药物对映体手性萃取及支载液膜分离理论与应用研究
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摘要
药物对映体的制备性分离研究为当前最热门的课题之一。手性液-液萃取是药物对映体制备性分离的一种十分重要方法，相对化学拆分法、酶或微生物法和色谱拆分法，分离体系的选择有一定的规律可循，并且适用范围也大大扩宽。中空纤维膜萃取是近年发展起来的一种高效分离技术，受到众多研究者的重视。本论文主要工作是研究氧氟沙星、氯噻酮、扁桃酸和叔丁喘宁四种对映体在含有手性选择体的水-有机溶剂两相系统中的萃取分配行为，考察pH、手性选择体浓度、有机溶剂等因素对萃取性能的影响；将手性液-液萃取和中空纤维膜萃取分离技术结合，建立手性分离数学模型，对药物对映体进行制备性分离。主要内容如下：
1．采用β-环糊精和L-苯丙氨酸-Cu~(2+)手性流动相添加剂法对氧氟沙星、氯噻酮、叔丁喘宁和扁桃酸四种对映体进行色谱分离和测定，该法具有良好的重现性和线性关系，相关系数均大于0.9993。
2．基于化学热力学原理和质量守恒定律，对手性萃取基本理论进行研究，指出手性萃取是依据手性选择体和药物对映体生成两个非对映体在疏水性有机相中的自由能差-△(△G)来实现的。理论上，只要-△(△G)大于0，即分离因子(α)大于1，就能实现对映体的萃取分离。
3．采用具有应用前景的酒石酸衍生物作为手性选择体，从分配系数、分离因子及分配自由能差-△(△G)三个方面考察pH、手性选择体浓度、有机溶剂等因素对氧氟沙星、扁桃酸、氯噻酮等药物对映体萃取性能的影响，研究具有不同取代基的酒石酸衍生物手性选择体的萃取性能及手性识别规律。
4．以四苯硼钠(NaBPh_4)为疏水性相转移试剂，研究不同酒石酸衍生物手性选择体对叔丁喘宁对映体萃取性能。疏水性相转移试剂NaBPh_4与叔丁喘宁对映体阳离子形成疏水性复合盐，促进叔丁喘宁对映体在有机溶剂中的溶解，大大增大了两对映体的分配系数；但分配系数的增大以损失分离因子为代价，实验中采用0.0045 mol／LNaBPh_4，适合萃取分离叔丁喘宁对映体。
博士学位论文
摘要
5.合成N一n一十二烷基一L一脯氨酸和N一n一十二烷基一L一轻基脯氨
酸，以这两种氨基酸衍生物为手性选择体，采用手性配体交换萃取，
研究了两种氨基酸衍生物手性选择体对氧氟沙星和扁桃酸对映体的
萃取性能，考察了铜离子浓度、pH、有机溶剂等因素对萃取性能的
影响。两种氨基酸衍生物手性选择体对氧氟沙星和扁桃酸对映体的
立体选择性比酒石酸衍生物手性选择体大大提高。
6.基于质量守恒定律和传统非手性逆流分级萃取理论，研究中
空纤维膜0/W逆流分级手性萃取理论，建立侧S或S瓜~NTU和
卜NTU数学模型，对数学模型进行研究和讨论。运用Visual Basic
程序，对数学模型进行模拟;同时通过对数学模型模拟，对中空纤
维膜0/W逆流分级手性萃取的操作参数进行优化。
7.采用水凝胶负载和磷酸氢二钠/磷酸缓冲溶液浸泡两种方法
对聚矾中空纤维膜进行改性;使用改性的中空纤维膜，对氧氟沙星
对映体进行膜萃取分离，考察了中空纤维膜传质性能和萃取平衡时
间。氧氟沙星对映体经过2X5(5个萃取和5个反萃取)水凝胶负
载的聚矾中空纤维膜O/W分级手性萃取后，出口水相氧氟沙星对映
体浓度比值达3.4，实验值和从数学模型计算得到的理论值非常接
近。
8.基于手性液一液萃取理论，提出了支载液膜双有机相手性萃取
新方法;采用中空纤维支载液膜和分别含有相反手性选择体的双有机
相对氧氟沙星对映体进行了萃取分离及机理研究。研究表明，支载液
膜双有机相手性萃取能够获得几乎双倍的手性萃取分离推动力和更
大的分离因子。使用2 xs(5个萃取和5个反萃取)水凝胶负载的聚
矾中空纤维支载液膜双有机相手性萃取对氧氟沙星外消旋体进行了
分离，得到膜内相出口氧氟沙星对映体浓度比值分别约为9.8。中空
纤维支载液膜双有机相手性萃取比中空纤维膜0/W逆流分级手性萃
取具有更强的分离能力，为外消旋体制备性分离开拓了一个新的领
域，具有十分广阔的应用前景。
Preparative techniques for the separation of drug enantiomers have a great interesting potential. Chiral extraction is a very important method for preparative separation of enantiomers. It has some regularity and a larger application range in contrasting to chemical resolution, fermentation and enzymatic transformation and chromatography. Hollow fiber membrane extraction is a very effective separation technique with great promise. In the thesis, distribution behaviors of ofloxacin, chlorthalidone, mandelic acid and terbutaline enantiomers were examined in the aqueous-organic solvent of a two-phase systerm containing a chiral selector. Influence of pH value, organic solvents and concentrations of chiral selector on the partition coefficients(k) and separation factors( a ) of enantiomers, were investigated. Drug enantiomers were separated by combining chiral extraction and hollow fiber membrane extraction, and mathematical models were established for chiral separation. The main content and results can be summa
