Impact of mixing method on amorphous solid dispersions fabricated via vacuum compression molding: dissolution and degree of fusion.

Amorphous solid dispersions (ASD) melting-based methods such as hot-melt extrusion (HME) provide effective mixing during processing, whereas vacuum compression molding (VCM) lacks intrinsic mixing. Cryo-milling (CM) is commonly employed prior to VCM to enhance powder mixing; however, it remains unclear what particle size characteristics are required to ensure sufficiently homogeneous, single-phase ASDs. This study evaluated the impact of mixing methods on dissolution performance of ritonavir (RTV)/poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) ASD discs fabricated by VCM, comparing physical blending (PB) and CM. Solid-state properties were characterized. Discs with 5-50% drug loadings (DLs) were analyzed by microscope-enabled disc dissolution system (MeDDiS). Although attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) and pigment tests indicated similar bulk mixing uniformity, dissolution behavior of PB and CM discs differed significantly. CM discs showed a distinct "cliff" near 30% DL, while PB discs were generally inferior, showing progressively reduced release. ATR- FTIR further revealed that PB led to localized amorphous drug-rich domains, whereas CM promoted more uniform dispersion. Collectively, these findings highlight that effective ASD performance was governed not only by powder mixing, but also by the extent of microstructural fusion achieved during molding as a result of improved spatial proximity between drug and polymer within pre-VCM powder.