(165d) Prenucleation Clusters in Solutions of Mefenamic Acid

Crystallization starts with nucleation, which selects the structure of the emerging crystals and determines their numbers and sizes. Crystal nucleation often adopts nonclassical pathways, which pass through disordered precursors that host and facilitate the formation of structured embryos. In contrast to water-based crystallization, the mechanisms that govern the properties of the precursors to crystal nuclei in purely organic systems are poorly understood. Here we explore the disordered aggregates that exist in solutions of mefenamic acid (MFA), a pain-relief medication, in seven organic solvents used in pharmaceutical crystallization. To distinguish the found MFA aggregates from crystals, we exclusively employ concentrations below the solubilities of its most stable form in the respective solvents. The aggregates exhibit features that are incompatible with dense liquids, micelles, or amorphous agglomerates. The observed behaviors identify the aggregates as mesoscopic-solute-rich clusters, a class of condensates known to host crystal nucleation in numerous systems. We find that MFA forms dimers bound by weak p-p stacking forces, an essential prerequisite for mesoscopic cluster assembly. We demonstrate that the fraction of MFA captured in clusters is governed by the thermodynamic characteristics of the solution that, in turn, represent the solute-solvent interactions. The proposed mechanism of cluster formation relies on forces and interactions typical for organic systems, suggesting the mesoscopic clusters and the associated nonclassical crystal nucleation pathways may be common in organic crystallization.