Characterization of the inclusion complex formed by the antihelmintic drug Mebendazole and b-cyclodextrin. Molecular modeling and FT-IR analysis

SAIDMAN, E.; ARAGON, L.; SANCHO, M.I; LONGHI, M

Córdoba

Congreso; 3 Reunión Internacional de Ciencias Farmacéuticas; 2014

Universidad Nacional de Córdoba

Mebendazole (MBZ) is commonly used as a broad spectrum antihelmintic drug, commercialized as a tablet formulation or as a suspension. However, this drug is associated with a low aqueous solubility and therefore, a poor absorption from the intestinal tract. Different methods can be used to increase the aqueous solubility of a drug, being the formation of inclusion complexes with cyclodextrins one of the most employed. A molecular modeling analysis and FT-IR spectroscopy measurements were performed in order to elucidate the intermolecular interactions between MBZ and B-cyclodextrin (BCD). The inclusion process between neutral and protonated MBZ (MBZ-H+) with BCD was simulated with the PM3 semiempirical method, and two possible orientations were considered for each complex, Head up and Head Down, following a previously published report. The more stable complexes were further optimized with a two-layer ONIOM (B3LYP/6-31G(d):PM3) method and the interactions between the guest drug and BCD were quantified with a NBO population analysis. The FT-IR spectra of MBZ, BCD, the inclusion complex obtained by freeze dried and the physical mixture were registered in a Shimadzu IRAffinity-1 spectrophotometer, with a spectral resolution of 4 cm-1.The PM3 and ONIOM calculations indicated that the Head Down orientation is the preferred one for MBZ and MBZ-H+ inclusion complexes, by 5 and 9 kJ/mol, respectively. The benzimidazolic moiety was completely embedded in the BCD cavity in both cases. The NBO results showed an intermolecular H-bond between the imidazolic N of MBZ and one OH group from BCD, with a bond length of 2.61 Å and with stabilization energy of 7.9 kJ/mol. This interaction was further confirmed by FT-IR spectroscopy, where the MBZ stretching C=N band is located at 1645 cm-1 in the free drug and at 1653 cm-1 in the freeze dried MBZ:BCD complex.