Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 553, Issue 1-2, Pages 454-466Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2018.10.055
Keywords
Amorphous solid dispersion; Hot melt extrusion; Melting point depression; Phase diagram; Residual crystallinity; Process operating design space
Categories
Funding
- U.S. Food and Drug Administration (FDA) [1U01FD005259-01]
- Dane O. Kildsig Center for Pharmaceutical Processing Research
- Purdue University Graduate School Summer Research Grant
- National Science Foundation Graduate Research Fellowship Program [DGE-1333468]
Ask authors/readers for more resources
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 (T-c) as identified from the phase diagram, with a range of residence times, and characterized for crystallinity. Below the T-c, a fully amorphous sample could not be prepared. Above T-c, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available