Application Of Two Cyclodextrin Derivatives In Common Pharmaceutical Enantioseparation By Capillary Electrophoresis

During the past thirty years, the safety of drug becomes more and more important, so more attentions have been paid to drug stereochemistry issues. It is no exaggeration to say that the chiral separation is an important branch of analytical chemistry. And now, capillary electrophoresis (CE) is regarded as one of the best techniques in the pharmaceutical enantioseparation. Cyclodextrins (CDs) and their derivatives were very popular and widely used as chiral selectors in CE. Cyclodextrin chiral separation is still very hot and difficult in present research. Therefore, two cyclodextrin derivatives were chosen as CE chiral selectors and used to study the enantioseparation of several kinds of common chiral drugs in this dissertation.On the basis of the previous literatures, in this dissertation, some original studies are carried out as followings:(1) Using neutral cyclodextrin HP-β-CD as chiral selector, a new capillary zone electrophoresis method was described for the enantioseparation of the positively charged isomers of palonosetron hydrochloride; a microemulsion electrokinetic chromatography method was successfully developed for the two kinds of uncharged drug enantiomers for the first time.(2) Using random methylated cyclodextrin (RM-β-CD) as chiral selector, four common chiral drugs were successfully separated by capillary zone electrophoresis. Multi-component chiral selector was successfully applied to chiral separation in the dissertation.This dissertation consists of four chapters.Chapter 1:ReviewThis chapter outlines the theories of capillary electrophoresis chiral separation, and summarizes the latest researches of chiral selectors. Cyclodextrin and its derivatives were specifically summarized. Finally, the further study of chiral separation was discussed.Chapter 2-4 Experimental partsChapter 2:A new capillary zone electrophoresis (CZE) investigation on the enantiomeric separation of palonosetron hydrochloride was described. Baseline separation of the isomers was achieved by using hydroxypropyl-β-cyclodextrin (HP-β-CD) as chiral selector. For method optimization, parameters influencing separation, including HP-β-CD concentration, buffer pH, organic modifier concentration and applied voltage, were discussed. The optimized CD-CZE conditions were that 40 mmol/L phosphate buffer (pH 3.10) containing 30 mmol/L HP-β-CD and 20%(v/v) methanol with an applied voltage of 15 kV. In this study, the four isomers can be completely separated within 25 min.Chapter 3:In this chapter, new CZE methods for the enantioseparation of four chiral drugs were built by using randomly methylated-β-cyclodextrin (RM-β-CD) of high degree substitution as chiral selector. The average molecular degree of substitution of RM-β-CD is 14.0. The enantiomers of ofloxacin and ketoconazole can be baseline separated under the best condition. For method optimization, the influence of experimental parameters on separation of ofloxacin and ketoconazole including RM-β-CD concentration, buffer pH and applied voltage were examined. And the peaks'sequence of ofloxacin was confirned. Mixture CD should be widely used in chiral separation.Chapter 4:In the chapter, neutral cyclodextrin HP-β-CD modified microemulsion electrokinetic chromatography (MEEKC) was used in chiral separations of two acidic drugs. The microemulsion was comprised of 1.5%(m/v) SDS,6.8%(v/v) 1-butanol and 0.2%(v/v) octane. The enantiomers of warfarin and ketoprofen can both be baseline separated under the optimum experimental condition. For method optimization, the influence of experimental parameters on enantioseparations of warfarin and ketoprofen, including HP-β-CD concentration, buffer pH and applied voltage, were examined.