ROY (the most polymorphic small molecule known) selects different polymorphs under identical chemical conditions when only the mixing mode differs: yellow and orange needles (YN, ON) appear only under gentle, quiescent mixing (diffusion, rotation), while fast mixing by magnetic stirring or piezoacoustic streaming suppresses them. Whether needles fail to nucleate under fast mixing because their nucleation intrinsically requires longer timescales, or because shear and acoustic-streaming flow actively suppress needle nucleation, is unresolved, and no polymorph-specific nucleation kinetics exist for ROY. A dedicated nucleation study is required to distinguish between these possibilities and to establish the nucleation kinetics of the polymorphs involved in the mixing-controlled selection.

Background

Polymorphism — the ability of one molecule to crystallize in several distinct crystal structures — strongly affects material properties, especially of pharmaceuticals. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, called ROY after its red/orange/yellow crystals, is the most polymorphic small molecule on record, with fourteen known polymorphs, thirteen of which have solved crystal structures (Y, ON, R, OP, YN, ORP, YT04, Y04, R05, PO13, R18, Y19, O22), plus an unsolved red-plate form (RPL), arising from different molecular conformations that interconvert in solution (Yu et al. 2000; Chen, Guzei and Yu 2005; Weatherston et al. 2025). ROY is therefore the standard model system for polymorph selection. In antisolvent crystallization, a solution of ROY in a good solvent (e.g. acetone or methanol) contacts a miscible antisolvent (water), creating local supersaturation that drives nucleation; which polymorph appears is governed by the interplay of thermodynamic stability and nucleation kinetics. Hydrodynamics matters: Ziemecka et al. (2019) showed in a quasi-two-dimensional confined geometry that radial flow of an ROY solution into water selects polymorphs by position (red prisms near the injection center, yellow needles near the edge), with flow-rate-dependent buoyancy-driven mixing. Van Nerom et al. (2022) then made the mixing variable controlled and reproducible with a two-parallel-flow microfluidic chip whose piezoceramic element can drive acoustic mixing (piezoelectrically excited surface waves that induce acoustic streaming — a steady circulating flow that accelerates transport and exerts viscous shear on the fluid). They found that identical samples (same ROY concentration, same solvent/antisolvent ratio) yield different polymorphs depending only on the mixing mode: gentle mixing by molecular diffusion or slow rotation allows nucleation of the needle polymorphs YN and ON, whereas magnetic stirring and acoustic streaming suppress needles in favor of prisms/plates; the orange-red-plate polymorph ORP appeared only sporadically and seemed unstable in the tested concentration domain. Two competing explanations exist for the needle suppression: (i) a timescale explanation — needle nucleation is slow, and fast mixing rapidly homogenizes supersaturation so that faster-nucleating forms win before needles can appear; or (ii) an active-suppression explanation — shear or acoustic-streaming flow directly raises the needle nucleation barrier (shear is known in theory to modify nucleation barriers; Mura and Zaccone 2016). Distinguishing them requires decoupling shear from supersaturation-exposure history, which no experiment has done, and requires polymorph-resolved nucleation kinetics, complicated by the fact that metastable ROY polymorphs undergo solution-mediated transformation to the stable form Y, so observed product mixtures conflate nucleation with later transformation (Hussain et al. 2025). Reliable production of ORP, whose conditions and relative stability remain unknown, is a further open target in the same system (Chen, Guzei and Yu 2005 solved its structure; Weatherston et al. 2025 found it in only 3 of 1536 high-throughput droplet experiments, exclusively with water antisolvent).

Problem Statement

For antisolvent crystallization of ROY from solution, determine the mechanism and the polymorph-specific nucleation kinetics by which the mixing mode controls polymorph selection. Specifically: (1) distinguish whether the needle polymorphs YN and ON nucleate only under gentle mixing because their nucleation intrinsically requires longer timescales, or whether shear and the flow generated by magnetic stirring and acoustic streaming actively suppress needle nucleation; (2) establish the nucleation kinetics of the ROY polymorphs involved in the mixing-controlled selection — the needle polymorphs YN and ON and the competing plate/prism forms OP, Y and R — under the controlled-mixing conditions, separating primary nucleation from growth and from solution-mediated transformation to more stable forms; the sporadic orange-red-plate form ORP is a separate open target in the same system and is not part of this kinetics deliverable.

References

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