Experimentally Derived Hansen Solubility Parameters as a Screening Tool for the Formulation of Amorphous Solid...

A major challenge in pharmaceutical development is the poor aqueous solubility of crystalline active pharmaceutical ingredients (APIs) generated during the API discovery. Amorphous solid dispersions (ASDs) improve solubility by molecularly dispersing amorphous APIs within a glassy polymer matrix; however, their utility is often constrained by limited API loading capacity and incomplete API release. To address these challenges, this study employs experimentally derived Hansen solubility parameters (HSP) as a predictive tool to assess polymer/API compatibility early in formulation development, rather than relying on conventional trial-and-error approaches. HSP values for ten commercially relevant ASD polymers and three APIs were determined using an experimental solubility screening method in conjunction with HSPiP software. Guided by these miscibility predictions, ASDs were prepared by materials-sparing hot-melt extrusion using only 2-7 g of API. A linear relationship was observed between the relative energy difference (RED) and the maximum amorphous API soluble (MADS), where lower RED values led to higher API loadings, up to 45%. Polymer/API interactions characterized using FTIR and DSC revealed that specific intermolecular interactions significantly influence dissolution behavior. Notably, the release of amorphous griseofulvin increased by up to 235% in ASD formulations exhibiting minimal intermolecular interactions compared to the crystalline API. Collectively, these results demonstrate the reliability of experimentally derived HSP for predicting ASD miscibility and API loading capacity, while complementary physicochemical characterization provides mechanistic insight into dissolution behavior. This integrated framework enables the rational design of high API-loaded, high-performance ASD formulations.