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| Contributors | |
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| Preface | |
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| Chiral chromatography in support of pharmaceutical process research | |
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| Introduction | |
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| A brief introduction to chirality | |
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| Why chirality is important | |
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| Accessing enantiopurity: a brief overview of approaches | |
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| Enantiopure starting materials: the chiral pool | |
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| Removable enantioenriched auxiliaries | |
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| Enantioselective catalysis | |
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| Resolution technologies: introduction | |
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| Chromatographic productivity is the key metric for preparative chromatography | |
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| Stationary phases for preparative chiral chromatography | |
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| Advantages of preparative chiral chromatography over other approaches for accessing enantiopure materials | |
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| Simulated moving bed enantioseparation | |
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| Green enantioseparation | |
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| What is the appropriate role of preparative chromatography in organic synthesis? | |
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| Fording the river at the easiest point: some observations on the appropriate placement of a chromatographic resolution within a chiral synthesis | |
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| Origins of preparative chiral chromatography | |
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| Practical tips for preparative chromatographic enantioseparation | |
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| Conclusion | |
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| Introduction to preparative chromatography | |
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| Introduction | |
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| Adsorption isotherms | |
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| The simple case - the Langmuir isotherm | |
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| Other isotherms | |
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| Competitive isotherms | |
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| Kinetics | |
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| Metrics for preparative operations | |
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| Throughput | |
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| Production rate | |
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| Productivity | |
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| Specific productivity | |
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| Cost | |
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| The influence of chromatographic parameters on preparative chromatography | |
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| Effect of particle size on preparative performance | |
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| Effects of pressure | |
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| Effects of column efficiency | |
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| Effect of column length | |
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| The effects of selectivity | |
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| Economics of preparative separations | |
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| Point of insertion of the chromatographic resolution in the synthetic route | |
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| Chiral stationary phases for preparative enantioselective chromatography | |
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| Summary | |
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| Introduction | |
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| Historical development of CSPs for preparative chromatography | |
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| Preparative CSPs | |
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| Classification of CSPs | |
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| Polymeric phases | |
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| Brush-type CSPs | |
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| Chiral phases for ligand-exchange chromatography | |
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| Imprinted phases | |
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| Chemical and physical properties of CSPs | |
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| Loading capacity | |
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| Chemical and physical stability | |
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| Solubility of the chiral solute | |
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| New and future developments in the field of preparative CSPs | |
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| CSPs with improved loading capacity | |
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| CSPs with improved selectivity | |
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| Immobilised polysaccharide-based CSPs | |
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| Conclusion | |
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| Method development for preparative enantioselective chromatography | |
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| Introduction | |
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| Chiral stationary phases for enantioselective chromatography | |
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| Screening and optimisation strategy for preparative chiral chromatography | |
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| Choice of the stationary phase | |
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| Choice of the mobile phase | |
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| Screening and optimisation of specific phases | |
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| Additives in the mobile phase | |
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| Preparative separations, criteria and objectives | |
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| Loadability and productivity | |
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| Selectivity and productivity | |
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| Solubility and productivity | |
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| Viscosity and productivity | |
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| Chemical and enantiomeric stability | |
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| Scale-up issues | |
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| Laboratory-scale separations | |
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| Large-scale separations | |
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| Conclusion | |
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| Scaling-up of preparative chromatographic enantiomer separations | |
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| Introduction | |
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| Analytical screening models | |
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| Standard procedure | |
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| Fast analytical screening process | |
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| Scaling-up from milligram to kilogram quantities | |
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| Introduction | |
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| Separation of a xanthone derivative | |
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| Separation of 'dibenzocycloheptanol' derivative | |
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| Separation of a 'pyrido-pyrimidin-4-one' derivative | |
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| Separation of a piperazinyl-piperidine derivative | |
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| Summary - scale-up | |
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| Larger scale separations | |
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| Introduction | |
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| Separation of a 'pyrolidino-quinolinone' derivative | |
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| Scale-up problems in early development | |
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| Introduction | |
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| Separation of a 'tetracyclic' compound | |
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| Non-natural amino acids | |
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| Separation of an 'indole' derivative | |
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| Summary | |
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| General conclusions | |
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| Steady-state recycling and its use in chiral separations | |
