Jul 2026· Journal of the American Chemical Society· Vol 148, pp. 30224 - 30237· 0 citations· 51 references
Medicine
Abstract
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.
Synthesis of a target polymorph remains more empirical than predictive because crystallization often selects the most accessible nucleation pathway rather than the thermodynamically most stable phase. Here, we show that oxygen stoichiometry converts this empirical synthesis variable into a kinetic control parameter for anatase-rutile selection in TiO$_{2-x}$. Enhanced-sampling simulations reveal that oxygen content alters the nucleation-barrier landscape, switching the relative accessibility of anatase and rutile, even while rutile remains thermodynamically favored. Molecular dynamics simulations show the presence of a diffuse intermediate shell around the nucleus, where oxygen deficiency alters Ti-O coordination and connectivity and drives shell-local motif evolution from anatase-like toward rutile-like environments. A coupled-flux model that integrates barrier competition with shell-mediated attachment/exchange yields a relative nucleation-rate map consistent with reported oxygen-dependent synthesis trends. These results establish stoichiometry-controlled intermediate-shell motif evolution as a kinetic origin of polymorph selection and provide a framework for predicting target phases in composition-coupled crystallization.
Deciphering the microscopic details of crystal nucleation remains a key open problem in chemical physics. For aqueous sodium chloride (NaCl), the extent to which nucleation involves amorphous ion aggregation, and the supersaturation regime in which two-step-like behavior emerges, remains actively debated. In this work, we examine NaCl nucleation at 12, 13, and 14 mol/kg ($S = 3.2, 3.5, 3.8$) using unbiased path sampling with $\infty$RETIS. Through a combination of reaction coordinate analysis, joint and conditional probability distributions, diffusion tensor analysis, and conditional free energy landscapes, we identify nucleation pathways without a priori mechanistic assumptions. While all concentrations are governed by the same reaction coordinate, indicating that nucleus growth and structural ordering are central to crossing the barrier, the nature of reactive trajectories changes with supersaturation. At lower concentrations, nucleation mainly occurs via tightly coupled increases in cluster size and ordering, compatible with a one-step-like mechanism. As concentration increases, amorphous aggregation becomes increasingly decoupled from crystallization, and pathways involving substantial amorphous growth prior to crystallization become progressively more probable. Importantly, these pathways coexist within a single broad reaction channel rather than proceeding through distinct metastable intermediate states. Together, these results reconcile earlier, contradictory reports on NaCl nucleation mechanisms and support a view of nucleation as an ensemble of competing reactive pathways whose relative probabilities vary continuously with supersaturation. More broadly, our findings illustrate that substantial mechanistic diversity can emerge within a classical nucleation framework, without requiring distinct non-classical descriptions.
Gas hydrate formation poses critical flow assurance challenges in natural gas production and transportation systems, yet the facet-dependent growth kinetics of hydrates and its modulation by external agents remain poorly understood. In this work, molecular dynamics simulations were employed to systematically investigate methane hydrate growth on different crystal facets and to elucidate the corresponding kinetic regulation under varying spatial distributions of kinetic hydrate inhibitors (KHIs). The results demonstrate pronounced facet-dependent growth kinetics, with growth rates following the order (100) > (110) > (111), governed by differences in methane transport pathways and interfacial structural constraints. A transition from transport-dominated to interfacial assembly controlled growth is suggested across crystal facets, revealing the important roles of methane enrichment and water structuring at the interface. Furthermore, kinetic regulation exhibits strong facet and location dependence. KHIs at the gas-liquid interface primarily regulate methane transport and interfacial water organization, whereas those near the hydrate surface appear to directly disrupt the cooperative assembly of methane and water molecules, resulting in enhanced inhibition efficiency, particularly on the (111) facet. These findings establish a mechanistic link between hydrate growth behavior and inhibitor action, providing molecular-level insights into facet-dependent hydrate formation and its kinetic regulation.
