Thermodynamics of amitriptyline recognition by native and modified cyclodextrins: An isothermal titration calorimetry and NMR study

The supramolecular interactions between amitriptyline hydrochloride (AMT) and natural (αCD, βCD, γCD) and modified cyclodextrins (MβCD, HPβCD) were investigated by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. ITC experiments performed at four temperatures provided binding constants and thermodynamic parameters (ΔG°, ΔH°, TΔS°, and ΔCp). βCD exhibited the highest affinity toward AMT, whereas γCD showed weaker interactions due to its larger cavity, and MβCD and HPβCD displayed reduced affinity because of steric effects from substituents. Enthalpy-entropy compensation was observed for all systems, while negative ΔCp values indicated water displacement from the CD cavity and reduced molecular flexibility upon complexation. NMR, including 2D NOESY experiments, supported host–guest inclusion. These findings demonstrate that cavity size, substitution, hydration, and molecular flexibility govern the thermodynamics of AMT-CD recognition in aqueous solution.