The Synthesis Of Series Of Sulfobutyl Ether-β-cyclodextrins And Its Inclusion Complexes With Nateglinide

In this paper,a series of sulfobutyl ether-β-cyclodextrins with specific average degree of substitution were synthesized by adding the alkali stepwise under the conditions of water bath and microwave irradiation heating,respectively.The effects of molar ration of 1,4-butane sultone toβ-cyclodetrin,reaction temperature and initial amount of alkali on the degree of substitution were investigated,and the response surface experiments were conducted to optimize the synthesis process of SBE₇-β-CD regarding the DS as response value under the condition of microwave irradiation heating.The average degree of substitution and the characterization of SBE-β-CD were investigated by means of IR,NMR,MS and Capillary Electrophoresis after being purified by Sephadex G-25 chromatography.After which the inclusion ratio,stability constants of inclusion complex,and thermodynamic parameters between SBE-β-CD and nateglinide were studied at 27℃,37℃,50℃.The inclusion complex of SBE-β-CD/NTG was prepared by freeze-drying method.Its structure and possible inclusion model were investigated by means of FT-IR,DSC,XRD,SEM,and NMR.The results were as follows:（1）When the reaction temperature was 85℃and the molar ratios of 1,4-butane sultone toβ-cyclodetrin were 1:1,5:1,8:1,the DS of products were 1.24,4.12,6.39 separately,and the reaction time was 20³0h under water bath heating.At the same reaction temperature and molar ratios,the DS of products were 1.12,3.96,6.83 separately,and the reaction time was only 2³h under microwave irradiation heating.The optimal conditions obtained by response surface experiments were as follows:n（1,4-butane sultone）/n（β-cyclodetrin）was 7.84:1,n（1,4-butane sultone）/n（initial alkali）was 1:0.7,under which the DS of SBE-β-CD was 7.07.（2）Compared with the process heated by water bath,microwave irradiation heating process has advantages of shorter reaction time,less alkali,and higher utilization rate of materials.（3）SBE₇-β-CD and nateglinide formed a soluble inclusion complex with a 1:1 stoichiometry,which was in an amorphous state.Besides,the inclusion process was a spontaneous exothermic process（ΔG（27）-19kJ/mol）,and driven mainly by Van der Waals force,hydrophobic action and the release of high energy water molecules from the cavity of SBE-β-CD.