NMR Spectroscopy in Pharmaceutical Analysis

Cover......Page 1
Preface......Page 2
List of Contributors......Page 3
List of Editors......Page 6
FUNDAMENTALS AND TECHNIQUES......Page 7
1: Principles in NMR Spectroscopy......Page 8
Short History......Page 9
Excitation, relaxation and sensitivity......Page 10
Relaxation......Page 12
Electronic density......Page 15
Anisotropy......Page 16
Steric effects......Page 18
Calibration and Relative Scale ppm......Page 19
The coupling constant......Page 20
Multiplicity......Page 21
Roof effect......Page 22
Heteronuclear coupling......Page 23
Heteronuclear Spectra......Page 26
Quantitative heteronuclear NMR......Page 27
Molecular Dynamics......Page 28
Deuterium exchange and solvent effects......Page 29
Chemical Derivatisation......Page 32
Diastereomerism......Page 33
Enantiomeric excess......Page 34
Diastereotopy......Page 35
Two-dimensional Methods for Structure Elucidation......Page 38
References......Page 45
2: Quantitative NMR in the Solution State NMR......Page 47
Basics......Page 48
Relative method......Page 49
Absolute method......Page 50
Validation......Page 51
Linearity......Page 52
Acquisition parameters......Page 53
Spectra evaluation (integration)......Page 55
Specificity and selectivity......Page 56
Accuracy......Page 57
Precision......Page 58
Measurement uncertainty......Page 59
Round robin tests......Page 60
Sensitivity......Page 63
Conclusion......Page 64
References......Page 65
Introduction to Solid-state NMR......Page 67
Quantitative Aspects of Solid-state NMR, Protocol for Quantitation......Page 74
An Example: Quantitation of Pseudoephedrine in Dosage Form......Page 77
Quantitation of Polymorphs and Formulated Drugs......Page 82
References......Page 86
4: Microcoil Nuclear Magnetic Resonance Spectroscopy......Page 87
Intrinsic NMR Sensitivity......Page 88
Saddle/Helmholtz coils......Page 90
Solenoidal coils......Page 91
Planar RF coils......Page 96
Novel microcoil designs......Page 97
High-temperature superconducting microprobes......Page 99
Sensitivity Comparisons......Page 101
Nanoliter Volume Applications of RF Microcoils – Hyphenated cITP–NMR......Page 102
Solenoidal coils......Page 105
Superconducting microcoils......Page 108
Hyphenation of Microseparation Techniques with Microliter NMR Detection......Page 112
Multiple Coil Probeheads......Page 121
Solid-State Applications of Small Coils......Page 127
Conclusion......Page 129
References......Page 131
Introduction......Page 135
NMR Spectroscopy in International Pharmacopoeias......Page 136
Tests......Page 137
Validation......Page 139
References......Page 140
GENERAL APPLICATIONS......Page 142
Introduction......Page 143
Solvent......Page 144
pH value......Page 145
Auxiliary reagents......Page 146
Limitations......Page 147
1H NMR spectroscopy......Page 148
13C NMR spectroscopy......Page 152
High-performance liquid chromatography......Page 154
HPLC versus NMR spectroscopy......Page 155
References......Page 156
Introduction......Page 158
Polydimethyl Siloxane......Page 159
Polysaccharides......Page 162
Polyether Formulation Aids......Page 166
Formaldehyde......Page 171
Polyester......Page 174
Poly- and Oligopeptides......Page 175
Polyvinyl Compounds......Page 179
References......Page 180
thinspIntroduction......Page 182
Characterisation of Natural Substances as a Finger Print Analysis......Page 183
Characterisation of Natural Substances According to Single Target Molecules......Page 185
Characterisation and Definition of Primary Reference Standards......Page 188
Extracts from medical plants......Page 192
Lipids......Page 194
Lecithin......Page 195
Fats and oils......Page 198
References......Page 201
4: Solid-State Measurements of Drugs and Drug Formulations......Page 202
Solid-state NMR in Pharmacy......Page 203
Amphetamine and ephedrine hydrochlorides and related compounds......Page 205
