Preparative Enantioselective Chromatography

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Edition: 1st
Format: Hardcover
Pub. Date: 2005-06-17
Publisher(s): Wiley-Blackwell
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Summary

The development of chiral liquid chromatography, facilitating the straightforward separation of enantiomers, was a significant advance in chromatography, leading to widespread application in analytical chemistry. Application in preparative chromatography has been less rapid, but with the development of single enantiomer pharmaceuticals its use is increasingly common in chemical synthesis at laboratory, pilot plant and even full production scale. Written for chemists, chemical engineers and analytical chemists, Preparative Enantioselective Chromatography demonstrates the considerable utility of the technique in contemporary discovery, development and production scale chemistry. By briefly covering basic preparative chromatography then developing the discussion to cover chiral stationary phases for preparative use, method development and practical applications, the first part of this book serves as an ideal introduction to the technology for laboratory and pilot plant scale application. The more detailed information presented in the later chapters, on applications in discovery, process development and large scale or production environments, including case studies and equipment selection issues, ensures the book will serve as a sound reference for experienced separation scientists.

Author Biography

Dr Geoffrey B Cox

(Editor)VP & General Manager, Separation Solutions

Table of Contents

Contributorsp. xi
Prefacep. xiii
Chiral chromatography in support of pharmaceutical process researchp. 1
Introductionp. 1
A brief introduction to chiralityp. 1
Why chirality is importantp. 2
Accessing enantiopurity: a brief overview of approachesp. 2
Enantiopure starting materials: the chiral poolp. 2
Removable enantioenriched auxiliariesp. 3
Enantioselective catalysisp. 3
Resolution technologies: introductionp. 4
Chromatographic productivity is the key metric for preparative chromatographyp. 7
Stationary phases for preparative chiral chromatographyp. 8
Advantages of preparative chiral chromatography over other approaches for accessing enantiopure materialsp. 8
Simulated moving bed enantioseparationp. 9
Green enantioseparationp. 9
What is the appropriate role of preparative chromatography in organic synthesis?p. 10
Fording the river at the easiest point: some observations on the appropriate placement of a chromatographic resolution within a chiral synthesisp. 11
Origins of preparative chiral chromatographyp. 12
Practical tips for preparative chromatographic enantioseparationp. 13
Conclusionp. 15
Introduction to preparative chromatographyp. 19
Introductionp. 19
Adsorption isothermsp. 19
The simple case - the Langmuir isothermp. 20
Other isothermsp. 22
Competitive isothermsp. 24
Kineticsp. 31
Metrics for preparative operationsp. 34
Throughputp. 34
Production ratep. 35
Productivityp. 35
Specific productivityp. 35
Costp. 36
The influence of chromatographic parameters on preparative chromatographyp. 36
Effect of particle size on preparative performancep. 36
Effects of pressurep. 38
Effects of column efficiencyp. 39
Effect of column lengthp. 40
The effects of selectivityp. 42
Economics of preparative separationsp. 44
Point of insertion of the chromatographic resolution in the synthetic routep. 46
Chiral stationary phases for preparative enantioselective chromatographyp. 48
Summaryp. 48
Introductionp. 48
Historical development of CSPs for preparative chromatographyp. 49
Preparative CSPsp. 52
Classification of CSPsp. 52
Polymeric phasesp. 53
Brush-type CSPsp. 59
Chiral phases for ligand-exchange chromatographyp. 60
Imprinted phasesp. 62
Chemical and physical properties of CSPsp. 62
Loading capacityp. 62
Chemical and physical stabilityp. 63
Solubility of the chiral solutep. 65
New and future developments in the field of preparative CSPsp. 65
CSPs with improved loading capacityp. 66
CSPs with improved selectivityp. 66
Immobilised polysaccharide-based CSPsp. 69
Conclusionp. 70
Method development for preparative enantioselective chromatographyp. 78
Introductionp. 78
Chiral stationary phases for enantioselective chromatographyp. 78
Screening and optimisation strategy for preparative chiral chromatographyp. 80
Choice of the stationary phasep. 81
Choice of the mobile phasep. 82
Screening and optimisation of specific phasesp. 87
Additives in the mobile phasep. 88
Preparative separations, criteria and objectivesp. 89
Loadability and productivityp. 89
