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

Abstract

The inclusion complex formation of a water‐soluble β1‐selective adrenoreceptor antagonist Metoprolol (Met) with α‐cyclodextrin (α‐CyD), β‐cyclodextrin (β‐CyD), γ‐cyclodextrin (γ‐CyD), and 2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐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 α‐CyD, β‐CyD, and HP‐β‐CyD in a stoichiometry of 1:1, whereas γ‐CyD forms the 2:1 complex where two Met molecules are included in one γ‐CyD cavity. NMR spectroscopic studies, including ROESY and GROESY techniques, clearly indicated that α‐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 β‐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 γ‐CyD cavity, and the benzene moieties of Met are in contact with each other. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1659–1671, 2004