Amorphous solid dispersions (ASDs) are often used for formulating poorly water-soluble active pharmaceutical ingredients (APIs). In an ASD, the amorphous API is embedded in a suitable matrix excipient in order to stabilize the amorphous state and control the dissolution performance. ASDs can be prepared by commonly dissolving the API and the polymer in a suitable organic solvent which is evaporated afterward (e.g., via spray drying) aiming at a homogeneous API distribution in the polymer matrix. Sometimes, unexpected solvent influences on the heterogeneity of the dry ASD are observed. Thermodynamic predictions using the Perturbed-Chain Statistical Associating Fluid Theory combined with experimental investigations via Raman spectroscopy, differential scanning calorimetry, and microscopy performed in this work revealed the amorphous phase separation (APS) between the solvent and the polymer as causing the ASD heterogeneities. It will be shown that thermodynamic modeling allows for identifying appropriate solvents that will neither show APS with the polymeric excipient nor at any time of the drying process of ASD formulations.