Polymorphic ROYalty: The 14th ROY Polymorph Discovered via High-Throughput Crystallization.

Area of Science:

• Solid-state chemistry
• Materials science
• Crystallography

Background:

• Polymorphism, the ability of a substance to exist in multiple crystalline forms, significantly impacts material and pharmaceutical properties.
• Characterizing the full solid-state landscape of polymorphic molecules is challenging with traditional crystallization methods.
• Exhaustive experimental screening is crucial for understanding polymorph behavior and properties.

Purpose of the Study:

• To evaluate the efficacy of high-throughput Encapsulated Nanodroplet Crystallization (ENaCt) for exploring the solid-state landscape of highly polymorphic compounds.
• To investigate the crystallization behavior of 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (ROY), the most polymorphic small molecule known.
• To identify new crystalline forms and solvates of ROY.

Main Methods:

• Utilized high-throughput Encapsulated Nanodroplet Crystallization (ENaCt) with 1536 experiments across 320 conditions.
• Applied ENaCt to study the polymorphism of 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (ROY).
• Employed X-ray diffraction analysis for crystal structure determination.

Main Results:

• ENaCt successfully yielded single crystals for all six known solution-accessible polymorphs of ROY (Y, R, YN, ON, ORP, R18).
• Discovered two previously inaccessible polymorphs (Y04, Y19) and a new polymorph (O22) of ROY.
• Identified the first ROY solvate (ROY· methyl anthranilate) and a novel ROY dimer via in situ oxidation.

Conclusions:

• ENaCt is a powerful tool for rapid and efficient exploration of the solid-state landscape of polymorphic molecules.
• The study confirmed ROY's status as the most polymorphic small molecule, now tetradecamorphic, with the discovery of O22.
• ENaCt facilitates the discovery of new crystalline forms, solvates, and molecular associations, advancing materials and pharmaceutical development.