Identification and Determination of Impurities in Drugs: Progress in Pharmaceutical and Biomedical Analysis

Impurity profiling is the common name of a group of analytical activities, the aim of which is the detection, identification/structure elucidation and quantitative determination of organic and inorganic impurities, as well as residual solvents in bulk drugs and pharmaceutical formulations. Since this is the best way to characterise the quality and stability of bulk drugs and pharmaceutical formulations, this is the core activity in modern drug analysis. Due to the very rapid development of the analytical methodologies available for this purpose and the similarly rapid increase of the demands as regards the purity of drugs it is an important task to give a summary of the problems and the various possibilities offered by modern analytical chemistry for their solution. That is the aim of this book. The book is methodology-oriented. In the first chapter some important aspects of the background of impurity-related analytical studies (toxicological, pharmacopoeial aspects, the characterisation of the sources of impurities and the role of impurity profiling in various fields of drug research, production and therapeutic use) are summarised. Chapter two deals with related organic impurities, the strategies for impurity profiling, the use of chromatographic and related separation methods, spectroscopic, and hyphenated techniques. The subject of the third chapter is the identification and determination of residual solvents. The determination of inorganic impurities is discussed in chapter four. The special problems of degradation products as impurities are dealt with in chapter five. A separate chapter has been compiled to deal with one of the most up-to-date problems in contemporary pharmaceutical analysis, the estimation of enantiomeric purity of chiral drugs. Chapter seven is devoted to various approaches to solve the problem of polymorphic modifications as impurities. Since in the broader sense of the word the microbiological purity of drugs and drug products also belongs to this circle, the most important information from this field is summarised in chapter eight. After the mainly methodology-oriented chapters, the final one concentrates on four groups of drugs (peptides, biotechnological products, antibiotics and steroids) in order to demonstrate the use of the methods described earlier. Content: Preface Pages v-vi Sándor Görög List of contributors Pages xxi-xxiii 1.1. Introductory remarks Original Research Article Pages 1-8 Sándor Görög 1.2 The nature and origin of the impurities in drug substances Original Research Article Pages 9-22 Sándor Görög 1.3. Toxicological aspects Original Research Article Pages 23-37 Richard Lee 1.4. The role of impurity profiling in drug research, development and production Original Research Article Pages 38-47 Sándor Görög 1.5. Regulatory aspects: ICH and pharmacopoeial perspectives Original Research Article Pages 48-66 Judy P. Boehlert 2.1. Strategies in impurity profiling Original Research Article Pages 67-83 Sándor Görög 2.2. UV-VIS spectroscopy and fluorimetry Original Research Article Pages 84-96 Sándor Görög 2.3. Mass spectrometry in impurity profiling Original Research Article Pages 97-108 Marianna Mák, Gábor Czira, János Brlik 2.4. NMR spectroscopy Original Research Article Pages 109-145 Csaba Szántay Jr., Ádám Demeter 2.5. Planar chromatography Original Research Article Pages 146-182 Katalin Ferenczi-Fodor, Zoltán Végh 2.6. Gas chromatography (GC) and related techniques Original Research Article Pages 183-209 Anna Laukó 2.7 High performance liquid chromatography (HPLC) and related techniques: 2.7.1 Separation, detection and determination of impurities by HPLC Original Research Article Pages 210-239 Mária Gazdag 2.7 High performance liquid chromatography (HPLC) and related techniques: 2.7.2. Isolation of impurities by (semi)preparative HPLC Original Research Article Pages 240-251 Antal Aranyi 2.7 High performance liquid chromatography (HPLC) and related techniques: 2.7.3. The role of the diode-array UV spectra in the identification of impurities Original Research Article Pages 252-265 Sándor Görög 2.7 High performance liquid chromatography (HPLC) and related techniques: 2.7.4 HPLC/MS for drug impurity identification Original Research Article Pages 266-298 Lars Tollsten 2.7.5. HPLC/NMR and related hyphenated NMR methods Original Research Article Pages 299-322 Ian D. Wilson, Lee Griffiths, John C. Lindon, Jeremy K. Nicholson 2.8. Determination of drug related impurities by capillary electrophoresis Original Research Article Pages 323-345 Kevin D. Altria 2.9. Capillary electrochromatography (CEC): 2.9.1 Separation, detection and determination of impurities by CEC Original Research Article Pages 346-358 Melvin R. Euerby 2.9. Capillary electrochromatography (CEC): 2.9.2. CEC/MS Original Research Article Pages 359-381 Steve J. Lane 2.10. Supercritical fluid chromatography (SFC) Original Research Article Pages 382-395 Olle Gyllenhaal 2.11. Purity check by differential scanning calorimetry Original Research Article Pages 396-400 Imre Péter 3.1. Thermoanalytical methods Original Research Article Pages 401-408 Imre Péter 3.2. Gas chromatography and GC/MS Original Research Article Pages 409-440 Jürgen Bertram 3.3. NMR spectroscopy Original Research Article Pages 441-447 Gábor Balogh 3.4. Miscellaneous Original Research Article Pages 448-449 Sándor Görög 4.1. Classical methods Original Research Article Pages 451-457 Sándor Görög 4.2. Atomic spectroscopy Original Research Article Pages 458-467 Alexandra Lásztity 4.3. Other methods Original Research Article Pages 468-471 Sándor Görög 5.1. The relation between drug stability studies and the estimation of impurity profiles Original Research Article Pages 473-476 Sándor Görög 5.2. Aims, forms and conditions of drug stability testing Original Research Article Pages 477-479 Sándor Görög 5.3. Elucidation of degradation pathways Original Research Article Pages 480-496 Sándor Görög 5.4. Elucidation of light-induced degradation pathways Original Research Article Pages 497-505 Sándor Görög 5.5. Methodological aspects of quantitative drug stability studies based on degradates Original Research Article Pages 506-524 Sándor Görög 6.1.Introduction Original Research Article Pages 525-527 Sándor Görög 6.2. Chromatographic methods Original Research Article Pages 528-539 Sándor Görög 6.3. Capillary electrophoretic (CE) methods Original Research Article Pages 540-552 Jacques Crommen 6.4. Polarimetry, ORD and CD spectroscopy Original Research Article Pages 553-561 András Gergely 6.5. NMR spectroscopy Original Research Article Pages 562-574 Gábor Tárkányi 7.1. The phenomenon and importance of polymorphism Original Research Article Pages 575-579 Béla Hegeds 7.2. Infrared and Raman spectroscopy Original Research Article Pages 580-591 Béla Hegeds 7.3 Thermoanalytical methods Original Research Article Pages 592-600 Imre Péter 7.4. X-ray crystallography Original Research Article Pages 601-607 Márta Bálint 8.1. Introductory remarks Original Research Article Pages 609-637 Hans van Doorne 9.1. Peptides Original Research Article Pages 639-659 Sándor Görög 9.2. Biotechnological products Original Research Article Pages 660-683 Katalin Ganzler, Aharon S. Cohen 9.3. Antibiotics Original Research Article Pages 684-711 Ann van schepdael, Erwin Adams, Eugène Roets, Jos Hoogmatens 9.4. Steroids Original Research Article Pages 712-731 Sándor Görög Subject index Pages 733-748