Ying-Xu Lu, Z. Li, Liwei Cheng et al.· Langmuir· 0 citations
High-entropy alloys combine multiple principal elements and can exhibit exceptional mechanical properties and catalytic activity. However, how they crystallize remains poorly understood because early nuclei are small, transient and chemically complex. Here we advance atomic electron tomography to determine the three-dimensional atomic structures and local chemical order of 8,160 high- and medium-entropy alloy nuclei. We find that nucleation proceeds through gradient ordering, in which structural order is highest at the core, decreases smoothly towards the boundary and is coupled to local chemical order. Most nuclei coalesce with nearly aligned crystal lattices, whereas a minority form twin boundaries. We develop the gradient nucleation pathways model, which generalizes classical nucleation theory by incorporating spatially varying structural order within each nucleus. The model captures diffuse, partially ordered nuclei, recovers classical nucleation theory in the sharp-interface limit and reveals multiple intermediate states. These results provide an atomistic framework for understanding crystal nucleation and growth across a broad range of materials.
Yakun Yuan, S. Moniri, Yao Yang et al.· Nature Materials· 0 citations
The morphology of thin-film composite membranes is encoded during interfacial polymerization (IP) by competing monomer transport and reaction kinetics, yet molecular control remains limited due to their intrinsic coupling. Herein, we show that counterions decouple solvation-controlled transport from transition-state energetics, enabling deterministic control over nonequilibrium thin-film morphogenesis. Using a model polyester IP system, we demonstrate that varying phenoxide counterions (Li+, Na+, K+, TBA+) reveals anomalous energetic trends, with transition-state energies (ΔG‡ ≈ 6.9-21.7 kcal mol-1) and interfacial partitioning energies (ΔGpartition ≈ 11.2-0.7 kcal mol-1) spanning more than an order of magnitude. Despite faster intrinsic kinetics, Li+ produces ultrathin, smooth films (≈9.4 nm thickness; Rq ≈ 1.9 nm), whereas TBA+ yields substantially thick films with rough architectures (≈32 nm; Rq ≈ 27-30 nm). This inversion is attributed to a kinetically locked regime, where confined ultrafast reactions suppress reaction-diffusion instabilities before morphological amplification. Consequently, resulting networks exhibit tunable surface roughness (∼1.9 to ∼27 nm). The controlled ∼14-fold increase in surface roughness from Poly-Li to Poly-TBA yields 75% enhanced water permeance at equivalent solute rejection. These findings establish a predictive energetic framework that connects interfacial energetics to reaction-diffusion instability, membrane morphology, and transport behavior.
Priyanka Dobariya, A. A., Karan Marvaniya et al.· Journal of the American Chem...· 0 citations
Nucleation is a fundamental step in the formation of new materials, with nucleation rates governing phase-transition pathways and outcomes that influence material properties across chemistry, physics, and biology. Nevertheless, extracting nucleation rates remains challenging: experiments are limited by the microscopic length scales involved, while molecular simulations are hindered by the rare-event nature of nucleation and the large system sizes required to sample low-supersaturation regimes typical of experiments and industrial processing. Here, we build on the established thermodynamic correspondence between stable clusters in small, closed systems and critical clusters in open systems and develop a multicomponent extension, the Critical Cluster Equivalence Principle, that transforms this correspondence into a practical workflow for calculating nucleation rates. We employ this equivalence to determine solvent-mediated NaCl crystal nucleation driving forces and rates over a wide range of supersaturations (SNaCl ∈ [1.5, 4]) and further validate the framework by benchmarking against curvature-corrected homogeneous nucleation rates for argon vapor condensation. This has been achieved using a small number of brute-force, finite-size simulations in which cluster-size statistics and monomer-exchange dynamics in the steady-state map directly onto critical clusters in macroscopic systems. By combining this multicomponent correspondence with the computational approach developed here, the current investigation has obtained nucleation rates in excellent agreement with experiments and enhanced sampling simulations. This approach provides a unified and generalizable tool for predicting nucleation rates with minimal computational effort, enabling routine application across a wide range of material systems.
Lun-Na Li, Fabienne Bachtiger, A. Finney et al.· Journal of the American Chem...· 1 citation
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