| The major goal of this study is to investigate whether easily and rapidly calculated model results could predict the chemical stability of drug-like compounds, to facilitate new drug discovery and the following pre-formulation and development studies. Several rationale approaches are taken to achieve the goal. One useful method is to apply empirical correlations derived from physical organic chemistry principles and/or computer models on drug stability prediction, primarily based on the chemical structures. Although these correlation models are shown to be quite useful tools, they are not expected to provide reliable predictions for all chemicals, especially for bigger molecules with complex structure. Therefore, Paclitaxel and its related taxanes are selected for further stability study, partially because their chemical stability in aqueous solution has not been thoroughly studied yet. The epimerization of paclitaxel and several related taxanes have been examined in aqueous solution, and the rate constants of the interconversion of the R- and S-epimers determined in near neutral and basic pH range. The solution kinetics of degradation of these compounds under acid, near neutral, and basic pH conditions has been also investigated. The various mechanisms of epimerization and degradation, as well as the influence of the ring system and substituents are discussed in detail. Another important part of this work is to explore a proto-type of a comprehensive Windows-based program, STARs (Stability daTa Automatic Reference system), to manage drug stability information.;Overall, efforts have been taken to explore various ways that would allow one to predict, with some confidence, the chemical stability of hydrolytically degradable drug molecules. Coupling this with modern computer informatics techniques, the traditional prediction methods can be greatly enhanced, leading to more reliable and accurate predictions. In addition, such techniques and compilations serve as the complementary tools to experimental observations and play a more important role in new drug discovery and development in the future. |
