Changes in naproxen (NAP) 13C-chemical shifts were measured as a function of the concentration of alpha-, beta-, and gamma-cyclodextrin (alpha Cd, beta Cd, and gamma Cd, respectively) in aqueous solution in order to obtain details on the mechanism, geometry, and stoichiometry of the respective interactions. The probable structures of the inclusion compounds of NAP with natural cyclodextrins were constructed using a molecular graphics program. The higher stability of the beta Cd:NAP 1:1 (mol/mol) complex in comparison with alpha Cd:NAP 2:1 (mol/mol) and gamma Cd:NAP 1:1 or 1:2 (mol/mol) complexes was accounted for in terms of a deeper, more complete, and better fitting inclusion of the drug into the cavity of beta Cd. The inclusion behavior of NAP with some statistically substituted beta Cd derivatives [hydroxyethyl-beta Cd (HE beta Cd), hydroxypropyl-beta Cd (HP beta Cd), and methyl-beta Cd (M beta Cd)] was also investigated through 13C-NMR, UV, circular dichroism spectroscopy, and phase-solubility analysis. The stoichiometry of host:guest interactions was the same as with beta Cd, as were thermodynamics and basic complexation mechanisms. The binding between the host and guest molecules is thought to be mainly due to van der Waals, dipole-dipole, and hydrophobic interactions. The inclusion ability of the parent beta Cd was enhanced by the introduction of methyl, hydroxyethyl, and hydroxypropyl groups. The M beta Cd formed the most stable inclusion complex (apparent formation constant K(1:1) = 6892 L.mol-1 at 298 K); it was about three times more stable than those with HP beta Cd or HE beta Cd and four times more stable than that with beta Cd.(ABSTRACT TRUNCATED AT 250 WORDS)