A novel empirical analytical approach for estimating solubility of crystalline drugs in polymers has been developed. The approach utilizes a combination of differential scanning calorimetry measurements and a reliable mathematical algorithm to construct complete solubility curve of a drug in polymer. Compared with existing methods, this novel approach reduces the required experimentation time and amount of material by approximately 80%. The predictive power and relevance of such solubility curves in development of amorphous solid dispersion (ASD) formulations are shown by applications to a number of hot-melt extrudate formulations of ibuprofen and naproxen in Soluplus. On the basis of the temperature-drug load diagrams using the solubility curves and the glass transition temperatures, physical stability of the extrudate formulations was predicted and checked by placing the formulations on real-time stability studies. An analysis of the stability samples with microscopy, thermal, and imaging techniques confirmed the predicted physical stability of the formulations. In conclusion, this study presents a fast and reliable approach for estimating solubility of crystalline drugs in polymer matrixes. This powerful approach can be applied by formulation scientists as an early and convenient tool in designing ASD formulations for maximum drug load and physical stability.