Mimicking mollusks to control crystal forms

September 10, 2003
Written By:
Nancy Ross-Flanigan
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ANN ARBOR—In the quest for new and better drugs, researchers typically concentrate on a compound’s chemical structure. But a given compound may exist in more than one form, depending upon how the molecules are assembled into crystals.

“Increasingly, we’re realizing that it’s not just the compound itself but how it exists as a solid that can affect its properties, such as solubility and shelf life,” said Adam Matzger, assistant professor of chemistry at the University of Michigan. Researchers would like to control the crystal form a solid takes so that they can explore and manipulate the properties of the various forms, known as polymorphs. Matzger described a new approach to doing that at the annual meeting of the American Chemical Society this week.

“People have long known that just by changing the conditions under which you crystallize a drug—the temperature, the solvent, the growth method—you can sometimes get different polymorphs,” Matzger said. “But we introduced an alternate approach, which is to grow the crystals on polymers.”

Matzger’s method mimics a natural process that clams and their kin use to control the composition of their shells. “Mollusks can selectively deposit a specific polymorph of calcium carbonate in their shells by growing the crystals on particular proteins (which are polymers). We thought we could apply the same approach to polymorphs of pharmaceuticals.”

Crystals develop when molecules in a solution find each other and stick together—a process called nucleation. Often, the surface of some other solid material in the solution serves as a meeting place for the particles. Matzger’s strategy was to provide a variety of surfaces, in the form of various polymers, on which crystals could form. “Polymers are good because you can buy or synthesize many different types, so you can get a lot of diversity,” Matzger said.

In one set of experiments, the U-M researchers grew crystals of acetaminophen, the active ingredient in Tylenol, on a wide assortment of polymers. They found that certain polymers, such as nylons and polyvinyl chloride (the plastic used in plumbing pipe), encouraged the growth of one polymorph of acetaminophen, while other polymers promoted growth of an alternate form. Still others led to mixtures of the two polymorphs.

In other work with carbamazepine, the active ingredient in the epilepsy drug Tegretol, the researchers used polymers to produce four different crystal forms of the drug, including one that was previously unknown.

Discovering all the forms that a drug can exist in is important to pharmaceutical companies, not only because some forms may be more effective than others, but also because of patent issues. “If you make a different polymorph of a top-selling drug, that’s considered a different form of matter, so it provides a means for a company to extend a patent that’s about to expire or for another company to apply for a separate patent,” said Matzger. “That’s where the polymorph issue is becoming really interesting.”

For more information about Matzger, visit http://www.umich.edu/~michchem/faculty/matzger/ For more about crystals, visit http://www.unmuseum.org/crystals.htm and http://www.chemistry.co.nz/crystals_forming.htm