表面印迹材料的制备及用于氨氯地平药物的手性分离研究

发布时间：2018-06-18 06:18

本文选题：手性分离 + 苯磺酸氨氯地平　；参考：《湘潭大学》2017年博士论文

【摘要】：使用纯对映异构体作为新药原料是近年来制药领域的一个重要趋势。目前在临床上使用的药物一半以上具有手性结构,且销售领先的药物品种中,多数药物是存在手性活性的。目前对手性药物的分离多为实验室规模的微量分离分析,而能用于放大并进行较大规模甚至工业化生产的外消旋拆分方法难以建立。本论文对一种手性降压药苯磺酸氨氯地平进行手性分离研究,采用表面印迹技术和膜技术,制备了几种不同的表面印迹复合材料,展现出对苯磺酸氨氯地平一定的分离能力。实验中所采用的方法适于进一步放大,有望为该药物大规模化手性分离提供潜在的技术参考。具体研究工作如下:1.以聚偏氟乙烯中空纤维膜为支撑载体制备了分子印迹中空纤维复合膜,结合自制的膜组件,对苯磺酸氨氯地平进行错流萃取分离。优化了各种错流萃取实验条件,通过D-酒石酸和磺丁基醚-β-环糊精双手性添加剂的使用,在最佳条件下,错流萃取分离系统的最佳对映异构体过量值达到了17.84%。实验发现,基于分子印迹孔穴的选择性渗透和双手性添加剂分别对两种不同对映异构体的优先俘获作用构成了三重识别机制,并很好地解释了该错流分离系统的手性选择性。该方法结合了膜分离的易于扩大生产和分子印迹膜的选择性和稳定性,可连续操作,有望为氨氯地平的工业化手性分离提供一定的理论参考。2.以介孔二氧化硅微球为载体,采用表面印迹技术,通过沉淀聚合法,分别以甲基丙烯酸及乙二醇二甲基丙烯酸为单体和交联剂,制备了对S-苯磺酸氨氯地平特异性识别的高性能表面印迹介孔微球。通过热重分析和透射电镜表征,发现制备的表面印迹微球具有较薄的印迹层,约为45 nm。制备的表面印迹微球具有快速的吸附动力学和较大的吸附能力,在20 min内达到饱和吸附,最大吸附量为245 mg/g。这证明制备的印迹材料表面存在大量的识别位点,有利于模板分子与分子印迹材料再结合,减小了吸附过程的传质阻力。将印迹材料制备成分离柱(3.0 cm柱长),对苯磺酸氨氯地平进行动态分离,获得了对映异构体过量值为11.3%的分离效果。该方法操作简便,易于工业放大。3.对介孔二氧化硅微球进行双键化和羧基化改性,制备成羧基化硅球。将模板分子S-苯磺酸氨氯地平提前固定在羧基化硅球上,采用表面印迹技术,通过用乙二醇二缩水甘油醚对硅球表面羧基进行水解缩合反应,制备了高性能的表面印迹微球。对比了羧基化硅球和表面印迹微球的吸附动力学和吸附性能,发现表面印迹微球在20 min内达到饱和吸附,最大吸附能力为137 mg/g,均比羧基化硅球吸附能力略低。这是因为表面羧基水解缩合反应后,印迹材料表面的功能基团减少。将印迹材料制备成分离柱(2.3 cm柱长),对苯磺酸氨氯地平进行动态分离,发现最佳羧基改性条件下制备的分离柱获得了对映异构体过量值为13.8%的分离效果。通过采用该模板固定法,提高了分子印迹程序中的模板利用率,从而进一步提高了表面分子印迹效率。4.以介孔二氧化硅微球为载体,采用表面印迹技术,通过沉淀聚合法,分别以N-异丙基丙烯酰胺及N,N-亚甲基双丙烯酰胺为单体和交联剂,制备了温敏型的对S-苯磺酸氨氯地平特异性识别的表面印迹微球。透射电镜表征发现表面印迹微球具有较薄的印迹层,约为16 nm。制备的表面印迹微球具有非常快速的吸附动力学和非常大的吸附能力,在5 min内达到饱和吸附,最大吸附量达到441mg/g。这证明制备的印迹材料极薄的表面印迹层存在大量的识别位点,更利于模板分子与表面印迹材料再结合,减小了吸附过程的传质阻力。发现该材料在质子性溶剂中吸附能力降低,但印迹材料表现出对温度的敏感性,在35℃时获得了最佳吸附效果;材料的温敏特性可用于控制目标分子洗脱。将印迹材料对苯磺酸氨氯地平进行柱分离,获得了对映异构体过量值为10.2%的分离效果。5.以stober二氧化硅微球为载体,采用表面印迹技术,通过溶胶-凝胶聚合法,分别以3-氨丙基三乙氧基硅烷及硅酸四乙酯为单体和交联剂,制备了S-苯磺酸氨氯地平的表面印迹微球。制备的表面印迹微球在60 min内达到饱和吸附,最大吸附能力约为94 mg/g,印迹因子为1.52。通过测定材料的重复使用性能,材料能在使用7个吸附-释放周期后基本维持其吸附性能,证明以硅材料制备的印迹层稳定性好,满足多次重复使用的要求。将印迹材料制备成分离柱,获得对苯磺酸氨氯地平一定的动态分离效果。该方法在室温下容易制备、不受热力学或化学分解的影响、应用环境友好的反应溶剂(常用水或乙醇),成本低廉。
[Abstract]:The use of pure enantiomers as new drug materials is an important trend in the pharmaceutical field in recent years. At present, more than half of the drugs used in clinical use are chiral structures, and most drugs are chiral in the leading drug varieties. In this paper, the chiral separation method of amlodipine, a chiral hypotensive drug, was studied in this paper. Several different surface imprinting materials were prepared by surface imprinting technology and membrane technology. The method used in the experiment is suitable for further enlargement, and it is expected to provide potential technical reference for the large-scale chiral separation of the drug. The specific research work is as follows: 1. the molecularly imprinted hollow fiber composite membrane was prepared with polyvinylidene fluoride hollow fiber membrane as the support carrier, and the homemade membrane module was combined with the amhilylidene sulfonic acid. The experimental conditions of different flow extraction were optimized. Through the use of D- tartaric acid and sulfonyl ether - beta cyclodextrin double hand additive, the best enantiomer overvalue of the staggered extraction separation system reached the 17.84%. experiment under the best conditions. The selective infiltration and hands based on the molecular imprinting hole were found. The sex additive constitutes a three recognition mechanism for the first capture of two different enantiomers, and the chiral selectivity of the system is well explained. This method combines the selectivity and stability of the membrane separation and the selectivity and stability of the molecularly imprinted membrane. It can be operated continuously and is expected to be the industrialization of amlodipine. Chiral separation provides a theoretical reference.2. with mesoporous silica microspheres as the carrier. The high performance surface imprinted mesoporous microspheres for the specific identification of amlodipine S- benzensulfonic acid are prepared by surface imprinting technology and by precipitation polymerization, respectively, with methacrylic acid and ethylene glycol two methacrylic acid as monomers and crosslinker. The surface imprinted microspheres prepared by the reanalysis and transmission electron microscopy show that the imprinted microspheres have a thin imprinting layer. The surface imprinted microspheres prepared by 45 nm. have a rapid adsorption kinetics and a larger adsorption capacity. The surface of the imprinted microspheres is saturated in 20 min and the maximum adsorption amount is 245 mg/g.. The surface