The thermodynamic parameters, Delta(B)G degrees, Delta H-B degrees, Delta S-B degrees, and Delta C-B(p), of the drugs flurbiprofen (FLP), nabumetone (NAB), and naproxen (NPX) binding to beta-cyclodextrin (beta CD) and to gamma-cyclodextrin (gamma CD) 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 center dot mol(-1) center dot K-1 for FLP and -(238 +/- 90) J center dot mol(-1) center dot K-1 for NAB binding in the beta CD cavity to 0 for FLP and -(25.1 +/- 9.2) J center dot mol(-1) center dot K-1 for NPX binding in the larger gamma CD cavity, implying that the structure of water is reorganized in the beta CD binding reactions but not reorganized in the gamma CD 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 beta CD binding reactions indicated that some localized water was retained in the FLP-beta CD complex and almost none in the NAB-beta CD complex. No fluorescence change occurs with drug binding in the larger gamma CD cavity, indicating the retention of the bulk water environment in the drug-gamma CD complex. Since the specific drug binding interactions are essentially the same for PCD and gamma CD, these differences in the retention of bulk water may account for the enthalpically driven nature of the beta CD binding reactions and the entropically driven nature of the gamma CD binding reactions. (C) 2007 Elsevier Ltd. All rights reserved.