Carbon-13 nuclear magnetic resonance study of naproxen interaction with cyclodextrins in solution

Changes in naproxen (NAP) 13C‐chemical shifts were measured as a function of the concentration of α‐, β‐, and γ‐cyclodextrin (αCd, βCd, and γCd, 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 βCd:NAP 1:1 (mol/mol) complex in comparison with αCd:NAP 2:1 (mol/mol) and γCd: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 βCd. The inclusion behavior of NAP with some statistically substituted βCd derivatives [hydroxyethyl‐βCd (HEβCd), hydroxypropyl‐βCd (HPβCd), and methyl‐βCd (MβCd)] 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 βCd, 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 βCd was enhanced by the introduction of methyl, hydroxyethyl, and hydroxypropyl groups. The MβCd 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 HPβCd or HEβCd and four times more stable than that with βCd. The MβCd also showed the highest solubilizing effect for NAP, whose aqueous solubility at 298 K increased 377 times in the presence of 0.1 mol · L−1 of MβCd. The C‐13 nuclear relaxation measurements revealed that the molecular motion of NAP was reduced in a solution of HEβCd, indicating that the drug was located inside the hydrophobic core or at least in contact with the macrocycle. The importance of apolar binding in the complexation of NAP with βCds was also demonstrated from the positive entropy values and from the dioxane‐induced solvent C‐13 NMR shifts.