Structured Ternary Fluids Promote Crystallization and Detection of...

Polymorph screens are typically resource- and time-intensive, requiring multiple solvent systems. Here, we report that structured ternary fluids (STFs), dynamic analogues of microemulsions, facilitate the simultaneous crystallization of multiple 5-methyl-2-[(2-nitrophenyl)-amino]-3-thiophenecarbonitrile (ROY) polymorphs from a single composition, despite the dominance of the stable Y form as both the thermodynamic and kinetic product. Previously, we demonstrated that STFs enable selective crystallization of all three ambient-pressure polymorphs of glycine. Here, we extend this approach to ROY, using toluene-water-isopropanol STFs to access metastable polymorphs that remain elusive in conventional toluene-isopropanol mixtures. Additionally, at high supersaturations, an amorphous phase can initially precipitate before being consumed by crystalline forms. We attribute these findings to the ability of STFs to maintain elevated local supersaturations and to generate higher nucleation rates and lower crystal growth rates than conventional solvents. A new STF pipetting perturbation strategy, after sedimentation of the first-formed Y prisms, promotes selective autocatalytic secondary nucleation of the metastable polymorphs, facilitating their isolation. This study reveals the potential of STFs for rapid polymorph screening.