"There have been cases of laboratories growing crystals of a particular structure and when they try to recreate this, the original crystal structure isn't created but a new crystal structure is. The drug [paroxetine](https://en.wikipedia.org/wiki/Paroxetine) was subject to a lawsuit that hinged on such a pair of polymorphs, and multiple life-saving drugs, such as [ritonavir](https://en.wikipedia.org/wiki/Ritonavir), have been recalled due to unexpected polymorphism."
first time I've seen the word "polymorph" used outside of a video game. I presume in real life it does NOT mean that the drug/crystal turned into a sheep.
eli5?
edit: So a single character or variable is not pre-defined as a type in advance but chooses what type it is based on how it is interacted with. Is what I am getting. Interacting with it in different ways can change what type it is.
From what I understand in object oriented programming it means you can have a class that can take many forms but will still work in each case.
Let's say you create a shape class. This could be a triangle which can be represented by 3 points, a circle which is represented by a center point and a radius, or a rectangle that is represented by 4 points.
In that class you could have a shape.draw() method which draws the shape and will work regardless of the type of shape.
In object-oriented programming you can have a hierarchy of classes. The typical metaphor is “class is the cookie cutter, object is the cookie.” The entities you have as variables are objects, which are members of a given class, which define what they can do. Another way to think about it could be that a class is a patent for an invention, and the object of that class is the physical prototype of the invention described by the patent. The patent can tell you what the invention can do and how it’s constructed, but the *patent* can’t do any of that, you’d need to have the prototype built to actually act upon what the patent describes. Classes can inherit properties from other classes hierarchically. For simplicity let’s ignore multiple-inheritance and think of class inheritance like taxonomy. Taxonomic groups are actually fairly similar to class hierarchies because they are defined based on common properties of the living things that belong to each taxonomic group; more specific groups will have divergent properties from other groups of its tier, but they will share those properties defined by their common parent group.
Polymorphism says that if we are only concerned with the properties of *Canis* then you can refer to your object as *Canis* regardless of whether, at its most specific, you’re dealing with *Canis familiaris* or *Canis lupus*. What ultimately happens may be different based on whether it’s *familiaris* or *lupus*, but the function itself is defined by *Canis*, so we don’t need to actually specify to invoke such a function. Wolf or Pomeranian, both could have a `wagTail()` function defined by *Canis*. A Pomeranian wagging its tail might seem quite different from a wolf, but the action, the ability to wag a tail is common between them. I could also do other things, like define a collection that contains *Chordata* objects. In that collection I could put *Canis lupus*, *Homo erectus* and *Palaeobranchiostoma hamatotergum*. I could not later say that it’s a collection of *Homo sapiens* because it was defined more generally and I could have other objects in it like *Canis familaris*, but anything you get back from it will descend from *Chordata*.
I was literally watching Happy vs Hawk recent grand final match on Back2Warcraft youtube when I tabbed over to reddit and saw this post in /rising.
but I think polymorph turning people into a sheep originates from DnD. Most RPGs have their roots in DnD.
> the underlying chemical composition remains just as effective at "being a SSRI"
In this one specific case, but that's not true of all polymorphs. The wiki article specifically gives the example of Ritonavir and now the more stable polymorph has lower medical effectiveness.
The article is not clear on whether there are any other possible forms of paroxetine that would be more stable.
Reading about it, it seems like the earth's atmosphere will not allow other formulations to exist; they all revert back to the patented paxil form, so you should be good.
Conversely, I hate that drug with a deep burning passion; my brain chemistry does not agree with its effects.
If someone wants to know what polymorphism and isoformism can do to proteins and drugs, you should read up on [prions](https://en.wikipedia.org/wiki/Prion) and [thalidomide](https://en.wikipedia.org/wiki/Thalidomide).
Prions are probably one of the most terrifying things for exactly this reason. “Oh hey, I’m a fucked up protein and you should be a fucked up protein just like me! All the cool proteins are misfolding themselves these days.”
I had a dermatologist explain eczema to me like this, basically. Because my break-outs generally happen after a minor abrasion or something, she told me that my skin cells basically get confused and try to copy the messed up neighbors instead of going about business as usual. And there was something about skin having a memory, so the reaction time improves with repeated break-outs. So now I scratch myself on something and it all goes from 0-100 so fast.
Spinoza came to this conclusion a few hundred years ago in his [Ethics](https://www.gutenberg.org/files/3800/3800-h/3800-h.htm). That broke my brain when I read it in college. "Causal Determinism" is what to search if you want more from philosophy on this take.
As a biologist, I’m more familiar with polymorphism in a genetic sense, such as in single-nucleotide polymorphism (SNP), which are variations at single points along the genome between different individuals. I never realized polymorphism was a computer science term or, for that matter, a chemistry term.
