厚体液膜和泡沫分馏技术拆分药物对映体的应用及其机理研究

【作者】 杨玲；

【导师】 陈晓青；

【作者基本信息】 中南大学 ， 分析化学， 2009， 硕士

【摘要】 本文研究了手性流动相添加法拆分手性药物的分析方法及其热力学性质,分别用厚体液膜技术和泡沫分馏技术拆分扁桃酸对映体和蛋氨酸对映体,研究了各因素对拆分效果的影响,并对拆分机理进行了初步探讨。（1）分析方法的建立。采用手性流动相添加法建立了扁桃酸和氧氟沙星手性分析方法,手性固定相法为蛋氨酸建立手性分析方法,分别确定各药物对映体最适宜的分析条件。（2）手性流动相添加剂法拆分氧氟沙星对映体的热力学性质研究。在C18高效液相色谱柱上,以L-苯丙氨酸和硫酸铜为手性配体流动相,在温度293～313K范围内,考察了氧氟沙星对映体的保留和分离行为。在实验范围内,温度升高对分离不利,随着温度的升高,对映体的保留时间、分离度和选择性因子均减少。通过对拆分中焓变、焓变差值和熵变差值等热力学参数的计算,确定在所测温度范围内其手性拆分过程为焓控过程。（3）厚体液膜技术拆分扁桃酸对映体。以D2EHPA和L-（-）-DBTA二元手性载体,正辛醇为膜溶剂,采用厚体液膜法拆分了扁桃酸外消旋体。考察了拆分时间、各物质浓度比、搅拌转速、反应温度各参数对拆分的影响,得到最佳拆分条件:拆分时间4h,C_MA:C_D2EHPA:C_{L-（-）-DBTA}=0.05:0.2:0.3,搅拌转速400r/min,反应温度35℃,此时得到最大分离因子2.74,对映体过剩值46.47%。（4）泡沫分馏技术拆分蛋氨酸对映体。采用泡沫分馏技术,分别用不同的手性捕收剂分离扁桃酸对映体和蛋氨酸对映体。主要考察手性捕收剂的筛选、捕收剂/手性药物质量浓度比、回流时间、空气流速、分馏柱填料层高度及溶液pH值对拆分性能的影响,并使用正交实验法考察了各因素对蛋氨酸外消旋体的拆分影响,通过正交实验方差分析发现回流气速和样品溶液中组分浓度比两个因素对泡沫分馏法拆分手性药物的效果影响较大。更多还原

【Abstract】 In this paper,the establishment of analytical methods about separation of chiral drugs and their thermodynamic properties of chiral mobile phase addition（CMPA） method were investigated.Additionally mandelic acid enantiomers and methionine enantiomers were separated by the techniques of bulk liquid membrane and foam fractionation respectively,while the influencing factors of separation and the separation mechanism was also discussed.（1） Establishment of analytical methods.The chiral analysis methods were established for mandelic acid and ofloxacin by CMPA and methionine by chiral stationary phase,respectively.Furthermore,the optimal conditions for enantiomeric analysis was confirmed.（2） Investigation of the thermodynamic properties of resolution of ofloxacin enantiomers by CMPA.The effect of temperature（293～313K） on chromatographic separation of ofloxacin over a C18 column was investigated with L-phenylalanine-CuSO₄ aqueous solution and methanol as the chiral ligand mobile phase.Higher column temperature was found to be disadvantageous to the enantiomer separation for the retention time, resolution and selectivity of the chiral separation were decreased with the increase of temperature.Moreover and very importantly,the enantiomeric separation is a enthalpy controlled process in the examined temperature range by calculation of thermodynamic functions(△H°,△_S,R△H°,△_S,R△S°).（3） Resolution of mandelic acid enantiomers by the technique of bulk liquid membrane.A new method of bulk liquid membrane using complex of D2EHPA and L-（-）-DBTA was developed for the resolution of racemic mandelic acid.The influences of time,the concentration ratio of MA,D2EHPA and L-（-）-DBTA,rotated speed and temperature on chiral separation were studied and optimized.The biggest separation factor （α）2.74 and the enantiometric excess value（ee%） 46.47%were obtained when the separation time was 4 hour,the concentration ratio of MA, D2EHPA and L-（-）-DBTA was 0.05:0.2:0.3,the rotated speed was 400r/min and the temperature was 35℃.（4） Resolution of methionine enantiomers by the technique of foam fractionation.Mandelic acid and methionine enantiomers were separated using different chiral collectors by the technique of foam fractionation. The species of chiral collectors,the concentration ratio of collectors and chiral enantiomers,reflux equilibriation time,gas flow rate,packing height and pH of buffer on resolution performances were investigated, respectively.The effects of different factors on resolution of methionine enantiomers were studied by Orthogonal experiment.After variance analysis,it was found that the influences of reflux equilibriation time and the concentration ratio of sample solution were greater in resolution of methionine enantiomers by the technique of foam fractionation.更多还原