Pharmaceutical Process Development -- Contents -- Contributors -- Chapter 1 Introduction -- 1.1 Process Research and Development in Context -- 1.2 Aims and Scope of the Book -- 1.3 Outline of Contents -- 1.4 Developed Processes in Exemplar Commercial Drugs -- References -- Chapter 2 Process Research and Development in the Pharmaceutical Industry: Origins, Evolution and Progress -- 2.1 Historical Perspective -- 2.2 The Chemical Complexity of Modern Drugs -- Implications for Process R&D -- 2.3 The Trend Towards Outsourcing -- 2.4 The Improvement in Process Safety Evaluation -- 2.5 The Environment, Effluent Minimisation and Green Chemistry -- 2.6 Significant Changes in Process R&D in the Last 20 Years -- 2.7 The Literature of Process Chemistry -- 2.8 The Future -- References -- Chapter 3 Active Pharmaceutical Ingredients: Structure and Impact on Synthesis -- 3.1 Introduction: What is the Active Pharmaceutical Ingredient? -- 3.2 Physicochemical Considerations -- 3.3 Common Features of Active Pharmaceutical Ingredients -- 3.4 The Synthetic Sequence -- 3.5 Reactions Commonly Used -- 3.5.1 Introduction -- 3.5.2 Construction versus Modification -- 3.5.3 Chirality -- 3.5.4 Substituted Aromatic Starting Materials -- 3.5.5 Heterocycle Occurrence and Formation -- 3.5.6 Protections and Deprotections -- 3.5.7 Acylation -- 3.5.8 Heteroatom Alkylations and Arylations -- 3.5.9 Oxidation Reactions -- 3.5.10 Reduction Reactions -- 3.5.11 C-C Bond-forming Reactions -- 3.5.12 Functional Group Interconversions -- 3.5.13 Functional Group Additions -- 3.6 Constraints on the Process Chemist -- References -- Chapter 4 Rapid Early Development of Potential Drug Candidates -- 4.1 Introduction -- 4.2 Criteria for Rapid Fit-for-purpose Enabling -- 4.2.1 Safety -- 4.2.2 Reliability -- 4.2.3 Efficiency -- 4.3 Technology for Rapid Fit-for-purpose Enabling -- 4.4 Conclusion.

References -- Chapter 5 Route Design and Selection -- 5.1 Introduction -- 5.2 Responding to the Needs of the Drug Development Programme -- 5.3 Criteria for Route Evaluation and Selection -- 5.3.1 Safety -- 5.3.2 Environmental -- 5.3.3 Legal -- 5.3.4 Economics -- 5.3.5 Control -- 5.3.6 Throughput -- 5.4 Generation and Prioritisation of Ideas for Route Design -- 5.5 Maximising the Value of Experimental Work -- 5.6 Conclusions: Route Selection -- Acknowledgements -- References -- Chapter 6 The Importance of Green Chemistry in Process Research & Development -- 6.1 Introduction -- 6.2 Solvents and Solvent Selection -- 6.3 Green Chemistry Metrics -- 6.3.1 Atom Economy -- 6.3.2 Environmental Factor -- 6.3.3 Reaction Mass Efficiency -- 6.3.4 Process Mass Intensity -- 6.4 The Importance of Biocatalysis in Green Chemistry -- 6.5 Case Histories -- 6.5.1 Pregabalin -- 6.5.2 Sitagliptin -- 6.5.3 A Rosuvastatin Intermediate -- 6.6 Future Trends -- References -- Chapter 7 Kinetic Approaches for Faster and Efficient Process Development -- 7.1 Introduction -- 7.2 Reagent and Processing Condition Design Based on Kinetic Experimentation -- 7.3 Robustness and Process Understanding from Kinetic Trends and Rate Analysis -- 7.3.1 Reaction Profiling for Robustness and Process Understanding -- 7.3.2 Heat flow as a Tool for Rate Analysis and Process Development -- 7.4 Reaction Progress Kinetic Analysis in Process Development -- 7.5 Role of Theoretical Kinetic and Reactor Modelling in Process Development -- 7.6 Choosing the Right Experimental Tool for Kinetic Studies -- 7.7 Analytics: the Backbone of Kinetic Approaches -- 7.8 Summary -- Acknowledgements -- References -- Chapter 8 The Design of Safe Chemical Reactions: It's No Accident -- 8.1 Introduction -- 8.2 Background -- 8.3 Reaction Hazards -- 8.3.1 Runaway Reactions -- 8.3.2 Thermal Instability Issues.

