Optimizing the molar ratio in co-amorphous systems: Molecular mechanisms, screening methods, and critical quality attributes

Co-amorphous systems (CAMS) are promising for formulating poorly water-soluble drugs and enhancing their oral bioavailability, without the high mass-fraction burdens and hygroscopic instability associated with traditional polymer-based amorphous solid dispersions. Recent progress notwithstanding, the selection of component stoichiometry remains an empirical bottleneck as formulation workflows have traditionally assumed a 1:1 equimolar ratio. A 1:1 default can be associated with excess localized free volume and uncomplexed polyfunctional binding sites that promote homonucleation and phase separation. This review evaluates the molecular, thermodynamic, and physical mechanisms dictating optimal co-amorphous molar ratios. We discuss glass transition-based screening as a quick first filter, and the orthogonal and confirmatory tests (spectroscopic, solid-state NMR, dielectric, stability studies) needed to select a formulation, including a proposed strategy for cases where the optimal ratios for stability and dissolution differ. Crucially, the optimal ratio is conditional and can shift with humidity and preparation route. A systematic analysis of recent literature (2021-2026) demonstrates that while 67.7% of dedicated optimization studies identified non-equimolar optimal compositions, only 11.3% of publications systematically screen composition. Finally, we outline emerging in silico approaches that may reduce the experimental effort of ratio screening.