两种晶型硫酸氢氯吡格雷片稳定性的比较

Comparative study of stability on clopidogrel bisulfate tablet polymorphs

目的建立高效液相色谱法测定硫酸氢氯吡格雷片中的有关物质,并对2种晶型片剂的稳定性进行考察。方法采用ULtron ES-OVM手性色谱柱(150 mm×4.6 mm,5μm),流动相:0.01 mol.L-1磷酸二氢钾溶液-乙腈(体积比为75∶25),流速:1.0 mL.min-1,进样量:10μL,检测波长:220 nm,柱温:25℃。结果在该色谱条件下,杂质A、杂质B的第一个异构体(杂质B1)、杂质C质量浓度分别在0.3～3.0、0.45～4.50、1.4～14.0 mg.L-1内与峰面积呈良好的线性关系,硫酸氢氯吡格雷与杂质B1之间的分离度大于2.5。稳定性试验表明,在高温条件下,两种晶型硫酸氢氯吡格雷片中杂质B、C含量明显增加,晶型I杂质A略有增加;在高湿条件下2种晶型均易产生杂质A;在光照条件2种晶型的杂质均未明显增加。结论高温是影响2种晶型硫酸氢氯吡格雷片稳定性的主要因素,2种晶型中Ⅱ型硫酸氢氯吡格雷片稳定性更佳。

Objective To develop an HPLC method for determining the related substances and stability of clopidogrel bisulfate tablet polymorphs.Methods The separation was performed on a ULtron ES-OVM column（150 mm×4.6 mm,5 μm）,the mobile phase was composed of 0.01 mol · L-1 potassium dihydrogen phosphate-acetonitrile（V∶ V=75∶ 25）,the flow rate was set at 1.0 mL · min-1,the injection volume was 10 μL and the determination wavelength was set at 220 nm,the column temperature was 25 ℃.Results Using this method,the linearity ranges of impurity A,the first enantiomer of impurity B（impurity B1） and impurity C were 0.3-3.0,0.45-4.50 and 1.4-14.0 mg · L-1,respectively;and the resolution（R） between clopidogrel bisulfate and related compound B1 was greater than 2.5.In stability test,for two kinds of polymorphs of clopidogrel bisulfate tablets,the contents of impurities B and C increased obviously and that of impurity A increased slightly under high temperature;the content of impurity A increased under high humidity;there were no changes of impurity contents under light.Conclusions The temperature is the main factors of stability for the two kinds of polymorphs of clopidogrel bisulfate tablets,and Ⅱ-polymorphs clopidogrel bisulfate tablet is relatively stable.