纤维素键合型手性固定相分离二氢吡啶类钙离子拮抗剂药物对映体
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摘要
目的采用HPLC手性固定相法拆分6种二氢吡啶类钙离子拮抗剂药物对映体。方法采用Chiralpak IC[纤维素-三(3,5二氯苯基氨基甲酸酯)共价键合硅胶]手性色谱柱,考察了流动相中有机改性剂的种类和比例、碱性添加剂、柱温及流速对对映体分离的影响。结果最终确定分离尼莫地平的最优条件为正己烷-正丙醇(体积比90∶10);分离西尼地平的最优条件为正己烷-正丙醇(体积比85∶15);分离尼索地平、阿折地平的最优条件为正己烷-正丙醇-二乙胺(体积比92∶8∶0. 01);分离阿雷地平的最优条件为正己烷-正丙醇-二乙胺(体积比90∶10∶0. 01);分离贝尼地平的最优条件为正己烷-正丙醇-二乙胺(体积比95∶5∶0. 01);柱温为25℃,流速为1. 0 mL·min~(-1)。以上6种化合物均可在Chiralpak IC手性固定相上得到完全分离。且热力学研究结果表明尼莫地平、西尼地平、阿折地平、贝尼地平对映体的手性拆分过程均受焓驱动影响,低温有利于对映体分离。而阿雷地平、尼索地平既受焓驱动,同时也受熵驱动影响。结论该纤维素键合型手性固定相对以上6种二氢吡啶类化合物表现出良好的对映体选择性。
Objective To establish a high performance liquid chromatography method for the chiral separation of six dihydropyridine calcium antagonists. Methods With the application of Chiralpak IC [cellulose-tris(3,5-dichlorobenzene carbamate) immobilized to silica gel]column under normal phase,the factors influencing the chiral separation including the type and concentration of organic modifier,the addition of alkaline additive,column temperature and flowrate were investigated. Results Complete separation of nimodipine and cilnidipine were achieved with the mixture of n-hexane-n-butanol( 90 ∶ 10,V/V) and n-hexane-n-butanol(85∶15,V/V),respectively. Nisoldipine and azelnidipine were well separated with the mobile phase of the mixture of n-hexane-n-butanol-diethylamine( 92 ∶ 8 ∶ 0. 01,V/V/V),and aranidipine was successfully separated with the mixture of n-hexane-n-butanol-diethylamine( 90 ∶ 10 ∶ 0. 01,V/V/V). M oreover,the optimal mobile phase was the mixture of n-hexane-n-butanol-diethylamine( 95 ∶ 5 ∶ 0. 01,V/V/V) for separating benidipine. The column temperature was 25 ℃,and the flowrate was 1. 0 mL·min~(-1). All the six dihydropyridine calcium antagonists were well separated from baseline. Besides,the thermodynamic study indicated that the enantioseparation of nimodipine,cilnidipine,azelnidipine and benidipine was enthalpically driven and showed that lowcolumn temperature was beneficial to separation. However,the process of the enantioseparation of nisoldipine and aranidipine was both enthalpy-controlled and entropy-controlled.Conclusion The column exhibits high enantiomeric selectivity to these seven dihydropyridine calcium antagonists enantiomers.
Objective To establish a high performance liquid chromatography method for the chiral separation of six dihydropyridine calcium antagonists. Methods With the application of Chiralpak IC [cellulose-tris(3,5-dichlorobenzene carbamate) immobilized to silica gel]column under normal phase,the factors influencing the chiral separation including the type and concentration of organic modifier,the addition of alkaline additive,column temperature and flowrate were investigated. Results Complete separation of nimodipine and cilnidipine were achieved with the mixture of n-hexane-n-butanol( 90 ∶ 10,V/V) and n-hexane-n-butanol(85∶15,V/V),respectively. Nisoldipine and azelnidipine were well separated with the mobile phase of the mixture of n-hexane-n-butanol-diethylamine( 92 ∶ 8 ∶ 0. 01,V/V/V),and aranidipine was successfully separated with the mixture of n-hexane-n-butanol-diethylamine( 90 ∶ 10 ∶ 0. 01,V/V/V). M oreover,the optimal mobile phase was the mixture of n-hexane-n-butanol-diethylamine( 95 ∶ 5 ∶ 0. 01,V/V/V) for separating benidipine. The column temperature was 25 ℃,and the flowrate was 1. 0 mL·min~(-1). All the six dihydropyridine calcium antagonists were well separated from baseline. Besides,the thermodynamic study indicated that the enantioseparation of nimodipine,cilnidipine,azelnidipine and benidipine was enthalpically driven and showed that lowcolumn temperature was beneficial to separation. However,the process of the enantioseparation of nisoldipine and aranidipine was both enthalpy-controlled and entropy-controlled.Conclusion The column exhibits high enantiomeric selectivity to these seven dihydropyridine calcium antagonists enantiomers.
引文
[1]曾怀超.二氢吡啶钙拮抗剂对映体手性拆分及西尼地平与血浆蛋白结合选择性研究[D].杭州:浙江工业大学,2010.
