Chiral Separation Techniques: A Practical Approach

✍ Scribed by Ganapathy Subramanian

• Publisher: Wiley-VCH
• Year: 2007
• Tongue: English
• Leaves: 643
• Edition: 3rd, Completely Revised and Updated Edition
• Category: Library

✦ Synopsis

Thoroughly revised, with either entirely new or completely updated contents, this is a practical manual for the small and large-scale preparation of enantiomerically pure products. The result is a vital resource for meeting the highest purity standards in the manufacture of chiral pharmaceuticals, food additives and related compounds. All the approaches covered here are highly relevant to modern manufacturing and quality control schemes in the pharmaceutical and biotech industries, addressing the increasingly important issue of drug safety in view of tougher regulatory standards worldwide.

✦ Table of Contents

Chiral Separation Techniques......Page 5
Contents......Page 7
Preface......Page 19
List of Contributors......Page 21
1.1 Introduction......Page 25
1.2.1 Chiral Recognition Mechanisms......Page 26
1.2.2 Multi-modal Chiral Stationary Phases......Page 29
1.3.1.1 Polar Ionic Mode......Page 30
1.3.2 Neutral Molecules......Page 33
1.5 Method Development......Page 36
1.6.1 Polar Ionic Mode......Page 39
1.6.2.1 pH Effects......Page 43
1.6.2.2 Organic Modifier Effects......Page 44
1.6.3 Polar Organic/Normal-phase Mode......Page 45
1.6.4 Flow-rate and Temperature Effects......Page 46
1.7 Amino Acid and Peptide Analysis......Page 47
References......Page 51
2.1 Introduction......Page 53
2.2 Structures of Polysaccharide Chiral Selectors......Page 54
2.2.1 Synthesis of Polysaccharide Chiral Selectors......Page 56
2.2.2 Preparation of Polysaccharide Chiral Stationary Phases......Page 57
2.2.2.2 Preparation of CSPs by Immobilization......Page 58
2.3 Properties of Polysaccharide CSPs......Page 65
2.3.1 Enantioselectivities......Page 66
2.3.2 Spectroscopic Studies......Page 69
2.4.1 Analytical Separations......Page 72
2.4.2 Preparative Separations......Page 74
2.5 Optimization of Chiral Separations......Page 77
2.5.1 Mobile Phase Compositions......Page 78
2.5.3 Flow-rate......Page 88
2.5.4 Temperature......Page 92
2.5.5 Structures of Solutes......Page 96
2.6 Chiral Recognition Mechanisms......Page 100
2.7 Chiral Separation by Sub- and Supercritical Fluid Chromatography......Page 104
2.8 Chiral Separation by Capillary Electrochromatography......Page 108
2.9 Chiral Separation by Thin-layer Chromatography......Page 111
2.10 Chiral Separation by Capillary Electrophoresis......Page 112
2.11 Conclusion......Page 114
References......Page 115
3.1 Introduction......Page 123
3.1.1 Scientific Developments in Polysaccharide Immobilization with Chiral Recognition Purposes......Page 124
3.1.2 State of the Art on Immobilized Polysaccharide-derived CSPs......Page 128
3.2 Scope of Immobilized Polysaccharide-derived CSPs......Page 129
3.3 Beneficial Characteristics of Immobilized Polysaccharide-derived CSPs......Page 130
3.3.1 New Selectivity Profile on Immobilized CSPs......Page 131
3.3.2 Universal Miscibility of Non-standard Solvents and their Contribution to the Performance of Analytical Methods......Page 134
3.3.3 Various Sample Injection Media......Page 137
3.3.4 Inhibition or Minimization of Racemization by Mobile Phase Switch......Page 140
3.3.5 Preparative Potential of Immobilized CSPs......Page 142
3.3.6 CSP Stability......Page 144
3.4.1.1 Analytical Method Development......Page 146
3.4.1.2 Preparative Method Development......Page 149
3.4.3 A Powerful Hyphenation: DAD–ELSD......Page 150
