Dynamic Phase Behavior of Amorphous Solid Dispersions Revealed with <i>In Situ</i> Stimulated Raman Scattering Microscopy

This study reports the application of <i>in situ</i> stimulated Raman scattering (SRS) microscopy for real-time chemically specific imaging of dynamic phase phenomena in amorphous solid dispersions (ASDs). Using binary ritonavir and poly(vinylpyrrolidone-vinyl acetate) films with different drug loadings (0-100% w/w) as model systems, we employed SRS microscopy with fast spectral focusing to analyze ASD behavior upon contact with a dissolution medium. Multivariate unmixing of the SRS spectra allowed changes in the distributions of the drug, polymer, and water to be (semi)quantitatively imaged in real time, both in the film and the adjacent dissolution medium. The SRS analyses were further augmented with complementary correlative sum frequency generation and confocal reflection for additional crystallinity and phase sensitivity. In the ASDs with drug loadings of 20, 40, and 60% w/w, the water penetration front within the film, followed by both surface-directed and bulk phase separation in the film, was apparent but differed quantitatively. Additionally, drug-loading and phase-dependent polymer and drug release behavior was imaged, and liquid-liquid phase separation was observed for the 20% drug loading ASD. Overall, SRS microscopy with fast spectral focusing provides quantitative insights into water-induced ASD phase phenomena, with chemical, solid-state, temporal, and spatial resolution. These insights are important for optimal ASD formulation development.