Crystalline Polymorph Selection and Discovery with Polymer Heteronuclei

The discovery and selective production of crystalline polymorphs, an outstanding problem in
solid-state chemistry, is of great importance industrially in, for example, the manufacture of pharmaceuticals
and pigments. Despite considerable efforts, no reliable method exists to produce all of the stable polymorphs
of a given compound. Herein, we report methodology to control the phenomenon of crystal polymorphism
through the use of diverse libraries of polymer heteronuclei including both commercially available polymers
and combinatorially synthesized cross-linked polymers. This new approach for exploring polymorph space
offers the advantage of high throughput crystallization to discover multiple polymorphs combined with the
ability to selectively produce a given form from a single solvent and temperature condition by simply varying
the nature of the polymer substrate. This technique is successfully demonstrated on the pharmaceuticals
acetaminophen, sulfamethoxazole, and carbamazepine and on the pharmaceutical intermediate 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY). High throughput screening, accomplished by optical
microscopy and Raman spectroscopy, identified the selective production of the two stable polymorphs of
acetaminophen and all six stable forms of ROY. Furthermore, one new form of carbamazepine and two
new forms of sulfamethoxazole were discovered; in these cases, single crystals were obtained enabling
the structural characterization of two new tetramorphic systems.