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[10]李成平,曾怀超,鲁琳,等.二氢毗咤钙拮抗剂马尼地平和西尼地平对映体的手性拆分研究[J].药物分析杂志,2010,30(4):661-663.
[11]张恺.阿折地平的合成及手性拆分方法研究[D].石家庄:河北医科大学,2007.
[12]李芳.几种药物对映体的HPLC拆分方法及药动学研究[D].沈阳:沈阳药科大学,2009.
[13]LIU M,DENG M,ZHANG D,et al. A chiral LC-MS/MS method for the stereospecific determination of efo-nidipine in human plasma[J]. Journal of Pharmaceuticaland Biomedical Analysis,2016,122(15):35-41.
[14]LI M,YUAN L,LI X,et al. Studies on separation andpharmacokinetics of m-nisoldipine enantiomers in bea-gle dog plasma by LC/M S/M S[J]. Journal of Phar-maceutical and Biomedical Analysis,2013,85(11):61-66.
[15]AHMED A Y,HASRET A,DEBBY M,et al. A sepa-ration strategy combining three HPLC modes and pol-ysaccharide-based chiral stationary phases[J]. Journalof Pharmaceutical and Biomedical Analysis,2013,75(5):74-85.
[16]翁文,姚碧霞,陈秀琴,等.液相色谱手性拆分机理的热力学方法研究[J].化学进展,2006,18(7/8):1056-1064.
[17]MELANI F,PASQUINI B,CAPRINI C,et. al. Combi-nation of capillary electrophoresis,molecular modelingand NM R to study the enantioselective complexationof sulpiride w ith double cyclodextrin systems[J].Journal of Pharmaceutical and Biomedical Analysis,2015,114(10):265-271.
[2] MANVAR A T,PISSURLENKAR R R,VIRSODIAV R,et al. Synthesis,in vitro antitubercular acitivityand 3D-QSAR study of 1,4-dihydropyridines[J].M olecular Diversity,2010,14:285-305.
[3]李士敏,季红,黄碧云,等.二甲基-β-环糊精作为手性选择剂对尼索地平对映体的毛细管电泳拆分研究[J].分析测试学报,2010,29(4):376-378.
[4]付小帅,郭雯雯,姜珍,等.基于正交设计的毛细管电泳法分离尼卡地平等5种手性药物对映体[J].沈阳药科大学学报,2013,30(5):351-355.
[5]蔡诚,王园朝,邓飞.尼卡地平、尼莫地平和尼群地平毛细管电泳手性拆分研究[J].杭州师范大学学报,2012,11(2):122-125.
[6] CUI Y,MA X,ZHAO M,et al. Combined use of ionicliquid and hydroxypropyl-β-cyclodextrin for the enan-tioseparation of ten drugs by capillary electrophoresis[J]. Chirality,2013,25(7):409-414.
[7]聂桂珍,李来生,程彪平,等.磺丁基醚-β-环糊精修饰毛细管电色谱拆分地平类药物对映体[J].高等学校化学学报,2014,35(7):1414-1422.
[8] ZHANG L,SONG Z,DONG Y,et al. Enantiomericseparation of 1,4-dihydropyridines by liquid-phase mi-croextraction w ith supercritical fluid chromatography[J]. Journal of Supercritical Fluids,2016,107:129-136.
[9]方应国,丁潇潇,严小平,等.非洛地平和尼莫地平对映体的手性拆分研究[J].药物分析杂志,2012,32(10):1762-1765.
[10]李成平,曾怀超,鲁琳,等.二氢毗咤钙拮抗剂马尼地平和西尼地平对映体的手性拆分研究[J].药物分析杂志,2010,30(4):661-663.
[11]张恺.阿折地平的合成及手性拆分方法研究[D].石家庄:河北医科大学,2007.
[12]李芳.几种药物对映体的HPLC拆分方法及药动学研究[D].沈阳:沈阳药科大学,2009.
[13]LIU M,DENG M,ZHANG D,et al. A chiral LC-MS/MS method for the stereospecific determination of efo-nidipine in human plasma[J]. Journal of Pharmaceuticaland Biomedical Analysis,2016,122(15):35-41.
[14]LI M,YUAN L,LI X,et al. Studies on separation andpharmacokinetics of m-nisoldipine enantiomers in bea-gle dog plasma by LC/M S/M S[J]. Journal of Phar-maceutical and Biomedical Analysis,2013,85(11):61-66.
[15]AHMED A Y,HASRET A,DEBBY M,et al. A sepa-ration strategy combining three HPLC modes and pol-ysaccharide-based chiral stationary phases[J]. Journalof Pharmaceutical and Biomedical Analysis,2013,75(5):74-85.
[16]翁文,姚碧霞,陈秀琴,等.液相色谱手性拆分机理的热力学方法研究[J].化学进展,2006,18(7/8):1056-1064.
[17]MELANI F,PASQUINI B,CAPRINI C,et. al. Combi-nation of capillary electrophoresis,molecular modelingand NM R to study the enantioselective complexationof sulpiride w ith double cyclodextrin systems[J].Journal of Pharmaceutical and Biomedical Analysis,2015,114(10):265-271.