of the imprinted material has a large number of identification. The site, which is beneficial to the combination of template molecules and molecularly imprinted materials, reduces the mass transfer resistance in the adsorption process. The imprinted material is prepared from the column (3 cm column long), and the amlodipine sulfonic acid is separated dynamically. The separation effect of the overdose of enantiomers is 11.3%. This method is easy to operate and is easy to be amplified by industrial.3. to mediate Kong Er. The silicon oxide spheres were prepared by double bonding and carboxylation. The template molecule S- amlodipine was immobilized on the carboxylic silicon ball in advance. The surface imprinting technique was used to prepare a high performance surface imprinted microsphere by using ethylene glycol two glycidyl ether to hydrolyze the carboxyl group on the surface of silicon ball. The adsorption kinetics and adsorption properties of carboxyl silicon spheres and surface imprinted microspheres were found. It was found that the surface imprinted microspheres reached saturation adsorption in 20 min and the maximum adsorption capacity was 137 mg/g, which were slightly lower than that of carboxyl silicon spheres. This was due to the reduction of functional groups on the surface of trace materials after the hydrolysis and condensation reaction of the surface carboxyl group. The separation of amlodipine benzenate from the column (2.3 cm column length) was carried out. It was found that the separation column prepared under the optimum carboxyl modified conditions obtained the separation effect of 13.8% of the overdose of enantiomers. By using the template fixing method, the template utilization rate in the molecular imprinting program was improved and the surface fraction was further improved. .4. with mesoporous silica microspheres was used as the carrier. Surface imprinting technology was used to prepare the surface imprinted microspheres for the specific identification of amlodipine S- benzoate with N- isopropyl acrylamide and N, N- methylene diacrylamide respectively by precipitation polymerization. The surface imprinted microspheres for the specific identification of amlodipine by Wen Min type were prepared. The surface imprinted microspheres have a thin imprinting layer. The surface imprinted microspheres, about 16 nm., have very fast adsorption kinetics and very large adsorption capacity. The saturated adsorption is reached within 5 min, and the maximum adsorption capacity reaches 441mg/g.. It is proved that the extremely thin surface imprinting layer of the imprinted material has a large number of identification sites, which is more conducive to the template. It is found that the adsorptive capacity of the material is reduced by the combination of the surface imprinted material and the surface imprinting material. It is found that the adsorptive capacity of the material is reduced in the proton solvent, but the imprinted material shows the sensitivity to the temperature, and the best adsorption effect is obtained at 35 C. The temperature sensitive property of the material can be used to control the elution of the target molecules. The separation effect of chlordipine column was obtained. The separation effect of the overdose of enantiomers was 10.2%.5. with Stober silica microspheres as the carrier. The surface printing of amlodipine S- benzenic sulfonic acid was prepared by the surface imprinting technique and the sol-gel polymerization, with 3- amipropyl triethyl silane and four ethyl silicate as monomers and crosslinking agents, respectively. The surface imprinted microspheres reached saturation adsorption in 60 min, the maximum adsorption capacity was about 94 mg/g, and the imprinting factor was 1.52. by measuring the reusable properties of the material. The material could basically maintain its adsorption properties after using 7 adsorption release cycles. It was proved that the imprinting layer prepared by silicon material was stable and satisfied multiple repetitions. The dynamic separation effect of amlodipine benzoate was obtained by preparing the imprinted material from the column. This method is easy to be prepared at room temperature without the influence of thermodynamics or chemical decomposition. The application of environmentally friendly reaction solvent (commonly used water or ethanol) is low cost.
【学位授予单位】：湘潭大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ460.1;O631

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