Amorphous Engineering: Ball Milling vs HME for co-amorphous ASD development of Chrysin

Amorphous solid dispersions (ASDs) are a well-established strategy to overcome the limitations of poorly soluble compounds, but their broader applicability is still constrained by a critical bottleneck: physical instability. In this study, chrysin was selected as a model compound to investigate how formulation design, processing route, and short-range molecular organisation govern the persistence of the amorphous state. Binary ASDs with Soluplus® and ternary systems including meglumine were prepared by cryo-milling and hot-melt extrusion (HME), following initial melt-prep screening. In-line low-frequency Raman spectroscopy, supported by XRPD, DSC, and TGA, enabled real-time monitoring of residual crystallinity, while Pair Distribution Function (PDF) analysis offered a structural fingerprint and the identification of local structural motifs within the amorphous matrix. Under accelerated aging (40°C/75%RH), cryo-milled dispersions showed the poorest stability, binary formulations recrystallised progressively faster with increasing drug loading, and only the ternary HME systems maintained full amorphicity for prolonged periods. The presence of meglumine improved processability during extrusion and delayed recrystallisation, while short-range differences captured by PDF analysis were consistent with variations in molecular packing and local ordering, which in turn correlated with the observed differences in physical stability. Taken together, these findings demonstrate how the presence of meglumine, processing pathway, and atomic-scale disorder can be determinant for ASD stability, pointing toward more robust design principles for amorphous drug products.