Professor Rodríguez-Hornedo Zeroes in on Cocrystal Mysteries

The cover of the June 18, 2007 issue of Chemical & Engineering News(C&EN) carried a stunning photomicrograph of a crystal structure created in the research laboratory of Associate Professor of Pharmaceutical Sciences Naír Rodrí´guez-Hornedo, PhD. (See image, this page.) What’s more, the cover story inside C&EN quoted Rodríguez-Hornedo at length about her efforts to understand cocrystal formation and stability.

When formulating drugs for suspension in liquids, pharmaceutical manufacturing scientists will choose one crystalline phase over another in order to capitalize on that crystal’s structural utility in processing and storage. By offering an alternative form of an existing pharmaceutical crystal structure, cocrystals present potential new and better choices.

Unfortunately, pharmaceutical scientists often do not know if existing pharmaceutical crystals have alternative forms. Most pharmaceutical cocrystals are found by hit-or-miss approaches using solvents and potential salt or cocrystal formers. Depending on the thoroughness of screening methods, scientists may miss cocrystals altogether

Rodríguez-Hornedo’s research is focused on understanding cocrystal formation, dissolution, and stability and on developing theoretically based methods to explain cocrystal formation and behavior.

Her research group has identified conditions under which cocrystals become less soluble and form from solutions with environmentally friendly solvents. She has already demonstrated, mathematically, how solubility depends on the equilibrium between the cocrystal and its components.

Rodríguez-Hornedo reports that her research group has not encountered an existing cocrystal that it cannot create by solution methods. Further, her group has shown that even in solvents where the cocrystal is more soluble than the pure active pharmaceutical ingredient (API), the reaction can be reversed to form the cocrystal by increasing the concentration of reactant or ligand above a critical value.

“The ability to change the thermodynamic relationship between the cocrystal phase and pure API crystal is valuable to control cocrystal formation and stability,” Rodriguez-Hornedo told C&EN.

Her methods work in both organic and aqueous solvents, although both components must be at least somewhat soluble. Rodríguez-Hornedo’s graduate students typically test cocrystal solubility in methanol, ethanol, and water. These methods are also easily scaled up, applicable to high-throughput crystallization screens, and offer prospects for “greener” synthetic routes, she notes.

Rodríguez-Hornedo has found that even trace amounts of ambient air moisture facilitates cocrystal formation in physical mixtures that contain a deliquescent component; that is, a component which dissolves as it absorbs air moisture. Cocrystal ingredients dissolve in this deliquesced solution and then cocrystallize. Rodríguez- Hornedo points out that moisture can also increase molecular mobility via amorphous phases made during grinding (or, as she learned in work with collaborators at ScheringPlough and Amgen, in melts and amorphous films).

Other researchers have found that some cocrystal forms can be more stable than the pure API. For example, the physical stability of caffeine and the asthma drug theophylline can be increased in cocrystals with oxalic acid.

This is an important distinction, notes Rodríguez-Hornedo, because drug formulation frequently involves mechanical stress from grinding, milling, or blending. Also, products may be exposed to different levels of humidity during storage. These changes could either induce cocrystal formation or lead to degradation.

E-mail: nrh@umich.edu