The synthesis and process optimization of sulfobutyl ether β-cyclodextrin derivatives

A series of sulfobutyl ether β-Cyclodextrins (SBE-β-CDs) with specific average degree of substitution (DS) were successfully synthesized, using a three-step synthesis method, through the reaction between β-Cyclodextrin (β-CD) and 1, 4-butane sultone in the sodium hydroxide solution. Although the ratio of β-CD and 1, 4-butane sultone is a dominant factor affecting the average degree of substitution of products, a typical optimization on other synthesis parameters is also necessary to precisely obtain these products. The optimization includes the addition of sodium hydroxide solution, the range of pH and reaction time in different reaction stages. Actually, each product is a mixture with various degrees of substitution and different positional isomers. Under the optimal conditions, the average degree of substitution and the characterizations of SBE-β-CDs were investigated by means of FTIR, 1H NMR, 13C NMR, HRMS, Capillary Electrophoresis, DSC and HPLC. The results indicated that the substitution reaction occurred simultaneously on C6–OH and C2–OH in the moderate alkaline solution and the proportion of C2–OH substituted increased with the increase of DS. The DS of SBE-β-CDs had better reproducibility and the distribution of composition analyzed by capillary electrophoresis was a normal distribution. In the novel synthesis process, the yield of the products was significantly improved. For example, the yield of SBE7-β-CD reached up to 80%. Moreover, the DS of SBE7-β-CD was 6.68 and the purity of SBE7-β-CD was 96% in line with quality standards of United States Pharmacopeia.