Cat's Cradle by Kurt Vonnegut, Jr.

[james_davis_nicoll]

A writer documents a brilliant scientist's final gift to the world.

Cat's Cradle by Kurt Vonnegut, Jr.

Comments

[(Anonymous)]

Thanks! Enlightening answer.

Just browsed wikipidea on ritonavir. So the interesting behavior is `form i' transitioning to form ii,if even a trace of it is present? Totally cool, totally terrifying, so ice nine.

Is there a brief explanation why the less stable structures exist in the wild at all? The physical world is consistently surprising.

I probably should have asked not ` how do you predict that there isn't' but `how do you show that there isn't'. Or even 'can we show'? (Is it like one of the Clay problems, on mass gaps, or Navier-Stokes, or some such, where we honestly have no idea).

Thanks for your answer!

[brooksmoses]

In the case of ritonavir, the less stable structures exist because of very careful assembly at the molecular level by living cells. Life is very good at making lots of only-meta-stable things, in part because they are really useful as energy storage that will do something specific and useful later.

[(Anonymous)]

More creepy than that. Form I was stable for years - long enough for it to be tested and approved and sold as an AIDS drug. And then one day - like ice-9 driving out “our” ice - form I couldn’t be made anymore. The manufacturer went so far as to build a new plant in a different part of the world, only for form ii to start appearing after a bit. (Rumor has it that they - stupidly- flew someone who had been in the old plant to the new one, but the general consensus is that it was just a matter of time.) This was, I should stress, an AIDS drug, and people’s lives depended on it. Process chemistry is not easy, and years of work goes into developing the best way to make a drug - not only does it need to be bioavailable (a problem with form ii) but different crystal forms could also incorporate different levels of impurities and byproducts, which could be harmful to patients. Having to redo things after a drug is on the market not because the route is cheaper or easier but because you just can’t make the old drug anymore is devastating for everyone, and the politics at the time put massive pressure on the company to solve the problem immediately.

The technical term is “disappearing polymorphs,” and the explanation I’ve seen is that the first structure that’s formed upon drying is often the least stable, like if you pile a bunch of stuff together it might settle with time, but once another form is found it will just float around and seed everywhere else. We’ve got software these days that tries to predict possible polymorphs, but it’s not a certainty, and theoretically a lot of other compounds could just one day find another polymorph. (Emphasis on theoretically. In practice, it’s a mostly stochastic process, and if stuff has been around on Earth as a pure compound for long enough it’s probably found all the polymorphs that exist.)

IANA crystallographer; I am a chemist who works with process chemists. Technical errors are my own.

[brooksmoses]

Wow, that is deeply creepy, indeed!

[patrick_morris_miller]

Chemistry is stranger than we imagine. Biology is stranger than we can imagine.

[(Anonymous)]

Thank you. `disappearing polymorphs' made my day, a new term for me.

I didnt understand the resolution of the form ii/form i problems with ritonavar; I probably browsed the wiki article too superficially. How does replacing a capsule with a gelcap prevent form ii reversion? (This was different from the other, later, solution hinted at in the article, melt extrusion).

(Does working with process chemists mean you too work for a pharmaceutical company, or are you distanced by being in academia or independent consulting?)

Very informative thread! Thank you so much for the substantial content, new to me at least.

[(Anonymous)]

Not pharma, but other industry. Polymorphs are a problem other people deal with, I just hear them talk about it sporadically. And you’re welcome! Ritonavir is a fascinating (and horrifying) textbook case.

I misspoke slightly- form i doesn’t convert into form ii directly, but once form i goes into solution, it will crystallize again as form ii if you dry it. (The commentator upthread was right - ice-9 would solidify the oceans, but ice caps would remain “our” ice unless they temporarily thawed.) I assume the gel cap meant it was in solution rather than a solid (like a sugar syrup rather than a sugar cube - both form i and ii will be soluble in some solvents at a certain concentration, even if they’re not equivalent), which would explain the need for refrigeration. The extrusion was actually really clever- they figured out you could force the compound to crystallize as form i if there was already a lot of form i around (to act as a seed crystal), so instead of creating a large vat of solution and adding in a bit of form i the way people often do, they started with a small amount of form i and added the solution in dropwise so form i was the only thing created.

[(Anonymous)]

Thank you, again. So interesting.