Interaction of Omeprazole with a Methylated Derivative of β-Cyclodextrin: Phase Solubility, NMR Spectroscopy and Molecular Simulation

Abstract

Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of beta-cyclodextrin, methyl-beta-cyclodextrin (MbetaCD). A comparison with results obtained from the most commonly used natural cyclodextrin, beta-cyclodextrin (betaCD) is also presented in most cases. The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D (1)H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. (1)H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MbetaCD than in betaCD cavity, in agreement with a larger apparent stability constant (K (S)) obtained for the inclusion complex with MbetaCD. MbetaCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.