Thermodynamic Basis of Sugar-Dependent Polymer Stabilization: Informing Biologic Formulation Design

Abstract: The stabilization of macromolecules is fundamental to developing biological formulations, such as vaccines and protein therapeutics. In this study, we employ coarse grained polymer models to investigate the impact of four sugars: {\alpha}-glucose, {\beta}-fructose, trehalose, and sucrose on macromolecule stability. Free energy decomposition and preferential interaction analysis indicate that polymer-sugar interactions favor folding at low concentrations while driving unfolding at higher concentrations. In contrast, the polymer-solvent soft interaction entropy consistently favors unfolding across all sugar concentrations under study. At low sugar concentrations, polymer-solvent interactions predominantly govern stabilization, whereas at higher concentrations, entropic penalties dictate polymer stability. Local mixing entropy demonstrates that binary sugar mixtures introduce entropic contributions that preferentially stabilize the folded state. These findings contribute to a more nuanced understanding of sugar-based excipient stabilization mechanisms, offering guidance for the rational design of stable biological formulations.