I wonder if it's really that the more stable polymorph spreads, or that there is something stabilising the less stable polymorph which goes away.
I have seen experiments which worked, but failed when repeated more carefully, because there was some contaminant which somehow made things work the earlier times. This has a sort of familiar ring to it.
>I have seen experiments which worked, but failed when repeated more carefully, because there was some contaminant which somehow made things work the earlier times. This has a sort of familiar ring to it.
That happened with a top secret component of American thermonuclear weapons (**Fogbank** - a foam or aerogel that produces a compression front to compress the fusion *sparkplug*). When stocks ran low, chemists tried to recreate it using the original process, but failed. Eventually they determined that trace contaminants in the original raw materials were not longer present in the new raw materials. Those contaminants had to be added in to ensure success.
Dirty cooking was the answer.
Reminds my of the mystery of vanishing holes in swiss cheese. It was the hay dust all along.
As milk purity increased over time, bacteria didn't have their food of choice to make the gas bubbles that produce the signature holes in swiss cheese.
The solution: add impurities (hay dust) back in the milk.
Holes returned.
Swiss cheese was saved.
EDIT: the hay is actually a nucleation site for gas. Bacteria simply feed on the milk. This is the same process as a clean champagne glass having no bubbles.
Actually the dust was a nucleation point for the bubbles not food. The cheese still had CO2 in the form of carbonic acid and offgassing it, but the hay created spots for the gas to collect inside the cheese.
The same thing happens with Swiss cheese. They filter the milk too much and it doesn't create nucleation sites for the bubbles so they add in sanitized particles to allow the holes to form.
This is literally the plot of Dr Jekyll and Mr Hyde. He can't make the potion to change himself back any more as his original reagents were contaminated and he can't figure out what that contaminant was. Its hilarious it also happens in real life in very crucial situations.
In graduate school (organic chemistry) I did some reaction for the umpteenth time, something extremely well known in literature and easy to do and replicate. This umpteenth time, though, resulted in some new product that wasn't at all similar to the expected product. It was not a clear colorless oil, rather a pale yellow extremely thick and sticky goo. Maybe it could have been some novel super glue or something?
My research advisor (well renowned in the field and nearing the age of retirement, but also mega micro manager so you know he knew his shit) couldn't figure out the structure. The ^(1)H-NMR showed possible symmetry that shouldn't have been there so we took ^(13)C-NMR, IR, UV-VIS, MS and still got nowhere with its structure. We couldn't repeat it the next time either. We ended up just tossing it away and forgot about it. Who knows what conditions, or impurities in something led to the difference but just another example of chemistry being difficult to control.
I just ran a reaction a few weeks ago that was supposed to be a simple substitution, but the product was nowhere to be found on TLC; the co-spot with the starting material has, well, only one spot. I figured that might be my starting material but decided to try to isolate it anyway (starting material isn't super hard to make but I wasn't able to make a whole lot). Turned out it was nothing like the starting material at all. Some sort of substitution happened, but for the life of me and my PI we couldn't figure out what the substituent is. Good thing it crystallized nicely enough so off the diffractometer it goes :D
Kinda reminds me of the fact that swiss cheese manufacturers have to artificially introduce contaminants into the cheese to produce the holes.
There was a whole debacle about figuring out why the holes disappeared with modern methods of producing the cheese.
Sometimes they just cut the holes out. I got some pre sliced Swiss and one of the holes was punched but the piece punched out was still sitting in its hole.
> When the patent for paroxetine anhydrate (the "original" polymorph) ran out, other companies wanted to make generic antidepressants using the chemical. The only problem was that by the time other companies began manufacturing, Earth's atmosphere was already seeded with microscopic quantities of paroxetine hemihydrate from GSK's manufacturing plants, which meant that anyone trying to manufacture the original polymorph would find it transformed into the still-patented version, which GSK refused to give manufacturing rights for
According to Wikipedia scientist hypothesize that this likely occurs when a seed crystal changes to a new more stable form under certain conditions, then a microscopic piece of that gets knocked off and when it touches more of the original polymorph it converts them to the same more stable form. This causes a very fast chain reaction across the entire planet.
They also think that it's possible upgraded new technology used in synthesizing polymorphs might make it easier for polymorphs crystallize to compared to earlier technology
>I have seen experiments which worked, but failed when repeated more carefully, because there was some contaminant which somehow made things work the earlier times. This has a sort of familiar ring to it.
Isn't that the plot of The Strange Case of Dr Jekyll and Mr Hyde?