3.5 Regeneration of Immobilized CSPs – Why, How and When......Page 153
References......Page 156
4.2.1 Properties of Supercritical Fluids......Page 159
4.2.2 Comparison of LC and SFC......Page 161
4.2.3 Instrumentation for SFC......Page 162
4.3 Chiral Stationary Phases in SFC......Page 163
4.3.2 Brush-type (Pirkle-type)......Page 164
4.3.4 Polysaccharides......Page 165
4.4.1 Pressure Effects......Page 166
4.4.3 Temperature Effects......Page 167
4.4.4 Mobile Phase Modifier Effects......Page 168
4.4.5 Mobile Phase Additive Effects......Page 171
4.5 Preparative-scale Separations......Page 172
References......Page 176
5.1 Introduction......Page 179
5.2.1 Separation by LC on Chemically Bonded Chiral Stationary LE Phases......Page 180
5.2.2 Separation by HPLC on Chiral Coated LE Phases......Page 185
5.2.4 Separation by LE-TLC......Page 188
5.4.1 Separation by Capillary Zone Electrophoresis (CZE)......Page 189
5.4.2 Separation by Micellar Electrokinetic Chromatography (MEKC)......Page 195
5.4.4 Separation by Capillary Electrochromatography (CEC)......Page 196
List of Abbreviations......Page 199
References......Page 200
6.1 Introduction......Page 205
6.2.1 Real SMB......Page 207
6.2.1.1 Detailed Particle Model......Page 208
6.2.2 Equivalent TMB......Page 210
6.2.2.1 Detailed Particle Model......Page 211
6.3.1 Numerical Solution......Page 213
6.3.2 Case Study: Operating Conditions and Model Parameters......Page 214
6.3.3.1 Real SMB Models......Page 215
6.3.3.2 Equivalent TMB Models......Page 218
6.4.1.1 Varicol......Page 219
6.4.1.2 Multiple (Distributed) Feed......Page 222
6.5 Improvements in Operation Conditions Evaluation (Separation Volume Method)......Page 224
References......Page 225
7.1 Introduction – From an Emerging Technology to a Classical Unit Operation......Page 227
7.1.1 Less Common Applications of SMB Technology for Chiral Separations......Page 230
7.1.2 Design and Optimization of Operating Conditions for a Classical SMB Separation......Page 232
7.1.3 Chiral Stationary Phases......Page 235
7.2 Unbalanced Separations and Multi-component Separations Using SMB......Page 237
7.2.1 Binary Separations......Page 238
7.2.1.1 Case Study I: 1 : 1 vs. 10 : 1 and 1 : 10......Page 239
7.2.2 Three-component Separations......Page 241
7.2.2.1 Case Study II: Three-component Separations with Two Targets......Page 242
7.2.3.1 Case Study III: Multi-component Separation......Page 245
7.2.4.1 Detecting Problems......Page 247
7.3 Unusual Isotherms and Adsorption Behavior......Page 249
7.3.1 Langmuir Adsorption Isotherm......Page 250
7.3.2 Non-Langmuir Adsorption Isotherms......Page 251
7.3.2.1 Peak Shape and Form of Linear and Anti-Langmuir Isotherms......Page 253
7.3.2.2 Region of Complete Separation for an Anti-Langmuir Isotherm......Page 254
7.3.3 Case Studies......Page 255
7.3.3.1 Case Study IV: Both Compounds Show Anti-Langmuirian Behavior......Page 256
7.3.3.2 Case Study V: One Compound Shows Anti-Langmuirian Behavior......Page 258
7.4.1 Symmetrical Configurations......Page 261
7.4.1.1 Case Study VI: Comparing a 2–2–2–2 and a 1–2–2–1 Configuration......Page 264
7.4.1 Asymmetric Configurations......Page 265
7.5 Application of Solvent Gradients......Page 267
7.5.1 Solvent Gradient SMB......Page 268
7.5.1.1 Case Study VII: Preparative-scale SMB Applying a Reversed Solvent Gradient......Page 271
7.6 Chemistry and Racemization......Page 275
7.6.1 Racemization......Page 277
7.6.2.1 Case Study VIII: ASBAT Inhibitor......Page 281
7.6.2.2 Case Study IX: Antidepressant Oxetine Derivatives......Page 282
7.6.2.3 Case Study X: Zoloft, a Serotonin Reuptake Inhibitor......Page 283
