Effect of Drug–Polymer Interaction on Solid-State Stability and In Vitro Drug Flux of Amorphous Solid Dispersions

Polymers play a pivotal role in amorphous solid dispersion (ASD) formulations. An ideal polymer must possess several attributes: it must maintain solid-state stability (retention of drug in the amorphous state), sustain the drug in a supersaturated state in the GI fluids (following administration), and have no detrimental effect on the drug permeation potential. In this study, indomethacin (IMC) ASDs were prepared with each hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone vinyl acetate) (PVPVA), or amino methacrylate copolymer (Eudragit E PO, EPO) were evaluated for their solid-state stability, dissolution behavior, and in vitro drug permeation using the parallel artificial membrane permeability assay (PAMPA). Solid-state stability was investigated through Flory-Huggins interaction parameters, and the molecular mobility was quantified using dielectric spectroscopy. Additionally, water-solid interactions and stability under accelerated conditions provided an assessment of the impact of drug-polymer interactions. Stability was rank ordered: IMC-EPO > IMC-PVPVA > IMC-HPMCAS, with IMC-EPO demonstrating superior resistance to crystallization. With respect to achieving supersaturation, the rankings were: IMC-HPMCAS > IMC-PVPVA > Amorphous IMC > IMC-EPO. While PVPVA and HPMCAS helped achieved the highest supersaturation, EPO was comparable to the amorphous drug. The rank ordering with respect to drug flux was: IMC-PVPVA > IMC-HPMCAS > Amorphous IMC ≈ IMC-EPO > Crystalline IMC. Thus, IMC-PVPVA offered a favorable compromise between physical robustness and permeation efficiency. These findings highlight the importance of polymer selection in ASD design─not only for maintaining physical stability, but also for ensuring effective drug dissolution and permeation.