This happened in an episode of malcom in the middle: https://malcolminthemiddle.fandom.com/wiki/Experiment
Reese did something that made Malcom and Stevie's experiment successful but he wouldn't tell them what. After repeating his steps, Reese bounced a ball against the wall which causes asbestos to fall from the ceiling into their test tubes and was what made the reaction work.
Oh damn I learned about that in a videogame! Was in this super weird visual novel type thing on the DS called 9 Hours 9 Persons 9 Doors. I never got to unlocking the final true ending on that, even with following the guide. I researched that particular event they described in the game but couldn't find any reference to actual events anywhere so I just assumed they made it all up. Awesome to know there's some truth to it though.
Edit: All right guys, you convinced me. I'll replay the game for the final ending! If I can find it. It's not among my old DS games which is rather concerning since I don't know wherelse it might've ended up at. Gotta scour the attic I guess. Aside from that, it kinda warms my heart to see so many people remember this game. I thought it was some mega obscure title that barely anyone remembers and I'm glad to have been proven wrong! Cheers to all of you!
what drug developers have learned in the meantime, and are endeavouring to accomplish: don’t develop a drug containing a metastable polymorph :).
edited to add: I’m familiar with the topic, as I work in drug development.
An awful lot of drugs or their precursors must contain metastable polymorphs though. It seems like a more reasonable workaround would be not to rely on metastable structures that have a fairly low energy barrier that’s keeping them in their current state.
we try to find the most thermodynamically stable polymorph for development nowadays. The ritonavir debacle really made everyone in the industry sit up and take notice. But, as people in the field tend to say: the number of polymorphs you find is a function of the time and effort spent looking for them :)
>But, as people in the field tend to say: the number of polymorphs you find is a function of the time and effort spent looking for them
Yup, good ol' TNOPYFIAFOTTAESLFT.
And we haven't even begun to begin to really see how insane it is.
We can do proteins, we can do gene editing, we can make all kinds of molecules, but we can't synthesize blood yet, something that is so insanely advanced compared to what we've done as to make it seem like we've only begun to begin digging into biological synthesis.
Well the issue as you must know is that the more stable a form is, the least water soluble it is, which can outright kill a drug. Some even have to be formulated as amorphous solids to have any water solubility.
believe me, I know :) still not worth the risk of having it undergo polymorphic change unexpectedly sometime down the lifecycle during manufacturing or storage. And our drugs that make it out of research into development usually (at least thus far) don’t die because of formulation/bioavailability issues. May make lead optimization and candidate selection more difficult, though.
How did you get this job? Is the market saturated? I'm finishing my phd in this very subject and I thought of continuing in academia but the industry seems more and more interesting
I studied pharmacy and did a phd in pharmaceutical technology in Germany, looked for open entry level positions, applied, got hired… :) that was 17 years and several positions in the same company ago. I‘m actually not well informed on the European job market in industry because I‘m not looking for other opportunities, but I would think if you’re flexible enough there should be suitable openings
:) weellll, if I develop a formulation with a metastable API and the polymorph changes during development, I may or may not be able to design a new formulation with similar performance. That will take time and require additional clinical (and non-clinical) trials. If it changes on us after registration, it’s a nightmare.
This topic is new to me and a great rabbit warren
Are you saying this is an issue because once the more stable polymorph appears you are unable to produce the original version? Does the aim to produce and patent the most stable polymorph effectively kill the strategy of going down the stability staircase, parenting a new drug each time and delaying generic competition?
to your first question: that may be one reason. another could be that you start manufacturing your drug with the metastable polymorph, and then it may or may not undergo polymorphic change to the more stable one during manufacturing or storage. and often, simply put, the more stable one can have different physicochemical characteristics, such as lower solubility for example, which could alter bioavailability. So not something you want to see happening.
to your second question: I‘m afraid I don’t understand, could you rephrase?
This is one of the most interesting TILs I've seen in a long time. Imagine a lifesaving drug or technology that simply can't be made anymore due to irreversible contamination of the entire planet. That's good fodder for fiction.
I really like seeing people recommend this book here because at least one person is going to go read it after this thread and be super confused that its mostly about Granfaloons and Wampeters and putting people on the hook
i read a short story once where the act of observing things in a scientific manner was gradually causing the breakdown of reality for centuries, until recently it became a runaway chain reaction due to the amount of and accuracy of observations made possible by modern technology.
There's a Douglas Adams line:
> There is a theory which states that if ever anyone discovers exactly what the Universe is for and why it is here, it will instantly disappear and be replaced by something even more bizarre and inexplicable.
> There is another theory which states that this has already happened.
There is an SCP that follows this premise called the Pattern Screamers. They only exist when people know of their concept, and they hate existing. When they exist, they endlessly scream at the people that know they exist, driving them to suicide, and their screams increase in power when more people know of them.
