Influence of Co-Solutes and Solvents on Diffusion Interaction Parameters in Multicomponent Solutions: New Insights through the Kirkwood–Buff Theory

We introduce new mathematical expressions for the diffusion interaction parameter in liquid multicomponent solutions. Our theory, which incorporates Kirkwood-Buff integrals, expresses the diffusion interaction parameter as the derivative of the logarithmic solute thermodynamic activity coefficient with respect to solute concentration. Unlike previous approaches, our expressions do not rely on approximations or truncated Taylor series and are tailored differently for binary, ternary, and higher-order solutions. In binary solutions, the resulting expressions indicate that solvation properties primarily govern solute association. In ternary solutions, however, cross-interactions dominate, revealing mechanisms that can either suppress or induce aggregation effects. These findings are supported by experimental data from binary aqueous solutions containing urea and paracetamol, as well as from ternary solutions involving monoclonal antibodies (mAbs) in different formulations. Our results pave the way for the development of tailored formulations that mitigate protein aggregation and enhance shelf life. Overall, the proposed expressions offer a comprehensive framework that integrates diffusive and thermodynamic properties to deepen our understanding of solute behavior and stabilization in complex solution environments.