By: Robert Wenslow
Dear AAPS Blog: I am 40-something years old. I had, up until recently, believed in Santa Claus (errrrr…I mean disappearing polymorphs). Now, some colleagues are claiming he does not exist. Please tell me the truth: Do disappearing polymorphs exist? (I.e., Should I truly be worried about ice-nine?)
The term “disappearing polymorphs” refers to instances when novel polymorphs (whether active pharmaceutical ingredients [API] or intermediates) appear during development, rendering it very difficult to isolate previous polymorphs. This then invariably leads to control issues with the process in addition to potential catastrophic consequences. When I say polymorphs for the purposes of this blog, I am encompassing hydrates and solvates, even though that is blasphemy to some. We’ve all worked on projects that go something like this…we had never seen a hydrate crystal form even though the compound had seen water basically since its’ inception. Then all of a sudden, during isolation of phase 3 supplies, a stable hydrate is discovered, and we can no longer isolate the previous crystal form in the current solvent system…PRESTO. And as Kurt Vonnegut’s doomsday scenario in Cat’s Cradle predicts, polymorphs (disappearing polymorphs in particular) are not limited to API or intermediates.
When I first read about the “rebirth” of this topic, I was quite intrigued as I’m sure most solid state chemists would be. The discussion about whether disappearing polymorphs exist involves all kinds of interesting concepts such as polymorph prediction, crystal engineering, novelty, proper screening strategies, etc. In digging through the disappearing polymorph story, I uncovered a very interesting “early” perspective that I hadn’t seen before. I’ve also jointly published a case study paper concerning good, bad, and ugly polymorph changes during development, which might be of interest (shameless self-promotion and apologies to Mr. Eastwood). I am forced to believe, by experience, that disappearing polymorphs exist and all pharmaceutical development programs need to screen for forms early and often. And even so, there is no guarantee ice-nine is not out there…somewhere…waiting for someone to find the right conditions to nucleate it. Sleep well, bloggers.
And when you’re not sleeping, please share your thoughts and possibly some stories (we know they’re not all published) in the comments below.