Enantioseparation And Chiral Recognition Mechanism Of Fluoxetine Enantiomers

In this study, β-cyclodextrin (β-CD) and (cellulose-[4-methyl-phenyl carbamate)were used to separate the fluoxetine enantiomers ((R/S)-FLU). The β-CD was used toseparate the (R/S)-FLU as chiral mobile phase additive in the reversed phase. Theeffect of mobile phase composition, pH, ionic strength, the concentration of β-CD andtemperature on the separation of (R/S)-FLU was investigated. Relationships wereestablished between these factors and the two most important chromatographicparameters: retention time and selectivity. It was found that the unique selectivity ofβ-CD is due to inclusion complex formation, which provides the physical basis forenantiomeric resolution.After these studies, the chiral recognition mechanism of β-cyclodextrin andfluoxetine was described by the computer simulation. In this study, molecular dockingsimulations of fluoxetine and β-CD was executed with the automated dockingprogram (AutoDock) and the lowest binding energy configuration with the highestfrequency was selected as the representative. The results showed that host–guestinteraction of (R)-FLU/β-CD complex was stronger than that in (S)-FLU/β-CDcomplex. Then the dominating configurations of the (R/S)-FLU/β-CD complexeswere further optimizated by the two-layered ONIOM method. The modeling resultsshowed that the chiral carbons (C*) in (R)-FLU was closer to the XY flat and thechiral carbons of β-CD than that in (S)-FLU. Then the natural bond orbital analysis(NBO) was applied to study the interaction between subject and object. The results showed that the hydrogen bonding and hydrophobic interactions play an importantrole in the chiral recognition between β-CD and (R/S)-FLU.In the normal phase,(cellulose-[4-methyl-phenyl carbamate) was used toseparate the (R/S)-FLU as chiral stationary phase. The liquid chromatographicretention behavior of (R/S)-FLU on the (cellulose-[4-methyl-phenyl carbamate)bonded-phase column was investigated with respect to the mobile phase composition,the content of diethylamine and the temperature. The results showed that goodseparation of (R/S)-FLU was obtained when the liquid phase was isopropyl mixedwith n-hexane. At high temperature, the enantiomers migrated faster and lowseparation efficiency was obtained. The diethylamine concentration was found tomodulate the separation efficiency but the retention time did not have muchdiversification. Additionally, the thermodynamic parameters in the process ofenantioseparations were determined and found that the separation of (R/S)-FLU wasenthalpy-driven process.