Correlation between the Protein Pharmaceutical Surface Activity and Interfacial Stability

The interaction of protein drugs with the air–liquid interface plays a crucial role in the overall stability in aqueous formulations, particularly when the adsorbed proteins are subjected to the surface flow. Nonionic surfactants are usually added into the formulation solutions to address this issue. A diversity of studies have been focused on the usage of surfactants, the stability mechanism of surfactants, or seeking new pharmaceutical surfactants. However, the real protagonist, the basic properties of protein drugs, was neglected, which may play a vital role in the stability of protein drugs. Herein, we aim to clarify the correlation between the surface behavior of proteins and the interfacial stability. A force tensiometer is used to track the surface tension reduction and the competition between surfactants and proteins at the surface. We find that the surface behaviors of proteins vary with storage temperature and protein types including monoclonal antibodies (mAb), bispecific monoclonal antibodies (BsAb), and antibody–drug conjugates (ADCs). Especially for the protein stored at 5 °C, the surface activity of proteins is better than that of surfactants. It indicates that the ability of proteins to adsorb at the interface should not be ignored compared to surfactants. The significant difference in the interfacial stability of protein pharmaceuticals formulated in the same buffer and excipients as well as the surfactants with the same concentration further confirms the interfacial adsorption capacity of proteins that should not be ignored. These findings provide a new angle and valuable insights into the correlation between the surface activity of the proteins and interfacial stability, which may pave the way for future preformulation studies on therapeutic proteins and broaden the thoughts of formulation development.