盐酸二甲双胍缓释片中遗传毒性杂质N-亚硝基二甲胺的测定与来源分析  

Determination and source analysis of genotoxic impurity nitrosodimethylamine in Metformin hydrochloride sustained-release tablets

作　　者：李茜 王立萍 李洁 刘英 LI Qian;WANG Liping;LI Jie;LIU Ying(Henan Chemical Quality Evaluation and Control Engineering Technology Research Center,Henan Provincial Institute For Drug and Medical Device Control,Zhengzhou,Henan,450018 P.R.China)

机构地区：[1]河南省药品医疗器械检验院、河南省化学药品质量评价与控制工程技术研究中心,河南郑州450018

出　　处：《华西药学杂志》2024年第5期558-562,共5页West China Journal of Pharmaceutical Sciences

基　　金：河南省重点研发与推广专项-科技攻关(232102320288);河南省市场监督管理局科技计划项目(2022sj77)。

摘　　要：目的采用离子色谱法测定盐酸二甲双胍缓释片的原、辅料中亚硝酸盐的含量,并考察其对缓释片中遗传毒性杂质N-亚硝基二甲胺(NDMA)的影响。方法采用离子色谱法测定辅料中亚硝酸盐的含量;UPLC-MS法测定原料药中二甲胺的含量;GC-MS法测定缓释片中NDMA的含量。结果亚硝酸根的线性范围为0.0165~1.6450 g·mL^(-1),检测限为0.33 ng;原、辅料的平均加样回收率分别为93.6%、99.9%。原料中均未检出亚硝酸盐,辅料中亚硝酸盐的含量差异较大,为1~30 ppm。辅料中的亚硝酸盐与原料中的二甲胺均可促进NDMA产生,缓释制剂的生产工艺与贮藏过程均可导致NDMA增加。结论所用方法准确、专属性强、灵敏度高,可用于盐酸二甲双胍缓释片中亚硝酸盐的质量控制。同时建议生产企业严格控制辅料中亚硝酸盐与原料中二甲胺的含量,优化生产工艺,并防止贮藏过程中温度过高。OBJECTIVE To determine nitrite in Metformin hydrochloride raw materials and excipients by Ion chromatography method,and to investigate the generation path of nitrosodimethylamine(NDMA)in its sustained-release tables.METHODS The content of nitrite in excipients was determined by Ion chromatography,while the content of dimethylamine in metformin hydrochloride raw material was determined by UPLC-MS,and the content of NDMA in Metformin hydrochloride sustained-release tables was determined by GC-MS.RESULTS A good linear relationship was obtained between the peak areas and the concentrations of nitrite(NO^(-)_(2))in the range from 0.0165 g·mL^(-1)to 1.6450 g·mL^(-1).The detection limit of nitrite is 0.33 ng.The average recovery of raw materials was 93.6%,and the average recovery of excipients was 99.9%.Nitrite was not detected in the raw materials.However,the content of nitrite in excipients varied greatly,ranging from 1 ppm to 3 ppm.We found that nitrite in excipients and dimethylamine in raw materials could promote the production of NDMA.In addition,the production process of sustained-release tables and the storage process of sustained-release tables could lead to the increase of NDMA.CONCLUSION The method is accurate and sensitive,and can be used for the quality control of nitrite in metformin hydrochloride raw materials and excipients.It is suggested that the production enterprises should strictly control the content of nitrite in excipients and dimethylamine in raw materials,optimize the production process of sustained-release tablets,and prevent the high temperature during storage.

关 键 词：盐酸二甲双胍 缓释片 离子色谱法 液质联用法 气质联用法 遗传毒性杂质 亚硝酸盐 二甲胺 N-亚硝基二甲胺 质量控制 

分 类 号：R917[医药卫生—药物分析学]