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 ×0.25 μm),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.
Optimization of determination of N-nitrosodimethylamine in metformin hydrochloride sustained-release tablets
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 tab-lets,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 × 0.25 μm)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 so-lution.NDMA showed good linearity within the concentration range of 0.25-50 ng·mL-1(r＞0.999).The de-tection limit of the method was 0.1 ng·g-1 and the quantification limit of the method was 0.2 ng·g-1.The av-erage recoveries(n=9)were 97.3％and 94.9％while using external standard and internal standard,respective-ly.Precision,repeatability and stability were good with RSD less than 8％.Ninety batches of metformin hydro-chloride 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 safe-ty of related products.
metformin hydrochloride sustained release tabletsN-nitrosodimethylamine(NDMA)gas chroma-tography-tandem mass spectrometry(GC-MS/MS)genotoxic impuritymonothioglycerol
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