NMR spectroscopic characterization of metoprolol/cyclodextrin complexes in aqueous solution: cavity size dependency

The inclusion complex formation of a water-soluble beta(1)-selective adrenoreceptor antagonist Metoprolol (Met) with alpha-cyclodextrin (alpha-CyD), beta-cyclodextrin (beta-CyD), gamma-cyclodextrin (gamma-CyD), and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in aqueous solution was studied by ultraviolet (UV), circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopies and the modes of interaction were assessed. Continuous variation plots revealed that Met forms the inclusion complexes with alpha-CyD, beta-CyD, and HP-beta-CyD in a stoichiometry of 1:1, whereas gamma-CyD forms the 2:1 complex where two Met molecules are included in one gamma-CyD cavity. NMR spectroscopic studies, including ROESY and GROESY techniques, clearly indicated that alpha-CyD with the small cavity includes the methoxyethylbenzene moiety of Met molecule shallowly in the cavity, depositing the benzene and the methoxy moieties around the secondary and primary sides, respectively, of the cavity. In the case of the beta-CyD complex, the methoxyethylbenzene moiety is more deeply included in the cavity, and it is feasible that Met may be able to enter from both primary and secondary hydroxyl sides of the cavity, forming the 1:1 complex. On the other hand, two Met molecules are included probably in an antiparallel orientation in the large gamma-CyD cavity, and the benzene moieties of Met are in contact with each other.