Hot-melt extruded ibuprofen ternary solid dispersions using in-line UV–Vis: Impact of an ionizable polymer on thermodynamics and dissolution

Amorphous solid dispersions (ASDs) remain a key strategy for enhancing the dissolution of poorly soluble APIs. Building on previous work with binary ibuprofen (IBU) blends, this study investigates the impact of incorporating poly(butyl methacrylate- co -(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), Eudragit EPO® (EPO), an ionizable third polymer into systems based on poly(vinylpyrrolidone- co -vinyl acetate), typically 60:40 VP:VA ratio, KOLVA64® (VA64), Polyvinylpyrrolidone, KOL17PF® (17PF) and hydroxypropyl methylcellulose acetate succinate, AQOAT AS-LMP (HPMCAS). Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) modeling was employed to predict solid–liquid (SLE) and liquid-liquid (LLE) phase equilibria using binary interaction parameters (k ij ). In comparison to Flory–Huggins's theory, PC-SAFT predicted broader metastable regions, corresponding to up to threefold higher achievable ibuprofen loadings. ASDs (35 wt%) with increasing EPO concentration (0–32.5 wt%) were successfully extruded using in-line UV–Vis spectroscopy for real-time monitoring, with samples grouped according to polymeric composition by principal component analysis (PCA). Solid-state analyses (FTIR, XRD, DSC) of extrudate samples confirmed no recrystallisation for up to six months (25 °C/70% RH). Small-scale DSC experiments within the PC-SAFT-predicted unstable zone confirmed crystallinity (95 wt% for VA64-EPO and 17PF-EPO; 50 wt% for HPMCAS-EPO). Dissolution studies under acidic conditions revealed complete release of blends with ≥20 wt% EPO within 5 min, outperforming binary formulations and maintaining supersaturation for hours. At pH 6.8, no significant dissolution improvement was seen, providing additional evidence of a diffusion-controlled release dependent on pH and API-polymer interactions. Overall, this work presents a novel PC-SAFT-based, predict-first approach to ternary ASD design, enabling higher drug loadings and controlled pH-responsive release.