Speedy Route to Polymorphs

DRUG DEVELOPMENT

Asystematic method has been developed for rapidly identifying different crystalline forms--polymorphs--of drugs and other compounds. The technique could have important implications for the manufacture of pigments and drugs.

Different crystalline forms of a drug can vary in solubility, absorption, and stability properties and are considered separate patentable entities. Abbott Laboratories, for example, had to temporarily withdraw the AIDS drug Norvir from the market when an unexpected crystal form was produced during manufacturing. Drug companies can also obtain better patent protection if they know as many of a drug's polymorphs as possible.

Yet "finding new polymorphs is currently rather hit-and- miss," says assistant professor of chemistry Adam J. Matzger of the University of Michigan, Ann Arbor. Three years ago, Matzger and coworkers showed that polymers could be used to nucleate crystallization and generate new polymorphs. Now, they've created a combinatorial version of that technique in which polymer libraries are used to screen compounds for polymorph formation in a high-throughput manner (J. Am. Chem. Soc. 2005, 127, 5512).

In the technique, libraries of chemically diverse cross-linked polymers are synthesized in wells of microtiter plates. The polymers induce and control differential crystallization of compounds screened in the wells, and optical microscopy and Raman spectroscopy are used to detect and identify the crystals formed.

Matzger and coworkers used the technique to quickly identify the two known stable polymorphs of acetaminophen and six crystal forms of a pharmaceutical intermediate called ROY. In addition, "crystallization of the pharmaceuticals carbamazepine and sulfamethoxazole in the presence of these libraries resulted in four polymorphic forms each, three of which were novel," Matzger says. "By using combinatorially synthesized, cross-linked polymer libraries, we provide ... access to new solid forms of compounds," he adds.

Chemistry professor Joel Bernstein of Ben-Gurion University of the Negev, Beer-Sheva, Israel, agrees that the technique can lead to new crystal forms. The technique can also be tuned to control the polymorph obtained, suggesting "that there may be considerable economic value to this strategy," he says. "As with virtually all crystallization procedures, however, the ability to obtain control will have to be developed and tested on a case-by-case basis."

rn Almarsson, senior director of pharmaceutical chemistry at TransForm Pharmaceuticals, Lexington, Mass., says that, in the technique, "the interactions between different polymers and crystallizing molecules are complex and clearly lead to multiple solid forms of the compounds. It would be interesting to gain a better understanding of the mechanisms behind the appearance of a particular form under a given condition."

Chemistry and chemical engineering professor Michael D. Ward of the University of Minnesota, Twin Cities, says that, by extending their previous work on polymer-induced crystallization, Matzger and coworkers "have demonstrated the potential universality of the approach. I think it's going to produce results faster than has been possible before."