8.3.3 Gas Evolution -- 8.4 Lifecycle Approach to Process Safety -- 8.4.1 Initial Route Assessment -- 8.4.2 Chemical Route Identification -- 8.4.3 Process Development and Optimisation -- 8.4.4 Scale-up -- 8.5 Process Development Synergies -- 8.6 Conclusion -- References -- Chapter 9 Physicochemical Data Requirements for the Design of Fine Chemical Processes: Acquisition and Application -- 9.1 Introduction -- 9.2 Strategy for Identifying Data Requirements -- 9.2.1 Phase Characteristics -- 9.2.2 Chemical Complexity -- 9.2.3 Physical Variables -- 9.3 Literature -- 9.4 Efficient Data Acquisition: Reaction Profiling -- 9.4.1 Equipment -- 9.4.2 Profiling Methods -- 9.5 Reaction Kinetics -- 9.5.1 Zero-order Reactions -- 9.5.2 First-order Processes -- 9.5.3 Second-order Processes -- 9.5.4 More Complex Kinetics -- 9.5.5 Application of Kinetic Information to Process Design -- 9.6 Pre-reaction Equilibria -- 9.7 Competing Reactions: Reaction Maps -- 9.8 Mixing Effects in Pseudo-homogeneous Systems -- 9.8.1 Diagnosis of Mixing Effects -- 9.8.2 Solving Mixing Problems -- 9.9 Multiphase Systems -- 9.9.1 Reaction in a Bulk Phase -- 9.9.2 Reaction in the Diffusion Film -- 9.9.3 Gas-Liquid Reactions: Catalytic Hydrogenation -- 9.9.4 Measurement of Gas-Liquid Mass Transfer Rate Constants -- 9.10 Scale-up -- 9.10.1 Processing Time -- 9.10.2 Heat Transfer -- 9.10.3 Maintaining Mixing Efficiency on Scale-up in Pseudo-homogeneous Systems -- 9.10.4 Mass Transfer and Mass Transport -- 9.10.5 A Protocol to Check the Level of Understanding before Scale-up -- 9.11 Conclusions -- Acknowledgements -- References -- Chapter 10 Liquid-Liquid Extraction for Process Development in the Pharmaceutical Industry -- 10.1 Introduction -- 10.1.1 What is Liquid-Liquid Extraction? -- 10.1.2 ICH Guidelines for Solvent Classification and Usage -- 10.1.3 Impurities.

