超高效液相色谱串联质谱法测定缬沙坦原料中4种亚硝胺类基因毒性杂质  

Determination of Four Nitrosamine Genotoxic Impurities in Valsartan by UPLC-MS/MS Method

作　　者：侯金凤 李珉 寇晋萍[1] 刘海涛[1] 车宝泉[1] 李文东[1] HOU Jin-feng;LI Min;KOU Jin-ping;LIU Hai-tao;CHE Bao-quan;LI Wen-dong(NMPA Key Laboratory for Research and Evaluation of Generic Drugs,Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine,Beijing Institute for Drug Control,Beijing 102206,China)

机构地区：[1]北京市药品检验所,国家药品监督管理局仿制药研究与评价重点实验室,中药成分分析与生物评价北京市重点实验室,北京102206

出　　处：《中国药学杂志》2021年第10期842-848,共7页Chinese Pharmaceutical Journal

摘　　要：目的建立超高效液相色谱-串联质谱法同时测定缬沙坦原料中N-亚硝基二甲胺(NDMA)、N-亚硝基二乙胺(NDEA)、N-乙基-N-异丙基亚硝胺(NIEA)和N,N-亚硝基二异丙胺(NIPA)4种亚硝胺类基因毒性杂质的含量。方法缬沙坦原料经甲醇-水提取,采用Waters HSS-T3(3.0 mm×100 mm,1.8μm)色谱柱,以0.1%甲酸水-甲醇为流动相进行梯度洗脱,流速为0.4 mL·min^(-1),APCI源正离子检测模式下,采用多反应离子监测(MRM)模式进行分析。结果该方法能同时测定NDMA、NDEA、NIEA和NIPA等4种基因毒性杂质。4个化合物线性范围、灵敏度、精密度、回收率均满足分析要求。在所收集的4批缬沙坦原料中,2批次检出NIEA,含量分别为0.090和0.241μg·g-1,其余3个杂质在4批样品中均未检出。结论本方法操作简便、快速、准确、灵敏度高、专属性好,适用于缬沙坦原料中NDMA、NDEA、NIEA和NIPA 4种基因毒性杂质的检测。OBJECTIVE To establish a UPLC-MS/MS method for simultaneous determination of four nitrosamine genotoxic impurities in valsartan,including N-nitrosodimethylamine(NDMA),N-nitrosodiethylamine(NDEA),N-ethyl-N-isopropyl nitrosamine(NIEA)and N,N-nitroso-di-iso-propylamine(NIPA).METHODS Valsartan was extracted with methanol-water.Then the chromatographic separation was achieved on a Waters HSS-T3(3.0 mm×100 mm,1.8μm)column with a gradient elution system,composed of 0.1%formic acid water and methanol,at the flow rate of 0.4 mL·min^(-1).In the positive ion detection mode of the APCI source,multiple reactive ion monitoring(MRM)mode was used for analysis.RESULTS This method simultaneously determined the four genotoxic impurities such as NDMA,NDEA,NIEA and NIPA.The linear range,sensitivity,precision and recovery rate of the four compounds met the analysis requirements.Four batches of valsartan samples were analyzed by this method,and NIEA was detected in two batches.The amount was about 0.090 and 0.241μg·g-1,respectively.The remaining three impurities were not detected.CONCLUSION The method is simple,rapid,accurate,highly sensitive and specific.It is suitable for the detection of NDMA,NDEA,NIEA and NIPA in valsartan.

关 键 词：缬沙坦 超高效液相色谱串联质谱法 亚硝胺类 基因毒性杂质 

分 类 号：R917[医药卫生—药物分析学]