The application of temperature-composition phase diagrams for hot melt extrusion processing of amorphous solid dispersions to prevent residual crystallinity.

ABSTRACT

Hot melt extrusion (HME) can be used to produce amorphous solid dispersions (ASDs) at temperatures below the drug's melting point if the drug and polymer exhibit melting point depression. However, the risk of residual crystallinity becomes significant. The purpose of this study was to apply the temperature-composition phase diagram to the HME process, correlating process conditions to ASD residual crystallinity, and identifying the formulation critical temperature, which defines the theoretical minimum processing temperature. The phase diagram of indomethacin (IDM) and polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA) was generated using melting point depression measurements coupled with Flory-Huggins theory. Extrudates were manufactured above, at, and below the formulation critical temperature (Tc) as identified from the phase diagram, with a range of residence times, and characterized for crystallinity. Below the Tc, a fully amorphous sample could not be prepared. Above Tc, sufficient residence time led to amorphous samples. A processing operating design space diagram with three regimes was generated to correlate temperature and residence time factors with process outcome. In conclusion, phase diagrams provide a rational basis for designing hot melt extrusion processes of amorphous solid dispersions to minimize residual crystalline content, delineating the minimum processing temperature based on thermodynamic considerations.