PROFILING DEGRADANTS OF PACLITAXEL USING LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY AND LIQUID-CHROMATOGRAPHY TANDEM MASS-SPECTROMETRY SUBSTRUCTURAL TECHNIQUES

A rapid and systematic strategy based on liquid chromatography-mass sp ectrometry (LC-MS) profiling and liquid chromatography-tandem mass spe ctrometry (LC-MS-MS) substructural techniques was utilized to elucidat e the degradation products of paclitaxel, the active ingredient in Tax ol. This strategy integrates, in a single instrumental approach, analy tical HPLC, UV detection, full-scan electrospray MS, and MS-MS to rapi dly and accurately elucidate structures of impurities and degradants. In these studies, degradants induced by acid, base, peroxide, and ligh t were profiled using LC-MS and LC-MS-MS methodologies resulting in an LC-MS degradant database which includes information on molecular stru ctures, chromatographic behavior, molecular mass, and MS-MS substructu ral information. The stressing conditions which may cause drug degrada tion are utilized to validate the analytical monitoring methods and se rve as predictive tools for future formulation and packaging studies. Degradation products formed upon exposure to basic conditions included baccatin III, paclitaxel sidechain methyl ester, 10-deacetylpaclitaxe l, and 7-epipaclitaxel. Degradation products formed upon exposure to a cidic conditions included 10-deacetylpaclitaxel and the oxetane ring o pened product, Treatment with hydrogen peroxide produced only 10-deace tylpaclitaxel. Exposure to high intensity light produced a number of d egradants. The most abundant photodegradant of paclitaxel corresponded to an isomer which contains a C3-C11 bridge. These methodologies an a pplicable at any stage of the drug product cycle from discovery throug h development. This library of paclitaxel degradants provides a founda tion for future development work regarding product monitoring, as well as use as a diagnostic tool for new degradation products. (C) 1997 El sevier Science B.V.