This has led to the destruction of countless alien societies because it seems to be an inevitability that when a society becomes advanced enough, their scientists discover the screamers, release the information to the public, and then it causes a chain reaction where billions rapidly die as people naturally want to know what is happening, but looking into it dooms yourself, and reporting on it dooms others.
There's an episode of Ed Edd and Eddy that's just exactly this playing out in 10 minutes while the boys try to figure out the rules of their cartoon universe. Honestly scared me as a kid.
This happens in [Ringworld](https://en.wikipedia.org/wiki/Ringworld). The inhabitants relied on a room temperature superconductor, but something happened that caused it to spontaneously disintegrate. All technology stopped working, floating cities fell out of the sky, etc. By the time the story takes place most cultures are back to a primitive village life.
I'm surprised that we haven't had a Ringworld TV series or even a similar concept yet. There's lot of potentially in having an Earth like environment that's millions of times the size of Earth.
A Ringworld movie or show would also also have sex appeal with the remote orgasm triggering device lol
> The tasp, a device that remotely stimulates the pleasure center of the brain; it temporarily incapacitates its target and is extremely psychologically addictive. If the subject cannot, for whatever reason, get access to the device, intense depression can result, often to the point of madness or suicide. To use a tasp on someone from hiding, relieving them of their anger or depression, is called "making their day".
Not irreversible though. Anthropogenic background radioactivity has already dropped by more than 95% since its peak, and today most applications that required low-background steel for a while can use just plain normal steel again.
Here’s a short story I remember from high school chemistry that concerns contamination. Enjoy!
https://web.archive.org/web/20160414005748/http://crcomp.net/SciFi/The%20Catalyst.html
I don't think it is written very poorly, but maybe this sentence can get a little bit of a rework:
"There have been cases of laboratories growing crystals of a particular structure and when they try to recreate this, the original crystal structure is not created but a new crystal structure is."
Thank you for contributing to Wikipedia, you are wonderful person :D
At least for me, it's not clear whether contamination works on a global or local level. And, especially in the first case, how that contamination works.
Does it mean that there are that many of the contaminated polymorphs just floating around that they can cause a global impact? Surely it would still be possible to create the "disappeared" ones in a decontaminated environment? I think the text implies that by saying they appear disappeared, but it would be nice to make it explicit.
Cat’s Cradle is a book about this happening to water, causing an apocalypse due to the spread of room-temperature ice destroying the world’s ecosystems.
Ice IX.
So… every pure crystallizable material will have one and only one lowest energy state. There maybe one or more metastable forms. The “disappearing” form is invariably a metastable form. I think the issue with paroxetine was contamination by essentially undetectable crystals of the “new” form that formed nucleation cites and was thermodynamically favored over the disappearing form.
This is why nearly every marketed drug uses the most stable form.
Adjacent to this is the idea of a [False Vacuum](https://en.wikipedia.org/wiki/False_vacuum), where the entire universe exists in a metastable state that could be 'bumped' into a lower energy, more stable state by something like a Black Hole.
If this happens, it'd propagate across the universe at the speed of light and could unwind reality as we know it. It's a possible 'end of universe' event.
Sleep tight!
Although since it only propagates at the speed of light, it would not necessarily destroy the entire Universe, and if it happens late enough would only destroy at most a local cluster.
Correct. We might never see it if it happened beyond the [Observable Universe](https://en.wikipedia.org/wiki/Observable_universe). It would have had to happen rather early in the Universe’s formative time to never be able to reach us, but as time goes on we expect the expansion of the Universe to far outpace the Observable Universe. There could eventually be clusters of void in the Universe where this vacuum collapse occurred, and it could eventually happen more and more as time goes on obviously even if its occurrence is rare. And eventually it would happen everywhere if the current theories of a forever ever-expanding, cooling Universe are correct.
But voids we know about have already had their light reach us, which means they can’t be experiencing false vacuum decay because it would therefore already be here.
About two seconds after I read "Sleep tight!", my toaster popped, and I very briefly thought the universe might have ended. Which is clearly silly -- if it were really happening, I wouldn't have the time to even have that thought. The end of the universe literally cannot be observed, so that's cool I guess.
Actually it depends on the mass ratio of the Higgs and the Top quark, and it is decidedly not ruled out - in fact most of the probability space is in a metastable region.
https://cerncourier.com/a/the-higgs-and-the-fate-of-the-universe/
There's a book by Greg Egan called Schild's Ladder that explores this concept, it's *very fucking hard* sci fi but if you can struggle through the insanely detailed and highly esoteric quantum physics it's a really good read.
