新药杂质评估02-Ealuating Impurities in Drugs 02.docVIP

Evaluating Impurities in Drugs (Part II of III) In Part II of a three-part article, the authors examine impurities from chiral molecules, polymorphic contaminants, and genotoxic impurities. Mar 2, 2012By: Kashyap R. Wadekar,?Mitali Bhalme,?S. Srinivasa Rao,?K. Vigneshwar Reddy,?L. Sampath Kumar,?E. BalasubrahmanyamPharmaceutical TechnologyVolume 36, Issue 3, pp. 58-72  The public and the pharmaceutical industry are placing greater attention on impurities in drug as evidenced by the attention given to pharmaceutical impurities in books, journal articles, and national and international guidelines (1–10). The health implications of impurities can be significant because of their potential teratogenic, mutagenic, or carcinogenic effects. Controlling and monitoring impurities in APIs and finished drug products, therefore, is a crucial issue in drug development and manufacturing. Part I of this article, which appeared in the February 2012 issue of Pharmaeceutical Technology, discussed the various types and sources of impurities with specific case studies (11). This article, Part II, discusses chiral, polymorphic, and genotoxic impurities (12, 13). Part III, to be published in the April 2012 issue of Pharmaceutical Technology, will examine various degradation routes of APIs, impurities arising from API–excipient interaction during formulation, metabolite impurities, various analytical methodologies to measure impurity levels, and measures to control impurities. Chiral impurities Impurities can be present in the enantiomers of chiral compounds. Differences in pharmacological and toxicological profiles have been observed with chiral impurities in vivo (14, 15). The significance of stereochemical purity may be illustrated by formoterol, a selective β2-adrenoceptor agonist (16). This compound contains two chiral centers. Initial investigations indicated that the β2-agonist activity resided in the stereoisomer with the (R, R) absolute configuration with a rank order