Thermodynamic parameters and molecular interactions governing chlorpropamide inclusion within cyclodextrins

Chlorpropamide is a sulfonylurea antidiabetic drug whose inclusion with cyclodextrins can modulate its aqueous behavior. The complexation of anionic chlorpropamide (CPM^-) with αCD, βCD, and HPβCD was investigated by phase-solubility studies, isothermal titration calorimetry (ITC), and DFT-based molecular modeling. At pH 7.0 and 298 K, phase-solubility and ITC data supported 1:1 complex formation. ITC revealed weak but measurable binding, with similar ΔG° values (between -2.17 and -2.74 kcalmol^-1) but distinct thermodynamic signatures: αCD complexation is enthalpy-driven, whereas βCD and HPβCD are mainly entropy-driven. The more negative ΔCp° of αCD (-119.20 calmol^-1 K^-1) is consistent with tight guest confinement, compact van der Waals contacts, and a distinct hydration environment in the narrow cavity, whereas βCD and HPβCD show profiles compatible with looser packing and more favorable solvent-related entropy. DFT modeling favors aromatic-ring orientation towards the secondary rim for the three hosts and highlights host-dependent differences in hydrogen bonding, dispersive contacts, deformation costs, and steric shielding by HP substituents. Free CPM^- displays eight low-energy conformers within 0.5 kcal mol^-1, consistent with a possible contribution from conformational selection. Speciation calculations indicate that HPβCD may achieve ∼83% complexation at saturation despite its lower affinity, suggesting practical advantages from its higher solubility in carbohydrate-based drug carriers.