Pharmaceutical Research and Development, Merck Research Laboratories, West Point, PA 19486, USA.
Eur J Pharm Sci. 2010 Mar 18;39(5):291-7. doi: 10.1016/j.ejps.2009.12.001. Epub 2009 Dec 16.
The degradation kinetics and reaction product profile of the antitumor agent 1 in aqueous solution was studied. Hydrolysis of the pendant imide ring of 1 is the primary mode of thermal degradation in aqueous solution, and the pH rate profile of 1 has a V-shape indicating that hydrolysis of the imide ring can be catalyzed by either acid or base. Hydrolysis of 1 to the anhydride derivative 3 or the dicarboxylic acid derivative 4 is stepwise and the intermediates 2a and 2b formed by initial hydrolytic attack have been observed under alkaline conditions. An overall mechanism for the hydrolysis of 1 in aqueous solution has been proposed. Extrapolating Arrhenius behavior to the hydrolysis reaction of 1 in aqueous solution maintained at a pH value of 4 suggests an aqueous buffered formulation has sufficient thermal stability to be considered a robust room temperature drug product.
研究了抗肿瘤剂 1 在水溶液中的降解动力学和反应产物分布。1 在水溶液中的热降解的主要方式是侧链酰亚胺环的水解，并且 1 的 pH 值速率曲线呈 V 形，表明酰亚胺环的水解可以被酸或碱催化。1 水解生成酸酐衍生物 3 或二羧酸衍生物 4 是分步进行的，在碱性条件下已经观察到初始水解攻击形成的中间体 2a 和 2b。提出了 1 在水溶液中水解的总机制。将 Arrhenius 行为外推至在 pH 值为 4 的水溶液中保持的 1 的水解反应，表明水缓冲制剂具有足够的热稳定性，可以被认为是一种稳健的室温药物产品。
