The role of water in the thermodynamics of drug binding to cyclodextrin

Abstract

The thermodynamic parameters, Δ B G ∘, Δ B H ∘, Δ B S ∘, and Δ B C p , of the drugs flurbiprofen (FLP), nabumetone (NAB), and naproxen (NPX) binding to β-cyclodextrin (βCD) and to γ-cyclodextrin (γCD) in 0.10 M sodium phosphate buffer were determined from isothermal titration calorimetry (ITC) measurements over the temperature range from 293.15 K to 313.15 K. The heat capacity changes for the binding reactions ranged from −(362 ± 48) J · mol −1 · K −1 for FLP and −(238 ± 90) J · mol −1 · K −1 for NAB binding in the βCD cavity to 0 for FLP and −(25.1 ± 9.2) J · mol −1 · K −1 for NPX binding in the larger γCD cavity, implying that the structure of water is reorganized in the βCD binding reactions but not reorganized in the γCD binding reactions. Comparison of the fluorescence enhancements of FLP and NAB upon transferring from the aqueous buffer to isopropanol with the maximum fluorescence enhancements observed for their βCD binding reactions indicated that some localized water was retained in the FLP–βCD complex and almost none in the NAB–βCD complex. No fluorescence change occurs with drug binding in the larger γCD cavity, indicating the retention of the bulk water environment in the drug–γCD complex. Since the specific drug binding interactions are essentially the same for βCD and γCD, these differences in the retention of bulk water may account for the enthalpically driven nature of the βCD binding reactions and the entropically driven nature of the γCD binding reactions.