Abstract <p>The compatibility of the active pharmaceutical ingredient (API) and the polymer excipient is a key factor in the development of amorphous formulations. This is especially important in light of new and diverse technologies for 3D printing of drugs. The aim of this study is to develop a theoretical approach to assessing the miscibility of the API with a polymer in amorphous solid dispersions. A mixture of paracetamol and polyethylene glycol with different molecular weights was used as a model system. The Flory–Huggins interaction parameter of the API and the polymer was estimated at different temperatures using two methods: decreasing the melting point of the drug in different ratios with the polymer and calculating the Hildebrand–Scott solubility parameter at 25°C. A simplified first-order relationship was established between the Flory–Huggins interaction parameter and temperature, which allows constructing a temperature-composition phase diagram for a two-component amorphous system. Spinodal and binodal curves were obtained, which provide an idea of the thermodynamic stability of the amorphous solid dispersion at different temperatures. The observed patterns and features of the systems under consideration were illustrated and discussed in detail. The proposed approaches can be used to optimize the compositions of amorphous solid dispersions to improve the bioavailability of active pharmaceutical ingredients.</p>