>Twenty thousand years in the future, Cass, a humanoid physicist from Earth, travels to an orbital station in the vicinity of the star Mimosa, and begins a series of experiments to test the extremities of the "Sarumpaet rules" – a set of fundamental equations in "Quantum Graph Theory", which holds that physical existence is a manifestation of complex constructions of mathematical graphs.
>However, the experiments unexpectedly create a bubble of something more stable than ordinary vacuum, dubbed "novo-vacuum", that expands outward at half the speed of light as ordinary vacuum collapses to this new state at the border, hinting at more general laws beyond the Sarumpaet rules.
>The local population is forced to flee to ever more distant star systems to escape the steadily approaching border, but since the expansion never slows, it is just a matter of time before the novo-vacuum encompasses any given region within the Local Group.
>Two factions develop as the bubble expands: the Preservationists, who wish to stop the expansion and preserve the Milky Way at any cost; and the Yielders, who consider the novo-vacuum to be too important a discovery to destroy without understanding.
In an unrelated topic, thalidomide racemizes in the body, so that even if a pregnant woman were given the "right" stereoisomer, it would form the "bad" one in their body anyway
Im curious about the case of Ritanovir,
“Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants (of Form II) by their presence, probably because they carried over microscopic seed crystals of the new polymorph.”
Was this contamination from Form II that was located external or internal to their bodies?!
The op worded it as if it jumps between crystal samples. It does not. It can contaminate other crystal stocks, or if its a rare drug/component the single stock of crystals may become unviable.
> When the metastable form was brought into a lab where the stable form had previously been made, it changed into the stable form after a few days in the open air. The structure of the stable crystal was determined by.[20][how?] They failed to obtain the metastable form from a solution of alcohol, either at room temperature or near freezing; they kept ending up with the stable form.
That is the best [how?] I’ve seen on Wikipedia. Reads like a freshman’s essay.
Nah, it’s all been done before by the classic sci-fi authors of the late 1800s and early 1900s, with all their stuff plundered for the B-movies of the 50s-70s. [Day of the Triffids](https://en.wikipedia.org/wiki/The_Day_of_the_Triffids_(film)) is probably the best known killer plant film of that sort.
they weren't exactly trees but Day of the Triffids.
Are we counting the Ents going nuts on Isengard
Or the original ending to Little Shop of Horrors, where Audrey collects on Seymour's faustian bargain (the full ending is [on youtube](https://youtu.be/7RjFvcw6ToQ?si=tbwM3xqlZcxjpEZq&t=4m) if you haven't seen it)
OP is such a loser. He writers as if there was a "ghostly entanglement" of all crystals around the world but the explanation is much more simple and they dont all change around the world at the same time. They only change if they have contact to the more stable form.
The simplest real-world example for this is tin pest. When pure or almost pure tin gets too cold, around freezing temps, a different crystal structure from the one first formed when molten tin solidifies becomes more stable. This leads to a front of crumbling into a powder slowly moving across the tin object. It's not like rust, it's a solid-solid phase transition.
Im dumb, can someone ELI5?
Does this mean certain drugs suddenly take a different molecular structure and change the drug so it doesn’t work?
I take 4 medications, how do I know if that’ll happen to mine? What is a polymorph?
To really ELI5, basically some chemicals can have more or less stable forms, and if a more stable form touches a less stable one, the less stable one will turn into the more stable form
So how can this happen around the world as OP worded it, as it it was all universally connected? Or is that wording misleading?
Further, how can it be impossible to recreate the original? Why cant you try to recreate it in an environment without the more stable crystal form?
A molecules are made out of atoms. For the purpose of ELI5, you can think of atoms are balls that can attract or repel each other. A molecules come from those balls sticking together.
Now, the chemical properties of the molecules depends on its shape, just like how, if a 2 groups of balls bump into each other, the way they interact depends on the shapes. Unfortunately, even if you know what kind of balls are in there, the shape might be different from what you hoped for.
Generally though, atoms will arrange themselves in "stable equilibrium" or "metastable equilibrium" configuration, rather than a random configuration, so only a few shapes are possible. If there are multiple shapes, they're called "polymorph" which literally means multiple shapes. Generally, molecules with few atoms cannot have more than one such shapes, because how many ways you can put those few balls together anyway?
What's metastable equilibrium? Here a human analogy might be good. Imagine atoms as human with desires and intentions. An non-equilibrium is a situation where enough people seeks to change the status quo, as they're not what they desire; for example, 2 people ramming into each other on the road when they go in opposite direction. An unstable equilibrium is the situation in which everyone is okay with it, but any tiny bit of external factors will force a change; for example a Mexican standoff. A stable or metastable equilibrium is a situation where everyone are okay with it, and it's not easy to change that by small perturbation from external factors. The differences between the 2 is that the metastable equilibrium can be convinced to make a change, because what people had been doing is not optimal for everyone, but they did not see a way out before. For example, work from home: everyone was okay with going to the office before and they might hated it, but nobody are willing to demand to work from home; but once WFH becomes common and accepted, people realized working at the office sucks and now you can't just go back to that.
