Proximity energies: a framework for understanding concentrated solutions

A high-concentration fluid may be defined as one in which the distance between the van der Waals surfaces of the molecules is on the same order of magnitude as the size of the molecules. Many biological fluids meet this definition of being concentrated. High concentration protein solutions are of commercial interest, too. In the biopharmaceutical industry, there is a desire to produce high concentration (>100 mg/ml) protein formulations. The goal of this paper is to provide an energetic framework for understanding the functional properties (e.g., solubility, stability and viscosity) of high concentration solutions. Using this framework not only provides a simple, clear view of protein behavior at high concentrations, it also provides insights into how modifications to the protein or the solvent affect solution behavior. Thus, the paper provides a starting point for the rational manipulation of protein solubility, viscosity and stability.