Puzzling polymorphs

Polymorphism is a common and sorta crazy issue in pharmaceutical process chemistry. Basically put, a drug molecule in the solid state can have multiple crystal forms. Different impurity profiles and different crystallization techniques (solvents, heating/cooling rates) can produce different polymorphs, which can have wildly different physical properties and bioavailabilities. A famous story of troublesome polymorphism is Abbott’s ritonavir, where in the middle of manufacturing for sale (not during the R&D phase!), a new, much less soluble polymorph started showing up in batches. Moreover, once the new polymorph showed up, it was very difficult to generate the previous polymorph. Even crazier, a team of scientists went to another plant in Italy where the process was still working as desired, and soon after the team left, the new polymorph appeared. It took a crash program to understand which conditions were generating the new crystal form to get it under control.

A recent article by Pradash et al. in Organic Process Research and Development illustrates the problems of polymorphism similarly: once the authors determined that there was another crystal form (‘Form A’) than the original (‘Form B’), they undertook a screening process (looking at varieties of solvent and crystallization techniques) to find other polymorphs. Interestingly, once they discovered a new polymorph (‘Form C’), they found that it was impossible to generate Form B in their laboratories. They selected Form C for its physical properties and moved it into the pilot plant; lo, they then found Form D. This new crystal form began predominating and “those seeded crystallization processes that consistently produced Forms A and C started to produce predominately Form D in the laboratory.” (Click on image to see pictures of the polymorphs and the structure itself.)

When I read these accounts, I am filled with admiration for pharmaceutical process chemists, the interesting science that they get to do and the vast reserves of patience and sangfroid they must have.  Chemistry (and manufacturing chemistry, especially!) is based on reproducibility and consistency; when issues arise, I suspect that there is a great deal of checking and double-checking to make sure that “this is really happening to us.” Also, I can’t help but wonder if those process chemists, when these issues are discovered, wonder if the laws of the physical universe are being temporarily suspended and some Loki-like diety is having its way with them.

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