Hplc Method Development for Pharmaceuticals

High pressure, or high performance, liquid chromatography (HPLC) is the method of choice for checking purity of new drug candidates, monitoring changes during scale up or revision of synthetic procedures, evaluating new formulations, and running control/assurance of the final drug product. HPLC Method Development for Pharmaceuticals provides an extensive overview of modern HPLC method development that addresses these unique concerns. Includes a review and update of the current state of the art and science of HPLC, including theory, modes of HPLC, column chemistry, retention mechanisms, chiral separations, modern instrumentation (including ultrahigh-pressure systems), and sample preparation. Emphasis has been placed on implementation in a pharmaceutical setting and on providing a practical perspective. HPLC Method Development for Pharmaceuticalsis intended to be particularly useful for both novice and experienced HPLC method development chemists in the pharmaceutical industry and for managers who are seeking to update their knowledge. * Covers the requirements for HPLC in a pharmaceutical setting including strategies for software and hardware validation to allow for use in a regulated laboratory * Provides an overview of the pharmaceutical development process (clinical phases, chemical and pharmaceutical development activities) * Discusses how HPLC is used in each phase of pharmaceutical development and how methods are developed to support activities in each phase

Preface	p. xiii
Contributors	p. xv
Overview of HPLC Method Development for Pharmaceuticals
Introduction	p. 1
Theoretical Considerations	p. 2
HPLC Columns and Column Packings	p. 2
Column Selection	p. 3
Chiral Separations	p. 3
Contemporary HPLC	p. 4
Hyphenated Methods	p. 5
Sample Preparation	p. 5
Instrument Qualification and Software Validation	p. 6
Pharmaceutical Development	p. 6
Drug Discovery	p. 7
Early Phase Method Development	p. 8
Late Phase Development	p. 8
In-Process Testing	p. 9
Method Development for Biomolecules	p. 9
Method Validation	p. 10
Troubleshooting	p. 10
Molecularly Imprinted Polymers	p. 10
References	p. 11
HPLC Theory
Abstract	p. 13
Introduction	p. 13
Basic Chromatographic Descriptors	p. 14
Efficiency	p. 15
Resolution	p. 20
Main Components of the Retention Mechanism	p. 22
General Column Mass Balance	p. 24
Partitioning Model	p. 27
Adsorption Model	p. 28
Void Volume Considerations	p. 29
Thermodynamic Relationships	p. 31
Secondary Equilibria	p. 35
Salt Effect	p. 37
Effect of Different Counteranions	p. 38
Inclusion of Secondary Equilibria in the Mass Balance	p. 40
Conclusions	p. 43
References	p. 43
HPLC Columns and Packings
Abstract	p. 45
Introduction	p. 46
Column Chemistry	p. 47
Speed and Resolution	p. 68
Specialty Columns from Nanobore to Preparative Chromatography	p. 77
Summary	p. 80
References	p. 80
Column Characterization and Selection
Abstract	p. 85
Introduction	p. 86
Characteristics of RP-HPLC Columns and Chromatographic Tests	p. 90
Column Classification and Selection	p. 101
Conclusions	p. 104
Acknowledgment	p. 105
References	p. 105
Chiral Separations
Abstract	p. 111
Introduction	p. 112
Separation of Enantiomers on HPLC Chiral Stationary Phases	p. 115
Practical Guidelines to Chiral HPLC of Pharmaceuticals	p. 135
Conclusions	p. 137
References	p. 138
Contemporary Liquid Chromatographic Systems for Method Development
Abstract	p. 145
Introduction	p. 146
Traditional Instrumentation for HPLC Method Development	p. 147
Contemporary Method Development Systems	p. 153
Migrating Methods from HPLC to UPLC	p. 169
UPLC Applications in Pharmaceutical Analysis	p. 174
Summary and Conclusions	p. 183
Acknowledgments	p. 184
References	p. 185
Further Reading	p. 186
Hyphenated Techniques
Abstract	p. 189
Introduction and Background	p. 190
Combined Liquid Chromatography/Mass Spectrometry	p. 191
