BACKGROUND: Two-phase partitioning bioreactors (TPPBs) employ an immiscible phase to partition toxic substrates/products to/away from cells to reduce cytotoxicity and improve bioprocess performance. Initially, immiscible organic solvents were used as the sequestering phase, and their selection included consideration of solute-solvent affinity, which can be predicted through first principles consideration of solute activity and phase equilibrium thermodynamics. Polymers can replace organic solvents in such systems, however, their selection has largely been via heuristic means, and a more fundamental approach is necessary for future success in rational polymer identification.