Mechanistic insights into dissolution of highly drug-loaded amorphous solid dispersions of a fast-crystallising drug

The dissolution behaviour of fast-crystallising amorphous solid dispersions (ASDs) at drug loadings (DLs) far exceeding the amorphous solubility limit remains poorly understood. In this study, we investigate how extreme DLs influence dissolution mechanisms in naproxen-copovidone VA64 ASDs prepared by hot-melt extrusion at 20, 50, and 70 wt% DL. Rapid post-extrusion cooling was applied at 70 wt% DL to kinetically suppress crystal growth, while lower DL formulations remained amorphous as confirmed by DSC and PXRD. Drug-polymer interactions were analysed using ATR-FTIR combined with principal component analysis. Saturation solubility measurements revealed moderate advantages of ASDs over physical mixtures, suggesting that polymer-mediated interfacial effects contribute to solubility enhancement independently of amorphisation. Non-sink dissolution testing revealed a non-monotonic, DL-dependent behaviour. At 20 wt% DL, naproxen remained amorphous for at least 2 h, enabling near-congruent drug-polymer release and the highest dissolution performance. At 50 wt% DL, rapid surface crystallisation within a dense swollen polymer layer restricted drug release. Unexpectedly, dissolution performance partially recovered at 70 wt% DL despite crystallization, as the reduced polymer fraction generated a more porous hydrated layer that facilitated liquid penetration and drug release compared with 50 wt% DL ASDs and physical mixtures. Spectroscopic analysis showed progressive loss of hydrogen bonding at intermediate and high DLs, while transient, non-specific drug-polymer associations persisted and likely contributed to improved wettability. These findings demonstrate that dissolution enhancement in fast-crystallising ASDs can be sustained above the amorphous solubility limit when the architecture of the hydrated layer - together with persistent non-specific drug-polymer interactions in aqueous media - governs drug transport rather than amorphous stability alone.