A UNIFAC–complexation framework for predicting solubility of amino acids and salts for CHO cell culture media

Abstract Intensified biomanufacturing with Chinese hamster ovary (CHO) cells requires highly concentrated nutrient media, making amino‐acid and trace‐element solubility central to robust formulation design. We present a CHO‐media‐focused computational framework that combines modified UNIFAC calculations for short‐range interactions, a modified Debye–Hückel correlation for long‐range ionic effects, and activity‐based equilibrium constraints for speciation, complexation, and precipitation. Group‐interaction parameters were fitted using binary and ternary amino‐acid datasets to establish the parameterization. The binary and ternary results define the thermodynamic foundation, while multicomponent CHO‐media case studies demonstrate how the framework can screen composition‐ and pH‐dependent solubility behavior. Together, these capabilities provide a practical foundation for designing concentrated basal and feed media and prioritizing formulation experiments in mammalian cell cultures.