Conformational Change in the Mechanism of Inclusion of Ketoprofen in β- Cyclodextrin: NMR Spectroscopy, Ab Initio Calculations, Molecular Dynamics Simulations and Photoreactivity

Inclusion of drugs in cyclodextrins is a recognised tool for modifying several properties such as solubility, stability, bioavailability and more. The photoreactive behavior of the β-Cyclodextrin/Ketoprofen complex upon UV exposure showed a significant increase of the photo-decarboxylation while the secondary degradation products by hydroxylation of the benzophenone moiety were inhibited. The results may account for an improvement of Ketoprofen photophysical properties upon inclusion, thus fostering better its topical use. To correlate the structural details of the inclusion with these results a NMR spectroscopic study of Ketoprofen upon inclusion in β-Cyclodextrin was performed. Effects of the magnetically anisotropic centers of ketoprofen, changing their orientations upon inclusion giving chemical shift variations, were specifically correlated to the results of the molecular dynamic simulations and ab initio calculations. In the large variety of papers focusing on the structural analysis of β-cyclodextrin complexes, this work represents one of the few examples in which a detailed analysis of these simultaneous upfield-downfield NMR shifts of the same aromatic molecule upon inclusion is reported. Interestingly the results demonstrate that the observed upfield and downfield shifts upon inclusion are not related to any direct magnetic role of the  cyclodextrin. The conformational change of Ketoprofen upon the inclusion process consists in a slight reduction of the angle between the two phenyl rings and in a remarkable reduction of the mobility of the carboxyl group, the latter being one of the main contributions to the NMR resonances shifts. These structural details help in understanding of the inclusion complex features and, eventually, of the driving force for its formation.