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HPLC for Pharmaceutical Scientists 2007 (Part 7A)

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The discovery of a new drug is a challenging task that includes (a) identifica- tion of a biochemical target for certain diseases and (b) screening of a large number of compounds from libraries of compounds arising from synthetic chemistry, combinatorial chemistry, and natural product isolation for lead gen- eration. The lead compound is then optimized based on biological activity, selectivity, pharmacokinetic property, and metabolism. | 7 LC MS THEORY INSTRUMENTATION AND APPLICATIONS TO SMALL MOLECULES Guodong Chen Li-Kang Zhang and Birendra N. Pramanik 7.1 INTRODUCTION The discovery of a new drug is a challenging task that includes a identification of a biochemical target for certain diseases and b screening of a large number of compounds from libraries of compounds arising from synthetic chemistry combinatorial chemistry and natural product isolation for lead generation. The lead compound is then optimized based on biological activity selectivity pharmacokinetic property and metabolism. This process produces a large volume of samples requiring rapid and accurate analysis with the speed of analysis contributing directly to the drug discovery cycle time. As one of primer analytical techniques mass spectrometry MS developed from nineteenth-century physics starting with the pioneering work of J. J. Thomson on the electrical discharges in evacuated tubes. In 1913 Thomson wrote I feel sure that there are many problems in Chemistry which could be tackled with far greater ease by this than any other method. The method is surprisingly sensitive more so than that of Spectrum Analysis requires infinitesimal amount of material and does not require this to be specially purified. Indeed MS offers speed high sensitivity and isotopic specificity. This technique separates mixtures of ions on the basis of mass-to-charge ratios HPLC for Pharmaceutical Scientists Edited by Yuri Kazakevich and Rosario LoBrutto Copyright 2007 by John Wiley Sons Inc. 281 282 APPLICATIONS TO SMALL MOLECULES providing the molecular weight of a compound and its structural information from fragment ions. It is widely used for identification and quantification of known unknown organic compounds. Rapid development of MS in recent decades has further expanded its role in the structural characterization of small molecules in the drug discovery process 1 . In combination with chromatographic separation techniques principally in the form of .