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NMR and Pharmacy - Long-Range Friends. Regulatory, Pharmaceutical Research and Biomedical Aspects

The discovery and development of a new drug constitute a process which runs a high risk of failure and is long and costly. Successful drug development entails highly coordinated interactions of numerous groups of individuals working in disciplines ranging from the basic sciences to the legal and biomedical professions. Nuclear magnetic resonance (NMR) spectroscopy is involved in many steps from the beginning of potential drug candidate design to clinical useful drug, therefore has an extremely important role in the process of drug discovery and development. Nowadays, NMR is employing in all institutions (academia, government-sponsored agencies, pharmaceutical industry) where the basic research aspects (synthetic-medicinal chemistry, pharmacology, molecular biology, etc.) of new drug may occur, as well as in regulatory agencies, and as MRI technique is in use in hospitals for diagnosis and prognosis of disease through metabonomic and metabolic measurements. MRI represents a noninvasive, unique and powerful method in detection and quantitative determination of endobiotics, drugs and toxic substances in the urine and other body fluids, drug metabolites and their structural related analogues which isolation or differentiation in biological material could be sometimes very complex. Monitoring of drug metabolites is of toxicological, pharmacological and biomedical interest. It seems ironic, that although about 90% of the pharmaceutical products on the market exist in the solid form, solid-state NMR is not in pharmaceutical use as solution-phase NMR. Nowadays it is becoming increasingly important to characterize the drug in its dispensed form, which is frequently solid, and not only at the bulk level due to possibility of alteration of solids or their interaction with excipients under the extreme conditions of processing the formulation into the dosage form. The usefulness of NMR spectroscopy in terms of identification and quantification of drugs and their impurities resulting from the synthesis pathway or degradation will be demonstrated on several examples. Structure elucidation problems in many courses of our research work (e.g. chemistry of 1, 3-dioxepins, hydroxyurea derivatives synthesis via isocyanate precursors, the fluoroquinolone complexation with metal ions, the salycilamide biotransformation to gentisamide by CYP enzyme), would be unimaginable without NMR and some of them will be presented and discussed. 1. U. Holzgrabe et al. NMR Spectroscopy in Drug Development and Analysis, Wiley-VCH, Veinheim 1999. 2. US Pharmacopoeia, 23. 3. EU Pharmacopoeia IV. 4. EU Directives 65/65/EEC and 75/318/EEC. 5. M. Jadrijević-Mladar Takač, I. Kos, M. Biruš, , I. Butula, M. Gabričević, A study of the physico-chemical properties of 1, 3, 5-trihydroxy-1, 3, 5-triazin-2, 4, 6(1H, 3H, 5H)-trione, J. Mol. Struct. 782 (2006) 24-31. 6. M. Jadrijević-Mladar Takač, D. Vikić-Topić, T. Govorčinović, FT-IR and NMR spectroscopic studies of salycilic acid derivatives. Part I and Part II, Acta Pharm. 54 (2004)163-101. 7. M. Jadrijević-Mladar Takač, I. Butula, D. Vikić-Topić, M. Dumić, Chemistry of 1, 3-dioxepins.XIII. (E)/(Z) Configurational Assignment of 4, 7-dihydro-4-hydroxyimino-6-nito-1, 3-dioxepins, Croat. Chem. Acta 71 (1998) 557-571.

NMR in drug research; NMR-biomedicine's aspect; NMR in pharmaceutical regulative; E/Z oxyme configurational assignments; spectroscopic study of NSAIDs and SAM metabolite; fluoroquinoline-metal complexes

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