Inclusion complexes formulation between benzimidazole compounds and carboxylic β-cyclodextrin derivatives

PRIOTTI, J.; LAMAS, M. C.; LEONARDI, D.; GARCÍA, A.

Rosario

Congreso; RICIFA 2016; 2016

RICIFA

Poorly soluble drugs often present a limited therapeutic activity, due to its low absorption and its consequent low bioavailability. Inclusion complexes formulation employing β-cyclodextrin (β-CD) is one of several approaches to enhance the physicochemical properties of pharmaceutical compounds. The aim of this work was to evaluate the affinity and solubility of two poorly soluble compounds for β-CD and two β-CD derivatives. Phase solubility studies were obtained according to Higuchi and Connors. Excess amount of each drug, mebendazole (MBZ) and ricobendazole (RBZ) was added to solutions containing different concentrations of β-CD (0-15 mM), succinyl-β-CD (0-50 mM) and citrate-β-CD (0-50 mM). Samples were shaken for 72 h at 25ºC. After that, samples were filtered and analyzed spectrophotometrically. In addition, inclusion complexes were prepared in solution and then sprayed in a Buchi Mini Spray Dryer B-290 to obtain the solid complexes. Physical mixtures were also prepared for comparison. NMR studies were conducted to determine the binding mode between the cyclodextrins and the drugs. Finally, the apparent solubility in water of each inclusion complex was assayed. The phase solubility diagrams displayed a linear relationship between the drugs and cyclodextrins, indicating complex formation in 1:1 molar ratio. The values of the complex formation constant (Kf) obtained for each drug and citrate-β-CD were higher than the Kf values for β-CD and succinyl-β-CD. ROESY spectra showed cross peaks between internal protons of β-CD derivatives and aromatic protons of benzimidazole compounds. These results showed that the non-polar portion of the guest structure was included. The apparent solubility of both drugs, MBZ and RBZ, was higher in citrate-β-CD complexes than in β-CD and succinyl-β-CD complexes. Therefore, we may conclude that citrate-β-CD would be a promising excipient for the development of new pharmaceutical formulations of poorly soluble drugs.