Chiral Separations by Nonaqueous Capillary Electrophoresis

Abstract

This paper reports successful chiral separations of pharmaceutical racemic amines by nonaqueous capillary electrophoresis (NACE) using β- and γ- cyclodextrins (CDs) and various derivatives of β-CDs. The results in three organic solvents, formamide (FA), N-methylformamide (NMF), and N,N-dimethylformamide (DMF) were compared to those in pure water and in 6 M urea in water systems. The binding constants of trimipramine, mianserin, and thioridazine with β-CD were determined in the following five solvent systems: water, 6 M urea in water, FA, NMF, and DMF. The binding constants decreased systematically from ∼10⁴ in water to ∼10 in FA and ∼10^-2 in DMF. As a result, the optimum CD concentration in the aqueous media is in the high micromolar range, while that in the FA is around 100 mM. In the aqueous media, the occurrence of the optimum at very low concentrations and the rapid changes in enantioselectivity with CD concentration would make it difficult to develop methods based on trial and error. Nevertheless, it is shown that, even under nonoptimum concentrations of the chiral selector, other experimental parameters such as ionic strength, addition of tetraalkylammonium (TAA⁺), and temperature can be adjusted to achieve acceptable resolutions. This, however, is often achieved at the expense of longer analysis times. In addition, the effects of apparent pH (pH*) and type of cyclodextrin on chiral separations in NACE are studied. The application of negatively charged β-CD in FA is also reported. Chiral separation of trimipramine was achieved at lower concentration of anionic CD due to the additional Coulombic interactions.