Nassar M N, House C A, Agharkar S N
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Syracuse, NY 13221-4755.
J Pharm Sci. 1992 Nov;81(11):1088-91. doi: 10.1002/jps.2600811109.
The degradation of batanopride hydrochloride, an investigational antiemetic drug, was studied in aqueous buffer solutions (pH 2-10; ionic strength, 0.5; 56 degrees C) in an attempt to improve drug stability for parenteral administration. Degradation occurs by two different mechanisms depending on the pH of the solution. In acidic media (pH 2-6), the predominant reaction was intramolecular cyclization followed by dehydration to form a 2,3-dimethylbenzofuran. There was no kinetic or analytical (high-performance liquid chromatography) evidence for the formation of an intermediate; therefore, the rate of dehydration must have been very rapid compared with the rate of cyclization. In alkaline media (pH 8-10), the primary route of degradation was cleavage of the C-O alkyl ether bond. In the intermediate pH range (pH 6-8), both reactions contributed to the overall degradation. Both degradation reactions followed apparent first-order kinetics. The pH-rate profile suggests that batanopride hydrochloride attains its optimal stability at pH 4.5-5.5. Citrate buffer was catalytic at pH 3 and 5, and phosphate buffer was catalytic at pH 8. No catalytic effect was observed for the borate buffer at pH 9-10.
为提高一种用于肠胃外给药的研究性止吐药物盐酸巴他必利的稳定性，研究了其在水缓冲溶液（pH 2 - 10；离子强度0.5；56℃）中的降解情况。根据溶液pH值的不同，降解通过两种不同机制发生。在酸性介质（pH 2 - 6）中，主要反应是分子内环化，随后脱水形成2,3 - 二甲基苯并呋喃。没有动力学或分析（高效液相色谱法）证据表明有中间体形成；因此，与环化速率相比，脱水速率必定非常快。在碱性介质（pH 8 - 10）中，主要降解途径是C - O烷基醚键的断裂。在中间pH范围（pH 6 - 8），两种反应都对整体降解有贡献。两种降解反应均符合表观一级动力学。pH - 速率曲线表明盐酸巴他必利在pH 4.5 - 5.5时达到最佳稳定性。柠檬酸盐缓冲液在pH 3和5时具有催化作用，磷酸盐缓冲液在pH 8时具有催化作用。在pH 9 - 10时，未观察到硼酸盐缓冲液有催化作用。
