地平类药物中的药物基质N-亚硝胺杂质研究  

Study on N-nitrosamine impurities in dipine drugs

作　　者：吴中礼 郑国钢 贾飞 李晨 周健 虞程雄 高颖 王博 楼金芳 WU Zhong-li;ZHENG Guo-gang;JIA Fei;LI Chen;ZHOU Jian;YU Cheng-xiong;GAO Ying;WANG Bo;LOU Jin-fang(Hangzhou Balan Testing Technology Co.,Ltd.,Hangzhou 310000,China;Hangzhou Bio-Sincerity Pharma-Tech Co.,Ltd.,Hangzhou 310000,China;Zhejiang Anglikang Pharmaceutical Co.,Ltd.,Shaoxing 312400,China)

机构地区：[1]杭州百伦检测技术有限公司,杭州310000 [2]杭州百诚医药科技股份有限公司,杭州310000 [3]浙江昂利康制药股份有限公司,绍兴312400

出　　处：《中国新药杂志》2025年第5期541-552,共12页Chinese Journal of New Drugs

摘　　要：目的:对地平类药物的药物基质N-亚硝胺杂质(nitrosamine drug substance-related impurities,NDSRI)进行研究。方法:以14种地平类原料药为原料,通过2种不同的亚硝化反应验证是否能够生成对应的原料药NDSRI,使用中控设备LC-MS进行反应追踪。结果:LC-MS对反应进行监控,全部地平类原料药均未生成NDSRI,在方法一条件下几乎所有地平类原料未发生降解,在方法二中大部分原料转化为对应的芳构化氧化杂质。方法二中的部分原料药如阿折地平、巴尼地平、尼卡地平、西尼地平发生了不同程度的降解,经过对这些降解杂质分离和结构确证,确定为其他NDSRI(非NDSRI)。结论:本文研究的14种地平类原料药在亚硝化环境中均无法产生NDSRI杂质,个别品种发生降解后再经过亚硝化反应产生非NDSRI,因此在进行相关研究时应重视非NDSRI杂质的研究。Objective:To research on active pharmaceutical ingredient(API)based NDSRI of dipine drugs.Methods:Using 14 dipine drugs as raw materials,the experiments were conducted to verify whether the corresponding API NDSRI could be generated through two different nitrosation reactions.Liquid chromatography-mass spectrometry(LC-MS)was used to monitor the impurities.Results:The reaction results indicate that no NDSRI were formed in all of the nitrosation reactions of 14 dipine drugs.Almost all of the dipine drugs did not undergo degradation under the conditions of method 1.Most of dipine drugs were oxidized to produce aromatization impurities under the conditions of method 2,some individual varieties,such as azelnidipine,barnidipine,nicardipine and cilnidipine,have undergone varying degrees of degradation,and the structures of these degraded impurities were ultimately determined to be non NDSRI through separation and structural confirmation.Conclusion:The 14 APIs of dipine drugs studied in this article did not produce NDSRI impurities in a nitrosation environment.Some varieties underwent nitrosation to produce non NDSRI after degradation.Therefore,it is also necessary to pay attention to the study of non NDSRI.

关 键 词：地平类药物 亚硝化反应 N-亚硝胺杂质 芳构化杂质 降解 

分 类 号：R914[医药卫生—药物化学]