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Article

Crystalline Polymorph Selection and Discovery with Polymer Heteronuclei

Supporting Info

Christopher P. Price, Adam L. Grzesiak, and Adam J. Matzger*

Contribution from the Department of Chemistry and the Macromolecular Science and Engineering Program, The University of Michigan, Ann Arbor, Michigan 48109-1055

J. Am. Chem. Soc., 2005, 127 (15), pp 5512–5517

DOI: 10.1021/ja042561m

Publication Date (Web): March 22, 2005

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, matzger@umich.edu

Abstract

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.

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