The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to small molecule binary mixtures and if this parameter can predict the phase stability of such amorphous binary mixtures. This study was based on the assumption that a thermodynamically miscible binary system is stable and cannot crystallize, and that phase separation is essential before the individual components can crystallize. The stabilization of a binary system is thought to derive from molecular interactions between components in a solid dispersion, which are characterized by the Flory-Huggins interaction parameter. Based on DSC experiments, drug molecules (39) in the present study were classified into three different categories according to their crystallization tendency; i.e., highly crystallizing, moderately crystallizing and noncrystallizing compounds. The Flory-Huggins interaction parameter was systematically calculated for each drug pair. The validity of this approach was empirically verified by hot-stage polarized light microscopy. If both compounds in the pair belonged to the category of highly crystallizing compound, the Flory-Huggins interaction predicted an amorphous or crystalline phase with approximately 88% (23 out of 26) confidence. If one or both compounds of the pair were either moderately crystallizing or noncrystallizing compounds, the binary mixture remained in the amorphous phase during the cooling phase regardless of the interaction parameter. The Flory-Huggins interaction parameter was found to be a reasonably good indicator for predicting the phase stability of small molecule binary mixtures. The method described can enable fast screening of the potential stabilizers needed to produce a stable amorphous binary mixture.