黄豆苷元杂质谱与其生产工艺的相关性研究  

Study on correlation between impurity profile and production process of daidzein

作　　者：邵鹏 张喆 张英 刘建祯 胡琴 SHAO Peng;ZHANG Zhe;ZHANG Ying;LIU Jian-zhen;HU Qin(Beijing Institute For Drug Control,NMPA Key Laboratory for Research and Evaluation of Generic Drugs,Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine,Beijing 102206,China;Shanxi Province Inspection and Testing Center,Taiyuan 030031,China)

机构地区：[1]北京市药品检验研究院、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 [2]山西省检验检测中心,太原030031

出　　处：《药物分析杂志》2023年第2期334-340,共7页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:研究黄豆苷元的杂质谱以及与其生产工艺的相关性。方法:通过高效液相色谱[色谱柱为C_(18)柱(250 mm×4.6 mm,5μm),流动相为水-乙腈(65∶35),检测波长249 nm,流速1.0 mL·min^(-1),柱温30℃,进样量20μL,运行时间为主成分保留时间的6倍]对最大未知杂质进行定量检测,结合高效液相色谱-离子肼质谱联用仪(一级、二级质谱)和核磁共振谱仪(氢谱、碳谱)对杂质结构进行确证。通过对生产工艺的分析研究推断杂质来源并提出工艺改进建议。结果:黄豆苷元原料药及制剂的主要杂质为杂质A,在原料药合成工艺中引入,与合成工艺中使用的N,N-二甲基甲酰胺二甲缩醛和乙醇有关。结论:本文主要研究了黄豆苷元杂质谱的液相检测方法,并利用核磁对最大未知杂质结构进行了确证,质谱研究进一步验证了异黄酮类化合物的质谱裂解规律,对生产工艺的提高、质量标准的修订以及黄豆苷元衍生物的合成研究具有重要的意义。Objective:To study the impurity profiling of Daidzein and its correlation with production process.Methods:Impurities were quantitatively detected by HPLC with a C_(18)column(250 mm×4.6 mm,5μm).Mobile phase was water-acetonitrile(65∶35)and detection wavelength was 249 nm.The flow rate was 1.0 mL·min^(-1),column temperature was 30℃and the injection volume was 20μL.The run time was 6 times of Daidzein retention time.The impurity structure was confirmed via liquid chromatography-ion trap mass spectrometry analysis(MS^(1)and MS^(2))and NMR analysis(^(1)H-NMR spectrum and^(13)C-NMR spectrum).Impurity source was proposed by the study of production process.Corresponding advice for process improvement was listed according to the analysis of impurity formation.Results:The main impurity in Daidzein bulk drug and pharmaceutical products was impurity A which was mainly introduced in synthesis process of bulk drug.Impurity A was related toN,N-dimethylformamide dimethyl acetal and ethanol used in process.Conclusion:This paper mainly studies detection of daidzein impurity via HPLC and structure confirmation of main impurity by NMR.Fragmentation behavior of isoflavones in mass spectrometry is elucidated.It is of great importance for process improvement,quality standard revision and daidzein derivatives synthesis.

关 键 词：黄豆苷元 异黄酮 质谱裂解规律 有关物质 生产工艺相关性研究 

分 类 号：R917[医药卫生—药物分析学]