基于LC-MS/MS法对N-亚硝基二乙胺检测中的未知峰调查及排除策略  

Investigation and exclusion strategy of an unknown peak in N-nitrosodiethylamine detection of irbesartan by LC-MS/MS

作　　者：蔡虹 谢鹤 李晓玲 赵诗怡 荆冰江 金建阳 陈文斌 叶坚 李敏 林金生 CAI Hong;XIE He;LI Xiao-ling;ZHAO Shi-yi;JING Bing-jiang;JIN Jian-yang;CHEN Wen-bin;YE Jian;LI Min;LIN Jin-sheng(Center of Excellence for Modern Analytical Technologies(CEMAT),Zhejiang Huahai Pharmaceuticals Co.,Ltd.,Linhai 317024,China;Analytical and Testing Center,Formulation Plant,Zhejiang Huahai Pharmaceuticals Co.,Ltd.,Linhai 317024,China;General Management Department,Zhejiang Huahai Pharmaceuticals Co.,Ltd.,Linhai 317024,China)

机构地区：[1]浙江华海药业股份有限公司高等分析技术中心,临海317024 [2]浙江华海药业股份有限公司制剂分厂分析检测中心,临海317024 [3]浙江华海药业股份有限公司综合管理部,临海317024

出　　处：《药物分析杂志》2025年第2期265-274,共10页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:采用检测厄贝沙坦中N-亚硝基二乙胺(NDEA)的高分辨LC-Q TOF MS法对未知峰[相对保留时间(RRT)为0.95]进行调查,确定该未知峰结构及产生来源,制定出相应的分析方法优化策略。方法:采用LC-Q TOFMS全扫描的方法对该未知峰进行质谱全扫描,确定出未知峰的结构式,比较该未知峰与NDEA一级质谱及二级质谱的差异,并参照LC-MS/MS方法对待测组分的定量离子选择,阐述NDEA检测中该未知峰出现的原因,制定相应的分析方法优化策略。结果:根据LC-Q TOF MS分析结果,推测该未知峰为1-戊酰胺,这是沙坦原料药样品中含有的微量常规杂质,并通过与1-戊酰胺对照品比对进行最终确认。由于1-戊酰胺摩尔相对分子质量比NDEA少1,因此,在ESI正离子模式下,1-戊酰胺氢离子加合离子[M+H]^(+)1的同位素峰m/z与NDEA[M+H]^(*)离子m/z相同,即103,并且与NDEA类似,1-戊酰胺氢离子加合离子[M+H]^(+1)同位素峰在MRM模式下也能裂解1个乙烯中性分子,产生m/z 75同位素离子,导致当选择m/z 103作为母离子,m/z 75为定量子离子时,1-戊酰胺会对NDEA的检测产生干扰。结论:在沙坦类药物NDEALC-MS/MS检测中RRT0.95的未知峰为1-戊酰胺,是沙坦类药物生产过程中产生的常规微量工艺杂质,而不是另外的亚硝胺杂质;在后续的研究中,将采用特征选择性更强的m/z47定量子离子模式,可以避免该未知峰产生。Objective:To investigate an unknown peak at relative retention time(RRT)0.95 of N-nitrosodiethylamine(NDEA)of irbesartan API with the LC-MS/MS detection method.To elucidate the structure and origin of this unknown peak.Its structure was confirmed with a reference compound,and a method optimization strategy was proposed to eliminate the impact of this unknown peak.Methods:The unknown peak causing interference in the determination of NDEA within sartan drug substances was examined using a full scan method of LC-MS/MS analysis.The unknown peak at RRT 0.95 was validated by conducting high resolution LC-MS analyses and comparing with that of a reference sample.Additionally,a strategy for resolving this issue was proposed in the further investigation.Results:According to the LC-Q TOF MS results,the unknown peak at RRT 0.95 was confirmed to be 1-pentanamide,a trace regular impurity commonly existing in the sartan samples.As the extract mass of 1-pentanamide was 1 less than that of NDEA,the m/z value of an isotope in 1-pentanamide([M+H]^(+1))was 103 and was equal to the m/z value of the main[M+H]^(+1)isotope of NDEA under the MRM mode.Furthermore,the[M+H]^(+1) isotope ion of 1-pentanamide could occur a neutral lose by leaving a molecule of ethylene to generate the isotope ion of m/z 75,which was similar to NDEA in the MRM analysis under ESI positive mode.Therefore,when m/z 103 was used as the precursor ion and m/z 75 was used as the quantitative ion,1-pentanamide will interfere with detection of NDEA.Conclusion:In the LC-MS/MS analysis for NDEA,the unknown peak observed at a retention time of 0.95 has been identified as 1-pentanamide.This compound is confirmed as a common trace impurity that regularly occurs during the production of sartan active pharmaceutical ingredients(APIs),rather than being another nitrosamine impurity.Subsequent research has revealed that employing a more selective quantitative model and choosing m/z 47 as the quantifier ion effectively avoid the unknown peak caused by 1-pentanamide.

关 键 词：沙坦类药物 N-亚硝基二乙胺(NDEA) 液相色谱质谱联用 未知峰 调查 同位素 干扰 MRM模式 1-戊酰胺 

分 类 号：R917[医药卫生—药物分析学]