rized as following:
1. The enantiomeric resolution of ofloxacin, chlorthalidone, mandelic acid and terbutaline was studied by reversed phase HPLC with
β -cyclodextrin and L-phenylalanine-Cu as chiral mobile phase additives. The method was applied to determination of amount of the enantiomers with good linear relationship and selection.
2. Based on chemical thermodynamic theory and mass balance, the theory for chiral extraction was studied. It is pointed that enantiomeric separation is dependent on the difference in free energy between the two diastereomeric complexes formed by a chiral selector and enantiomers, - A ( A G). Only if separation factor is more than 1, that is to say, - △(△G) is above 0, different degrees of separation of enantiomers can be achieved by chiral extraction.
3. The influence of pH, organic solvents and the concentrations of
chiral selector on K, a and - A (A G) for ofloxacin, chlorthalidone and mandelic acid enantiomers, was investigated with tartaric acid derivatives as chiral selectors. The extraction performance and chiral recognition mechanism were studied.
4. Distribution behaviors of terbutaline enantiomers were examined in the aqueous-organic of a two-phase system containing one of tartaric acid derivatives with Na-tetraphenylborate (NaBPlit) as a lipophlilic phase transfer reagent. BPri4~ can form lipophilic salt complexes with terbutaline enantiomers, which facilitates the solubility of the enantiomers in the organic phase. Partition coefficients increase with the rise of the concentrations of NaBPh4 at cost of loss of separation factor of terbutaline enantiomers by extraction. 0.0045 mol/L NaBPlij is suitable to separate terbutaline enantiomers.
5. N--dodecyl-L-proline(Ci2-Pro) and N--dodecyl-L-hydroxyprol-ine(Ci2-Hyp) were synthesized. With Ci2-Pro and Ci2-Hyp derivatives as chiral selectors, respectively, influence of pH value, Cu2+ concentrations and organic solvents on extraction performance was investigated. It is found that C-pro and Ci2-Hyp have stronger stereoselectivity for ofloxacin and mandelic acid enantiomers than tartaric acid derivatives.
6. Based on mass balance and fractional achiral extraction theory, fractional chiral extraction was studied, and mathematical models of R/S or S/R-NTU and Y-NTU were established. The models were simulated by Visual Basic program, and provided for separation of enantiomers by countercurrently fractional extraction with hollow fiber membrane.
