Exploring the effects of excipients on complex coacervation.

Complex coacervation is an associative liquid-liquid phase separation phenomenon that takes place due to the electrostatic complexation of oppositely-charged polyelectrolytes and the entropic gains associated with the release of bound counterions and rearrangement of solvent. The aqueous nature of coacervation has resulted in its broad use in systems requiring high biocompatibility. The significance of electrostatic interactions in coacervates has meant that studies investigating the phase behaviors of these systems have tended to focus on parameters such as the charge stoichiometry of the polyions, the solution pH, and the ionic strength. However, the equilibrium that exists between the polymer-rich coacervate phase and the polymer-poor supernatant phase represents a balance among attractive electrostatic interactions and excluded volume repulsions as well as osmotic pressure effects. As such, we hypothesize that it should be possible to tune coacervate phase behavior via the addition of non-electrostatic excipients which would partition between the two phases and potentially alter both the solvent quality and the osmotic pressure balance. In particular, our work focuses on small molecule excipients such as sugars, amino acids, and other additives that have a history of use in vaccine formulation. We quantified the ability of these excipients to partition into the coacervate phase, and their potential for destabilizing the phase separation. Furthermore, we demonstrate that these additives can be combined with complex coacervation in the context of a virus formulation.