基于氯霉素降解反应机理评价氯霉素滴眼液的稳定性

Chloramphenicol eye drop stability evaluation based on the degradation mechanism of chloramphenicol

目的评价国产氯霉素滴眼液的稳定性,讨论稳定性相关的影响因素。方法采用最小二乘法拟合水解动力学方程,比较水解反应的溶剂同位素效应,探讨氯霉素的水解反应机理,揭示影响氯霉素水解反应的诸因素;研究氯霉素在不同水溶液环境中的光反应特性,根据光降解杂质探讨氯霉素滴眼剂的光降解反应机理;根据氯霉素滴眼液的降解反应机理,评价制剂处方、工艺的合理性。结果氯霉素水溶液的水解反应为一般碱催化假一级反应,水解速度主要与缓冲盐的种类、pH和温度有关;氯霉素水溶液的光反应为自由基连锁反应;市场上不同企业的氯霉素滴眼液中未检出对硝基苯甲醛,但氯霉素二醇物在不同企业的产品中差异较大,不合格产品氯霉素二醇物的含量与贮存时间呈明显正相关。结论氯霉素滴眼液中氯霉素的光降解反应已经得到较好的控制,控制氯霉素的水解反应是质量控制的关键。

Objective To evaluate the stability of domestic chloramphenicol(CPL) eye drop, and discuss the influence factors related to the stability. Methods The hydrolysis kinetic equation with the least square method was obtained, and solvent isotope effects were compared, and the hydrolysis mechanism of chloramphenicol solutions were discussed. Effects related to CPL hydrolysis can be revealed. From photolysis characteristics of CPL in different solvents and photolysis degradation products, photolysis mechanisms of CPL solutions could be deduced. Under the guidance of mechanisms, whether the formula and manufacture process of domestic CPL eye drop was reasonable was evaluated. Results The hydrolysis of CPL water solution was an alkali-catalyzed pseudo first-order reaction. Species of buffer, pH values, and temperature affected the hydrolysis rate. The photolysis of CPL water solution was a free radical chain reaction. Domestic CPL eye drops were all free of p-nitrobenzaldehyde. But CPL eye drops from different manufactures were significantly different as to 1-p-nitropheny-2-amino-1,3-propanediol. The content of unqualified 1-p-nitrophenyl-2-amino-1,3-propanediol in CPL eye drop showed a marked positive correlation with the storage period. Conclusions Domestic CPL eye drops have a good control of photolysis. Reducing the hydrolysis rate is the key point of CPL eye drop quality control.