The molecular structure and crystal organization of rac-terfenadine/beta-cyclodextrin/tartaric acid multicomponent inclusion complex

Abstract

The crystalline ternary inclusion complex terfenadine/beta-cyclodextrin/tartaric acid (TFN/betaCD/TA, 2:4:1) has been prepared from a aqueous solution (terfenadine, TFN, rac-alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidine-butanol). The solubility of the multicomponent system in water is remarkably different from that of the single components. The crystal structure shows that the TFN guest adopts an extended conformation and that the diphenyl end of the molecule is docked in the cavity formed by the association of two independent betaCD molecules through hydrogen bonds connecting their wide rims. The structure of the dimer is deformed with respect to uncomplexed betaCDs, due to the shape of the guest. The two aromatic rings interact differently with the macrocycles forming the dimer, one being included perpendicular in the central cavity of one betaCD, the other laying parallel to the interface between the two rims. The t-Bu- end of the guest is included in the cavity of a betaCD belonging to a different dimer, entering from the side of the narrow rim. The central part of the guest is surrounded by water molecules and tartaric acid, which creates a hydrophilic microenvironment in the interstices among dimers. The enhanced solubility of the multicomponent system could be related to the hydrogen bonds between the tartaric acid and the oxygens belonging to the wide rims. The overall structural arrangement of the betaCD units is driven by the shape of the TFN guest which needs a hydrophobic environment at both ends. The lipophilic interactions between TFN and betaCD cavities are responsible for the relevant perturbation in the regularity of the packing of the hosts.