KINETICS AND MECHANISMS OF DEGRADATION OF ANTILEUKEMIC AGENT 5-AZACYTIDINE IN AQUEOUS-SOLUTIONS
KINETICS AND MECHANISMS OF DEGRADATION OF ANTILEUKEMIC AGENT 5-AZACYTIDINE IN AQUEOUS-SOLUTIONS
复制标题
DOI：
10.1002/jps.2600640704
复制
发表时间：
1975-01-01
影响因子：
3.8
通讯作者：
DEYOUNG, JL
中科院分区：
文献类型：
--
作者：
NOTARI, RE;DEYOUNG, JL
通过比色法研究了5-氮杂胞苷的水解降解与pH值、温度和缓冲液浓度的关系。在低于3的pH区域中，药物损失遵循表观一级动力学。在pH < 1时，检测到5-氮杂胞嘧啶和5-氮杂尿嘧啶;在较高pH值时，药物损失为产物，如果在酸性溶液中检查，则产物基本上不发色。报告了与从5-氮杂胞苷形成5-氮杂胞嘧啶和5-氮杂尿嘧啶相关的表观一级速率常数。在pH 2.6以上，药物降解的一级曲线为双相。双指数方程的表观一级速率常数和系数作为pH值和缓冲液浓度的函数给出。讨论了与数据一致的反应机制以及与定义药物在水溶液中的稳定性相关的问题。在50° C下，药物在稀磷酸盐缓冲液中在pH 6.5时表现出最大稳定性。将类似溶液储存在30° C下，以估计其有效保质期。在80 min内，6 × 10− 4 M 5-氮胞苷溶液根据与提出的机制相关的假设降低至原始效价的90%。
The hydrolytic degradation of 5‐azacytidine was studied spectrophotometrically as a function of pH, temperature, and buffer concentration. Loss of drug followed apparent first‐order kinetics in the pH region below 3. At pH < 1, 5‐azacytosine and 5‐azauracil were detected; at higher pH values, drug was lost to products which were essentially nonchromophoric if examined in acidic solutions. The apparent first‐order rate constants associated with formation of 5‐azacytosine and 5‐azauracil from 5‐azacytidine are reported. Above pH 2.6, first‐order plots for drug degradation are biphasic. Apparent first‐order rate constants and coefficients for the biexponential equation are given as a function of pH and buffer concentration. A reaction mechanism consistent with the data is discussed together with problems associated with defining the stability of the drug in aqueous solutions. At 50°, the drug exhibited maximum stability at pH 6.5 in dilute phosphate buffer. Similar solutions were stored at 30° to estimate their useful shelflife. Within 80 min, 6 × 10−4Msolutions of 5‐azacytidine decreased to 90% of original potency based on assumptions related to the proposed mechanisms.