Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution
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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.
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.
For felodipine, a small extent of supersaturation was generated via dissolution at 25°C but not at 37°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.
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.
KEY WORDSamorphous dissolution felodipine indomethacin metastable polymer supersaturation
We would like to acknowledge the PhRMA foundation for providing a pre-doctoral fellowship to David Alonzo, as well as funding from Abbott Labs. A special thanks to Davor Gusak and Sajeda Abdo for their help in the laboratory.
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- 9.Vaughn JM, McConville JT, Crisp MT, Johnston KP, Williams RO. Supersaturation produces high bioavailability of amorphous danazol particles formed by evaporative precipitation into aqueous solution and spray freezing into liquid technologies. Drug Dev Ind Pharm. 2006;32:559–67.CrossRefPubMedGoogle Scholar
- 16.Chikaraishi Y, Otsuka M, Matsuda Y. Dissolution phenomenon of the piretanide amorphous form involving phase change. Chem Pharm Bull. 1996;44:2111–5.Google Scholar
- 29.Sato T, Okada A, Sekiguchi K, Tsuda Y. Difference in physico-pharmaceutical properties between crystalline and noncrystalline 9, 3″-diacetylmidecamycin. Chem Pharm Bull. 1981;29:2675–82.Google Scholar
- 35.Lachman L, Lieberman HA, Kanig JL. The theory and practice of industrial pharmacy. Stipes Publishing LLC, 1986.Google Scholar
- 36.Mullin JW. Crystallization. 4th ed. Oxford: Elsevier Butterworth-Heinemann; 2001.Google Scholar
- 37.Garside J, Mersmann A, Nyvlt J. Measurement of Crystal Growth and Nucleation Rates. 2nd ed. Rugby: Institute of Chemical Engineers; 2002.Google Scholar