阿齐沙坦有关物质的LC-MS/MS测定与鉴定  

Determination and identification of related substances in azilsartan by LC-MS/MS

作　　者：杨大龙[1] 孔蓉[2] 柏植政 丁逸梅[1,2] YANG Da-long;KONG Rong;BAI Zhi-zheng;DING Yi-mei(Jiangsu Provincial Institute of Material Medica,Nanjing Teeh University,Nanjing 210009,China;School of Pharmaceutical Sciences,Nanjing Tech University,Nanjing 210009,China)

机构地区：[1]南京工业大学江苏省药物研究所有限公司,南京210009 [2]南京工业大学药学院,南京210009

出　　处：《药物分析杂志》2018年第7期1231-1237,共7页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:建立阿齐沙坦原料中有关物质的测定方法,鉴定主要降解产物并推测降解机理。方法:采用HPLC方法分离分析阿齐沙坦的有关物质,使用Inertsil ODS-SP色谱柱(150 mm×4.6 mm,5μm),流动相A为乙腈-水-冰乙酸(20∶80∶0.1),流动相B为乙腈-水-冰乙酸(80∶20∶0.1),梯度洗脱,流速1.0 m L·min^(-1),检测波长250 nm,柱温40℃;采用相同色谱条件,ESI正离子化方式LC-MS/MS进行杂质鉴定。结果:阿齐沙坦与有关物质均能有效分离;阿齐沙坦在酸中易水解,LC-MS/MS鉴定主要降解产物为杂质B(2-羰基-1-[[2′-(4,5-二氢-5-氧代-1,2,4-二唑-3-基)联苯-4-基]甲基]苯并咪唑-7-羧酸)。阿齐沙坦、杂质A(2-乙氧基-1-[[2′-(酰胺基)[1,1′-联苯基]-4-基]甲基]-1H-苯并咪唑-7-羧酸甲酯)和杂质B的检测下限及定量下限分别为8.4、8.1、8.2 ng·m L^(-1)和20.1、19.4、19.8ng·m L^(-1),且在各自的线性范围内线性关系良好(r>0.999,n=5);校正因子分别为1.00、1.09、1.08。经5批样品检验,均仅检出杂质B,均小于0.05%。结论:建立的方法可对阿齐沙坦的有关物质进行定量测定。Objective：To establish a method for the determination of related substances in azilsartan,and to identify the main degradation product and speculate mechanism of degradation.Methods：The related substances in azilsartan were separated by RP-HPLC on an Inertsil ODS-SP column（150 mm×4.6 mm,5μm）using acetonitrile-water-acetic acid（20∶80∶0.1）as mobile phase A and acetonitrile-water-acetic acid（80∶20∶0.1）as mobile phase B with gradient elution at a flow rate of 1.0 m L·min^（-1）.The detection wavelength was set at 250nm and the column temperature was 45℃.The major impurity was identified by using LC-MS/MS in positive mode with the same LC conditions.Results：The related substances in azilsartan could be separated effectively from azilsartan.The major impurity was identified using LC-MS/MS as impurity B（2-carbonyl-1-[[2′-（4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl）biphenyl-4-yl]methyl]benzimidazole-7-carboxylate）.The LOD and LOQ of azilsartan,impurity A（1-[[（2-ethoxy-（2’-amido））[1,1′-xenyl]-4-yl]methyl]-1H-benzimidazolyl-7-carboxylic methyl ether）and impurity B were 8.4,8.1,8.2 ng·m L^（-1） and 20.1,19.4,19.8 ng·m L^（-1）,respectively.The calibration curves of azilsartan and the impurities were linear in the concentration range（r0.999,n=5）.The calibration factors were 1.00,1.09 and 1.08,respectively.Impurities B detected in 5batches of samples were all less than 0.05%.Conclusion：The established method was accurate and effective for qualitative determination of related substances in azilsartan.

关 键 词：抗高血压药 阿齐沙坦 有关物质测定 降解产物鉴定 降解机理推测 高效液相色谱 液质联用 

分 类 号：R917[医药卫生—药物分析学]