Ultrafast solvent removal delivers high-loading of amorphous small-molecule drugs in polymeric microspheres with...

The clinical translation of long-acting injectable microspheres has been persistently hindered by manufacturing inconsistencies inherent to conventional batch processing. This variability compromises product quality and obstructs the establishment of reliable in vitro-in vivo correlations, a major bottleneck for pharmaceutical development. Here, we address this critical challenge with flow-solidify for poorly water-soluble small molecule drugs, an end-to-end continuous manufacturing platform that integrates controlled droplet formation with an ultra-fast solidification step. By applying accelerated solvent removal, this process kinetically traps the drug as a stable amorphous solid dispersion by enhancing drug-polymer interactions and suppressing drug crystallization. This yields microspheres with exceptional structural control, high drug loading, and consistent batch-to-batch quality. Crucially, the superior structural integrity of these microspheres enabled the development of a robust, Level A in vitro-in vivo correlation (R² = 0.9889). This model accurately predicted the complete in vivo pharmacokinetic profiles of distinct formulations based solely on their in vitro release data, with prediction errors for key pharmacokinetic parameters (Cₘₐₓ and AUC) falling within the stringent ±10% regulatory benchmark. By directly linking a precisely controlled manufacturing process to predictable in vivo outcomes, the flow-solidify platform represents a robust process-performance linkage, offering a practical route to accelerate the development of next-generation long-acting injectable microsphere formulations for poorly water-soluble small molecule drugs.