基于分子对接仿真技术研究头孢地尼杂质分离机制  

Research on mechanisms of cefdinir stereoisomer impurities separation based on molecular docking simulation technology

作　　者：苏夕桐 何汇洋 吴蕾 高梓森 张鹏[1] SU Xitong;HE Huiyang;WU Lei;GAO Zisen;ZHANG Peng(School of Waya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China;School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]沈阳药科大学无涯创新学院,辽宁沈阳110016 [2]沈阳药科大学制药工程学院,辽宁沈阳110016

出　　处：《沈阳药科大学学报》2019年第11期990-997,共8页Journal of Shenyang Pharmaceutical University

摘　　要：目的结合分子对接仿真技术,研究反相离子对色谱法(reversed phase ion chromatography,RPIC)对头孢地尼立体异构体杂质I、J、K、L、T、U的分离机制。方法采用RPIC对各杂质进行分离,考察在流动相中加入四甲基氢氧化铵(tetramethylammonium hydroxide,TMAH),体积分数分别为0.01%、0.05%、0.1%、0.25%、0.3%、0.5%的色谱条件下以及流动相pH在4.5~6.5内变化时,各杂质间的分离度以及保留时间的变化。采用分子对接仿真技术,研究各杂质与TMAH分子的结合能力的差异,阐明了RPIC洗脱过程中,在TMAH作用下,各杂质的分离度及保留行为产生差异的原因。结果TMAH与杂质I、J、K、L的结合能力存在差异。与TMAH结合后,杂质I形成3个分子内氢键,杂质J形成2个分子内氢键,且与TMAH之间存在1个分子间氢键,杂质K形成1个分子内氢键,杂质L无分子内氢键,杂质I、J、K、L与TMAH分子之间均存在静电作用力和疏水作用力。TMAH与杂质T、U的结合能力无显著性差异。杂质T、U均可以形成3个分子内氢键,与TMAH之间均存在静电作用力和疏水作用力。随着流动相中的TMAH浓度的增大,杂质I、J、K、L的保留时间延长,分离度逐渐增大,杂质T、U的色谱行为无显著变化。结论采用分子对接仿真技术,在分析各杂质与TMAH自身理化性质的基础上,研究各杂质在流动相环境中与TMAH之间的相互作用能够更加精确地阐述RPIC法中头孢地尼立体异构体杂质的分离机制。Objective To study the resolution mechanism of cefdinir stereisomer impurities in reversed phase ion chromatography(RPIC),combined with molecular docking simulation technology.Methods A RPIC method was established to investigate the chromatographic behaviors of impurities in mobile phase with different concentrations of tetramethylammonium hydroxide(TMAH)changed from 0.01%to 0.5%and different pH from 4.5 to 6.5.The binding capacity of impurities to TMAH was studied using molecular docking simulation technology,and the different effects of TMAH on impurities were also discussed.Results There were significant differences between the binding capacity of impurity I,J,K,L to TMAH.It was shown that 3,2,1,0 intra-molecular hydrogen bonds were built in impurity I,J,K,L respectively.One intermolecular hydrogen bond was produced between impurity J and TMAH.Moreover,electrostatic and hydrophobic interactions existed in the processes of impurity I,J,K and L docking with TMAH molecules.There was no significant difference in the binding capacity of impurity T,U to TMAH.Three intra-molecular hydrogen bonds were produced in impurity T and U,respectively.Furthermore,there were electrostatic and hydrophobic interactions between impurity T,U to TMAH.With the increasing of TMAH concentrations in the mobile phase,the chromatographic retention time of impurity I,J,K and L was prolonged,and the resolution was gradually increased.However,there was no significant change in the chromatographic behaviors of impuritiy T and U.Conclusion The combination of the analysis of physicochemical properties with the interaction between impurities and TMAH in the mobile phase studying by molecular docking simulation technology could elaborate the resolution mechanism of cefdinir stereisomer impurities in RPIC.

关 键 词：反相离子对色谱法 头孢地尼 四甲基氢氧化铵 立体异构体 杂质 分子对接仿真技术 

分 类 号：R917[医药卫生—药物分析学]