| The mechanisms of isomeric separation by capillary zone electrophoresis (CZE) of several pharmaceutical compounds are investigated.; In the first chapter, the mechanisms of various diastereomeric separations, such as those for cis- and trans-aminoindanols and diastereomers of dorzolamide, are discussed. The separations are achieved based upon differences in the pKa values of the cis- and trans-diastereomers. The separation of cis and trans-aminoindanols using non-aqueous CZE is also studied and shows better resolution in comparison to the aqueous system. The isomeric separation based on pKa differences can also be applied to various positional isomers. The cationic positional isomers of aminoquinoline and the anionic positional isomers of difluorophenyl-acetic acid are successfully separated.; In the second chapter, the separations of aminoindanol enantiomers through the utilization of {dollar}alpha{dollar}-and {dollar}beta{dollar}-cyclodextrins (CDs) as chiral selectors are discussed. Thermodynamic studies establish a dynamic separation model of the inclusion complex between the enantiomers and CDs. Binding of the cis-aminoindanol enantiomers to the CDs is stronger than the trans-enantiomers. van't Hoff plots indicate that inclusion complex formation is enthalpically-driven in the temperature range from 15{dollar}spcirc{dollar}C to 35{dollar}spcirc{dollar}C. The CZE separation mechanism is also supported by HPLC and molecular modeling calculation. The effects of the buffer pH, urea additive, size of the chiral selectors and the presence of a hydroxyl group on the analyte are analyzed by examining the thermodynamic parameters.; In the third chapter, the enantiomeric separation of a novel orally active growth hormone secretagogue, using {dollar}beta{dollar}-cyclodextrin as a chiral selector is discussed. The resolution, the effective electrophoretic mobility of analytes, and the electroosmotic flow are studied as function of the concentrations of {dollar}beta{dollar}-CD, organic modifier and ion pairing reagents in the electrolyte. The effects of CZE operating conditions, such as the temperature, the applied voltage, and the apparent pH of the electrolyte are also examined. The results of these experiments demonstrate that the concentrations of {dollar}beta{dollar}-CD and L-tartaric acid, pH, and temperature are the key parameters for the enantiomeric separation. This separation technique is fully validated according to cGMP standards for limits of detection (LOD) and quantitation (LOQ), detection linearity, precision, accuracy, and ruggedness. |
