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Synthesis

New methods to control small molecule crystallization

Robotic and mixed-crystal seeding techniques each generate new forms of ROY

by Mitch Jacoby
July 22, 2020 | APPEARED IN VOLUME 98, ISSUE 29

 

09829-scicon6-crystal.jpg
Credit: Chem
A high-throughput method produced this polymorph of ROY (red crystal, 0.27 mm long) by encasing droplets of ROY solution in an inert oil.

Only a handful of compounds have a knack for crystallizing into a variety of forms, or polymorphs. One of the most prolific, a small molecule known as ROY (so called because it crystallizes in multiple red, orange, and yellow forms), just added two more polymorphs to its growing list.

Polymorphs have been shown to exhibit unique solubility and stability properties that can affect their use in pharmaceuticals and other applications, so chemists have long devised methods to control crystallization. The aim is to produce only the targeted forms, including ones that have been predicted to be useful but have not yet been synthesized.

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For more than 20 years, researchers have intensely studied ROY (shown), slowly uncovering a dozen polymorphs and leaving some researchers wondering whether the thiophene-containing compound had any more polymorph tricks up its sleeve.

It does. Working independently, two groups developed new crystallization methods and used them to synthesize new ROY polymorphs. The studies bring the total number of polymorphs to a record-setting fourteen, eleven of which of have been fully characterized via single-crystal X-ray diffraction.

In one study, Alexandre Lévesque, Thierry Maris, and James D. Wuest of the University of Montreal prepared compounds that closely mimic ROY in molecular size and shape but differ slightly in composition. Then, working with supersaturated solutions of ROY, they used a mixed-crystal seeding method to induce subtle conformational and structural alterations, causing the compound to crystallize in a new form—pure pale orange needles (J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.0c04434).

In the other study, a team led by Michael J. Hall and Michael R. Probert of Newcastle University and Jonathan W. Steed of Durham University developed a robot-assisted high-throughput technique for screening large numbers of crystallization conditions in parallel. The method grows crystals in nanoliter droplets that contain the analyte, ROY in this case, and organic solvents, and are encapsulated within an inert oil to control the rate of solvent loss. The method yielded deep red block-shaped crystals of ROY (Chem 2020, DOI: 10.1016/j.chempr.2020.04.009).

Discovering and characterizing new ROY polymorphs is “a big deal,” says Sarah L. (Sally) Price, a polymorph expert at University College London. “The propensity to form so many polymorphs strikes at our fundamental understanding of the crystallization process, but is also practically important for controlling the physical properties of specialty chemicals like pharmaceuticals.”

Susan M. Reutzel-Edens, a senior research advisor at Eli Lilly and Company, says it’s impressive that after so many years of intense study, chemists have found new polymorphs of ROY.

“Given the importance of crystallization to purification and ensuring physical property control, these material-sparing and easy-to-implement platforms are likely to see widespread use across the pharmaceutical industry,” she says.

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