Interfacial Nucleation Pathways Governing Polymorph Selection Revealed by Synchrotron-Based In Situ GIWAXS and Molecular Simulations

Gas–liquid interfacial nucleation can influence organic crystallization, yet its mechanistic role in polymorph selection remains poorly understood. Here, we demonstrate that nucleation at the gas–liquid interface of flufenamic acid solutions governs polymorph selection and gives rise to a pronounced concentration-dependent polymorphism, wherein low initial concentrations favor the nucleation of form I, higher concentrations yield form III, and intermediate concentrations selectively produce the metastable form IV. In situ synchrotron-based grazing-incidence wide-angle X-ray scattering (GIWAXS) directly resolves the formation and evolution of prenucleation assemblies at the interface, revealing three distinct interfacial molecular evolution pathways correlated with the emergence of specific polymorphs. Molecular dynamics (MD) simulations combined with energy calculations within the hybrid quantum mechanics/molecular mechanics (QM/MM) embedded-cluster framework further reveal interfacial enrichment, orientational bias, and conformer-dependent stabilization of stacking motifs, providing a microscopic interpretation of the experimentally observed selectivity. Together, these results establish the gas–liquid interface as an active structural selector that reshapes molecular organization prior to nucleation, offering a mechanistic framework for understanding and controlling polymorphism in evaporation-driven crystallization.