Some Observations on the Liquid Crystalline and Gel Behaviors of Aqueous Dispersions of a Prodrug

BMS-830216 is a diprotic acid prodrug of two pK(a) values (<2 and 6.8) with high apparent solubility at pH >= 7. At similar to 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 similar to 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 (similar to 5 nm and similar to 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.