7. Polysulfone hollow fiber membranes were modified by filling hydrogel and immersing in NaH2PO4/H3PO4 buffer solution, respectively. Ofloxacin enantiomers were separated by hollow fiber membrane extraction. Good separation results were obtained with 3.4 of the ratio of the concentrations of ofloxacin enantiomers by 2 X 5 hollow fiber membrane modules filled with hydrogel.
8. Based on chiral O/W extraction theory, support-liquid membrane extraction with two organic phases containing D-selector and L-selector, respectively, was studied.
1．采用β-环糊精和L-苯丙氨酸-Cu~(2+)手性流动相添加剂法对氧氟沙星、氯噻酮、叔丁喘宁和扁桃酸四种对映体进行色谱分离和测定，该法具有良好的重现性和线性关系，相关系数均大于0.9993。
2．基于化学热力学原理和质量守恒定律，对手性萃取基本理论进行研究，指出手性萃取是依据手性选择体和药物对映体生成两个非对映体在疏水性有机相中的自由能差-△(△G)来实现的。理论上，只要-△(△G)大于0，即分离因子(α)大于1，就能实现对映体的萃取分离。
3．采用具有应用前景的酒石酸衍生物作为手性选择体，从分配系数、分离因子及分配自由能差-△(△G)三个方面考察pH、手性选择体浓度、有机溶剂等因素对氧氟沙星、扁桃酸、氯噻酮等药物对映体萃取性能的影响，研究具有不同取代基的酒石酸衍生物手性选择体的萃取性能及手性识别规律。
4．以四苯硼钠(NaBPh_4)为疏水性相转移试剂，研究不同酒石酸衍生物手性选择体对叔丁喘宁对映体萃取性能。疏水性相转移试剂NaBPh_4与叔丁喘宁对映体阳离子形成疏水性复合盐，促进叔丁喘宁对映体在有机溶剂中的溶解，大大增大了两对映体的分配系数；但分配系数的增大以损失分离因子为代价，实验中采用0.0045 mol／LNaBPh_4，适合萃取分离叔丁喘宁对映体。
博士学位论文
摘要
5.合成N一n一十二烷基一L一脯氨酸和N一n一十二烷基一L一轻基脯氨
酸，以这两种氨基酸衍生物为手性选择体，采用手性配体交换萃取，
研究了两种氨基酸衍生物手性选择体对氧氟沙星和扁桃酸对映体的
萃取性能，考察了铜离子浓度、pH、有机溶剂等因素对萃取性能的
影响。两种氨基酸衍生物手性选择体对氧氟沙星和扁桃酸对映体的
立体选择性比酒石酸衍生物手性选择体大大提高。
6.基于质量守恒定律和传统非手性逆流分级萃取理论，研究中
空纤维膜0/W逆流分级手性萃取理论，建立侧S或S瓜~NTU和
卜NTU数学模型，对数学模型进行研究和讨论。运用Visual Basic
程序，对数学模型进行模拟;同时通过对数学模型模拟，对中空纤
维膜0/W逆流分级手性萃取的操作参数进行优化。
7.采用水凝胶负载和磷酸氢二钠/磷酸缓冲溶液浸泡两种方法
对聚矾中空纤维膜进行改性;使用改性的中空纤维膜，对氧氟沙星
对映体进行膜萃取分离，考察了中空纤维膜传质性能和萃取平衡时
间。氧氟沙星对映体经过2X5(5个萃取和5个反萃取)水凝胶负
载的聚矾中空纤维膜O/W分级手性萃取后，出口水相氧氟沙星对映
体浓度比值达3.4，实验值和从数学模型计算得到的理论值非常接
近。
8.基于手性液一液萃取理论，提出了支载液膜双有机相手性萃取
新方法;采用中空纤维支载液膜和分别含有相反手性选择体的双有机
相对氧氟沙星对映体进行了萃取分离及机理研究。研究表明，支载液
膜双有机相手性萃取能够获得几乎双倍的手性萃取分离推动力和更
大的分离因子。使用2 xs(5个萃取和5个反萃取)水凝胶负载的聚
矾中空纤维支载液膜双有机相手性萃取对氧氟沙星外消旋体进行了
分离，得到膜内相出口氧氟沙星对映体浓度比值分别约为9.8。中空
纤维支载液膜双有机相手性萃取比中空纤维膜0/W逆流分级手性萃
取具有更强的分离能力，为外消旋体制备性分离开拓了一个新的领
域，具有十分广阔的应用前景。
Preparative techniques for the separation of drug enantiomers have a great interesting potential. Chiral extraction is a very important method for preparative separation of enantiomers. It has some regularity and a larger application range in contrasting to chemical resolution, fermentation and enzymatic transformation and chromatography. Hollow fiber membrane extraction is a very effective separation technique with great promise. In the thesis, distribution behaviors of ofloxacin, chlorthalidone, mandelic acid and terbutaline enantiomers were examined in the aqueous-organic solvent of a two-phase systerm containing a chiral selector. Influence of pH value, organic solvents and concentrations of chiral selector on the partition coefficients(k) and separation factors( a ) of enantiomers, were investigated. Drug enantiomers were separated by combining chiral extraction and hollow fiber membrane extraction, and mathematical models were established for chiral separation. The main content and results can be summa
rized as following:
