Stemm N L, Skoug J W, Robins R H
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
Pharm Res. 1995 May;12(5):738-45. doi: 10.1023/a:1016219927912.
A gradient high performance liquid chromatographic method was developed to determine degradation products of adinazolam mesylate in a sustained release tablet formulation. Sample preparations were chromatographed on a YMC-Basic column using a formate buffer/acetonitrile gradient with absorbance detection at 254 nm. Adinazolam mesylate was found to degrade at high relative humidity and temperature to form a major product, the 6-aminoquinoline analog, plus numerous other compounds. Five of these compounds were identified and their structures indicate that the solid-state degradation of adinazolam, in the presence of sufficient moisture, involves not only a hydrolytic mechanism, but also an oxidative mechanism. Potential process impurities were resolved from the drug and degradation products. Recovery was near 100% over the 0.5 to 10% range for the major degradate (6-aminoquinoline) and over the 0.5 to 1% range for the other analytes. The method was applied to tablet samples stressed at high relative humidity and temperature. The relative standard deviation of the assay for the 6-aminoquinoline was less than 2% and less than 13% for the minor components. Calculated mass balances (sum of adinazolam plus degradation products in the degraded tablet divided by the same sum in the undegraded tablet) were less than 100% and were dependent on the extent of degradation in the tablet. The average mass balance result obtained for samples that were an average of 9.5% degraded was 95.0 +/- 1.5%. It is possible that the decrease in mass balance with increase in percent degradation may be explained by the formation of many components at trace levels due to degradation by various permutations of hydrolytic and oxidative reaction pathways.
建立了一种梯度高效液相色谱法，用于测定甲磺酸阿地唑仑缓释片制剂中的降解产物。样品制备后在YMC - Basic柱上进行色谱分析，采用甲酸盐缓冲液/乙腈梯度洗脱，在254 nm处进行吸光度检测。发现甲磺酸阿地唑仑在高相对湿度和温度下会降解，形成一种主要产物，即6 - 氨基喹啉类似物，以及许多其他化合物。鉴定出其中5种化合物，其结构表明在有足够水分存在的情况下，阿地唑仑的固态降解不仅涉及水解机制，还涉及氧化机制。潜在的工艺杂质与药物及降解产物得以分离。主要降解产物（6 - 氨基喹啉）在0.5%至10%范围内的回收率接近100%，其他分析物在0.5%至1%范围内的回收率接近100%。该方法应用于在高相对湿度和温度下加速试验的片剂样品。6 - 氨基喹啉含量测定的相对标准偏差小于2%，次要成分的相对标准偏差小于13%。计算得到的质量平衡（降解片剂中甲磺酸阿地唑仑与降解产物的总和除以未降解片剂中相同总和）小于100%，且取决于片剂中的降解程度。对于平均降解率为9.5%的样品，获得的平均质量平衡结果为95.0 +/- 1.5%。质量平衡随降解百分比增加而降低，可能是由于水解和氧化反应途径的各种排列组合导致降解产生许多痕量成分所致。
