Mechanistic understanding of the precipitation inhibition effect of HPMCAS via thermodynamic modeling

Understanding the precipitation risk of active pharmaceutical ingredients (APIs) in amorphous solid dispersions (ASDs) is still a major challenge in their development. In a previous study (Nakhla et al., Int. J. Pharm. X, 11, 2026, 100475) (Nakhla et al. 2026), we demonstrated the dual functionality of HPMCAS in high drug-load nifedipine (NIF) ASD tablets prepared by hot-melt extrusion, where HPMCAS-H acted both as an effective dry binder and as a precipitation inhibitor. While the experimental data clearly showed prolonged supersaturation and improved tablet performance upon addition of HPMCAS-H, the thermodynamic origin of this precipitation inhibition remained unresolved. The present work directly builds upon these findings and provides a mechanistic interpretation of the observed release behavior using thermodynamic modeling. The dissolution behavior of binary NIF ASDs with either PVP-VA64 (a fully water-soluble polymer) or HPMCAS (a water-dispersible polymer) was analyzed with and without pre-dispersed polymers. Under the conditions investigated, both systems generated initial apparent supersaturation, followed by rapid loss of filter-passing NIF for PVP-VA64-based ASDs. Pre-dispersed PVP-VA64 and HPC-EXF did not prevent this decrease in the present NIF system. In contrast, pre-dispersed HPMCAS-H suppressed or substantially delayed the loss of filter-passing NIF, consistent with its stabilizing effect in ASD tablets. To rationalize these differences, ternary NIF/polymer/water phase diagrams were predicted using PC-SAFT. The calculations support formation of an HPMCAS-H-rich liquid/polymer-rich phase that can accommodate NIF and may manifest experimentally as a colloidal dispersion. Effective stabilization therefore depends on the specific balance of API-polymer and polymer-water interactions captured by the ternary phase diagrams.