1. The enantiomeric resolution of ofloxacin, chlorthalidone, mandelic acid and terbutaline was studied by reversed phase HPLC with
β -cyclodextrin and L-phenylalanine-Cu as chiral mobile phase additives. The method was applied to determination of amount of the enantiomers with good linear relationship and selection.
2. Based on chemical thermodynamic theory and mass balance, the theory for chiral extraction was studied. It is pointed that enantiomeric separation is dependent on the difference in free energy between the two diastereomeric complexes formed by a chiral selector and enantiomers, - A ( A G). Only if separation factor is more than 1, that is to say, - △(△G) is above 0, different degrees of separation of enantiomers can be achieved by chiral extraction.
3. The influence of pH, organic solvents and the concentrations of
chiral selector on K, a and - A (A G) for ofloxacin, chlorthalidone and mandelic acid enantiomers, was investigated with tartaric acid derivatives as chiral selectors. The extraction performance and chiral recognition mechanism were studied.
4. Distribution behaviors of terbutaline enantiomers were examined in the aqueous-organic of a two-phase system containing one of tartaric acid derivatives with Na-tetraphenylborate (NaBPlit) as a lipophlilic phase transfer reagent. BPri4~ can form lipophilic salt complexes with terbutaline enantiomers, which facilitates the solubility of the enantiomers in the organic phase. Partition coefficients increase with the rise of the concentrations of NaBPh4 at cost of loss of separation factor of terbutaline enantiomers by extraction. 0.0045 mol/L NaBPlij is suitable to separate terbutaline enantiomers.
5. N--dodecyl-L-proline(Ci2-Pro) and N--dodecyl-L-hydroxyprol-ine(Ci2-Hyp) were synthesized. With Ci2-Pro and Ci2-Hyp derivatives as chiral selectors, respectively, influence of pH value, Cu2+ concentrations and organic solvents on extraction performance was investigated. It is found that C-pro and Ci2-Hyp have stronger stereoselectivity for ofloxacin and mandelic acid enantiomers than tartaric acid derivatives.
6. Based on mass balance and fractional achiral extraction theory, fractional chiral extraction was studied, and mathematical models of R/S or S/R-NTU and Y-NTU were established. The models were simulated by Visual Basic program, and provided for separation of enantiomers by countercurrently fractional extraction with hollow fiber membrane.
7. Polysulfone hollow fiber membranes were modified by filling hydrogel and immersing in NaH2PO4/H3PO4 buffer solution, respectively. Ofloxacin enantiomers were separated by hollow fiber membrane extraction. Good separation results were obtained with 3.4 of the ratio of the concentrations of ofloxacin enantiomers by 2 X 5 hollow fiber membrane modules filled with hydrogel.
8. Based on chiral O/W extraction theory, support-liquid membrane extraction with two organic phases containing D-selector and L-selector, respectively, was studied.
引文
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