Imagine you’re making a pie. You follow the recipe to the letter, purchasing the recommended brands listed, using a thermometer to ensure your oven is calibrated, etc. But when you go to pull it out of the oven, you find it’s not a pie at all—it’s a cobbler. Confused, you call a friend who’s made the recipe before and gotten great results. She bakes the pie again and encounters the same problem—a mysterious cobbler where a pie should be. Then you both call a friend who made the pie just the other day, he brings the pie over to show it off, but after talking for a while, you discover it’s also turned into a cobbler.
Sounds weird, right? And yet this exact scenario happens in drug manufacturing with alarming frequency. Pharmaceutical manufacturers will follow a known process for creating a drug, but during the crystallization process, a slightly different version (or polymorph) shows up. It may have the same chemical formula, but this new polymorph has a slightly different shape that gives it dramatically different properties.
And the really spooky thing is that the new polymorph isn’t confined to any single lab, anyone who tries to make the first polymorph will find that it has simply vanished. In some cases, even bringing the old polymorph to a lab that’s made the new polymorph is enough to make that product transform as well. It’s as if the specific chemical product were erased from the planet by some supernatural force.
Perhaps the most famous disappearing polymorph was the antiretroviral ritonavir created by Abbott Laboratories and approved in 1996 for the treatment of HIV/AIDS. Form I of the drug was sold in gel capsules but then it got superseded by Form II in 1998. This form, which had the same formula, wasn’t as soluble, which rendered it ineffective. Abbott was forced to pull the drug from market until they could reformulate it as a caplet in 1999. The ordeal cost the company an estimated $250 million (not to mention the tens of thousands of patients who went without essential medication).
Disappearing polymorphs cause plenty of legal headaches for drugmakers too. For example, when a Canadian pharmaceutical company wanted to produce Form I of ranitidine (AKA Zantac) after the patent expired, they were sued by the drugmaker Glaxo. Glaxo held the initial patent on Form I, as well as the patent on Form II, and its lawyers argued that any attempts to produce the former would inevitably result in traces of the latter. (Glaxo lost the suit.)
So why do these polymorphs vanish in the first place? According to researchers who study solid-state chemistry, it all comes down to thermodynamics. The first version of a drug might be a less thermodynamically stable version, but one that forms more quickly. Crystals grow via nucleation (or seeding), where one provides a kind of scaffold or template for the others to form. If Form I nucleates faster, it might predominate until the more stable Form II pops up and takes over.
Of course, that doesn’t explain why polymorphs seem to vanish worldwide, and this is where things get speculative. The most compelling explanation for this particular mystery is that there are tiny seed molecules of these drugs just floating around in the atmosphere. In theory, it only takes one molecule to kickstart crystallization, so any lab that starts to grow the less stable Form I will find their culture seeded with the more stable Form II instead.
There’s at least some anecdotal evidence for this. Researchers working in Form II drug labs who were transferred to labs growing Form I discovered the “curse” of Form II seemed to travel with them. Additionally, some Form I drugs have been known to transform to Form II after even being in the same lab with them (like the third friend’s pie).
So is there anything we can do to stop it? Well, disappearing polymorphs are a relatively new phenomenon and an active area of research. In some cases, researchers have been able to recreate the vanished polymorphs in labs that have been protected from atmospheric and accidental contamination. In a paper published in 2024, researchers managed to recreate Form I of the HIV/AIDS drug ritonavir via ball-mill grinding (kind of a chemistry rock tumbler). In other words, there’s some hope on the horizon that these polymorphs haven’t vanished for good.
Still, it remains one of the spookier stories in chemistry.
Lead image: Prince Zaleski / Shutterstock
