Insights into Hydrophobic Ion Pairing from Molecular Simulation and Experiment

Hydrophobic ion pairing (HIP) is the process by which a charged hydrophilic molecule of interest is electrostatically coupled with an oppositely charged hydrophobic counterion to produce a complex with greater hydrophobicity than the original molecule. This process is of interest in drug delivery, but a molecular-based mechanistic understanding is still incomplete. In this work, we used molecular simulation and experiment to study a model system of Polymyxin B (drug) and oleic acid (hydrophobic counterion). Validation of the simulation system was performed by assessing HIP complex stability under various solvent conditions, and the results were found to be in good agreement with experiment. The effects of solvent composition, particle size, and charge ratio on the observed hydrophobicity, morphology, and stability were studied through the simulation of small HIP clusters. Microsecond simulation of a larger system was then used to characterize the kinetics of assembly. Particle formation over longer length (μm) and time scales (ms) was studied experimentally via flash nanoprecipitation, and the formation of electrostatically stabilized nanoparticles was observed. These results provide a mechanistic and morphological picture of the HIP event and will help inform the development of future formulations that utilize HIP.