Inclusion complex of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098) with heptakis(2,6-di-O-methyl)-β-cyclodextrin: Interaction and dissolution properties

Abstract

Interactions of KCA-098 with heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD) in solution and in the solid state were studied by the solubility method, UV and fluorescence spectroscopy, powder X-ray diffractometry, and thermal analysis. The KCA-098/DM-β-CyD system showed an A(L) type solubility diagram with stability constants of 5870 and 2220M-1 in aqueous and 10% methanol solutions, respectively. Following the addition of DM-β-CyD, the maximum UV wavelength of KCA-098 was shifted to a longer wavelength and the fluorescence intensity was decreased. A similar spectral change was observed when KCA-098 was dissolved in less polar solvents, especially in proton-acceptor solvents, such as acetone and dimethylsulfoxide, suggesting that KCA-098 interacts with DM-β-CyD through not only a hydrophobic interaction but also hydrogen bonding. The solid complex of KCA-098 with DM-β-CyD in a molar ratio of 1 : 1 was prepared by the kneading method and the solvent evaporation method, using organic solvents. Powder X-ray diffractometric and differential scanning calorimetric studies indicated that KCA-098 was dispersed as microparticles on the DM-β-CyD complex in the solid state prepared by the solvent evaporation method although it dispersed as crystals in the sample prepared by the kneading method. The dissolution of KCA-098 from the solid complex prepared by the former method was markedly faster than that prepared by the latter method, although it slowed down with the passage of time. The reduced dissolution of KCA-098 was explained by crystallization to the hydrate form in the medium. These data indicate that poorly water-soluble KCA-098 interacts with DM-β-CyD in water and in the solid state and that a fast-dissolving form of KCA-098 can be obtained by evaporating with DM-β-CyD using organic solvents.