Simple circular dichroism method for selection of the optimal cyclodextrin for drug complexation

Abstract

Abstract: Cyclodextrins are very important excipients in the pharmaceutical industry. Given the multitude of native and semisynthetic cyclodextrin derivatives, there is a need for a rapid and reliable method for the selection of the optimal cyclodextrins for further pharmaceutical testing. During our research, circular dichroism (CD) spectroscopy has been successfully used to describe the qualitative and quantitative complexation of model compounds with different cyclodextrins. For the appearance of a circular dichroism signal, either a chiral or a chirally perturbed chromophore is required. Achiral or racemic compounds do not have corresponding circular dichroism spectra and neither do chiral cyclodextrins due to the absence of a chromophore group. During complexation of a chromophoric guest molecule, its absorption transition becomes chirally perturbed in the proximity of a cyclodextrin molecule and an induced circular dichroism (ICD) signal appears. This phenomenon gives an inherent selectivity to the method. The sign and intensity of the induced circular dichroism signal in case of different cyclodextrins provides information about the approximate structure of the complex as well as their stability relative to each other. In this study, we report a straightforward induced circular dichroism -based approach for the rapid preselection of the optimal cyclodextrin. The distinctive features of the method were demonstrated using five azole-type antifungal drug molecules (fluconazole, miconazole, clotrimazole, bifonazole and tioconazole) along with native α-, β-, and γ-cyclodextrins, as well as dimethyl-, trimethyl-, carboxymethyl-, hydroxypropyl- and sulfobuthylether-β-cyclodextrins. In addition, with the aid of this method, 27 stability constants were determined, amongst which 16 have been unavailable in the literature previously. Graphic abstract: [Figure not available: see fulltext.].