Prediction of the Thermal Phase Diagram of Amorphous Solid Dispersions by Flory-Huggins Theory

Miscibility of drug and polymer is one of the key parameters in amorphous formulation design. The purpose of this work is to provide a theoretical approach to evaluate miscibility between drug and polymer in amorphous solid dispersions. The model system is indomethacin and polyvinylpyrrolidone-vinyl acetate copolymer. The Flory-Huggins ( F-H) interaction parameter, chi, of drug and polymer was estimated at different temperatures by two methods: melting point depression of drug in various polymer ratios at the melting temperature, and Hildebrand and Scott solubility parameter calculation at 25 degrees C. The simplified first-order relation between the F-H interaction parameter and temperature was established. This allows the construction of a temperature-composition phase diagram of a two-component amorphous system. The spinodal curve was generated and provides an insight into the thermodynamic stability of an amorphous solid dispersion at various temperatures. The predicted stability of the model system was compared with the experimental data. The merits and deficiency of the proposed approach were fully discussed. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3196-3207, 2011