Arginine regulates intermolecular interactions to stabilize lyophilized high-concentration omalizumab: dry-state characterizations and molecular dynamics insights into reconstitution and viscosity.

High-concentration monoclonal antibody formulations (HCMFs) are widely adopted in modern biopharmaceuticals owing to their suitability for subcutaneous administration and superior patient compliance. Nevertheless, lyophilized HCMFs face major technical obstacles, including high solution viscosity, prolonged reconstitution duration, and excessive bubble formation, which impair manufacturability and impede clinical translation. While arginine serves as an effective viscosity-lowering excipient for concentrated protein solutions, its low intrinsic glass transition temperature (Tg') leads to lyophilization instability and cake collapse. These drawbacks limit its applicability in freeze-dried products. In this work, a binary excipient system consisting of trehalose and low-dose arginine was developed to overcome the above limitations. The high Tg' of trehalose synergistically offsets the low-Tg'-associated deficiencies of arginine within concentrated protein matrices, thereby maintaining favorable long-term physical and chemical stability of lyophilized omalizumab. Molecular dynamics simulations of reconstituted high-concentration omalizumab solutions further revealed the underlying viscosity-reduction mechanism. Arginine attenuates attractive protein-protein interactions, enlarges the colloidal radius (Rc) of antibody assemblies, promotes water infiltration into colloidal voids, and intensifies molecular Brownian motion, which fundamentally reduces solution viscosity and improves reconstitution performance. Overall, this study clarifies the incompatibility between arginine and lyophilized omalizumab and provides mechanistic guidance for the molecular modulation of viscosity in high-concentration monoclonal antibody formulations.