Selectivity and productivityp. 93
Solubility and productivityp. 97
Viscosity and productivityp. 99
Chemical and enantiomeric stabilityp. 100
Scale-up issuesp. 101
Laboratory-scale separationsp. 101
Large-scale separationsp. 103
Conclusionp. 108
Scaling-up of preparative chromatographic enantiomer separationsp. 110
Introductionp. 110
Analytical screening modelsp. 111
Standard procedurep. 111
Fast analytical screening processp. 113
Scaling-up from milligram to kilogram quantitiesp. 115
Introductionp. 115
Separation of a xanthone derivativep. 115
Separation of 'dibenzocycloheptanol' derivativep. 117
Separation of a 'pyrido-pyrimidin-4-one' derivativep. 121
Separation of a piperazinyl-piperidine derivativep. 125
Summary - scale-upp. 126
Larger scale separationsp. 127
Introductionp. 127
Separation of a 'pyrolidino-quinolinone' derivativep. 127
Scale-up problems in early developmentp. 133
Introductionp. 133
Separation of a 'tetracyclic' compoundp. 135
Non-natural amino acidsp. 138
Separation of an 'indole' derivativep. 146
Summaryp. 148
General conclusionsp. 148
Steady-state recycling and its use in chiral separationsp. 149
Overviewp. 149
Introductionp. 149
SSR - concept and operationp. 150
Conceptp. 150
Operationp. 151
Role of the injection loopp. 152
Case studiesp. 153
Case study 1p. 153
Case study 2p. 163
Case study 3: collection of three SSR fractionsp. 171
Conclusionsp. 174
Simulated moving bed and related techniquesp. 176
Overviewp. 176
The SMB conceptp. 176
Modeling of SMB processesp. 180
Design of SMB processesp. 182
Simulation of SMB processesp. 184
Influence of the equilibrium adsorption isothermsp. 185
Influence of mass transfer resistancep. 192
SMB related techniquesp. 192
Varicol processesp. 192
Pseudo-SMB processesp. 198
Preparative-scale supercritical fluid chromatographyp. 205
Introductionp. 205
History of SFC at GlaxoSmithKlinep. 205
Principles of SFCp. 206
Advantages of SFCp. 208
Drawbacks of preparative SFCp. 209
Use of SFCp. 212
Chiral separation using SFCp. 213
Achiral separation using SFCp. 215
Consideration of preparative SFCp. 219
Future direction and developmentp. 219
Conclusionp. 220
Equipment for preparative and large size enantioselective chromatographyp. 224
Introductionp. 224
The heart of the chromatographic process: the columnp. 225
Packing technique, bed formation and bed consolidationp. 226
The wall regionp. 227
Heat dissipationp. 228
Column technologyp. 229
Column designp. 231
Equipment considerations for batch chromatographyp. 233
Recyclingp. 233
Detectionp. 234
Supercritical fluid chromatographyp. 235
Principlep. 235
Technical aspectsp. 236
Eluentp. 236
Pumpingp. 237
Injectionp. 238
Detectionp. 238
Product recoveryp. 239
Eluent recyclingp. 240
High-pressure technology, safety aspectsp. 241
Multicolumn continuous chromatographic processesp. 242
Simulated moving bedp. 242
VARICOLp. 246
Case study in production-scale multicolumn continuous chromatographyp. 253
Introductionp. 253
Chromatographic process researchp. 253
Introductionp. 253
Selection of racemate to separatep. 253
Choice of the chromatographic conditionsp. 255
Choice of the separation techniquep. 257
Process developmentp. 258
Optimisation of the chemical stepsp. 258
Production factsp. 266
Introductionp. 266
Implementation in a cGMP production environmentp. 267
Qualificationp. 268
Validationp. 271
Production and maintenance datap. 271
Further areas of developmentp. 273
Contract manufacturing and outsourcing considerationsp. 277
Introductionp. 277
The regulatory agencies and the chiral marketp. 278
Contract manufacturingp. 280
Time constraintsp. 280
Risk of capital investmentp. 280
Expertisep. 281
Intellectual propertyp. 282
Locationp. 282
Primary or secondary supplierp. 282
Selecting the outsourcing partnerp. 283
Expectationsp. 283
Auditp. 283
Decision gridp. 284
Communicationp. 284
Contact matrixp. 285
Frequent updatesp. 285
Project requirementsp. 285
R&D - method developmentp. 285
Clinical trial quantitiesp. 287
Trial runs vs production runsp. 287
Commercial-scale quantitiesp. 288
Schedulep. 289
Quantityp. 289
Product qualityp. 290
Transfer of informationp. 291
Feed characterizationp. 291
Separation conditionsp. 293
The chiral stationary phasep. 294
Analytical methodsp. 295
Impurity specificationsp. 296
Final productp. 296
Other considerationsp. 296
End of the projectp. 297
Economicsp. 297
Productivityp. 297
Production ratep. 298
Cost breakdownp. 298
Clinical trial quantitiesp. 300
Commercial-scale quantitiesp. 301
Conclusionp. 302
Advanced conceptsp. 303
Indexp. 325
Table of Contents provided by Ingram. All Rights Reserved.

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