Mechanism Study Of Chiral Separation Of β-blockers Using Cyclodextrins In Aqueous And Non-Aqueous Capillary Electrophoresis

Nowadays, there has been a growing interest in the separation of chiral drugs such as β-blockers due to its difference in pharmacodynamics and pharmacokinetics. Capillary electrophoresis(CE), owing to its high peak efficiency, fast and lower consumption of sample and solvent, has been widely applied in chiral separation. The advantages of non-aqueous capillary electrophoresis(NACE), such as low conductivity, favorable dissolution ability of hydrophobic compounds, improved compatibility with mass spectrometric detector compared to aqueous capillary electrophoresis(ACE), extended the chiral application. The reversal of enantiomer migration order(EMO) with aqueous and non-aqueous CE becomes a topic in past few years. Consequence, in this paper β-cyclodextrin(β-CD) and its derivatives were chosen as chiral selectors in order to develop a rapid method for the enantioseparation of eight β-blockers in both ACE and NACE systems. The chiral recognition mechanism was also investigated by the invert of EMO and enantiomer affinity pattern(EAP).Chapter 1. The importance of enantioseparation of β-blockers, the enantiorecognition principle of CE, the significance and application of β-CD in enantioseparation, common methods used for studying recognition mechanisms have been reviewed. The reversal of EMO and EAP which were played a significant role in chiral mechanism study was also discussed in this part. The innovation of this study was finally highlighted.Chapter 2. 2-hydroxypropyl-β-cyclodextrin(2-HP-β-CD) was chosen as chiral selector to investigate the effect of various factors, including buffer concentration, buffer p H, p H adjusters, and separation temperature and voltage in ACE. After optimizing the conditions, eight β-blockers were enantioseparated in both ACE and NACE mode using β-CD, 2-HP-β-CD, 6-sulfated-β-CD(6-S-β-CD), heptakis(2,3-diacetyl-6-sulfato)-β-CD(HDAS-β-CD) and heptakis(2,3-dimethyl-6-sulfato)-β-CD(HDMS-β-CD) as chiral selector, respectively. The results showed that HDAS-β-CD and HDMS-β-CD exhibited good enantioselectivity for compounds.Chapter 3. The EMO and EAP of eight β-blockers were systematically studied usingenantio-enriched samples. The reversal of EAP under different separation conditions was observed for some β-blockers. This phenomenon was explained based on the structure properties of compounds and CDs under different conditions(ACE and NACE).Chapter 4. In order to better understand the possible chiral recognition mechanism between β-blockers and two selected CDs, the molecular docking study was carried out using talinolol as compound. The binding free energy was calculated and the results showed that both hydrogen bonding interaction and hydrophobic interaction played an important role in the enantiorecognition process of two CDs to talinolol, which was responsible for the observed reversal of EMO and EAP in CE.Chapter 5. The conclusions and the future outlooks of this research were discussed.