盐酸溴己新注射液中溴己新与辅料反应杂质研究

Study on the Reaction Impurities Between Bromhexine Hydrochloride and Excipients in Bromhexine Hydrochloride Injection

关键词:  盐酸溴己新  杂质解析  未知杂质  高效液相色谱-质谱联用

Key words:  bromhexine hydrochloride  impurities analysis  unknown impurity  LC-MS/MS

摘要:

目的 对盐酸溴己新注射液中特有的未知杂质进行结构鉴定、合成和分析，并作为已知杂质控制。方法 通过二维液相色谱串联质谱推导了未知杂质的结构，根据产品的处方工艺推导出了杂质来源，分析杂质产生机制，采用定向合成的方式获得杂质单体，并采用二维液相色谱串联质谱、核磁共振等技术确证杂质的结构，最后采用HPLC对杂质进行分析方法验证。结果 确证该类杂质为溴己新与辅料葡萄糖反应生成，2个杂质与盐酸溴己新的校正因子分别为2.2和2.4，分析方法专属性和重现性良好。结论 将该2个注射液特有杂质分别命名为杂质1和杂质2，并作为已知杂质定入标准，按照自身对照加校正因子法计算杂质含量。本研究对指导盐酸溴己新注射液的杂质控制以及辅料葡萄糖筛选有着重要的意义。

Abstract:

OBJECTIVE To identify, synthesize and analyze the structure of unknown impurities unique to bromhexine hydrochloride injection and set the impurities as known impurity to control. METHODS The structure of unknown impurities was derived through two-dimensional liquid chromatography tandem mass spectrometry(2DLC-HRMS/MS), and the source of impurities was derived based on the product's prescription process. The mechanism of impurities generation was analyzed, and impurity monomers were obtained through directional synthesis. The structure of impurities was confirmed using techniques such as 2DLC-HRMS/MS and nuclear magnetic resonance. Finally, HPLC was used to verify the analysis method of impurities. RESULTS It was confirmed that such impurities were produced in a reaction between bromhexine and the excipient glucose. The correction factor of the two impurities were 2.2 and 2.4, the analytical method was specific and reproducible. CONCLUSION Name the two injection specific impurities as impurity 1 and impurity 2 respectively, and use them as known impurities to be included in the standard, calculate the impurity content using the self control and correction factor method. This study is of great significance in guiding the impurity control of bromhexine hydrochloride injection and the screening of excipient glucose.