I mentioned polymorphs the other day, and no mention of those should go by without a reference to the classic 1995 article on “disappearing polymorphs” and its 2015 follow-up. This is a controversial area, but what everyone can agree on is that there are numerous cases where some particular crystal form of a compound has been prepared and characterized, but later on becomes far more difficult to obtain at all. There are various values for the terms in that statement, but as the case of ritonavir shows, you can have a compound that has been worked on for years and produced commercially in bulk that hits upon a more stable solid phase. And since these more stable crystal forms tend to have very different solubilities, the effect on a drug development program (or in ritonavir’s case, a drug that is already rolling off the manufacturing line!) can be extremely unwelcome.
When this happens, it can seem as if the original crystal form is going extinct and never to be seen again, an effect that seems almost supernatural. But as these papers note, the “unintentional crystalline seed” hypothesis is surely the explanation. Organic chemists are well acquainted with the idea of seed crystals being added to a solution, but we’re adding them all the time whether we realize it or not. That’s both likely and plausible when you do the numbers:
Many laymen are initially skeptical about a phenomenon caused by particles that cannot be seen, although very few would accept an invitation for a casual—and unprotected— visit to the pneumonia ward at their local hospital. The approximate limit of visual detection for the naked eye is a crystal that weighs approximately 10-6g. We pointed out earlier that a speck of that size contains approximately 1016 molecules and while there are various estimates of the size of a critical nucleus that could act as a seed even the largest— a few million molecules—would mean that an invisible particle could contain up to 1010 of such unintentional seeds.
What’s more, a given cubic foot of air could easily contain a million or so particles under a half-micron size without anyone noticing at all. Consider also that such too-small-to-see particles can lurk in what looks like a clear solution, and you have plenty of opportunities to spread a given polymorph around by what seems like magic. The 2015 paper tracks down several examples of the spread of such material
It’s also not true that polymorphs can truly go extinct, either, although it’s understandable that it might appear that way. There are always conditions out there to obtain the old crystalline form, although there is no requirement that these be easy to find (!) Indeed, the original form of ritonavir was recovered and brought back into production after a great deal of effort, although not before HIV-positive patients had seen their medicine disappear from the shelves for months (and not before Abbott had lost a quarter of a billion dollars along the way). But as the authors point out, every one of these situations really is unique; that adjective is used here in its exact sense. There are compounds for which only one crystalline form has ever been reported, and there are others with two dozen polymorphs (and when that’s happening, you can be pretty sure that there are some others that haven’t shown up yet). Only one polymorph of aspirin was known until 2005, when another turned up, Since we are still no good at predicting polymorphs and crystallization conditions in general, anyone working on such a problem will have to prepare for a great deal of experimentation, both wide-ranging and precise, which is not such an easy combination to realize.
The 2015 paper goes into detail on several cases from the drug industry, and you will not be surprised to hear that this squarely intersects with patent issues. The legal landscape in this area is something of a mess, or at least that’s my impression. People sue claiming that Patent X is invalid because it didn’t actually cover useful polymorph number 18, and are countersued by the original holders claiming that there is no way that the procedures described could have produced what the plaintiffs are claiming, and on and on. Various legal teams have staked out positions over the years that range from “everything in the world is covered in microscopic seed crystals of everything” all the way to “there is no evidence for crystal seeding whatsoever”, depending on the issues at hand, which is of course what lawyers are paid to do. But there’s quite a bit of room between those two(!), and the “every single case is unique” aspect of crystallization does not blend well with the legal need for fundamental principles and rules that apply across different situations. Consider that the law not only has to deal with polymorphs but with hydrates and solvates as well (crystal forms that have water or other solvents as part of their lattice) and that those can form polymorphs all their own, and it’s no surprise that all this is still such a tangle in the courts. And on the lab bench!