[Solubilization and complexation of the antileukotrienic drug Quinlukast in aqueous solutions of cyclodextrins]

Abstract

Solubility of the new antileukotrienic drug quinlukast (4-{[4-(2-quinolylmethoxy)phenyl]sulfanyl}benzoic acid) was determined in water and in aqueous solutions of alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD, average degree of substitution 0.8), and methyl-beta-cyclodextrin (M-beta-CD, average degree of substitution 1.8). The determined solubility of quinlukast in water was 0.081 +/- 0.008 mmol/l (3.12 +/- 0.30 mg/100 ml) and only an insignificant increase in quinlukast solubility was observed in aqueous solutions of beta-CD. However, three well soluble cyclodextrins showed a marked solubilizing effect, in aqueous solutions with a moderate cyclodextrin concentration 5 g/100ml, a 12-fold increase in quinlukast solubility was observed in the case of M-beta-CD, and a 10-fold increase in the case of both HP-beta-CD and alpha-CD. Phase solubility diagrams of quinlukast in aqueous solutions of these cyclodextrins (up to 0.05 mol/l) were determined. In the cases of M-beta-CD and HP-beta-CD, the solubility diagrams were linear (AL) and they corresponded to the formation of a soluble inclusion complex quinlukast - cyclodextrin 1:1 with the evaluated stability constants K11 300 +/- 35 l/mol and 260 +/- 30 l/mol for M-beta-CD and HP-beta-CD, respectively. The phase solubility diagram of quinlukast in aqueous solutions of alpha-CD showed a marked positive deviation (AP) from linearity, the solubilization efficiency of dilute alpha-CD solutions was relatively low but it increased progressively with the increasing alpha-CD concentration. In the overall evaluation, the cyclodextrins alpha-CD, HP-beta-CD and M-beta-CD appeared to be suitable for the quinlukast solubilization into aqueous solutions.