Thermodynamic analysis of butylscopolamine bromide inclusion in native and modified cyclodextrins: an isothermal titration calorimetry investigation

The temperature-dependent thermodynamics of supramolecular complexation between butylscopolamine bromide (BSB) and native (α-, β-, and γ-cyclodextrins) and substituted β-cyclodextrins were investigated by isothermal titration calorimetry (ITC). Among the native CDs only β-CD exhibit a measurable heat flow, with a 1:1 stoichiometry, with binding predominantly entropic driven. The CMβ-CD: BSB system showed the strongest enthalpic stabilization, comparing all investigated systems, and a negative heat capacity change (ΔCp < 0), consistent with cavity dehydration and reduction of solvent-exposed nonpolar surface area upon inclusion. The enhanced affinity observed for CMβ-CD relative to neutral derivatives (native or substituted ones) indicates cooperative contributions from hydrophobic inclusion and electrostatic attraction between the cationic guest and anionic substituents. Linear correlation between ΔH° and TΔS° revealed near complete enthalpy-entropy compensation, leading to weak temperature dependence of ΔG°. The compensation behavior, supported by consistent stoichiometry and coherent ΔCp values, suggests intrinsic solvent mediated thermodynamic coupling. Overall, the results provide a comprehensive calorimetric description of BSB recognition by modified CDs and clarify how substituent chemistry modulates the balance between enthalpic stabilization and entropic penalty in aqueous supramolecular systems.