GC-MS/MS法同时测定氯沙坦钾原料药及其制剂中6种N-亚硝胺类基因毒性杂质  

Simultaneous determination of 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium rawmaterial and its formulations by GC-MS/MS

作　　者：李尚颖 岳青阳 张耀文 徐万魁 LI Shangying;YUE Qingyang;ZHANG Yaowen;XU Wankui(Liaoning Institute for Drug Control/NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drug,Shenyang 110036,China;Liaoning Inspection,Examination and Certification Centre,Shenyang 110036,China)

机构地区：[1]辽宁省药品检验检测院/国家药品监督管理局化学药品质量研究与评价重点实验室,沈阳110036 [2]辽宁省检验检测认证中心,沈阳110036

出　　处：《中国药房》2023年第15期1830-1834,共5页China Pharmacy

基　　金：辽宁省自然科学基金计划项目(No.2020-MS-073)。

摘　　要：目的 建立同时测定氯沙坦钾原料药及其制剂中6种N-亚硝胺类基因毒性杂质含量的方法。方法 采用气相色谱-串联质谱(GC-MS/MS)法测定氯沙坦钾原料药、氯沙坦钾片、氯沙坦钾胶囊、氯沙坦钾氢氯噻嗪片中N-亚硝基二甲胺(NDMA)、N-亚硝基二乙胺(NDEA)、N-亚硝基-N-乙基异丙胺(NEiPA)、N-亚硝基二异丙胺(NDiPA)、N-亚硝基二苯胺(NDPA)、N-亚硝基二丁胺(NDBA)6种N-亚硝胺类基因毒性杂质含量。色谱柱为SHIMADZU SH-L-17Sil MS毛细管柱;采用程序升温;进样口温度为250℃;进样量为1μL;载气为氦气,流速为1 mL/min。离子源为电子轰击源,离子源温度为250℃;溶剂延迟时间为3.1 min;采集模式为多反应监测模式。结果 NDMA、NDEA、NEiPA、NDiPA、NDPA、NDBA与其相邻色谱峰之间的分离效果均良好,分离度均大于3.8;其线性范围分别为4.9~486.0、4.9~488.5、4.5~451.5、6.8~683.5、5.2~525.0、5.2~520.0 ng/mL(r≥0.999 8),定量限分别为4.86、4.88、4.52、6.84、5.25、5.20 ng/mL,检测限分别为0.97、0.98、0.90、1.37、1.05、1.04 ng/mL,重复性试验的RSD为2.2%~5.6%(n=6),精密度试验的RSD为0.5%~1.4%(n=6),稳定性试验的RSD为1.5%~3.4%(n=5),低、中、高质量浓度回收率溶液的平均加样回收率为83.4%~103.0%(RSD为1.2%~6.3%,n=3)。在氯沙坦钾原料药及其制剂中均未检出6种N-亚硝胺类基因毒性杂质。结论 该法分离效果好、准确性高、灵敏、简便,可用于氯沙坦钾原料药及其制剂中6种N-亚硝胺类基因毒性杂质的检测。OBJECTIVE To establish a method for simultaneous determination of the contents of 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material and its formulations.METHODS GC-MS/MS was adopted to determine 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material,Losartan potassium tablet,Losartan potassium capsule and Losartan potassium hydrochlorothiazide tablets,such as N-nitrosodimethylamine(NDMA),N-nitrosodiethylamine(NDEA),N-ethyl-N-nitroso-2-propanamine(NEiPA),N-nitrosodiisopropylamine(NDiPA),N-nitrosodipropylamine(NDPA)and N-nitrosodibutylamine(NDBA).The separation was performed on SHIMADZU SH-L-17Sil MS capillary column by temperature-programmed GC,with injector temperature of 250℃,sample size of 1μL,carrier gas of helium,and carrier flow rate of 1 mL/min.Electron ionization and multiple reaction monitoring(MRM)data acquisition mode were used,with an ion source temperature of 250℃and solvent delay time of 3.1 min.RESULTS The separation among NDMA,NDEA,NEiPA,NDiPA,NDPA,NDBA and adjacent chromatographic peaks was good,and the separation rate was higher than 3.8;the linear ranges of them were 4.9-486.0,4.9-488.5,4.5-451.5,6.8-683.5,5.2-525.0 and 5.2-520.0 ng/mL(all r≥0.9998).The limits of quantitation were 4.86,4.88,4.52,6.84,5.25 and 5.20 ng/mL;the limits of detection were 0.97,0.98,0.90,1.37,1.05 and 1.04 ng/mL.RSDs of repeatability tests were 2.2%-5.6%(n=6),those of precision tests were 0.5%-1.4%(n=6),and those of stability tests were 1.5%-3.4%(n=5),respectively.Average recoveries of low-,medium-and high-concentration solution were 83.4%-103.0%(RSDs were 1.2%-6.3%,n=3),respectively.No one among the 6 kinds of N-nitrosamines genotoxic impurities was detected in both losartan potassium raw material and formulations.CONCLUSIONS The method is good in separation effect,highly accurate,sensitive and simple.It can be used in the determination of the 6 kinds of N-nitrosamines genotoxic impurities.

关 键 词：气相色谱-串联质谱法 氯沙坦钾 原料药 制剂 N-亚硝胺类 基因毒性杂质 

分 类 号：R917[医药卫生—药物分析学]