Unlocking the potential of alkaline polymethacrylates via ionic crosslinking in amorphous solid dispersions

Amorphous solid dispersions (ASDs) are a well-established strategy to enhance the oral bioavailability of poorly water-soluble drugs; however, their broader application remains limited by drug-polymer compatibility and pronounced pH-dependent performance. In this study, alkaline polymethacrylates (Eudragit® E) are investigated as versatile carrier systems for ASDs targeting poorly water-soluble BCS Class II drugs, using acid-modified formulations to enable functionality under physiological conditions. ASDs were prepared by hot-melt extrusion (HME) and vacuum compression molding (VCM) to assess process robustness, drug-polymer miscibility, thermal behavior, and dissolution performance. Solid-state characterization confirmed complete amorphization and stable glass formation across multiple drug loadings. The presence of organic acids induced controlled protonation of the polymer, giving rise to an ionically crosslinked polymer-acid network with distinct thermal signatures and enhanced structural stability. Dissolution studies demonstrated rapid generation and prolonged maintenance of supersaturation in phosphate buffer at pH 6.8, significantly exceeding the thermodynamic solubility of the investigated drugs. Supersaturation behavior correlated strongly with the calculated degree of polymer protonation rather than with acid content alone, indicating that protonation-controlled polymer solubilization governs dissolution performance. Long-term stability testing further demonstrated preserved amorphous structure and consistent dissolution behavior under both standard and accelerated storage conditions. Overall, this work establishes acid-modified alkaline polymethacrylates as a broadly applicable platform for ASD formulation. By decoupling solubility enhancement from specific drug chemistries through polymer-driven ionic crosslinking, this approach expands the design space of ASDs and enables the rational development of stable, high-performance formulations for poorly water-soluble drugs.