Succinyl-beta-cyclodextrin: influence of the substitution degree on albendazole inclusion complexes probed by solid-state NMR

LEONARDI, D.; NUNES, T. G.; PRIOTTI, J.; LAMAS, M. C.; GARCÍA, A.; FERREIRA, M. J. G.

Rosario

Congreso; 4ª Reunión Internacional de Ciencias Farmacéuticas; 2016

Universidad Nacional de Rosario y Universidad Nacional de Córdoba

The bioavailability of poor aqueous soluble drugs still represents a vital concern to the pharmaceutical industry. Cyclodextrin (CD) inclusion complexes have been reported to stabilize amorphous albendazole (ABZ), one of the most effective broad-spectrum anthelmintic agents, and consequently improve its solubility and dissolution rate in water. Solid-state NMR studies were reported on ABZ and several beta-CD derivatives. Three molecules were identified in the asymmetric unit of crystalline ABZ and a strong dependence of the number and type of ABZ species on the beta-CD substituent was revealed, under a non destructive mode. The highest ABZ solubilization was achieved in the presence of citrate-beta-CD and the dominant spectral signals were assigned to an inclusion complex (IC1). The aims of the present study were to elucidate the ABZ structure in inclusion complexes of ABZ:succinyl-beta-CD derivatives and the influence of the substitution degree (DS) in the number and type of the inclusion complexes. Succinyl-beta-CD derivatives were obtained by green synthesis with DS of 1.3 and 2.9, and solid dispersions with ABZ were prepared by the spray-drying technique. Comparable ABZ solubility was reached using citrate-beta-CD or succinyl-beta-CD derivative with DS of 2.9. However, unlike with citrate-beta-CD, at least two different ABZ amorphous species were identified in solid-state NMR data obtained from solid dispersions of ABZ: succinyl-beta-CD derivatives. Relevant chemical shifts of imidazole ring carbons were observed at 162 and 153 ppm (similar to IC1), and 155 and 149 ppm (IC2), suggesting two different electronic environments. Phase solubility studies indicated that both succinyl-beta-CD derivatives formed 1:1 inclusion complexes with ABZ, and the stability constants were 1164 M−1 (DS=1.3), and 515 M−1 (DS=2.9), respectively. ROESY spectra of ABZ:succinyl-β-CD systems showed strong correlation signals between the three aromatic protons of ABZ and the CD protons.The affinity and solid-state structure of ABZ: succinyl-beta-CD complexes were directly affected by DS.