Structural Effects on the Binding of Amine Drugs with the Diphenylmethyl Functionality to Cyclodextrins. I. A Microcalorimetric Study

Abstract

Solution calorimetry has been employed to evaluate the stability constants and enthalpy changes associated with complex formation between α-, β, or -γ-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. Data from thermal titrations of the compounds were analyzed using nonlinear least squares. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative standard enthalpy change (ΔH°). The standard entropy change (ΔS°) was negative, except in the case of complexes formed with γ-CD. Of the 13 compounds studied, only 2 formed complexes with 1:2 (compound: (β-CD) stoichiometry, terfenadine · HC1 and cinnarizine · 2HC1. All the others formed 1:1 complexes. The structural effect on the stability constants, thermodynamics, and inclusion geometry was explored by relating the calorimetric results to the chemical structures of the guest molecules and the cavity sizes of the CD molecules. The results suggest that one of the phenyl groups of the diphenylmethyl functionality resides in the CD cavity and is in van der Waals contact with the inside wall of the CD cavity. In the case of α- and β-CDs, van der Waals interaction dominates in the stabilization. On the other hand, the interaction between these compounds and γ-CD is largely entropically driven. Adiphenine · HC1 forms a more stable complex with β-CD than proadifen · HC1, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl group on the rim of the CD ring can influence the strength of the binding interaction.