Dual Mechanism of Microenvironmental pH Modulation and Foam Melt Extrusion to Enhance Performance of HPMCAS Based Amorphous Solid Dispersion

摘要

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is an excellent polymeric carrier for melt extrusion amorphous solid dispersion. However, its pH-dependent solubility limits its application, especially for narrow absorption window drugs. The current study proposed a novel dual approach of foam extrusion and microenvironmental pH modulation to overcome this limitation. Sodium bicarbonate was used as a blowing agent and the remaining sodium carbonate acted as an internal pH modifier. Compared with conventional extrusion, foam extrusion dramatically lowered the extrudate physical strength (breaking force and hardness decreased by 20-fold; breaking energy and deformation energy decreased by more than 30-fold). Milling efficiency of foam extrudate was largely improved compared with that of conventional extrudates, demonstrating smaller particle size, larger specific surface area, and ability to pass through a smaller milling screen. The foam extrudate could generate a supersaturation concentration up to 8-fold higher than the solubility of the pure drug. It also significantly enhanced drug dissolution in a two-step biorelevant medium (p < 0.05). This novel approach improved both manufacturing processability and dissolution of HPMCAS-based solid dispersions.