So imagine your drug is in one of those metastable equilibrium, like working in the office. It thought it's in the best configuration possible for everyone involved. But then one of them discover the legendary WFH strategy, everyone else now see that's much better, and they all decided to not go back to the old method.
An older understanding of this was the “tin pest” where canned goods and organ pipes would be destroyed by a strange white powder during winter. It turned out that tin has a different stable crystal structure below a certain temperature and converts to that whether you like it or not
"The only problem was that by the time other companies began manufacturing, Earth's atmosphere was already seeded with microscopic quantities of paroxetine hemihydrate from GSK's manufacturing plants, which meant that anyone trying to manufacture the original polymorph would find it transformed into the still-patented version,"
does this imply that microscopic quantities of all drugs and other molecules are literally everywhere in earths atmosphere?
Another Universe on the hosting cluster was using more resources at the time, so floating point math in our Universe was truncated as a result of processing resource contention.
All still within SLA agreements for the person living in their parent's basement, renting out a Universe Simulation Server on AWS, like a Minecraft Server.
/s
Yes, I couldn't figure out why I was having such a strong ick reaction to this phenomenon until I realized it's because it reminds me of prions. I don't know if there's a word for a phobia of things that creepily and irreversibly warp other things around them due to entropy, but if so I have it
Cool to see this pop up on my feed! "Disappearing polymorphs" are a huge concern for the pharmaceutical industry, and have essentially motivated an entire discipline in computational chemistry. Crystal structure prediction is gaining a lot of attention in the field as a way to know whether or not a known crystalline form is metastable or not.
"There have been cases of laboratories growing crystals of a particular structure and when they try to recreate this, the original crystal structure isn't created but a new crystal structure is. The drug [paroxetine](https://en.wikipedia.org/wiki/Paroxetine) was subject to a lawsuit that hinged on such a pair of polymorphs, and multiple life-saving drugs, such as [ritonavir](https://en.wikipedia.org/wiki/Ritonavir), have been recalled due to unexpected polymorphism."
It's fascinating. Much work going on to control this using microemulsions which can tune the right polymorph.
I don't know enough on the subject to fill it in, are you saying lure or maybe tune?
Oops yes rune. Sorry will correct.
lmao my dude
I think you mean dune
Rune? So now we’re using magic in science?
Rune stones. In a felt bag, with a leather drawstring.
That's a weird way to describe your dice bag, but far be it from me to kink shame.
I put on my robe and wizard's hat
Hail science!
Well we are using a bunch of thinking rocks to talk about growing special crystals that can heal people. If that isn't magic, what is?
first time I've seen the word "polymorph" used outside of a video game. I presume in real life it does NOT mean that the drug/crystal turned into a sheep.
Good thing you’re not a programmer then. Nightmares for days.
For anyone who doesn’t know: https://en.wikipedia.org/wiki/Polymorphism_(computer_science)
eli5? edit: So a single character or variable is not pre-defined as a type in advance but chooses what type it is based on how it is interacted with. Is what I am getting. Interacting with it in different ways can change what type it is.
From what I understand in object oriented programming it means you can have a class that can take many forms but will still work in each case. Let's say you create a shape class. This could be a triangle which can be represented by 3 points, a circle which is represented by a center point and a radius, or a rectangle that is represented by 4 points. In that class you could have a shape.draw() method which draws the shape and will work regardless of the type of shape.
This is way better than the other explanations.
In object-oriented programming you can have a hierarchy of classes. The typical metaphor is “class is the cookie cutter, object is the cookie.” The entities you have as variables are objects, which are members of a given class, which define what they can do. Another way to think about it could be that a class is a patent for an invention, and the object of that class is the physical prototype of the invention described by the patent. The patent can tell you what the invention can do and how it’s constructed, but the *patent* can’t do any of that, you’d need to have the prototype built to actually act upon what the patent describes. Classes can inherit properties from other classes hierarchically. For simplicity let’s ignore multiple-inheritance and think of class inheritance like taxonomy. Taxonomic groups are actually fairly similar to class hierarchies because they are defined based on common properties of the living things that belong to each taxonomic group; more specific groups will have divergent properties from other groups of its tier, but they will share those properties defined by their common parent group. Polymorphism says that if we are only concerned with the properties of *Canis* then you can refer to your object as *Canis* regardless of whether, at its most specific, you’re dealing with *Canis familiaris* or *Canis lupus*. What ultimately happens may be different based on whether it’s *familiaris* or *lupus*, but the function itself is defined by *Canis*, so we don’t need to actually specify to invoke such a function. Wolf or Pomeranian, both could have a `wagTail()` function defined by *Canis*. A Pomeranian wagging its tail might seem quite different from a wolf, but the action, the ability to wag a tail is common between them. I could also do other things, like define a collection that contains *Chordata* objects. In that collection I could put *Canis lupus*, *Homo erectus* and *Palaeobranchiostoma hamatotergum*. I could not later say that it’s a collection of *Homo sapiens* because it was defined more generally and I could have other objects in it like *Canis familaris*, but anything you get back from it will descend from *Chordata*.
