Promoting organic nucleation of diclofenac: hydrophobic interfacial interactions drive self-assembly

We compare the pH-triggered nucleation of the pharmaceutical diclofenac in bulk solution and at the air-water interface, using a combination of cryo-transmission electron microscopy, surface-specific spectroscopy and microscopy, and molecular dynamics simulations. In solution, simulation data reveal diclofenac forms dynamically ordered, liquid-like pre-nucleation clusters (PNCs), following a nonclassical nucleation pathway. At the air-water interface, nucleation occurs earlier during the titration process. The promoted nucleation is attributed to the interfacial enrichment of protons at this hydrophobic interface, elevated interfacial apparent pK _a for diclofenac, as well as the interface-induced ordered diclofenac-water structures. While hydrophobic interactions drive the first air-diclofenac-water layer, further diclofenac molecules tend to separate from water by forming hydrogen-bonded dimers, characteristic of the crystal structure. These findings provide molecular-level insights into organic nucleation, highlighting the importance of hydrophobic interfaces in controlling the process, with potential implications for various applications in pharmaceutical and materials science.