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.