Dynamic\nPhase Behavior of Amorphous Solid Dispersions\nRevealed with <i>In Situ</i> Stimulated Raman Scattering\nMicroscopy

This study reports the application of <i>in situ</i> stimulated\nRaman scattering (SRS) microscopy for real-time chemically specific\nimaging of dynamic phase phenomena in amorphous solid dispersions\n(ASDs). Using binary ritonavir and poly(vinylpyrrolidone-vinyl acetate)\nfilms with different drug loadings (0–100% w/w) as model systems,\nwe employed SRS microscopy with fast spectral focusing to analyze\nASD behavior upon contact with a dissolution medium. Multivariate\nunmixing of the SRS spectra allowed changes in the distributions of\nthe drug, polymer, and water to be (semi)quantitatively imaged in\nreal time, both in the film and the adjacent dissolution medium. The\nSRS analyses were further augmented with complementary correlative\nsum frequency generation and confocal reflection for additional crystallinity\nand phase sensitivity. In the ASDs with drug loadings of 20, 40, and\n60% w/w, the water penetration front within the film, followed by\nboth surface-directed and bulk phase separation in the film, was apparent\nbut differed quantitatively. Additionally, drug-loading and phase-dependent\npolymer and drug release behavior was imaged, and liquid–liquid\nphase separation was observed for the 20% drug loading ASD. Overall,\nSRS microscopy with fast spectral focusing provides quantitative insights\ninto water-induced ASD phase phenomena, with chemical, solid-state,\ntemporal, and spatial resolution. These insights are important for\noptimal ASD formulation development.