Erythromycin A – formation of a hemiketal......Page 206
Paracetamol – characterization of polymorphic forms......Page 207
Rifampicin – molecular structure of polymorphs......Page 208
Ketoconazole – amorphous form required......Page 209
Paclitaxel (Taxol) – molecular structure and interactions......Page 210
MAS NMR of steroids: finasteride, estradiol, testosterone......Page 211
Nifedipine and amlodipine......Page 213
Ibuprofen preparations......Page 216
Oxybuprocaine hydrochloride – NMR crystallography......Page 217
Warfarin – cyclic hemiketal......Page 218
Mixture of alpha-amyrin and beta-amyrin......Page 219
Euphol from Euphorbia......Page 220
Oxindole alkaloids from Uncaria tomentosa......Page 222
Lanatoside C......Page 224
13C CPMAS NMR of Excipients......Page 226
Drugs in Membranes......Page 229
References......Page 230
5: Metabolic Profiling......Page 233
Goals of metabolic profiling experiments......Page 234
Dynamic range of NMR measurements......Page 235
General considerations......Page 236
Replicates and variability......Page 237
pH and temperature......Page 239
Sample specific considerations......Page 240
Relaxation editing......Page 241
Tissue extracts......Page 243
HR-MAS analysis of intact tissues......Page 244
Microdialysis samples......Page 245
Data Acquisition......Page 246
Water suppression......Page 248
Experiments utilizing nuclei other than 1H......Page 249
Apodization......Page 251
Phasing and baseline correction......Page 252
Selection of integral regions......Page 254
Peak alignment......Page 256
Normalization......Page 257
Centering, scaling, and transformation......Page 258
Illustration......Page 259
Conclusions and Future Perspectives......Page 262
References......Page 263
Introduction......Page 268
Principle......Page 269
Experimental difficulties......Page 271
Data processing......Page 272
Principle......Page 274
Data acquisition......Page 275
DOSY 1H NMR analysis of ciprofloxacin formulations......Page 276
DOSY 1H NMR analysis of oral formulations of fluoxetine......Page 278
DOSY 1H NMR analysis of formulations of genuine Cialisreg and a Chinese imitation......Page 279
DOSY 1H NMR analysis of an herbal Chinese formulation......Page 281
TOSY NMR analysis of ibuprofen......Page 282
Advantages and Drawbacks of the Methods......Page 283
Conclusion......Page 286
References......Page 287
7: The Use of qNMR for the Analysis of Agrochemicals......Page 289
Purity and supply of standard reference materials......Page 290
Shortcomings of some official agrochemical analytical methods......Page 292
General considerations......Page 293
qNMR using the subtraction method......Page 294
qNMR using a standard of known purity......Page 295
The concept of universal standard reference material......Page 296
Practical analysis of technical grade agrochemicals by qNMR......Page 297
qNMR Analysis of Proscribed Impurities in Agrochemicals......Page 307
qNMR Analysis of Manufacturing Impurities in Agrochemicals......Page 309
Conclusion......Page 312
References......Page 313
SPECIAL APPLICATIONS......Page 314
1: NMR-Based Mixture Analysis on the Example of Fruit Juice Quality Control Using Statistics and Quantification......Page 315
Introduction......Page 316
Instrumental Aspects of Fruit Juice Quality Control......Page 318
Identification of Compounds in the Mixture......Page 322
Quantification of Compounds in Fruit Juice Spectra......Page 323
Ridge-Regression in Fruit Juice Quality Control......Page 325
Statistical Analysis on Fruit Juices Other than Ridge Regression......Page 326
Information on the Statistical Methods Applied......Page 332
References......Page 333
2: NMR Assays for Carbohydrate-Based Vaccines......Page 336
Vaccines Based on the Cell Surface Carbohydrates of Microbial Pathogens......Page 337
Carbohydrate-based vaccines......Page 338
