双丙酮-D-甘露糖醇-硼酸络合酸在NACE手性药物分离与检测中的应用
发布时间：2019-03-27 11:58
【摘要】：β-激动剂(β-agonists)类手性药物的两个对映异构体在药效学、药代动力学及毒理学等方面都存在较大差异,建立其手性分离与检测方法具有重要意义。毛细管电泳(Capillary electrophoresis,CE)是手性药物分离与检测常用的一种方法。非水毛细管电泳(Nonaqueous capillary electrophoresis,NACE)是CE的一个重要分支,在手性药物分离方面具有独特优势,近年来引起了人们的关注。本文在含有三乙胺的甲醇溶液中原位合成了双丙酮-D-甘露糖醇 硼酸络合酸手性选择剂,并将其应用于NACE中,成功实现了7种β-激动剂类手性药物的分离。紫外吸收光谱(Ultraviolet spectrometry,UV)和11B-核磁共振波谱(11B-nuclear magnetic resonance spectroscopy,11B-NMR)实验证明了双丙酮-D-甘露糖醇 硼酸络合酸的生成。本文还将建立的NACE手性分离方法应用于口服液中克仑特罗对映体的含量测定和饮用水及猪肝样品中克仑特罗对映体的残留量分析。全文共分六章:第一章:综述了β-激动剂类手性药物分离与检测的意义及β-激动剂类手性药物常用的分离与检测方法,并对NACE在手性药物分离检测中的应用进行了介绍。第二章:在非水溶液中制备了双丙酮-D-甘露糖醇 硼酸络合酸,并以其为手性选择剂,在NACE中对7种β-激动剂进行了分离。为了获得良好的手性分离效果,实验分别考察了双丙酮-D-甘露糖醇、硼酸和三乙胺浓度对分离效果的影响。在优化的NACE手性分离条件下,所有7种药物均可获得基线分离,其中6种分离时间在12分钟之内。第三章:分别采用UV和11B-NMR方法考察了双丙酮-D-甘露糖醇 硼酸络合酸在NACE缓冲溶液中的生成情况。第四章:根据人用药物注册技术要求国际协调会(International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,ICH)指导原则对所建立的NACE手性分离方法进行了方法学验证。结果表明,5种测试药物的两个对映体在1.25~100.00μg mL-1范围内线性关系良好,相关系数(r)≥0.9992;检测限(Limit of determination,LOD)和定量限(Limit of quantification,LOQ)分别小于1.25μg mL-1和5.00μg mL-1,加标回收率为98.2~101.9%,精密度RSD小于0.9%(n=9)。将建立的NACE法成功应用于氨溴特罗口服液中克仑特罗对映体的含量测定。第五章:结合选择性阳离子电动进样和扫集技术,建立NACE手性富集分离方法用于饮用水及猪肝样品中克仑特罗对映体的残留量分析。方法学验证结果显示,克仑特罗的两个对映体在0.25~12.50 ng mL-1浓度范围内均具有良好的线性关系,线性相关系数(r)≥0.9984,检测限(LOD)和定量限(LOQ)分别为0.05 ng mL-1和0.25 ng mL-1。第六章:结论与展望。
[Abstract]:The two enantiomers of 尾-agonists (尾-agonists) have great differences in pharmacodynamics, pharmacokinetics and toxicology. It is of great significance to establish chiral separation and detection methods for 尾-agonists. Capillary electrophoresis (Capillary electrophoresis,CE) is a commonly used method for separation and detection of chiral drugs. Non-aqueous capillary electrophoresis (Nonaqueous capillary electrophoresis,NACE) is an important branch of CE. It has unique advantages in chiral drug separation and has attracted much attention in recent years. In this paper, diacetone-D-mannitol / boric acid chiral selector was in situ synthesized in methanol solution containing triethylamine and applied to NACE. Seven chiral drugs of 尾-agonists were successfully separated. The formation of diacetone-D-mannitol boric acid complex acid was confirmed by UV absorption spectroscopy (Ultraviolet spectrometry,UV) and 11B-nuclear magnetic resonance (11B-nuclear magnetic resonance spectroscopy,11B-NMR). The NACE chiral separation method has also been applied to the determination of clenbuterol enantiomers in oral liquid and the determination of clenbuterol enantiomers in drinking water and pig liver samples. The thesis is divided into six chapters: chapter one: the significance of separation and detection of 尾-agonists chiral drugs and the commonly used separation and detection methods of 尾-agonists chiral drugs are reviewed, and the application of NACE in the separation and detection of chiral drugs is introduced. In chapter 2, diacetone-D-mannitol borate complex acid was prepared in non-aqueous solution and used as chiral selector, seven 尾-agonists were separated in NACE. In order to obtain a good chiral separation effect, the effects of diacetone-D-mannitol, boric acid and triethylamine concentration on the separation efficiency were investigated. Under the optimized conditions of NACE chiral separation, baseline separation was obtained