Molecular modeling (MM2 and PM3) and experimental (NMR and thermal analysis) studies on the inclusion complex of salbutamol and beta-cyclodextrin

The inclusion complex of salbutamol and beta -cyclodextrin (beta -CD) is st udied 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. Howe ver, in aqueous solution both computational methods predict the introductio n of the alkyl chain instead of the aromatic ring in the beta -CD cavity co ntrary to experimental results published previously. These quantitative pre dictions were experimentally confirmed here by studying the inclusion compl ex in solution by NMR. A 1:I stoichiometry was found by H-1 NMR studies for this complex. A 2D ROESY (rotating-frame Overhauser enhancement spectrosco py) experiment shows that: there are no cross-peaks between the aromatic pr otons 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.C13H2 1NO3.8H(2)O) and dissociation process studied by thermogravimetric analysis .