酒石酸美托洛尔原料及其片剂有关物质检查方法研究

Investigation on the determination method of related substances in metoprolol tartrate and metoprolol tartrate tablets

目的:改进酒石酸美托洛尔现行标准中有关物质的测定方法,为修订和提高标准中的有关物质测定方法提供参考和依据。方法:采用高效液相色谱法,色谱柱为Waters Xbridge C 18(4.6 mm×150 mm,5μm),以醋酸盐缓冲液(取醋酸铵3.9 g,加水810 mL溶解后,加三乙胺2.0 mL,冰醋酸10.0 mL,磷酸3.0 mL,摇匀)为流动相A,乙腈为流动相B,梯度洗脱,流速为2.0 mL·min-1,检测波长为280 nm,柱温为30℃,进样量为20μL;采用线性斜率法计算各杂质校正因子。结果:在拟定的色谱条件下,酒石酸美托洛尔色谱峰与相关杂质完全分离,制剂中的辅料对主成分及有关物质测定无干扰;杂质A^H、杂质J、杂质235和杂质B(USP)的校正因子分别为0.74、0.36、0.048、0.61、1.01、1.47、0.33、0.76、0.99、0.22和0.84;6家企业6批原料的单杂均小于0.049%,杂质总量为0~0.10%;6家企业6批片剂的单杂均小于0.082%,杂质总量为0.0057%~0.23%。结论:改进后的方法更具合理性、准确性和专属性,可用于酒石酸美托洛尔及其片剂有关物质测定。

Objective:To improve the methods of related substances in the current specifications of metoprolol tartrate and metoprolol tartrate tablets and to provide the reference and basis for revision of the determination method of related substances.Method:The test was performed in Waters Xbridge C 18 column(4.6 mm×150 mm,5μm)under the gradient elution of mobile phase A of acetate buffer(take 3.9 g ammonium acetate,add 810 mL water to dissolve,add 2.0 mL triethylamine,10.0 mL glacial acetic acid and 3.0 mL phosphoric acid,then shake well)and mobile phase B of acetonitrile.The flow rate was 2mL·min-1,the detection wavelength was 280 nm,the column temperature was 30℃and the injection volume was 20μL.The relative correction factor of impurities was calculated by linear slope method.Results:Under the proposed chromatographic conditions,the principal component peaks of metoprolol tartrate and peaks of impurities were separated completely,and the excipients in the tablets did not interfere the determination of principal component and impurities.The relative correction factors of specified impurities A^H,J,235 and B(USP)were measured by standard curve method as 0.74,0.36,0.048,0.61,1.01,1.47,0.33,0.76,0.99,0.22 and 0.84 respectively.The individual impurities of six batches of API from six manufacturers all were less than 0.049%,and the total impurities were 0-0.10%.The individual impurities of six batches of tablets from six manufacturers all were less than 0.082%,and the total impurities were 0.0057%-0.23%.Conclusion:The improved method has better specificity and accuracy.It can be applicable to determination of the related substances of metoprolol tartrate and metoprolol tartrate tablets.