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| Overview | |
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| Introduction | |
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| SSR - concept and operation | |
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| Concept | |
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| Operation | |
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| Role of the injection loop | |
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| Case studies | |
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| Case study 1 | |
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| Case study 2 | |
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| Case study 3: collection of three SSR fractions | |
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| Conclusions | |
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| Simulated moving bed and related techniques | |
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| Overview | |
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| The SMB concept | |
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| Modeling of SMB processes | |
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| Design of SMB processes | |
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| Simulation of SMB processes | |
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| Influence of the equilibrium adsorption isotherms | |
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| Influence of mass transfer resistance | |
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| SMB related techniques | |
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| Varicol processes | |
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| Pseudo-SMB processes | |
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| Preparative-scale supercritical fluid chromatography | |
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| Introduction | |
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| History of SFC at GlaxoSmithKline | |
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| Principles of SFC | |
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| Advantages of SFC | |
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| Drawbacks of preparative SFC | |
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| Use of SFC | |
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| Chiral separation using SFC | |
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| Achiral separation using SFC | |
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| Consideration of preparative SFC | |
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| Future direction and development | |
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| Conclusion | |
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| Equipment for preparative and large size enantioselective chromatography | |
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| Introduction | |
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| The heart of the chromatographic process: the column | |
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| Packing technique, bed formation and bed consolidation | |
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| The wall region | |
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| Heat dissipation | |
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| Column technology | |
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| Column design | |
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| Equipment considerations for batch chromatography | |
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| Recycling | |
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| Detection | |
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| Supercritical fluid chromatography | |
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| Principle | |
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| Technical aspects | |
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| Eluent | |
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| Pumping | |
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| Injection | |
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| Detection | |
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| Product recovery | |
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| Eluent recycling | |
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| High-pressure technology, safety aspects | |
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| Multicolumn continuous chromatographic processes | |
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| Simulated moving bed | |
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| VARICOL | |
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| Case study in production-scale multicolumn continuous chromatography | |
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| Introduction | |
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| Chromatographic process research | |
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| Introduction | |
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| Selection of racemate to separate | |
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| Choice of the chromatographic conditions | |
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| Choice of the separation technique | |
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| Process development | |
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| Optimisation of the chemical steps | |
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| Production facts | |
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| Introduction | |
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| Implementation in a cGMP production environment | |
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| Qualification | |
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| Validation | |
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| Production and maintenance data | |
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| Further areas of development | |
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| Contract manufacturing and outsourcing considerations | |
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| Introduction | |
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| The regulatory agencies and the chiral market | |
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| Contract manufacturing | |
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| Time constraints | |
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| Risk of capital investment | |
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| Expertise | |
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| Intellectual property | |
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| Location | |
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| Primary or secondary supplier | |
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| Selecting the outsourcing partner | |
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| Expectations | |
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| Audit | |
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| Decision grid | |
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| Communication | |
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| Contact matrix | |
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| Frequent updates | |
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| Project requirements | |
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| R&D - method development | |
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| Clinical trial quantities | |
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| Trial runs vs production runs | |
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| Commercial-scale quantities | |
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| Schedule | |
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| Quantity | |
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| Product quality | |
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| Transfer of information | |
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| Feed characterization | |
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| Separation conditions | |
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| The chiral stationary phase | |
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| Analytical methods | |
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| Impurity specifications | |
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| Final product | |
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| Other considerations | |
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| End of the project | |
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| Economics | |
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| Productivity | |
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| Production rate | |
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| Cost breakdown | |
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| Clinical trial quantities | |
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| Commercial-scale quantities | |
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| Conclusion | |
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| Advanced concepts | |
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| Index | |