Integrated computational-experimental workflow for feasibility assessment of amorphous solid dispersion preparation by hot melt extrusion using <1 g API

Amorphous solid dispersions (ASDs) are widely used to enhance the solubility of poorly water-soluble drugs. Among commercial manufacturing approaches, hot melt extrusion (HME) is increasingly favored over spray drying due to its smaller environmental and physical footprint, low cost, continuous nature, and scalability. However, HME remains underutilized in early drug development due to the mismatch between minimum batch size requirements and availability of active pharmaceutical ingredient (API). To address this gap, we developed and evaluated a material-sparing workflow which could be applied in early development for HME feasibility using encorafenib (ENC) as a model compound, targeting API consumption below 1 g. Perturbed-chain statistical associating fluid theory (PC-SAFT) was first applied as an in silico technique to predict polymer compatibility, leading to the selection of appropriate polymer systems defined within a suitable process operating design space. Vacuum compression molding (VCM) was then utilized as a material-sparing technique to prepare several formulations, which experimentally validated PC-SAFT predictions through solid state characterization (amorphous/crystalline), chemical purity (thermal degradation), and non-sink dissolution performance. Four polymers were evaluated: Soluplus (SP), polyvinylpyrrolidone-vinyl acetate (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and Affinisol hydroxypropyl methylcellulose (HPMC). PC-SAFT and VCM screening identified PVPVA and SP as the most compatible polymers which enable ENC processing at lower temperatures, thereby reducing the risk of thermal degradation of the drug or polymer. Degradation analysis revealed that HPMCAS-based ASDs had the lowest thermal stability. Non-sink dissolution performance ranked the ASDs prepared from the corresponding polymer as PVPVA > HPMCAS > HPMC > SP. Based on overall performance, PVPVA was selected as the optimal polymer, consistent with the current commercial ENC ASD formulation. Importantly, this workflow required < 500 mg API, demonstrating its suitability for early-stage development. The integrated computational-experimental approach can enable API-sparing HME feasibility assessments, facilitating earlier adoption of HME in the development process and potentially accelerating timelines toward scalable commercial ASD manufacturing.