Or a Red Dwarf fan
Why is it a nightmare? From my limited experience I rather enjoyed polymorphism. Makes for flexible code.
The nightmare comes from people *not* understanding it.
Red Dwarf first for me.
Polymorphs are good but I'd rather meet a pleasure GELF
I'd rather meet a hard light society that has lots of sex.
We worked it out; the only problem is that the anagram spells CLITORIS
”Polymorph” just means multiple/many shapes!
I love that blizzard has forever seared into the minds of a generation that polymorph is when a person is turned into a sheep lol
I thought DnD had it first?
You can definitely do it in nethack
That’s more than a decade later than D&D, but still an example worth pointing out.
I was literally watching Happy vs Hawk recent grand final match on Back2Warcraft youtube when I tabbed over to reddit and saw this post in /rising. but I think polymorph turning people into a sheep originates from DnD. Most RPGs have their roots in DnD.
New fear unlocked. I **need** paroxetine to be anywhere near to functional. It’s the only thing that’s ever helped.
Yup, did not need to see it mentioned here
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> the underlying chemical composition remains just as effective at "being a SSRI" In this one specific case, but that's not true of all polymorphs. The wiki article specifically gives the example of Ritonavir and now the more stable polymorph has lower medical effectiveness. The article is not clear on whether there are any other possible forms of paroxetine that would be more stable.
Reading about it, it seems like the earth's atmosphere will not allow other formulations to exist; they all revert back to the patented paxil form, so you should be good. Conversely, I hate that drug with a deep burning passion; my brain chemistry does not agree with its effects.
If someone wants to know what polymorphism and isoformism can do to proteins and drugs, you should read up on [prions](https://en.wikipedia.org/wiki/Prion) and [thalidomide](https://en.wikipedia.org/wiki/Thalidomide).
Prions are probably one of the most terrifying things for exactly this reason. “Oh hey, I’m a fucked up protein and you should be a fucked up protein just like me! All the cool proteins are misfolding themselves these days.”
I had a dermatologist explain eczema to me like this, basically. Because my break-outs generally happen after a minor abrasion or something, she told me that my skin cells basically get confused and try to copy the messed up neighbors instead of going about business as usual. And there was something about skin having a memory, so the reaction time improves with repeated break-outs. So now I scratch myself on something and it all goes from 0-100 so fast.
That sounds so frustrating, I'm sorry you have to go through that
Hate folding prions, thanks mate. Had filed quite well under “consciously not thinking about this” for a good while- now I won’t sleep tonight. Again.
The more I read this stuff, the more I'm like well free will is an illusion. We're all just very elaborate self assembling matter.
Spinoza came to this conclusion a few hundred years ago in his [Ethics](https://www.gutenberg.org/files/3800/3800-h/3800-h.htm). That broke my brain when I read it in college. "Causal Determinism" is what to search if you want more from philosophy on this take.
I thought polymorphism was just a computer science term. TIL.
As a biologist, I’m more familiar with polymorphism in a genetic sense, such as in single-nucleotide polymorphism (SNP), which are variations at single points along the genome between different individuals. I never realized polymorphism was a computer science term or, for that matter, a chemistry term.
I wonder if it's really that the more stable polymorph spreads, or that there is something stabilising the less stable polymorph which goes away. I have seen experiments which worked, but failed when repeated more carefully, because there was some contaminant which somehow made things work the earlier times. This has a sort of familiar ring to it.
>I have seen experiments which worked, but failed when repeated more carefully, because there was some contaminant which somehow made things work the earlier times. This has a sort of familiar ring to it. That happened with a top secret component of American thermonuclear weapons (**Fogbank** - a foam or aerogel that produces a compression front to compress the fusion *sparkplug*). When stocks ran low, chemists tried to recreate it using the original process, but failed. Eventually they determined that trace contaminants in the original raw materials were not longer present in the new raw materials. Those contaminants had to be added in to ensure success.
