| Pharmacologically active substance containing chiral centers can exist as pairs of enantiomers,which exhibit the same physical properties, but show a different molecular conformation.So preparation techniques for resolution of enantiomers of drug have a great interesting potential. The present main methods of chiral resolution and their research progress, advantages and disadvantages were reviewed in this paper.The three representational methods of chiral resolution were investigated and discussed in detail by taking the racemicβ-adrenergic drugs as target materials,of which the study on chiral resolution by liquid membrane was not reported in our country so far.It develops an new area for resolution of enantiomers of drug.The main contents and results can be summarized as following:The first part:Chromatographic resolutionResolution of clenbuterol enantiomers using the chiral selector impregnated thin-layer chromatography were studied,the composition and ratio of mobile phase,the quantity of impregnated chiral selector were studied,respectively.And the favourable conditions of resolution were obtained.The effects of thin-layer chromatography using mobile phase additive and chiral selectors-impregnated thin-layer chromatography were contrasted,the ability of resolution of chiral selectors impregnated thin-layer chromatography was more excellent.To investigate the behavior of chiral separation,the mechanism of resolution by impregnated thin-layer chromatography was discussed.Resolution of chlorthalidone enantiomers were established usingβ-CDs as chiral mobile phase additive.The thermodynamic parameters of chromatographic resolution were studied especially on column temperature.In addition,the different ability of resolution ofβ-CDs were compared.The results obtained indicated the enthalpic contribution to the overall chlorthalidone enantiomers transfer energy was more significant than the entropic one.The different resolution ability ofβ-CDs were determined by several interactions.However,hydrogen bond interactions played an important role in chiral resolution process.Chromatographic resolution of naproxen has been studied using HP-β-CD as chiral mobile phase additive.The effects of mobile-phase composition were researched in detail.The appropriate composition of mobile phase was 85:15(v/v)aqueous with 0.5%TEA at pH 3.5/ethanol containing 25 mmol/L HP-β-CD,and the column temperature was set of 25℃and wave length of 254 nm.The retention characteristics and separation mechanism will be discussed emphatically.The apparent thermodynamic parameters were also calculated from plots of the natural logarithm of separation factor versus reciprocal of temperature.The quantitative standard curve of naproxen enantiomers was obtained under the optimal chromatographic conditions.A chiral stationary phase for resolution of naproxen has been prepared by molecular imprinting,in which 4-vinylpyridine(functional monomer)and trimethylol propane trimethacrylate were copolymerized in the presence ofS-naproxen.Racemic naproxen was efficiently resolved on the molecular imprinting polymer.Furthermore,different functional monomers,flow rate in the mobile phase,column temperature were investigated,respectively.The thermodynamic parameters were estimated. It was found that the resolution process was enthalpy controlled.A method for capillary electrophoretic enantiomeric resolution of racemic clenbuterol has been established with HP-β-CD as the chiral selector.General equations and data analysis approach are presented to relate molibilities to equalibrium constants in simple binding equilibria and used to determine binding constants and thermodynamic parameters for host-guest complexation of clenbuterol enantiomers with HP-β-CD. The effects of type and concentration ofβ-CDs,buffer type and its concentration,pH of buffer,separation voltage and capillary temperature were investigated in detail,respectively.The appropriate conditions was: 30 mmol/L HP-β-CD,50 mmol/L phosphate solution(pH 2.5)as running buffer,separation voltage in 24 kV,and operation temperature of 20℃, the baselines separation could be obtained with resolution of 6.78.The quantitative ability of capillary zone electrophoresis also be researched.The second part:Extractive resolution Distribution behavior of propranolol enantiomers was examined in the aqueous and organic solvent of a two-phase systems containing S, S-tartaric ester as chiral selector,the influence of pH in aqueous phase, initial concentration of propranolol enantiomers,different solvent and different alkyl chain of S,S-tartraic ester on the performances of chiral extraction were investigated,respectively,the better conditions of extractive resolution were established in experiments.S, S-di-n-dodecylltartrate was used as chiral selector,chloroform was used as organic solvent,the pH in aqueous phase was about 4.4,and the enantiomers concentration was about 5.0 mmol/L.The calorimetry was analysed on this process based on the better conditions of extraction.The third part:Chiral resolution by liquid membraneResolution of salbutamol solute was carried out in liquid-supported membrane using a polyvinylidene fluoride hollow-fiber module.The enantioselective transport of solute was facilitated by combinatorial chiral selectors,which were dissolved in n-octanol organic solvent.The molar concentration ratios of salbutamol to combinatorial chiral selectors and the pH of buffer solution were investigated.The results show that when the molar concentration ratio is 2:1:1,the maximum separation factor and enantiomer excess are 1.49 and 19.74%,respectively,and the appropriate range of pH in buffer is 7～7.2.Based on the chiral ligand exchange,the enantioselective extraction of mandelic acid enantiomers was studied firstly in the emulsion liquid membranes system using copper(Ⅱ)N-n-dodecyl-L-hydroxyproline as chiral selector.The effects of initial racemic mandelic acid concentration, the direction of chiral extraction,the volume ratio of organic solvent and surfactant,the pH gradient from external to internal phase and the pH of external aqueous phase,on performances of enantioselective extraction, were discussed,respectively.Consequently,appropriate extractive conditions were established.Bulk liquid membrane containing chiral carrier was used for resolution of racemic clenbuterol,the optimal chiral separation conditions and the kinetic resolution model were established in this experiment.The influences of the molar concentration ratio of chiral carrier and pH in aqueous phase on performances of chiral resolution were investigated. The chiral resolution of bulk liquid membrane was analysed by means of a kinetic model involving two consecutive irreversible first order reactions.The pseudo-first order apparent rate constants,kl or k2 of interfacial reactions in membrane-feed solution interface or membrane-stripping solution interface were determined.The results show that the separation factor is above 1.08 under the conditions of pH 7 in aqueous phase with the molar concentration ratio of 1:4,and the kinetic resolution of clenbuterol can be evaluated by two consecutive irreversible first order reactions under the optimal conditions.
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