Dissolution Behavior of an Amorphous Solid Dispersion in Surfactant Containing Media

G. Ma, B. S. Levine, D. J. Lavrich Merck & Co., Inc. Purpose Amorphous solid dispersions have been increasingly used to enhance the bioavailability for poorly soluble drugs. Dissolution method development for these formulations has faced challenges due to their unstable super saturation state in aqueous media. Whether the dissolution sink condition should be based on API crystalline solubility or amorphous solubility is debatable. In this work the dissolution behavior of a poorly soluble API in a HPMCAS spray dried formulation and the function of surfactant in dissolution media were studied in order to develop an appropriate QC dissolution method. Methods Equilibrium solubility of the drug substance in crystalline form and apparent solubility of the spray dried intermediate (SDI) in media containing 0% to 5% of polysorbate 80 was measured by HPLC. Crystalline API solubility was also mapped with varying levels of polysorbate 80 and HPMCAS at room temperature and 37°C by HPLC. 60 minutes and 24 hours dissolutions of tablets containing the SDI were performed at 0% to 3% of polysorbate 80. The tendency of the API precipitation was evaluated at room temperature and 5°C by seeding different forms of the crystalline API in the dissolution vessels. Results Solubility measurement shows that polysorbate 80 increases solubility for both crystalline and amorphous API. However the API crystalline equilibrium solubility (0.09 mg/mL) is still a little lower than target dissolution concentration (0.11mg/mL) even at 5% polysorbate 80 while the amorphous solubility reaches sink condition (3x target concentration) at 3% polysorbate 80 (0.40 mg/mL). On the other hand API solubility mapping shows HPMCAS almost does not increase API crystalline solubility (Figure 1).