Combined Liquid Chromatography/Nuclear Magnetic Resonance Spectroscopy	p. 218
Conclusions	p. 231
Acknowledgments	p. 231
References	p. 232
HPLC Sample Preparation
Abstract	p. 237
Introduction	p. 238
Fundamentals of Extraction and Chemical Equilibrium	p. 239
Choice of Samples Preparation	p. 245
Direct Injection	p. 246
Liquid-Liquid Extraction	p. 247
Solid-Phase Extraction	p. 248
Solid Samples	p. 254
Additional Sample Preparation Methods	p. 256
Conclusions	p. 263
References	p. 263
Instrument Qualification and Software Validation
Abstract	p. 270
Introduction	p. 270
Definitions	p. 271
Qualification Model	p. 278
Discussion: Case Study HPLC	p. 291
Summary and Conclusions	p. 294
Acknowledgments	p. 295
References	p. 295
Pharmaceutical Development: From Pre-Clinical to Post Approval
Abstract	p. 297
Introduction	p. 298
The Role of HPLC in Drug Discovery	p. 300
The Role of HPLC in Pre-clinical Development	p. 303
The Role of HPLC in Clinical Development	p. 307
Post Approval	p. 312
Conclusions	p. 315
References	p. 315
HPLC Method Development for Drug Discovery LC-MS Assays in Rapid PK Applications
Abstract	p. 318
Introduction	p. 318
Tandem MS Selected Reaction Monitoring (SRM) Development	p. 319
HPLC Method Development	p. 322
Sample Preparation	p. 324
Matrix Effects	p. 329
Background Interference: Enhanced Mass Resolution Strategy	p. 334
Limit of Quantitation, Dynamic Range and Linearity	p. 340
Assay Samples and Generate Pharmacokinetic Reports	p. 344
Conclusions	p. 345
Acknowledgment	p. 345
References	p. 345
HPLC Method Development in Early Phase Pharmaceutical Development
Abstract	p. 353
Introduction	p. 354
Forced Decomposition and Impurity Profiling	p. 355
Orthogonal Screening	p. 357
Method Selection and Optimization	p. 362
Additional Methods	p. 366
Setting the Stage for Late Phase HPLC Method Developments	p. 367
Conclusions	p. 369
Acknowledgments	p. 369
References	p. 369
HPLC Method Development in Late Phase Pharmaceutical Development
Abstract	p. 373
Introduction	p. 374
Goals of Development	p. 375
Planning Phase	p. 377
Method Development Phase	p. 382
Method Evaluation Phase	p. 394
Method Transfer Phase	p. 398
Method Performance Monitoring and Feedback	p. 400
Method Development Cycle Times and Documentation	p. 403
Conclusions	p. 403
References	p. 404
Use of HPLC for In-process Testing
Abstract	p. 407
Introduction	p. 407
Various Examples of In-Process Testing in Drug Substance Development	p. 409
Fast HPLC	p. 419
In-Process Testing in Chemical Production	p. 420
In-Process Testing in Pharmaceutical Production	p. 422
Conclusions and Future Directions	p. 423
Acknowledgments	p. 423
References	p. 423
Method Development for Biomolecules
Abstract	p. 425
Introduction	p. 426
Protein and Peptide Separations by HPLC	p. 430
Case Studies	p. 434
Summary and Conclusions	p. 437
Abbreviations	p. 438
References	p. 438
Method Validation
Abstract	p. 441
Introduction	p. 442
Validation Process	p. 444
Validation Characteristics	p. 444
Additional Validation Characteristics	p. 450
Robustness Testing	p. 452
Conclusions	p. 457
References	p. 457
Troubleshooting in High Performance Liquid Chromatography
Abstract	p. 459
Introduction	p. 460
Problems Observed in Chromatograms	p. 460
Operating Parameters	p. 468
Leaks	p. 472
Pressure Problems	p. 474
Troubleshooting Action Plan	p. 475
Conclusions	p. 477
References	p. 477
Internet Resources	p. 477
Molecularly Imprinted Polymers as Sorbents for Separations and Extractions
Abstract	p. 479
Introduction	p. 479
MIP Theory	p. 481
Synthesis	p. 487
Use of Imprinted Polymers in Separation Science	p. 491
Pharmaceutical Application for MIPs	p. 493
Pros and Cons of MIP Sorbents	p. 495
Conclusions and Future Outlook	p. 496
References	p. 497
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Hplc Method Development for Pharmaceuticals

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