The development of an amorphous solid dispersion (ASD) is a promising strategy for stabilizing the amorphous form of poorly water-soluble active pharmaceutical ingredients (APIs). An API–polymer temperature–composition (T–C) phase diagram can facilitate a rational approach to successful ASD formulation design. Since it is typically challenging to accurately measure the API solubility in a polymer under ambient conditions, differential scanning calorimetry (DSC) is employed to measure it at elevated temperatures. The experimental dataset is subsequently extrapolated to lower temperatures of interest using a solid-liquid equilibrium (SLE) curve modeling approach (e.g., the PC-SAFT equation of state (EOS)). However, the currently followed DSC-based protocols (e.g., the melting point depression (MPD) method) are inefficient and cannot provide reliable data points close to the API–polymer glass-transition temperature line. Hence, the “step-wise dissolution” (S-WD) method was recently developed, which is a new DSC-based protocol that is both cost- and time-effective. The S-WD method was employed to assess the veracity of the purely-predicted PC-SAFT EOS-based SLE curve for more than fifteen API–polymer combinations. In general, the PC-SAFT EOS provided satisfactory qualitative descriptions, but not necessarily accurate quantitative predictions. The identification of different API–polymer case types (i.e., Case I/II/III) based on the pure component physicochemical properties was a key finding, which will play an important role in the future development of ASDs comprising expensive anticancer compounds. Both the S-WD and MPD methods were subsequently modified and an optimal protocol was proposed for each one, which can significantly reduce the required experimental effort.