Inclusion complexes of nabumetone with β-cyclodextrins: Spectroscopic, spectrometric and calorimetric studies in solution

The complexation of nabumetone (NAB) with various cyclodextrins (CDs): beta-cyclodextrin (beta-CD), hydroxypropyl-beta-CD (HP beta CD), randomly methylated beta-CD (RM beta CD), and sulfobutylether sodium salt beta-CD (SBE beta CD), was investigated as a mean to increase the poor solubility of NAB both in water and simulated biorelevant media (pH = 1.0 (HCl) and pH = 4.5 and 6.8 (phosphate buffer)). An approximately 170 times increase in NAB solubility was achieved for SBE beta CD in all media. The formation of 1:1 complexes was confirmed by phase-solubility measurements, spectrofluorimetric titration and high resolution mass spectrometry. Additionally, isothermal microcalorimetric titrations were employed to determine thermodynamic parameters (lgK, Delta(r)G(0), Delta H-r(0), Delta S-r(0)). Stability constants (lgK = 3.42; 3.41; 3.47 and 3.62 for NAB complexes with beta-CD, HP beta CD, RM beta CD, and SBE beta CD, respectively) agree with those obtained by phase-solubility experiments and spectrofluorimetric titrations. The inclusion was enthalpy and entropy favorable. NMR analyses showed two possible orientations of NAB in the beta-CD cavity simultaneously exist in the solution, with a naphthalene ring inside the beta-CD cavity and methoxy or butanone substituent oriented towards the narrow beta-CD rim. All experimental results are in good agreement with those based on molecular modeling previously reported in the literature.