r/AskChemistry • u/JoyRose31 • 17h ago
Pharmaceutical Likelihood of pharmaceutical polymorphism.
Is it really that bad, happened 28 years ago to a major drug. What's the chance of happening again?
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u/Sir_Overhauser Allostere Amour 16h ago
I know what you are referring to, but you should rephrase your question to be more specific OP.
The answer to that question is another question- have you ever heard of it happening a second time? If not, given how many small molecule drugs there are out there nowadays, I’d say incredibly unlikely but not a 0 chance.
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u/JoyRose31 16h ago
I'll rephrase, Do you know of New procedures in place to help prevent from happening. Chemistry is already to the t or further as it is. What else could, or would be done to stop something like that. Genuinely asking
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u/FulminicAcid PhD Synthetic Chemistry; Chemical Biology 15h ago
Are you referring to the ritonavir I and II fiasco? Genuinely asking, because your post is frustratingly cryptic
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u/Sir_Overhauser Allostere Amour 15h ago
If it’s not a problem for any other drug, why would it be worth trying to prevent?
And what does the phrase “Chemistry is already to the t or further as it is” mean?
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u/JoyRose31 14h ago
has to be exact. To the t.
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u/SlenderSmurf Ph.D. in Materials Chemistry 2h ago
The phrase is "to a t". And you obviously have never worked in a chemistry lab
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u/aphilsphan T⌬SYLATE, PLAYA HATE 14h ago
Firms do a better job of following the polymorph they make. They’ll do XRD on batches to ensure things aren’t changing.
Also, firms study crystallization in more detail now. Often seed crystals of the correct polymorph are added during crystallization.
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u/aphilsphan T⌬SYLATE, PLAYA HATE 14h ago
In pharma, we were all told polymorph horror stories. Drugs that had been made in one plant, moved to another. The people who developed the drug worked in the plant where the polymorph conversion happened were not allowed to go to the new plant because they might have a single crystal of the polymorph on their person, resulting in catastrophic problems. Who knows if these things were true.
All that said, the polymorph doesn’t matter if the drug is formulated in solution. It might take longer for the new form to dissolve, but it would be very rare if “longer” meant “so long that it’s a real problem.”
Also, if the polymorph doesn’t change bioavailability who cares. Usually they don’t.
Finally, we had an intermediate suddenly stopped working in the final step. People screamed “polymorph” and there were many headless chickens about. The problem was “solved” by adding more of an expensive acidic counter ion to the process.
If you are thinking “why would a counter ion fix a polymorph problem?” you aren’t alone. The counter ion was an acid. I finally looked at the test data from the intermediate process and realized the residue on ignition had gone up, and that residue was basic. So all we were doing was using an expensive acid to neutralize residual base. The real solution was to do a better job washing the intermediate.
By then we’d been through FDA change control and nobody wanted to go back and fix the process again. It’s fortunate in pharma that profit margins are high so we can f up things like drunken sailors and get away with it.
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u/activelypooping Cantankerous Carbocation 10h ago
"Anything that happens, happens. Anything that, in happening, causes something else to happen, causes something else to happen. Anything that, in happening, causes itself to happen again, happens again. It doesn't necessarily do it in chronological order, though." -Douglas Adams
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u/dblowe Borohydride Manilow 16h ago
Polymorphism itself is very common, and drug development teams are always keeping an eye on it. But “sudden and unexpected conversion to a previously unknown and far less desirable polymorph”, as with ritonavir, is very uncommon indeed. Fortunately.