for all seven drugs, six of which were separated within 12 minutes. Chapter 3: the formation of diacetone-D-mannitol borate complex acid in NACE buffer solution was investigated by UV and 11B-NMR, respectively. In chapter 4, the methodology of chiral separation of NACE is verified according to the technical requirements of (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,ICH (International Coordination Committee for the Registration of drugs for Human use). The results showed that there was a good linear relationship between the two enantiomers in the range of 1.25 ~ 100.00渭 g / mL-1, and the correlation coefficient (r) was 鈮，
本文编号：2448153
[Abstract]:The two enantiomers of 尾-agonists (尾-agonists) have great differences in pharmacodynamics, pharmacokinetics and toxicology. It is of great significance to establish chiral separation and detection methods for 尾-agonists. Capillary electrophoresis (Capillary electrophoresis,CE) is a commonly used method for separation and detection of chiral drugs. Non-aqueous capillary electrophoresis (Nonaqueous capillary electrophoresis,NACE) is an important branch of CE. It has unique advantages in chiral drug separation and has attracted much attention in recent years. In this paper, diacetone-D-mannitol / boric acid chiral selector was in situ synthesized in methanol solution containing triethylamine and applied to NACE. Seven chiral drugs of 尾-agonists were successfully separated. The formation of diacetone-D-mannitol boric acid complex acid was confirmed by UV absorption spectroscopy (Ultraviolet spectrometry,UV) and 11B-nuclear magnetic resonance (11B-nuclear magnetic resonance spectroscopy,11B-NMR). The NACE chiral separation method has also been applied to the determination of clenbuterol enantiomers in oral liquid and the determination of clenbuterol enantiomers in drinking water and pig liver samples. The thesis is divided into six chapters: chapter one: the significance of separation and detection of 尾-agonists chiral drugs and the commonly used separation and detection methods of 尾-agonists chiral drugs are reviewed, and the application of NACE in the separation and detection of chiral drugs is introduced. In chapter 2, diacetone-D-mannitol borate complex acid was prepared in non-aqueous solution and used as chiral selector, seven 尾-agonists were separated in NACE. In order to obtain a good chiral separation effect, the effects of diacetone-D-mannitol, boric acid and triethylamine concentration on the separation efficiency were investigated. Under the optimized conditions of NACE chiral separation, baseline separation was obtained for all seven drugs, six of which were separated within 12 minutes. Chapter 3: the formation of diacetone-D-mannitol borate complex acid in NACE buffer solution was investigated by UV and 11B-NMR, respectively. In chapter 4, the methodology of chiral separation of NACE is verified according to the technical requirements of (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,ICH (International Coordination Committee for the Registration of drugs for Human use). The results showed that there was a good linear relationship between the two enantiomers in the range of 1.25 ~ 100.00渭 g / mL-1, and the correlation coefficient (r) was 鈮，
本文编号：2448153
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