10.1.4 Commonly Encountered Reactions in the Pharmaceutical Industry -- 10.2 Theoretical Considerations for Liquid-Liquid Extraction -- 10.2.1 Phase Equilibria -- 10.2.2 Multicomponent Systems -- 10.2.3 Interphase Mass Transfer -- 10.2.4 Phase Dispersion and Separation -- 10.3 Liquid-Liquid Process Development Considerations -- 10.3.1 Process Chemistry -- 10.3.2 Process Heuristics -- 10.3.3 Predictive Screening of Solvents -- 10.3.4 Unit Operation Design and Laboratory Testing -- 10.4 Case Studies in Liquid-Liquid Extraction -- 10.4.1 Liquid-Liquid Extraction and Process Safety -- 10.4.2 Toluene/Water Separation during the Manufacture of Benzoic Acid -- 10.4.3 Analysis of the Suzuki-Miyauri Reaction -- 10.5 Summary -- Acknowledgements -- References -- Chapter 11 Development Enabling Technologies -- 11.1 Introduction -- 11.1.1 Process Enabling Technologies -- 11.2 Technology Applied to Parallel Experimentation: Pre-2000 -- 11.3 Developments Since 2000 -- 11.3.1 Enabling Technologies at Route Scouting/Screening Stage of API Development -- 11.3.2 Enabling Technologies at Route Optimisation Stage of API Development -- 11.3.3 Design Space and Enabling Technologies at Process Validation Stage of API Development -- 11.3.4 Tools for Optimisation of Hydrogenation/Carbonylation: Across Scales -- 11.4 Process Intensification -- 11.4.1 Continuous Flow Processing -- 11.4.2 Microwave Heating -- 11.4.3 Process Analytical Technology: Application to Process Development -- 11.5 Conclusions -- References -- Chapter 12 The Analytical Interface and the Impact on Pharmaceutical Process Development -- 12.1 Introduction -- 12.2 Evolution of Analytical Techniques -- 12.3 HPLC Theory and the van Deemter Equation -- 12.3.1 Eddy Diffusion -- 12.3.2 Longitudinal Diffusion -- 12.3.3 Mass Transfer -- 12.4 Rapid HPLC Analysis -- 12.4.1 The Effect of Particle Size.

12.4.2 Sub 2 mm HPLC Packing Material -- 12.4.3 Semi-porous HPLC Stationary Phases -- 12.5 Gas Chromatography -- 12.5.1 Low Thermal Mass Gas Chromatographic Instruments -- 12.6 Chromatographic Method Development -- 12.6.1 HPLC Column Screening -- 12.6.2 Achiral HPLC Screening -- 12.6.3 Chiral HPLC Screening -- 12.6.4 Multi-channel Column Screening -- 12.6.5 Screening Using Supercritical Fluid Chromatography -- 12.6.6 GC Column Screening -- 12.7 Preparative Chromatography -- 12.7.1 Supercritical Fluid Preparative Chromatography -- 12.8 On-line/In-line Analytical Techniques -- 12.8.1 On-line HPLC -- 12.8.2 In-line Near/Mid-infrared Spectroscopy -- 12.9 Validation of Analytical Procedures -- 12.9.1 Accuracy -- 12.9.2 Linearity/Range -- 12.9.3 Precision -- 12.9.4 LOD/LOQ -- 12.9.5 Specificity -- 12.9.6 Robustness -- 12.10 Genotoxic Assessment -- 12.11 Mass Spectrometric Detection -- 12.12 Conclusion -- Acknowledgements -- References -- Chapter 13 Materials Science: Solid Form Design and Crystallisation Process Development -- 13.1 Introduction and Context -- 13.2 The Crystal -- 13.2.1 Crystallography -- 13.2.2 Crystal Chemistry and Crystal Packing of Drug Molecules -- 13.2.3 Polymorphism, Thermodynamic Stability and Solubility -- 13.2.4 Particle Morphology and Surface Structure -- 13.2.5 Particle Size -- 13.3 Crystal Formation -- 13.3.1 Solubility, Supersaturation and the Metastable Zone -- 13.3.2 Nucleation Processes -- 13.3.3 The Crystal Growth Process -- 13.3.4 Growth Stability and Interface Roughening -- 13.3.5 Nucleation and Growth Control -- 13.4 Industry Practices -- 13.4.1 Salt Screening and Selection -- 13.4.2 Polymorph Screening -- 13.4.3 Hydrate Screening -- 13.4.4 Crystallisation Process Design -- 13.4.5 Particle Reduction Techniques -- 13.5 Future Outlook -- 13.5.1 Changing the Drug Product Design Paradigm -- 13.5.2 Cocrystals.

13.5.3 Solid Form Design.