Advancing amorphous solid dispersions through empirical and hybrid modeling of drug–polymer solubility and miscibility: a case study using Ibuprofen

This study investigates the solubility and miscibility of ibuprofen (IBU) with four pharmaceutical polymers, KOLVA64®, KOL17PF®, HPMCAS, and Eudragit® EPO, using a combination of empirical and hybrid modeling approaches, supported by differential scanning calorimetry (DSC) experiments. Traditional group contribution methods based on Hildebrand and Hansen solubility parameters (Fedors, Hoftyzer–van Krevelen, and Just–Breitkreutz) showed variability in solubility predictions but consistently classified all polymer–API blends as miscible (Δδ < 7 MPa^½). Bagley plots reinforced these findings, although borderline miscibility was indicated for HPMCAS and EPO depending on the method used. A novel attempt to derive the Flory–Huggins (FH) interaction parameter (χ) from solubility parameters at near-melting temperatures showed poor agreement with experimental data, underscoring the limitations of such extrapolations and the semi-empirical nature of the FH model. Phase diagrams were constructed from DSC-based melting point depression data using three modeling strategies: FH theory, the empirical approach by Kyeremateng (with two fitting methods), and the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state, both in pure predictions and with fitted binary interaction parameters (k_ij). The glass transition temperature (T_g) of the mixtures was modeled using the Gordon–Taylor and Kwei equations. All models provided a consistent polymer ranking based on their solubilizing capacity, with KOL17PF as the most compatible and HPMCAS as the least. Demixing zones (liquid-liquid equilibrium - LLE) predicted by FH and PC-SAFT models suggest that for HPMCAS-based ASDs only very low drug loadings (< 5 % w/w) could potentially be stable at room temperature. In contrast, higher drug loadings (> 10 % w/w) fall under a meta-stable zone with the other polymers, making them better candidates for IBU formulation. HPMCAS also exhibited consistently prediction errors across all T_g models, (AARD ∼4.5 %), indicating poorer agreement with experimental data. By integrating empirical and hybrid modeling approaches, this study highlights the strengths and limitations of commonly used solubility prediction methods and advocates for a shift toward a harmonized framework.