The Separation Of Ketoconazole And Other Two Chiral Drugs By High-speed Counter-current Chromatography

This thesis mainly study on the method using high-speed countercurrent chromatography(HSCCC) to separate chiral medicine, and the related theoretical parts has been discussed. Beta cyclodextrin(beta- CD) and its derivatives added in the water phase, tartaric acid esters derivatives chiral selection agent added to the organic phase, and sodium tetraphenylborate as hydrophobic phase transfer agent have been used for the HSCCC separation of ketoconazole enantiomer, phenyllactic acid enantiomer and terbutaline enantiomer. Successful separation and ideal effect were obtained. The mainly experimental work and results were as follows:(1) high speed countercurrent chromatography applied to the separation of ketoconazole enantiomer: a series of liquid- liquid extraction studys were carried on to selecte an ideal solvent system for the separation of ketoconazole enantiomer by high speed countercurrent chromatography. The solvent system obtained is: n-hexane-acetic acid isobutyl ester-0.1 mol L-1 phosphate buffer solution with pH=8.5 containing 0.1 mol L-1 HP-?-CD(2:3:5, v/v/v). Using single-phase identification model and recycling high-speed countercurrent chromatography, 20 mg ketoconazole raceme has been successfully separated. Key impacts of type and concentration of beta cyclodextrin derivatives, aqueous phase experimental conditions such as pH and temperature on enantiomeric distribution ratio and separation effect has been simulated and optimized.(2) high speed countercurrent chromatography applied to the separation of phenyllactic acid enantiomer: a series of liquid- liquid extraction studys were carried on to selecte an ideal solvent system for the separation of phenyllactic acid enantiomer by high speed countercurrent chromatography. The solvent system obtained is: methyl tert-butyl ether-0.1 mol L-1 phosphate buffer solution with pH=5.0 containing 0.1 mol L-1 SEB-?-CD(2:3:5, v/v/v). Using double-phase identification model and recycling high-speed countercurrent chromatography, phenyllactic acid enantiomer has been successfully separated. Key impacts of type and concentration of beta cyclodextrin derivatives and tartaric acid esters derivatives, aqueous phase experimental conditions such as pH and temperature on enantiomeric distribution ratio and separation effect has been optimized. Discusses of some main technical points of high-speed countercurrent chromatography separation of chiral drugs have been studie, which is of great significance.(3) high speed countercurrent chromatography applied to the separation of terbutaline enantiomer: a series of liquid- liquid extraction studys were carried on to selecte an ideal solvent system for the separation of terbutaline enantiomer by high speed countercurrent chromatography. The solvent system obtained is: acetic acid butyl ester with 5mmol L-1 sodium tetraphenylborate- 0.1 mol L-1 phosphate buffer solution with pH=8.5 containing 0.1 mol L-1 HP-?-CD(2:3:5, v/v/v). Using single-phase identification model and sodium tetraphenylborate as hydrophobic phase transfer agent, terbutaline raceme has been successfully separated. Key impacts of concentration of beta cyclodextrin derivatives and sodium tetraphenylborate, aqueous phase experimental conditions such as pH and temperature on enantiomeric distribution ratio and separation effect has been studied. The first apply of hydrophobic phase transfer agent sodium tetraphenylborate was of great importance as it solved the problem that many chiral drugs which show poor solubility in organic phase are difficult to be sapareted by HSCCC.