Organic Nucleation: Water Rearrangement Reveals the Pathway of Ibuprofen

The organic nucleation of the pharmaceutical ibuprofen is investigated, as triggered by the protonation of ibuprofen sodium salt at elevated pH. The growth and aggregation of nanoscale solution species by Analytical Ultracentrifugation and Molecular Dynamics (MD) simulations is tracked. Both approaches reveal solvated molecules, oligomers, and prenucleation clusters, their size as well as their hydration at different reaction stages. By combining surface‐specific vibrational spectroscopy and MD simulations, water interacting with ibuprofen at the air–water interface during nucleation is probed. The results show the structure of water changes upon ibuprofen protonation in response to the charge neutralization. Remarkably, the water structure continues to evolve despite the saturation of protonated ibuprofen at the hydrophobic interface. This further water rearrangement is associated with the formation of larger aggregates of ibuprofen molecules at a late prenucleation stage. The nucleation of ibuprofen involves ibuprofen protonation and their hydrophobic assembly. The results highlight that these processes are accompanied by substantial water reorganization. The critical role of water is possibly relevant for organic nucleation in aqueous environments in general. Combining experimental and simulation approaches have been applied to investigate the nucleation of ibuprofen both in solution and at model hydrophobic interface. The macroscopic nucleation is followed, nanoscale species are identified, and the interfacial interaction between ibuprofen and water during nucleation is tackled. The multi‐scale analysis implies that the structure of water changes substantially and reports the non classical pathway of ibuprofen nucleation.