Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487323 | Journal of Pharmaceutical Sciences | 2008 | 12 Pages |
Abstract
Paclitaxel and other taxanes have complex structures including the presence of numerous hydrolytically sensitive ester groups and a chiral center that readily undergoes epimerization thus making their kinetics complex. The present study attempts to understand the mechanism of epimerization at the 7âposition of paclitaxel, 7âepiâtaxol, 10âdeacetyltaxol, 7âepiâ10âdeacetyltaxol, baccatin III and 10âdeacetylbaccatin III. Kinetics were studied as function of temperature, pH and buffer concentration and analyzed using a stability indicating assay and LC/MS to identify degradation products. Epimerization was base catalyzed with no evidence of acid catalysis noted. The observed equilibrium constant for epimerization, K, indicated a thermodynamically more favorable Sâepimer and a small free energy change between the two epimers. For all of the compounds in this study, removal of the C10 acetyl group increases the epimerization rate in basic aqueous solutions. The observed baseâcatalyzed epimerization in near neutral to higher pH range suggests a possible rapid deprotonation/protonation of the C7 -OH, followed by a structural rearrangement through a retroaldol/aldol mechanism to form the epimer. Moreover, the rateâlimiting step of structure rearrangement most likely occurs with the formation of an enolate intermediate. © 2007 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 97:1224-1235, 2008
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Authors
Jiaher Tian, Valentino J. Stella,