盐酸二甲双胍缓释片中N-亚硝基二甲胺测定方法的优化  

Optimization of determination of N-nitrosodimethylamine in metformin hydrochloride sustained-release tablets

作　　者：梁梓洋 罗辉泰 张秋炎 梁维维 梁梓豪 周熙 吴惠勤 黄芳 黄飞云 罗向东 LIANG Zi-yang;LUO Hui-tai;ZHANG Qiu-yan;LIANG Wei-wei;LIANG Zi-hao;ZHOU Xi;WU Hui-qin;HUANG Fang;HUANG Fei-yun;LUO Xiang-dong(Institute of Analysis,Guangdong Academy of Sciences(China National Analytical Center,Guangzhou),Guangdong Provincial Key Laboratory of Chemical Measurement and Emergency Test Technology,Guangdong Provincial Engineering Research Center for Quality and Safety of Traditional Chinese Medicine,Guangzhou 510070,China;Guangdong Sinocorp Pharmaceutical Co.,Ltd.,Huizhou 516820,China)

机构地区：[1]广东省科学院测试分析研究所(中国广州分析测试中心)广东省化学测量与应急检测技术重点实验室广东省中药质量安全工程技术研究中心,广州510070 [2]广东赛康制药厂有限公司,惠州516820

出　　处：《药物分析杂志》2024年第6期1089-1096,共8页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:建立一种稳定且可靠的气相色谱-串联质谱法测定盐酸二甲双胍缓释片中N-亚硝基二甲胺(NDMA),同时通过考察异丙醇和硫代甘油2个添加剂对供试品溶液稳定性的影响,确定了最优的提取条件。方法:采用聚乙二醇为固定相的AB-InoWax毛细管柱(30 m×0.25 mm×0.25μm),利用电子轰击电离源(EI),在多反应监测(MRM)模式下检测,分别以外标法和内标法定量。结果:添加硫代甘油可显著改善供试品溶液稳定性,NDMA在0.25~50 ng·mL^(-1)浓度范围内有良好的线性(r>0.999),方法检测限为0.1 ng·g^(-1),方法定量限为0.2 ng·g^(-1),分别在内标法和外标法计算下,平均加标回收率(n=9)均为97.3%和94.9%,精密度、重复性、稳定性及耐用性的RSD均小于8%。对90批次的盐酸二甲双胍缓释片进行检测,结果均小于国家药品监督管理局以及FDA规定的可接受限度的30%之内。结论:本文建立的方法灵敏度高,专属性强,结果准确且稳定性好,适用于盐酸二甲双胍缓释片中NDMA的定量分析,可为有关产品的质量安全提供技术支撑。Objective:To establish a stable and reliable gas chromatography-tandem mass spectrometry method for the determination of N-nitrosodimethylamine(NDMA)in metformin hydrochloride sustained-release tablets,and to optimize extraction conditions by investigating the effects of isopropyl alcohol and thioglycerin on the stability of the tested solution.Methods:Separation was achieved on AB-InoWax capillary column(30 m×0.25 mm×0.25μm)with polyethylene glycol as the stationary phase.Electron ion(EI)source and multiple reaction monitoring(MRM)mode were used.Quantitative determination was performed by both external standard and internal standard.Results:The addition of thioglycerin could significantly improve the stability of the test solution.NDMA showed good linearity within the concentration range of 0.25-50 ng·mL^(-1)(r>0.999).The detection limit of the method was 0.1 ng·g^(-1) and the quantification limit of the method was 0.2 ng·g^(-1).The average recoveries(n=9)were 97.3%and 94.9%while using external standard and internal standard,respectively.Precision,repeatability and stability were good with RSD less than 8%.Ninety batches of metformin hydrochloride sustained release tablets were tested.NDMA content in all detected samples were all less than 30%of the acceptable limit set by the National Medical Products Administration and FDA.Conclusions:This method shows satisfactory sensibility,specificity,accuracy,stability and durability,which is suitable for quantitative analysis of NDMA in metformin hydrochloride sustained-release tablets,providing technical support for the quality and safety of related products.

关 键 词：盐酸二甲双胍缓释片 N-亚硝基二甲胺(NDMA) 气相色谱-串联质谱(GC-MS/MS) 基因毒性杂质 硫代甘油 

分 类 号：R917[医药卫生—药物分析学]