硫酸氢氯吡格雷异构体的手性拆分及其限量检查

丁锐; 纪宏; 吕雯; 周长明; 李志刚; 张首国; 彭涛; 王林

硫酸氢氯吡格雷异构体的手性拆分及其限量检查

Chiral separation and limit test of clopidogrel bisulfate isomers

摘要

摘要: 采用卵类黏蛋白手性固定相键合硅胶(Ultron ES-OVM)色谱柱(150 mm×4.6 mm，5 μm)，建立手性固定相HPLC直接拆分硫酸氢氯吡格雷对映异构体和位置异构体的方法，并通过对溶质计量置换保留模型、热力学参数、熵焓驱动过程及影响色谱行为的因素等内容进行研究，对手性拆分过程进行探讨。经优化，确定色谱条件为：流动相0.02 mol/L磷酸二氢钾-乙腈(80∶20)，流速0.8 mL/min，检测波长220 nm，柱温30 ℃。硫酸氢氯吡格雷的对映异构体和位置异构体之间的分离度均大于1.6；S-硫酸氢氯吡格雷、R-硫酸氢氯吡格雷及其各自位置异构体的定量限分别为0.115，0.102，0.118，0.106 mg/L，在0.33～20.68,0.63～40.20,0.32～20.20,0.31～19.28 mg/L浓度范围内线性关系良好；按外标法计算，加样回收率在98.2%～101.7%之间；RSD小于2.0%。经方法学验证，该方法可用于硫酸氢氯吡格雷异构体杂质含量测定。

Abstract: The Ultron ES-OVM (150 mm×4.6 mm，5 μm) column was used as the chiral stationary phase to establish an HPLC method for the chiral separation of clopidogrel bisulfate enantiomers and its positional isomers.The process of enantioseparation was studied by stoichiometric displacement model for retention,thermodynamic parameters,enthalpy entropy-driven process and factors that affect the chromatographic behavior.The final chromatographic conditions were established as follows:a mixture of 0.02 mol/L KH₂PO₄-acetonitrile (80∶20) as the mobile phase with the flow rate of 0.8 mL/min,the detection wavelength of 220 nm,and the column temperature of 30 °C.The _{resolution data of clopidogrel bisulfate enantiomers and its positional isomers was more than 1.6.The limit of quantification (LOQ) of S-clopidogrel bisulfate,R-clopidogrel bisulfate and their clopidogrel bisulfate positional isomers were 0.115,0.102,0.118 and 0.106 mg/L;the linear ranges were 0.33-20.68,0.63-40.20,0.32-20.20 and 0.31-19.28 mg/L.According to general external standard method,the recoveries of clopidogrel bisulfate enantiomer and its positional isomers were in the range of 98.2%-101.7%,RSD＜2.0%.Method validation experiments show that this method was accurate and reliable to determine the content of clopidogrel bisulfate impurity isomers.}

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