Degradation of paclitaxel and related compounds in aqueous solutions I: Epimerization

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 7-position of paclitaxel, 7-epi-taxol, 10-deacetyltaxol, 7-epi-10-deacetyltaxol, baccatin III and 10-deacetylbaccatin 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 S-epimer 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 base-catalyzed 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 rate-limiting step of structure rearrangement most likely occurs with the formation of an enolate intermediate.