“Perverse Polymorphism”, 2019-11-26 (; backlinks; similar):
…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 [disappearing polymorphs]. 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.
…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).
…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.
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