Molecular modeling (MM2 and PM3) and experimental (NMR and thermal analysis) studies on the inclusion complex of...

The inclusion complex of salbutamol and beta-cyclodextrin (beta-CD) is studied by computational (MM2 and PM3) and experimental techniques. Molecular modeling calculations predict two different orientations of salbutamol in the beta-CD cavity in vacuo and in aqueous solution. In vacuo calculations show that the introduction of the aromatic ring of salbutamol is preferred to the introduction of the tert-butyl group into the beta-CD cavity. However, in aqueous solution both computational methods predict the introduction of the alkyl chain instead of the aromatic ring in the beta-CD cavity contrary to experimental results published previously. These quantitative predictions were experimentally confirmed here by studying the inclusion complex in solution by NMR. A 1:1 stoichiometry was found by (1)H NMR studies for this complex. A 2D ROESY (rotating-frame Overhauser enhancement spectroscopy) experiment shows that there are no cross-peaks between the aromatic protons of salbutamol and any of the protons of beta-CD. Cross-peaks for the protons of the tert-butyl group and protons inside the cavity of beta-CD demonstrate the full involvement of this group in the complexation process and confirm the orientation of the complex predicted by molecular modeling. The solid-state complex was prepared and its stoichiometry (beta-CD.C(13)H(21)NO(3).8H(2)O) and dissociation process studied by thermogravimetric analysis.