Nucleation of Elusive Crystal Polymorphs at the Solution–Substrate Contact Line

Abstract

While metastable crystal forms are kinetically favored at higher supersaturation conditions, more stable polymorphs often crystallize under the control of competing kinetic processes such as solvent-mediated polymorphic transformation and/or preferential molecular self-assembling in solution. In such cases, alternative methodologies are required to facilitate nucleation and growth of a metastable polymorph. In this study, the metastable polymorphs of d-mannitol (δ form) and glycine (β form) — which are usually difficult to isolate by classical solution crystallization methods — were obtained by slow evaporation of aqueous solution microdroplets. The metastable forms preferentially nucleated at the “contact line” where the solution–air interface meets the glass substrate surface. In contrast, the thermodynamically stable polymorph of mannitol (β form) and kinetically stable polymorph of glycine (α form) crystallized within the solution drop. Upon nucleation at the contact line, δ mannitol grew out from the solution drop by entrapping the solution in the region between the dendrite-shaped crystals. Evaporation of the thin film of solution effectively removed the water around the crystals and consequently prevented any solution-mediated transformation to the stable form. On the other hand, β glycine crystals nucleated at the contact line partially transformed to the α form through solvent-mediated transformation. By analyzing the nucleation behavior of mannitol and glycine polymorphs under fast solvent evaporation conditions, we surmise that preferential nucleation of the metastable polymorphs from aqueous solution microdroplets is not controlled solely by the rate of supersaturation generation. Alternatively, development of higher supersaturation at the solution–substrate contact line via a Marangoni-driven convective solute transport in the solution drop could influence crystallization of the metastable polymorph.