University of Missouri professor discovers new method of compound crystallization

University of Missouri professor and his team discover that applying carbon dioxide under pressure to the well-known drugs Biaxin and Prevacid provides a way of performing crystallization in a fraction of the normal time

Kelsey Kaustinen
COLUMBIA, Mo.—Pharmaceutical companies may have just been granted a revolutionary new method of drug production thanks to the University of Missouri (MU). That's the institution through which Jerry Atwood, Curator's Professor and Chair of the Department of Chemistry in the MU College of Arts and Science, and other researchers recently published a paper detailing how highly pressurized carbon dioxide can bring about crystallization of drug compounds in a fraction of the time.

In the paper, Atwood details how he and his team experimented on the well-known drugs clarithromycin (Biaxin) and lansoprazole (Prevacid), demonstrating the relative ease with which applying carbon dioxide under pressure can cause crystallization.

"For Biaxin, at 350 psi we were able to get complete conversion at room temperature in about four hours," says Atwood. "At just a pressure of roughly 28 psi, tire pressure, we could see conversion at room temperature, though it was very slow. And likewise, the results were similar for the Prevacid molecule."

The current industrial method for processing Biaxin, Atwood explains, is that the material is crystallized, then heated for 18 hours at about 110 degrees Celsius. For Prevacid, Atwood notes that the problem with the drug is achieving the right crystal and removing water or solvent molecules from the crystal. Additionally, the compound for Prevacid, he adds, begins to decompose at 50 degrees Celsius. According to Atwood, "these two examples of blockbuster pharmaceutical drugs typify the problems the pharmaceutical companies face in bringing their products to market in drugs in a tablet."

Atwood notes that another issue associated with the current methods of crystallization is the retention of solvent molecules. Atwood describes current pharmaceutical compounds as "generally large, floppy molecules" that don't pack together well in crystal form, and as a result, the extra space is taken up by solvent molecules. He explains that in their experiment, a solvent was included in the crystal material, and that in using the carbon dioxide pressure, "we're able to get rid of the solvent in the process."

"What the CO2 does in some fashion—we're not sure of the exact mechanism—but it allows the molecules to glide over each other in a fashion so that they can find a better way of packing," Atwood explains. "It allows the molecules to find a good resting place next to each other, to pack more efficiently and to utilize the space that's available to them to the exclusion of solvent molecules."

The discovery of the effects of pressurized carbon dioxide were a happy surprise, Atwood admits, one that came as a result of a previous paper he worked on in Sept. 2009 while studying clarithromycin.

"We showed that water could diffuse into the crystal structure and be associated in the interior," Atwood explains. "And I was thinking about this—that if H2O can diffuse into the crystal, perhaps CO2, a gas, could also diffuse. So we did our initial experiment…we put a pressure of CO2 on the crystal material and saw that it did indeed absorb CO2. Not only was the crystal form absorbing the CO2, but the CO2 was altering the crystal form of the drug."

"It's one of those interesting moments of science when one isn't expecting anything to happen, and something special does happen," says Atwood.

Atwood points to control of the crystal form as being "absolutely necessary to the effective production of many treatments these days," citing the drug Ritonavir, produced by Abbott Laboratories, as an example. The drug was originally produced in a tablet form, until Abbott discovered that it could not produce the correct crystal form of the drug. The only form that they could produce, says Atwood, was "so insoluble that it rendered Ritonavir useless." Abbott could not control the crystal form and eventually reformulated the drug as a gel cap.

"(Pharmaceutical companies) want to control the form they're producing at the plants so as to control the properties, like solubility and bioavailability," says Atwood. "What we're offering in the more far-reaching terms of this paper is a new way to control the crystal form of the drug."

Atwood says that they are testing this process with other drugs and getting "very nice results," adding that the ultimate goal with the carbon dioxide method is to use it at pressures of 50 to 100 psi. He believes the carbon dioxide process has potential for use in the processing of other drugs.

"I think it will prove to be a generally useful tool in our group of methods for determining the crystal form of the drug we're using," Atwood says. "Most drugs have the active ingredient in crystal form. Anything we can do to gain control of the crystal form is an important advancement for the field."

The paper, "A New Strategy of Transforming Pharmaceutical Crystal Forms," was co-authored by Jian Tian and Scott J. Dalgarno. It was published in a recent edition of the Journal of the American Chemical Society, and according to the MU website, was cited by Chemical & Engineering News in its "News of the Week."


Kelsey Kaustinen

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