7.6.2.4 Case Study XI: Synthesis of Enantiomerically Pure Amines via Schiff Bases......Page 286
7.6.2.5 Case Study XII: Synthesis of COX-2 Inhibitors......Page 287
7.7 Future Developments......Page 288
7.7.1 Non-HPLC Enantioselective SMB Modes......Page 289
7.7.2 Operation Modes, Modeling Software, Control of SMB Units, and Stationary Phases......Page 290
7.8 Conclusion......Page 291
Acknowledgments......Page 292
References......Page 293
8.1 Introduction......Page 299
8.2.1 CSPs Based on Chiral Crown Ethers Incorporating a Chiral 1,1'-Binaphthyl Unit......Page 300
8.2.2 CSPs Based on Chiral Crown Ethers Incorporating a Tartaric Acid Unit......Page 301
8.2.3 CSPs Based on Phenolic Pseudo Chiral Crown Ethers......Page 305
8.3.1 Resolution of Primary Amino Compounds......Page 306
8.3.2 Resolution of Non-primary Amino Compounds......Page 309
8.4.1.1 Organic Modifier in Aqueous Mobile Phase......Page 312
8.4.1.2 Acidic Modifier in Aqueous Mobile Phase......Page 314
8.4.1.3 Inorganic Cationic Modifier in Aqueous Mobile Phase......Page 317
8.4.2 Nonaqueous Mobile Phase......Page 318
8.5 Temperature Effect......Page 319
8.6 Conclusion......Page 321
References......Page 322
9.1 Introduction......Page 325
9.2.1.1 Enantiomeric Separation of Free D,L-Amino Acids......Page 327
9.2.1.2 Enantiomeric Separation of D,L-Dns-Amino Acids......Page 332
9.2.1.3 Enantiomeric Separation of α-Hydroxy Acids and Dicarboxylic Acids......Page 333
9.2.2.1 Enantioseparation of Unmodified Amino Acids......Page 336
9.2.2.2 Enantioseparation of Dns-Amino Acids......Page 338
9.2.3 Tetradentate Ligands......Page 339
9.2.3.1 Enantiomeric Separation of Unmodified Amino Acids......Page 340
9.2.3.2 Chiral separation of Dns-Amino Acids......Page 342
9.3 Dynamically Coated Stationary Phases......Page 343
9.4 Comparison Between Enantiomeric Separations Obtained with the Chiral Selector Bound to the Stationary Phase or Added to the Eluent......Page 344
9.5 Mixed Inclusion–Ligand-exchange Chromatography......Page 349
9.6 Ligand Exchange in Fast Sensing Systems......Page 351
References......Page 353
10.1 Introduction......Page 357
10.3.1 Basics of Capillary Electrophoresis......Page 358
10.3.2 Chiral Separations......Page 359
10.4 Enantiomer Separations......Page 361
10.4.2 Direct Chiral Separations......Page 362
10.4.2.1 Cyclodextrins......Page 367
10.4.2.2 Macrocyclic Antibiotics......Page 370
10.4.2.3 Chiral Crown Ethers......Page 373
10.4.2.5 Chiral Ion-pair Reagents......Page 374
10.4.2.6 Chiral Surfactants......Page 375
10.4.2.7 Miscellaneous Chiral Selectors......Page 377
10.5 Applications......Page 378
10.6 Method Development and Validation......Page 382
10.7 Migration Models......Page 386
10.8 Enantiomer Migration Order......Page 388
10.9 Future Trends......Page 389
References......Page 390
11.1 Introduction......Page 393
11.2 Instrumentation......Page 395
11.3 Some Thoughts on CCC Enantioseparation......Page 396
11.4.1 Chiral Recognition in the Aqueous Phase......Page 399
11.4.2 Chiral Recognition in the Organic Phase......Page 404
11.5 pH-zone-refining CCC......Page 411
11.6 Sample Resolution in CCC......Page 416
11.7 Continuous CPC......Page 417
Acknowledgments......Page 418
References......Page 419
12.1 Introduction......Page 423
12.2 Fundamental Studies Using Enantiomers as Model Templates......Page 425
12.3 Using Frontal Analysis to Elucidate Retention Mechanisms......Page 430
12.4 Approaches to Binding Site Design......Page 436
12.4.1 Combinatorial and Computational Techniques to Optimizing MICSPs......Page 437
12.4.2 MICSPs by Rational Design......Page 439
