LC-MS/MS法测定盐酸二甲双胍缓释片中N-亚硝基二甲胺及其产生原因初探

Determination of N-Nitrosodimethylamine in Metformin Hydrochloride Sustained-release Tablets by LC-MS/MS and Preliminary Study on Its Causes

建立了液相色谱串联质谱(LC-MS/MS)法测定盐酸二甲双胍(1)缓释片中N-亚硝基二甲胺(NDMA)的含量,对其进行方法学验证并考察1缓释片、1原料药和1缓释片中辅料在多种破坏条件下NDMA的产生情况。结果显示,各项方法学考察结果均良好。在光照条件下,1缓释片的辅料和1缓释片中NDMA均有所增加;在碱性条件和氧化条件下,1原料药、1缓释片的辅料和1缓释片中NDMA均有所增加。1缓释片中的NDMA可能是由于在缓释片的制备工艺或贮存过程中,原料药自身、原料药与辅料之间以及不同辅料之间的相互作用产生的,因此在生产和贮存过程中需注意避免光照、强碱性和氧化条件。

A LC-MS/MS method was established to determine the content of N-nitrosodimethylamine(NDMA)in metformin hydrochloride(1)sustained-release tablets.The methodologies were validated and used and used to investigate the NDMA formation in 1 sustained-release tablets,the bulk drug and the excipients of 1 sustained-release tablet under various stress conditions.The results of various methodological investigations were good.The contents of NDMA in 1 sustained-release tablets and its excipients increased under light condition.And under the alkaline and oxidative conditions,the contents of NDMA increased in the bulk drug,1 sustained-release tablet excipients and 1 sustained-release tablets.The formation of NDMA in 1 sustained-release tablets might be due to the interactions between the drug substance itself,the drug substance and excipients,as well as different excipients during the processes of preparation and storage.Therefore,in the process of production and storage,care should be taken to avoid light,strong alkaline and oxidizing conditions.