氯沙坦钾原料药降解途径与降解杂质分析

Analysis of degradation pathways and impurities of losartan potassium

目的 通过强制降解试验探讨氯沙坦钾原料药的降解杂质和降解途径。方法 建立氯沙坦钾及其有关物质的高效液相(HPLC)分析方法,采用Waters XBridge BEH C18(4.6 mm×250 mm, 5μm)色谱柱,流动相为0.05%磷酸水溶液-乙腈,梯度洗脱,流速为1.0 mL·min^(-1),柱温设置为30℃,检测波长210 nm,对氯沙坦钾降解溶液中主峰含量进行测定,探讨氯沙坦钾原料药在氧化、酸、碱、高温、光照条件下的降解率。结果 在本实验设计的67种降解条件中,氯沙坦钾原料药对氧化(加热和室温)、高温高湿、酸环境敏感,同时在溶液状态下对高温和光照条件敏感。并确定氯沙坦钾强制降解后的4个降解杂质的分子结构及其质谱裂解反应机理。结论 本试验以强制降解中所涉及的多种环境模拟对氯沙坦钾降解过程的研究,有助于探索药品贮藏及药品制剂生产中的杂质变化。

Objective To explore the degradation pathway of losartan potassium active pharmaceutical ingredient(API)through forced degradation test.Methods A high performance liquid chromatographic(HPLC)method was developed for the determination of losartan potassium and its related substances on a Waters XBridge BEH C 18(4.6 mm×250 mm,5μm)column with a mobile phase of 0.05%aqueous phosphoric acid solution-acetonitrile,gradient elution,flow rate of 1.0 mL·min^(-1),column temperature set at 30℃,detection wavelength 210 nm.The content of the main peak in the degradation solution of losartan potassium was determined to explore the degradation rate of losartan potassium API under the conditions of oxidation,acid hydrolysis,alkaline hydrolysis,thermal and photolysis.Results Among the 67 degradation conditions designed for this experiment,losartan potassium API was sensitive to oxidation(heating and room temperature),high temperature accompanied with high humidity,acidic condition environment,while in solution state it was sensitive to high temperature and light conditions.The molecular structures of four degradation impurities of losartan potassium were determined,and their mass spectrum cleavage reaction mechanisms were clarified.Conclusion This experiment was conducted to simulate the degradation process of losartan potassium with a variety of environments involved in forced degradation.The study helps to explore the changes in impurities in drug storage and drug formulation production for quality control of losartan potassium API and its formulations.