12.5 Other Formats: Beads, Monoliths, and Films......Page 442
12.5.1 Beads and Nanoparticles......Page 443
12.5.2 Layers and Films......Page 445
12.5.3 Superporous Monoliths......Page 449
12.6 Other Matrices for Imprinting of Enantiomers......Page 450
References......Page 453
13.2 The Design of Enantioselective Electrochemical Biosensors......Page 457
13.3.2 Angiotensin-converting Enzyme Inhibitors......Page 458
13.3.4 Alanine......Page 459
13.3.6 Lysine......Page 460
13.3.8 Pipecolic Acid......Page 461
References......Page 462
14.1 Introduction......Page 465
14.2.1 Packed Capillaries......Page 467
14.2.2 Open-tubular Capillaries......Page 469
14.2.3.1 Inorganic Monolith-based Columns......Page 471
14.2.3.2 Organic Polymeric Monolithic Columns......Page 472
14.2.3.3 Particle-loaded Monolithic Columns......Page 474
14.3 Chiral Stationary Phases for CEC......Page 475
14.3.1 Brush-type CSPs......Page 477
14.3.2 Cyclodextrins and their Derivatives......Page 480
14.3.3 Macrocyclic Glycopeptide-bonded CSPs......Page 484
14.3.4 Polysaccharide-based CSPs......Page 490
14.3.5 Protein-based CSPs......Page 497
14.3.6 Molecular Imprinting-based CSPs......Page 499
14.3.7 Ligand Exchange-based CSPs......Page 501
14.3.8 Ion Exchange-based CSPs......Page 503
14.3.9 Miscellaneous......Page 507
14.4 Chiral CEC Coupled to Mass Spectrometric Detection......Page 509
14.4.1 CEC/MS Instrumentation and Column Technology......Page 510
14.4.2 Chiral CEC/MS Applications......Page 515
14.5 Conclusions......Page 523
List of Abbreviations......Page 524
References......Page 525
15.1 Introduction......Page 529
15.2.1 Amino Acid-based Polymeric Chiral Anionic Surfactants with Amide Linkage......Page 533
15.2.2 Peptide-based Polymeric Chiral Anionic Surfactants with Amide Linkage......Page 549
15.2.3 Amino Acid-based Polymeric Chiral Anionic Surfactants with Carbamate Linkage......Page 561
15.3.1 Single Amino Acid-based Cationic Surfactants with Amide Linkage......Page 568
15.4 Coupling of MEKC to Mass Spectrometry Using Polymeric Surfactants......Page 569
15.4.1 MEKC/MS Method Development......Page 571
15.4.2 MEKC/MS of (±)-1,1'-Binaphthol (BOH)......Page 572
15.4.3 MEKC/MS of β-Blockers......Page 574
15.4.4 MEKC/MS of Benzodiazepines and Benzoxazocine......Page 579
15.5 Conclusions......Page 580
List of Abbreviations......Page 581
References......Page 583
16.1 Introduction......Page 585
16.2 Theory of Operation......Page 586
16.4.1 Chemical Purity (cp)......Page 589
16.5 Automation of Method Development and Preparative Purifications......Page 590
16.6 Method Development......Page 592
16.7 Preparative Purifications......Page 593
16.8.1 Small Molecule Pharmaceutical Candidates......Page 596
16.8.2 Antibiotics and Sugars: Compounds without Chromophores......Page 598
16.8.5 Foods, Flavors, and Fragrances......Page 599
16.8.6 Fertilizers and Pesticides......Page 600
16.9.2 Example: QA/QC of Antibiotic Residues in Milk – Gentamicin [1]......Page 601
16.9.4 HPLC/SFC Preparative Purification – Fraction Collection......Page 604
16.9.5 Process Monitoring [2]......Page 605
References......Page 608
17.1 Introduction......Page 609
17.2.1 Selecting the Chiral Stationary Phase......Page 610
17.3.1 Column Screen and Optimization......Page 612
17.3.2.1 Choice of the Chromatography Mode......Page 614
17.3.2.2 Loadability......Page 615
17.3.2.3 Solubility......Page 616
17.4.1 Resolution of DNZ-β-Phenylalanine Isomers......Page 617
17.4.2 Resolution of a Chiral Acid in Late-stage Discovery Phase......Page 619
17.6 Conclusions......Page 622
References......Page 623
Subject Index......Page 625