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The Study of Chiral Recognition Mechanism and High Sensitivity Method of Chiral Drugs by Capillary Electrophoresis

Author: WangYongLe
Tutor: XuZhongQi
School: Donghua University
Course: Applied Chemistry
Keywords: capillary electrophoresis chiral drug preconcentration technique chiralrecognition mechanism
CLC: O658.9
Type: Master's thesis
Year: 2014
Downloads: 72
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Abstract


Chiral drugs has been a research hotspot in drug development field because its different enantiomer may possess different pharmacodynamic and pharmacokinetics effects in absorption, translocation, effect, metabolism and excretion process because there are chiral locus in most endogenous substance. At the moment of pharmacological and pharmacokinetic study of chiral drugs, high sensitivity method is undoubted important because the concentration of the enantiomers in the body are quite low, and the study of chiral recognition mechanism is quite important to reveal the separation principle. Among so many chiral separation methods, capillary electrophoresis (CE) was applied to chiral separation by many researchers because of its short analysis time, high resolving power and less reagent consumption. This study investigated the chiral recognition mechanism and high sensitivity method by CE, and explored the preparation of monoenantiomer basing on CE technology.Chapter one introduced the principle of CE at first. Then interpreted the different effects of different enantiomers of chiral drugs. Moreover, the application of CE in pharmaceutical analysis was summarized. Finaly, the ideas of this thesis was raised after summary the application in pharmaceutical analysis by CE enrichment method and the chiral recognition mechanism.Chapter two investigated a series of contribution to the verteporfin (VER), which is a kind of new photodynamic therapy drug. Firstly, a new method to chiral separate the four isomers of VER by CE has been developed. Moreover, according to the different binding behaviors of four cholate salts with analytes, it displayed that the H-bonds formed by carbonyl group on isomers and the hydroxyls at the outboard of cholate salts micelle shown to be primarily responsible for stereoselectivity. What’s more, in order to improve the sensitivity of method, the pressure-assisted electrokinetic injection (PAEKI) was developed to chiral separate enantiomer of drugs for the first time and the sensitivity was improved116times compared to hydraulic injection. By investigating the preconcentration mechanism, a simple and feasible method was proposed to optimize the condition of PAEK.I. The PAEKI method was developed to chiral separate the four isomers of VER, and applied to chiral separate the four isomers of VER in artificial urine successfully.Chapter three investigated chiral separation method of the two enantiomers of citalopram (CIT) by CE technology. Basing on hydraulic injection, a simple and receivable method to chiral separate CIT was developed and applied to the quality control of two enantiomers in Escitalopram tablet. To improve the sensitivity of method, the PAEKI method which improved sensitivity at40-80times was developed to chiral separate the two enantiomers of CIT, and the effect of changing the flush BGE was studied to avoid the electric discrimination caused by chiral selector.Chapter four explored a new method to separate prepare the monoenantiomer of CIT by CE method. Basing on the phenomenon that suitable chiral selector may control the two enantiomer appear at the two side of electroosmotic flow (EOF), we designed the preparation and detection processes though studying the effect of the sample dispose, buffer condition and the concentration of chiral selector. At last, we applied this method to prepare the monoenantiomer from2.0mg/L CIT and the results show that the quantity of (S)-enantiomer and (R)-enantiomer remained in sample vial were42.7%and85.2%, respectively, and the ratio of them decreased from100%to50%after four hours. This method may be used extensively to prepare monoenantiomer by megaobore columnin or industrial method in the future.

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