罗红霉素原研制剂与自研制剂有关物质及降解机制研究

Study on the Related Substances and Mechanism of Degradation of Reference Listed Drug and Self-prepared Formulation of Roxithromycin

关键词:  罗红霉素  杂质谱  原料药  降解机理

Key words:  roxithromycin  impurity spectrum  active pharmaceutical ingredient  degradation mechanism

摘要:

目的 对比研究自研制剂与原研制剂的杂质谱和杂质水平，初步探索罗红霉素的降解机理。方法 采用HPLC考察原研和自研制剂的有关物质，通过LC-MS定位EP系统适用性对照品的11种杂质，进而利用LC-MS对2种制剂的有关物质进行辅助结构确证。进行原研和自研制剂的强制降解实验，通过HPLC对比研究两者的主要降解途径，并利用LC-MS初步鉴定降解杂质的结构。结果 原研制剂检出的主要杂质为杂质F、杂质G、杂质H、杂质I，其中最大单杂为杂质G，含量为0.439%，自研制剂检测到杂质C、杂质D、杂质H、杂质I、杂质J，其中最大单杂为杂质C，含量为0.196%。原研制剂在碱、高温、光照条件下较稳定，强酸条件下主要产生杂质B、杂质D，强氧化条件下生成的杂质未能归属到EP系统适用性对照品的11种杂质中，已通过质谱确定分子量，推测可能为罗红霉素N氧化物。自研制剂主要降解途径及产生的杂质与原研制剂一致。2种制剂加速实验有关物质均无明显变化。结论 由于国产原料药和进口原料药的差异，自研制剂与原研制剂杂质谱不完全一致，自研制剂的杂质水平低于原研制剂。罗红霉素主要降解途径为水解、异构化和N的氧化，分别产生杂质B、D以及N氧化杂质（m/z=853.531 8）。

Abstract:

OBJECTIVE To compare the impurity spectrum and impurity level between self-prepared formulation and reference listed drug, and explore the mechanism of degradation of roxithromycin. METHODS The related substances of self-prepared formulation and reference listed drug were investigated by HPLC. The structure of related substances of two preparations were auxiliary confirmed on the basis of 11 known impurities, which were located by detecting the EP system suitability standard using LC-MS. The forced degradation experiments of self-prepared formulation and reference listed drug were carried out, including comparing the main degradation pathways by HPLC and preliminarily identifying the structure of degradation impurities using LC-MS. RESULTS The main impurities in the reference listed drug were impurity F, impurity G, impurity H, impurity I. The maximum impurity was impurity G and the content was 0.439%. Impurity C, impurity D, impurity H, impurity I, impurity J had been detected in the self-prepared formulation. The maximum impurity was impurity C and the content was 0.196%. The reference listed drug was stable under alkaline degradation, thermal degradation and photolytic degradation. The impurity B and impurity D were mainly produced under acid degradation. The impurity produced under oxidative degradation failed to locate in the 11 known impurities, by determing molecular weight presumably speculated N-oxide of roxithromycin. The mechanism of degradation of self-prepared formulation and reference listed drug were similar, such as the main degradation pathways and the impurities produced by the main degradation pathways. There was no significant change in the related substances of the two preparations in accelerated tests. CONCLUSION The differences between the domestic and imported active pharmaceutical ingredient lead to the differences of impurity spectrum between self-prepared formulation and reference listed drug. The impurity level of self-prepared formulation is surprisingly lower than reference listed drug. The main degradation pathways of roxithromycin are hydrolysis, isomerization and oxidation of N, respectively producing impurity B, impurity D and N-oxide(m/z=853.531 8).