Degradation of paclitaxel and related compounds in aqueous solutions II: Nonepimerization degradation under neutral to basic pH conditions.
Paclitaxel and other taxanes have complex structures that include the presence of numerous hydrolytically sensitive ester groups. The present study attempts to make sense of the kinetics of the base catalyzed hydrolysis of various ester groups found in paclitaxel by also studying the hydrolysis of 7-epi-taxol, 10-deacetyltaxol, 7-epi-10-deacetyltaxol, baccatin III, 10-deacetylbaccatin III and N-benzoyl-3-phenylisoserine ethyl ester. Kinetics were studied as function of pH, buffer concentration and temperature, and analyzed using a stability indicating HPLC assay and LC/MS to identify degradation products. The kinetics were complicated by the epimerization reaction occurring at the 7-position but isolation of the hydrolytic components of the kinetics was possible. All ester hydrolysis reactions observed above pH 6-7 were, as expected, base catalyzed. After epimerization at the C7, paclitaxel hydrolysis occurs mainly due to cleavage of the side chain with further hydrolysis of the ester bonds at C10, C2 and C4 with the C10 acetate hydrolysis being the relatively next most facile. By studying the hydrolysis of 10-deacetyltaxol, 7-epi-10-deacetyltaxol, baccatin III, 10-deacetylbaccatin III and N-benzoyl-3-phenylisoserine ethyl ester, good insight into the hydrolysis of the larger more complex taxanes was possible.
Tian
Jiaher
J
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
Stella
Valentino J
VJ
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D013058:Mass Spectrometry; D017239:Paclitaxel / Q000737:chemistry*; D012996:Solutions; D013237:Stereoisomerism; D043823:Taxoids / Q000737:chemistry; D013696:Temperature; D014867:Water / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D012996:Solutions; D043823:Taxoids; D014867:Water; C042213:10-deacetylbaccatine III; D017239:Paclitaxel