Some observations on the liquid crystalline and gel behaviors of aqueous dispersions of a prodrug

Abstract

BMS-830216 is a diprotic acid prodrug of two pKa values (<2 and 6.8) with high apparent solubility at pH ≥ 7. At ∼ pH 4 solutions of BMS-830216 appear to be surface active, in which their surface tension can be reduced from 72 to 65 dynes when its concentrations is above the critical aggregation concentration (CAC∼0.2 mM). Additionally, at this pH, BMS-830216 tends to form liquid crystalline phases (at ≥ 2 mg/mL) in acetate buffer when using tris salt. Furthermore, after raising the concentration beyond 20 mg/g, formation of gel-like dispersions was noted. These gel-like dispersions exhibited a strong elastic strength, significantly impacting the dissolution behavior of the tris salt. Mechanistically, it is likely that BMS-830216 tris salt in solution first forms a lamellar phase followed by formation of a gel phase at higher concentrations (≥20 mg/mL). As indicated by SAXS, the lamellar phase formed seems to have two d-spacing values (∼5 nm and ∼10 nm (weak), which seems to correspond to two molecules connected tail by tail (5 nm). Further investigation is needed for phase identification, as their properties can affect the physical behavior of BMS-830216 in the development of pharmaceutical dosage forms.