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1. Tuning chain interaction entropy in complex coacervation using polymer stiffness, architecture, and salt valency

   https://doi.org/10.1039/c7me00108h  

   Lytle, Tyler K.; Sing, Charles E. (January 2018, Molecular Systems Design & Engineering)

   Oppositely-charged polyelectrolytes can undergo a liquid–liquid phase separation in a salt solution, resulting in a polymer-dense ‘coacervate’ phase that has found use in a wide range of applications from food science to self-assembled materials. Coacervates can be tuned for specific applications by varying parameters such as salt concentration and valency, polyelectrolyte length, and polyelectrolyte identity. Recent simulation and theory has begun to clarify the role of molecular structure on coacervation phase behavior, especially for common synthetic polyelectrolytes that exhibit high charge densities. In this manuscript, we use a combination of transfer matrix theory and Monte Carlo simulation to understand at a physical level how a range of molecular features, in particular polymer architecture and stiffness, and salt valency can be used to design the phase diagrams of these materials. We demonstrate a physical picture of how the underlying entropy-driven process of complex coacervation is affected by this wide range of physical attributes. 

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2. The effect of comb architecture on complex coacervation

   https://doi.org/10.1039/c7ob01314k  

   Johnston, Brandon M.; Johnston, Cameron W.; Letteri, Rachel A.; Lytle, Tyler K.; Sing, Charles E.; Emrick, Todd; Perry, Sarah L. (January 2017, Organic & Biomolecular Chemistry)

   Complex coacervation is a widely utilized technique for effecting phase separation, though predictive understanding of molecular-level details remains underdeveloped. Here, we couple coarse-grained Monte Carlo simulations with experimental efforts using a polypeptide-based model system to investigate how a comb-like architecture affects complex coacervation and coacervate stability. Specifically, the phase separation behavior of linear polycation-linear polyanion pairs was compared to that of comb polycation-linear polyanion and comb polycation-comb polyanion pairs. The comb architecture was found to mitigate cooperative interactions between oppositely charged polymers, as no discernible phase separation was observed for comb-comb pairs and complex coacervation of linear-linear pairs yielded stable coacervates at higher salt concentration than linear-comb pairs. This behavior was attributed to differences in counterion release by linear vs. comb polymers during polyeletrolyte complexation. Additionally, the comb polycation formed coacervates with both stereoregular poly( l -glutamate) and racemic poly( d , l -glutamate), whereas the linear polycation formed coacervates only with the racemic polyanion. In contrast, solid precipitates were obtained from mixtures of stereoregular poly( l -lysine) and poly( l -glutamate). Moreover, the formation of coacervates from cationic comb polymers incorporating up to ∼90% pendant zwitterionic groups demonstrated the potential for inclusion of comonomers to modulate the hydrophilicity and/or other properties of a coacervate-forming polymer. These results provide the first detailed investigation into the role of polymer architecture on complex coacervation using a chemically and architecturally well-defined model system, and highlight the need for additional research on this topic. 

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3. Molecular design of self-coacervation phenomena in block polyampholytes

   https://doi.org/10.1073/pnas.1900435116  

   Danielsen, Scott P. O.; McCarty, James; Shea, Joan-Emma; Delaney, Kris T.; Fredrickson, Glenn H. (April 2019, Proceedings of the National Academy of Sciences)

   Coacervation is a common phenomenon in natural polymers and has been applied to synthetic materials systems for coatings, adhesives, and encapsulants. Single-component coacervates are formed when block polyampholytes exhibit self-coacervation, phase separating into a dense liquid coacervate phase rich in the polyampholyte coexisting with a dilute supernatant phase, a process implicated in the liquid–liquid phase separation of intrinsically disordered proteins. Using fully fluctuating field-theoretic simulations using complex Langevin sampling and complementary molecular-dynamics simulations, we develop molecular design principles to connect the sequenced charge pattern of a polyampholyte with its self-coacervation behavior in solution. In particular, the lengthscale of charged blocks and number of connections between oppositely charged blocks are shown to have a dramatic effect on the tendency to phase separate and on the accessible chain conformations. The field and particle-based simulation results are compared with analytical predictions from the random phase approximation (RPA) and postulated scaling relationships. The qualitative trends are mostly captured by the RPA, but the approximation fails catastrophically at low concentration. 

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4. Transfer matrix theory of polymer complex coacervation

   https://doi.org/10.1039/c7sm01080j  

   Lytle, Tyler K.; Sing, Charles E. (January 2017, Soft Matter)

   Oppositely charged polyelectrolytes can undergo a macroscopic, associative phase separation in solution, via a process known as complex coacervation. Significant recent effort has gone into providing a clear, physical picture of coacervation; most work has focused on improving the field theory picture that emerged from the classical Voorn–Overbeek theory. These methods have persistent issues, however, resolving the molecular features that have been shown to play a major role in coacervate thermodynamics. In this paper, we outline a theoretical approach to coacervation based on a transfer matrix formalism that is an alternative to traditional field-based approaches. We develop theoretical arguments informed by experimental observation and simulation, which serve to establish an analytical expression for polymeric complex coacervation that is consistent with the molecular features of coacervate phases. The analytical expression provided by this theory is in a form that can be incorporated into more complicated theoretical or simulation formalisms, and thus provides a starting point for understanding coacervate-driven self-assembly or biophysics. 

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5. Exploring the effects of excipients on complex coacervation

   https://doi.org/10.1016/j.jcis.2025.137808  

   Zeng, Xianci; Joshi, Pratik U; Lawton, Alexander; Manchester, Lynn; Heldt, Caryn L; Perry, Sarah L (October 2025, Journal of Colloid and Interface Science)

   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. 

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