SOLUBILIZATION OF THIAZOLOBENZIMIDAZOLE USING A COMBINATION OF PH ADJUSTMENT AND COMPLEXATION WITH 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN

The thiazolobenzimidazole ifluorophenyl)-1H,3H-thiazolo[3,4-a]benzimid azole, TBI,is an experimental drug for the treatment of AIDS which exh ibits a low water solubility (11 mug/mL) and is therefore difficult to administer in an injectable solution dosage form at a target solution concentration of 10 mg/mL. The compound has a single ionizable functi onal group and exhibits an increase in solubility with decreasing pH c onsistent with a pK(a) of 3.55, but the maximum solubility attainable by pH adjustment has been shown to be only 0.4 mg/mL (at pH 2). TBI ha s been found to form inclusion complexes in either its neutral or its protonated form with 2-hydroxypropyl-beta-cyclodextrin (HPCD). The equ ilibrium constants for 1:1 complex formation were found to be 81 and 1 033 M-1 for the protonated and neutral species, respectively. Although the formation of protonated complex is less favored in comparison to the neutral complex, the contribution of this species to the overall s olubility of TBI predominates at low pH. Thus, using a combined approa ch of pH adjustment and complexation with HPCD, a solubility enhanceme nt of 3 orders of magnitude is possible. NMR proton spectroscopy and m olecular modeling studies, conducted to understand the orientation of TBI in the complex and the effect of protonation, are described.