<p>The objective of this study was to develop stable amorphous drug nanoparticles with high drug loading and bioavailability advantages to overcome the drug-loading limitations of conventional amorphous solid dispersion (ASD) formulations. Amorphous drug nanoparticles were prepared <i>via</i> liquid-liquid phase separation in solution using various stabilizers, and their stability upon thermal drying and subsequent re-dispersion was evaluated. Zein, a stabilizer partitioning in the nanoparticle core alongside the active, was found to be highly effective in stabilizing said nanoparticles upon thermal drying. In contrast, most other stabilizers categorized as “wall materials”, required substantially higher amounts to achieve effective stabilization of the amorphous drug particles. Of these, the wall materials exhibiting ionic interactions with the drug, were found to markedly enhance nanoparticle stability during drying. Despite the use of stabilizers, nanoparticle drying stability varied with batch size, suggesting the need to consider the effects of both scale-up and process parameters for the development of this type of formulation. Subsequent membrane permeability studies with dried amorphous nanoparticles showed their membrane permeability to be comparable to that of fast-releasing ASDs. This phenomenon was found to be independent of drug-stabilizer ionic interactions in the nanoparticles. These results confirm amorphous drug nanoparticles to be an effective strategy for overcoming drug-loading constraints in ASD formulations without compromising bioavailability. Our results also provide insights into excipient-drug interactions and their impact on the drying stability of amorphous drug nanoparticles, which is critical for the development of stable, high drug-loading amorphous nanoparticle formulations.</p> Graphical Abstract <p></p>