Inclusion complexes of (S)-naproxen and native cyclodextrins: Supramolecular structure and stability

Abstract

Cyclodextrins/naproxen inclusion complexes were formed by a modified ball-milling technique and compared with those obtained by the pharmaceutically approved kneading method. The inclusion was proved by FT-IR and NMR spectroscopies. For both β- and γ-CD the inclusion of naproxen was found to be fast and efficient. An indirect additional proof for the complex formation was obtained by DSC, a method also offering a quantitative estimation of the degree of complexation, which was shown to be almost full (>99%) for γ-CD and a little lower for β-CD. Molecular modeling approaches provide insights into the structure of the CDs/naproxen complexes at a molecular level and represent the ideal choice for a detailed understanding of the major driving forces for the CDs complex formation. The calculated thermodynamic parameters showed spontaneous complex formation of β-CD/naproxen and γ-CD/naproxen complexes. The stability of the host-guest complexes was found to depend substantially on the orientation of the incoming guest molecule (on its binding mode inside the CD cavity). From both the experimental and theoretical studies can be concluded that the naproxen molecule is entering into the CD cavity with its carboxylic group (COO−) oriented towards the narrower CD rim and participates in hydrogen bonding with its OH-groups.