Degradation of paclitaxel and related compounds in aqueous solutions III: Degradation under acidic pH conditions and overall kinetics.

Paclitaxel and related taxanes are complex molecules with numerous hydrolysable ester groups, possible epimerization at the 7-position, and possessing a strained oxetane ring, a possible site for acid-catalyzed cleavage. Presented here is the stability of paclitaxel, 10-deacetylbaccatin III, baccatin III, and N-benzoyl-3-phenylisoserine ethyl ester in aqueous solution over a pH range of 1-5 at various temperatures. Analysis of various samples was by HPLC-UV and LC-MS. Baccatin III, 10-deacetylbaccatin III, and N-benzoyl-3-phenylisoserine ethyl ester were found to undergo acid catalysis since pH-rate profiles all followed a first-order dependency in hydrogen ion concentration. No evidence of any epimerization was noted at acidic pH values. Baccatin III and 10-deacetylbaccatin III showed similar degradation rates with possible products being possible dehydration around the 13-hydroxy group and cleavage of the oxetane ring. Cleavage of the 10-acetyl group of baccatin III was a minor initial pathway. N-Benzoyl-3-phenylisoserine ethyl ester degraded significantly slower than both 10-deacetylbaccatin III and baccatin III. At pH 2, paclitaxel degraded at a rate between that of N-benzoyl-3-phenylisoserine ethyl ester and 10-deacetylbaccatin III. The pH of maximum stability for all compounds appeared to be around pH 4. 2009 Wiley-Liss, Inc. and the American Pharmacists Association