Improvement of Solubility and Antifungal Activity of a New Aminothiophene Derivative by Complexation with 2-Hydroxypropyl-β-cyclodextrin

This study aimed to prepare a complex of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and 6CN10, a poorly water soluble 2-aminothiophene derivative with antifungal properties, by freeze-drying technique. The complex was characterized by thermal analysis, infrared/Raman spectroscopy, X-ray diffraction and scanning electron microscopy. In addition, we used the data of the phase solubility study, H-1, and 2D NMR spectroscopy and molecular modeling in order to investigate the interactions between 6CN10 and HP-beta-CD. The apparent solubility of 6CN10 with HP-beta-CD increased more than 29 fold. The phase solubility assay in water at 25 degrees C showed an A(P)-type curve, with an apparent stability constant K-1:1 and K-1:2 of 96 and 0.1989 M-1, respectively. The results of IR, NMR and docking indicate that 6CN10 is able to form complexes with HP-beta-CD (1:1 and 1:2 stoichiometric ratios), generating the formation of inclusion and preferably, non-inclusion complexes. The antifungal activity against Cryptococcus neoformans demonstrated the superior performance of the complex (46.66 mu g mL(-1)) when compared with the free drug (166.66-333.33 mu g mL(-1)). The present study provides useful information for the potential application of complexation with low soluble compounds and about the type of complex formation between 6CN10 and HP-beta-CD.