STUDIES OF CYCLODEXTRIN INCLUSION COMPLEXES .2. MOLECULAR MODELING AND H-1-NMR EVIDENCE FOR THE SALBUTAMOL-BETA-CYCLODEXTRIN COMPLEX

β-Cyclodextrin (β-CYD) has a hydrophobic cavity in which salbutamol may be clathrated. The ability of a guest molecule to penetrate the CYD host is determined by its size, stereochemistry and polarity. Intermolecular interactions such as the hydrophobic interaction, van der Waals forces, H bonding and other physical forces are involved in the inclusion complexation process. Proton-NMR was employed to assess the mode of inclusion of salbutamol within the β-CYD cavity. The technique is based on the shielding of the CYD and drug protons. If inclusion does occur, protons located within or near the CYD cavity should be strongly shielded. The spectra showed upfield shifts of the CYD protons in the presence of salbutamol and the salbutamol protons shifted downfield in the presence of β-CYD. The downfield shifts of the aromatic protons were greater than those of the aliphatic protons, suggesting that the aromatic ring of salbutamol interacts more strongly with the β-CYD. The interior protons of the CYD molecule were shielded as a result of the anisotropy of the guest aromatic moiety. The highest shifts of β-CYD protons occurred for a molar ratio of 1:1 (salbutamol:β-CYD) indicating the probable stoichiometry of the complex. Molecular graphical computation showed that the minimum van der Waals energy positioning of salbutamol relative to β-CYD occurs when the aromatic ring of salbutamol penetrates the cavity leaving the aliphatic chain externalised. © 1990.