Structure determination of drug

The Use of High-Accuracy Mass Measurements in Combination with LC-MS for the Structure Determination of Drug Metabolites... 

Within various pharmaceutical laboratories (industrial and academic), the mul-tinuclear technique of solid state NMR has primarily been applied to the study of polymorphism at the qualitative and quantitative levels. Although the technique ideally lends itself to the structure determination of drug compounds in the solid state, it is anticipated that in the future, solid state NMR will become routinely used for method development and problem solving activities in the analytical/materials science/physical pharmacy area of the pharmaceutical sciences. During the past few years, an increasing number of publications have emerged in which solid state NMR has become an invaluable technique. With the continuing development of solid state NMR pulse sequences and hardware improvements (increased sensitivity), solid state NMR will provide a wealth of information for the physical characterization of pharmaceutical solids. 

Liu and Hop [19] have reviewed various LC-tandem MS strategies, with or without chemical modification or derivatization, which have been successfully applied in the identification and the rational, but tentative, structural determination of drug metabolites. These techniques are equally applicable to the analysis of known plant secondary metabolites or to the de novo structural identification of new compounds. 

Autoradiography can be used to document chromatograms containing samples labeled with radioactive isotopes (see Chapter 13). Digital autoradiography combined with TLC-MS-MS was used for the structure determination of drug metabolites (Ludanyi, 1997). 

Barbuch, R.J., Campanale, K., Hadden, C.E. et al. (2006) In vivo metabolism of [14C]ruboxistaurin in dogs, mice, and rats following oral administration and the structure determination of its metabolites by liquid chromatogra-phy/mass spectrometry and NMR spectrometry. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 213-224. 

As liquid chromatography plays a dominant role in chemical separations, advancements in the field of LC-NMR and the availability of commercial LC-NMR instrumentation in several formats has contributed to the widespread acceptance of hyphenated NMR techniques. The different methods for sampling and data acquisition, as well as selected applications will be discussed in this section. LC-NMR has found a wide range of applications including structure elucidation of natural products, studies of drug metabolism, transformation of environmental contaminants, structure determination of pharmaceutical impurities, and analysis of biofiuids such as urine and blood plasma. Readers interested in an in-depth treatment of this topic are referred to the recent book on this subject [25]. 

Determination of elemental compositions is an important step towards the structural elucidation of drug impurities. Elemental composition of an unknown compound can only be derived from the measurement of its exact mass. In combination with the knowledge of the physiological or chemical process, elemental compositions alone may be enough to propose a correct structure. 

A.N. Hata, T.P. Lybrand, L.J. Marnett, R.M. Breyer, Structural determinants of aryla-cetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2, Mol. Pharmacol. 67 (2005) 640. 

IR spectroscopy is useful in biochemical research and has aided in the structural determinations of amino acids, nucleic acids, and polypeptides the IR spectra of viruses and bacteria have been studied.9 The controversial cancer drug Krebiozen was identified by its IR spectrum as the amino acid derivative creatine, which is present in humans in large quantities.10... 

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