高温条件下盐酸雷尼替丁中N-亚硝基二甲胺及其前体化合物二甲胺和亚硝酸盐研究  

N-nitrosodimethylamine and its precursors dimethylamine and nitrite in ranitidine hydrochloride under high temperature

作　　者：杜冬生 钟鸿姣 胡杰 吴静 刘永 DU Dong-sheng;ZHONG Hong-jiao;HU Jie;WU Jing;LIU Yong(College of Life Sciences,Anhui Normal University,Wuhu Anhui 241000;Wuhu Food and Drug Inspection Center of Anhui,Wuhu Anhui 241007;Anhui Food and Drug Inspection Institute,Hefei 230051)

机构地区：[1]安徽师范大学生命科学学院,安徽芜湖241000 [2]芜湖市食品药品检验中心,安徽芜湖241007 [3]安徽省食品药品检验研究院,合肥230051

出　　处：《中南药学》2024年第8期2191-2197,共7页Central South Pharmacy

基　　金：2021年度安徽省药品监督管理局科技创新项目(No.AHYJ-KJ-202103);2020年度安徽省高校自然科学研究项目(No.KJ2020A0082);2023年度芜湖市重点研发与成果转化项目(No.2023yf001)。

摘　　要：目的考察盐酸雷尼替丁原料药中的N-亚硝基二甲胺(NDMA)及其前化合物二甲胺(DMA)和亚硝酸盐(NO_(2)^(-))在高温条件下含量变化。方法盐酸雷尼替丁原料药分别置于有氧和无氧环境中,在40℃和60℃的条件下破坏5、10和30 d。采用超高效液相色谱串联质谱法(UPLC-MS/MS)、阳离子和阴离子色谱法,分别测定破坏后样品中NDMA、DMA和NO_(2)^(-)的含量。结果建立的3种检测方法的专属性、灵敏度、线性、回收率和重复性均满足要求。在有氧和无氧环境中,60℃破坏的盐酸雷尼替丁样品中3种物质的含量均高于40℃;另外,在有氧条件下,3种物质的含量也明显高于相应的无氧条件,其中第30日,60℃有氧条件下NDMA、DMA和NO_(2)^(-)分别增长至1.92、55.50和44.76μg·g-1。结论温度和氧气是盐酸雷尼替丁产生NDMA及其前体化合物DMA和NO_(2)^(-)的重要因素;同时,间接验证盐酸雷尼替丁产生NDMA可能的机制为首先降解生成DMA和NO_(2)^(-),并进一步反应生成NDMA。本研究可为盐酸雷尼替丁贮存条件设置和质量标准提升提供参考。Objective To determine the content change of N-nitrosodimethylamine(NDMA),and its precursor compounds dimethylamine(DMA)and nitrite(NO_(2)^(-))in ranitidine hydrochloride drug substance under high temperature.Methods Ranitidine hydrochloride was exposed to aerobic and anaerobic environments at 40℃and 60℃for 5,10 and 30 days.The content of NDMA,DMA and NO_(2)^(-)in the degraded samples was determined by ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS),cation chromatography and anion chromatography,respectively.Results The specificity,sensitivity,linearity,recovery,and repeatability of the three methods all met the requirements.In both aerobic and anaerobic conditions,the content of the three substances in ranitidine hydrochloride samples degraded at 60℃was higher than that at 40℃.In addition,the amount of the three substances was much higher under aerobic conditions compared with that under anaerobic conditions.On the 30th day,at 60℃under aerobic conditions,the content of NDMA,DMA and NO_(2)^(-)increased to 1.92,55.50 and 44.76μg·g-1,respectively.Conclusion Temperature and oxygen are crucial factors for ranitidine hydrochloride to produce NDMA and its precursor compounds DMA and NO_(2)^(-).The study indirectly verifies that the possible mechanism of ranitidine hydrochloride producing NDMA is the primary degradation to DMA and NO_(2)^(-),and further reaction to NDMA.This research also provides a reference for storage conditions and quality standards of ranitidine hydrochloride.

关 键 词：超高效液相色谱串联质谱法 离子色谱法 盐酸雷尼替丁 N-亚硝基二甲胺 二甲胺 亚硝酸盐 高温破坏 

分 类 号：R927[医药卫生—药学]