Understanding the behavior of amorphous pharmaceutical systems during dissolution.

PURPOSE: To investigate the underlying physical processes taking place during dissolution of amorphous pharmaceuticals and correlate them to the observed solution concentration-time profiles. Felodipine and indomethacin were used as model hydrophobic compounds.
METHODS: Concentration-time profiles were monitored during dissolution of the model amorphous compounds using in situ fiber-optic ultraviolet spectroscopy. Crystallization of the solid exposed to an aqueous environment was monitored using Raman spectroscopy and/or powder X-ray diffraction. Polarized light microscopy was used to provide qualitative information about crystallization processes.
RESULTS: For felodipine, a small extent of supersaturation was generated via dissolution at 25 degrees C but not at 37 degrees C. The amorphous solid was found to crystallize rapidly at both temperatures upon exposure to the dissolution medium. Addition of low concentrations of polymers to the dissolution medium was found to delay crystallization of the amorphous solid, leading to the generation of supersaturated solutions. Amorphous indomethacin did not crystallize as readily in an aqueous environment; hence, dissolution resulted in supersaturated solutions. However, crystallization from these supersaturated solutions was rapid. Polymeric additives were able to retard crystallization from supersaturated solutions of both indomethacin and felodipine for up to 4 h.
CONCLUSIONS: The dissolution advantage of amorphous solids can be negated either by crystallization of the amorphous solid on contact with the dissolution medium or through rapid crystallization of the supersaturated solution. Polymeric additives can potentially retard both of these crystallization routes, leading to the generation of supersaturated solutions that can persist for biologically relevant timeframes.