The structures of bacterial polysaccharides......Page 339
Traditional chemical approaches......Page 340
Polysaccharide identity determination by NMR spectroscopy......Page 342
NMR analysis of blends and CPSs in the presence of excipients......Page 345
Quantitation of the O-acetyl contents of CPSs......Page 346
Quantitation of contaminants and process-related impurities......Page 347
Process-related impurities......Page 348
Identification of End Groups as Markers of Polysaccharide Degradation......Page 349
Characterisation of Activated Intermediates in Vaccine Manufacture......Page 351
Combined activation and depolymerisation using periodate oxidation or acid hydrolysis......Page 352
Random activation without depolymerisation......Page 353
Identity and integrity of the saccharide component of glycoconjugate vaccines......Page 355
Determination of polysaccharide-protein ratio in glycoconjugate vaccines......Page 357
Conclusions......Page 359
References......Page 360
3: Fluorine-19 or Phosphorus-31 NMR Spectroscopy: A Powerful Technique for Biofluid Metabolic Studies and Pharmaceutical Formulation Analysis of Fluorinated or Phosphorylated Drugs......Page 364
Introduction......Page 365
Advantages and Limitations of 19F and 31P NMR for in vitro Studies......Page 366
Anti-bacterials......Page 368
Neuroleptics......Page 370
Anti-inflammatory drugs......Page 371
Anaesthetics......Page 372
FU catabolism......Page 377
FU degradative pathway and FU cardiotoxicity......Page 381
Capecitabine......Page 383
Gemcitabine......Page 385
Anti-fungals......Page 387
Amifostine......Page 389
Overview of the metabolism......Page 390
Cyclophosphamide......Page 393
Ifosfamide......Page 394
References......Page 396
Introduction......Page 402
GAGs characterization via 1D NMR......Page 406
2D NMR Approach......Page 409
Setup of the 2D NMR method......Page 410
Choice of analytical signals......Page 412
2D analysis of a simple oligosaccharide mixture......Page 414
Low-Molecular-Weight Heparin Analysis......Page 416
References......Page 422
Introduction......Page 424
Spectral Comparison......Page 425
Conclusions......Page 430
References......Page 431
Introduction......Page 432
Current Status of NMR Spectroscopy and MRI......Page 433
High Throughput in NMR......Page 434
Assessment of the Inhibitory Potency of Antimicrobials......Page 435
Assessment of the Inhibitory Potency by MRI......Page 437
Marker of bacterial growth......Page 438
NMR growth curves and determination of the MIC......Page 440
References......Page 442
Introduction......Page 444
Concatenated FIA Systems......Page 446
Hybrid Concatenated/Hypernated FIA–MS/LC–NMR Systems......Page 449
Hypernated LC–UV–NMR–MS Combinations......Page 450
LC–NMR–MS with Superheated D2O as the Eluent......Page 454
LC–NMR and LC–NMR–MS with on-Line Collection for Off-Line IR......Page 455
Fully On-Line LC–UV–NMR–IR–MS Systems......Page 456
LC–UV–IR–NMR–MS with Hot and Superheated D2O as the Eluent......Page 457
The Practice of Concatenation and Hypernation......Page 461
References......Page 462
8: Quantitative High-Resolution Online NMR Spectroscopy in Pharmaceutical Reaction and Process Monitoring......Page 465
Quantitative Flow NMR Spectroscopy......Page 466
Deuterium-free samples and solvent suppression techniques......Page 467
Solvent suppression techniques......Page 468
Flowing samples......Page 469
Peak deconvolution......Page 470
Field homogeneity......Page 471
Flow scheme......Page 472
Residence times......Page 473
Heterogeneously catalyzed ester formation reaction......Page 476
Autocatalyzed ester formation reaction......Page 477
Hydroxymethylation of urea......Page 479
Solid-liquid heterogeneous reaction......Page 480
Scaling up: simultaneous flow NMR and NIR monitoring of a demesitylation reaction......Page 483
References......Page 484
Index......Page 486