling

8.5.4. Milling

8.5.5. Compaction

8.6. Amorphous content quantification

8.6.1. Calibration standards

8.6.2. DSC for amorphous content quantification

8.6.3. DVS for amorphous content quantification

8.7. Summary

Chapter 9. Stability assessment

9.1. Introduction

9.2. Degradation mechanisms

9.2.1. Hydrolysis

9.2.2. Solvolysis

9.2.3. Oxidation

9.2.4. Photolysis

9.3. Reaction kinetics

9.3.1. Solution-phase kinetics

9.3.2. Zero-order reactions

9.3.3. First-order kinetics

9.3.4. Second-order reactions

9.3.5. Solid-state kinetics

9.4. The temperature dependence of reaction kinetics

9.5. Stress testing

9.5.1. Stress testing in solution

9.5.2. Stress testing in the solid-state

9.5.3. Drug-excipient compatibility testing

9.6. Summary

Chapter 10. Particle properties

10.1. Introduction

10.2. Microscopy

10.2.1. Light microscopy

10.2.2. Hot-stage microscopy

10.2.3. Electron microscopy

10.3.4. Atomic force microscopy

10.4. Particle shape

10.4.1. Habit

10.4.2. Particle sizing

10.4.3. Particle size distributions

10.5. Summary

Chapter 11. Powder properties

11.1. Introduction

11.2. Powder flow and consolidation

11.2.1. Carr?s Index

11.2.2. Hausner ratio

11.2.3. Angle of repose

11.2.4. Mohr diagrams

11.2.4.1. Mohr diagrams and consolidation

11.2.4.2. Determination of the yield locus

11.3. Compaction properties

11.3.1. Compaction simulators

11.4 Summary