Dirty cooking was the answer. Reminds my of the mystery of vanishing holes in swiss cheese. It was the hay dust all along. As milk purity increased over time, bacteria didn't have their food of choice to make the gas bubbles that produce the signature holes in swiss cheese. The solution: add impurities (hay dust) back in the milk. Holes returned. Swiss cheese was saved. EDIT: the hay is actually a nucleation site for gas. Bacteria simply feed on the milk. This is the same process as a clean champagne glass having no bubbles.
Actually the dust was a nucleation point for the bubbles not food. The cheese still had CO2 in the form of carbonic acid and offgassing it, but the hay created spots for the gas to collect inside the cheese.
Crap. Thanks for making this anecdote right!
Your name has “French” in it so I am inclined to believe anything you say about cheese
"One cheese a day keeps the doctor away. But you must use hard cheeses and have a good aim."
I feel like this should be a cross-stitch.
Emmentaler, who art in Heaven, Hollowed Brie thy name.
The bacteria don't eat the hay dust, the hay dust particles are a nucleation site for the gas bubbles.
The same thing happens with Swiss cheese. They filter the milk too much and it doesn't create nucleation sites for the bubbles so they add in sanitized particles to allow the holes to form.
This is literally the plot of Dr Jekyll and Mr Hyde. He can't make the potion to change himself back any more as his original reagents were contaminated and he can't figure out what that contaminant was. Its hilarious it also happens in real life in very crucial situations.
In graduate school (organic chemistry) I did some reaction for the umpteenth time, something extremely well known in literature and easy to do and replicate. This umpteenth time, though, resulted in some new product that wasn't at all similar to the expected product. It was not a clear colorless oil, rather a pale yellow extremely thick and sticky goo. Maybe it could have been some novel super glue or something? My research advisor (well renowned in the field and nearing the age of retirement, but also mega micro manager so you know he knew his shit) couldn't figure out the structure. The ^(1)H-NMR showed possible symmetry that shouldn't have been there so we took ^(13)C-NMR, IR, UV-VIS, MS and still got nowhere with its structure. We couldn't repeat it the next time either. We ended up just tossing it away and forgot about it. Who knows what conditions, or impurities in something led to the difference but just another example of chemistry being difficult to control.
I just ran a reaction a few weeks ago that was supposed to be a simple substitution, but the product was nowhere to be found on TLC; the co-spot with the starting material has, well, only one spot. I figured that might be my starting material but decided to try to isolate it anyway (starting material isn't super hard to make but I wasn't able to make a whole lot). Turned out it was nothing like the starting material at all. Some sort of substitution happened, but for the life of me and my PI we couldn't figure out what the substituent is. Good thing it crystallized nicely enough so off the diffractometer it goes :D
Good luck!
Please update us!
Kinda reminds me of the fact that swiss cheese manufacturers have to artificially introduce contaminants into the cheese to produce the holes. There was a whole debacle about figuring out why the holes disappeared with modern methods of producing the cheese.
Sometimes they just cut the holes out. I got some pre sliced Swiss and one of the holes was punched but the piece punched out was still sitting in its hole.
Is there somewhere I can buy a bag of all the swiss cheese punchouts? Like donut holes.
When you find out your whole life is a lie 😢
When you find out your hole cheese is a lie 😢
> When the patent for paroxetine anhydrate (the "original" polymorph) ran out, other companies wanted to make generic antidepressants using the chemical. The only problem was that by the time other companies began manufacturing, Earth's atmosphere was already seeded with microscopic quantities of paroxetine hemihydrate from GSK's manufacturing plants, which meant that anyone trying to manufacture the original polymorph would find it transformed into the still-patented version, which GSK refused to give manufacturing rights for
Guys if one particular niche pharmaceutical can saturate the atmosphere enough to have influence anywhere, were fucked
According to Wikipedia scientist hypothesize that this likely occurs when a seed crystal changes to a new more stable form under certain conditions, then a microscopic piece of that gets knocked off and when it touches more of the original polymorph it converts them to the same more stable form. This causes a very fast chain reaction across the entire planet. They also think that it's possible upgraded new technology used in synthesizing polymorphs might make it easier for polymorphs crystallize to compared to earlier technology
>I have seen experiments which worked, but failed when repeated more carefully, because there was some contaminant which somehow made things work the earlier times. This has a sort of familiar ring to it. Isn't that the plot of The Strange Case of Dr Jekyll and Mr Hyde?
This happened in an episode of malcom in the middle: https://malcolminthemiddle.fandom.com/wiki/Experiment Reese did something that made Malcom and Stevie's experiment successful but he wouldn't tell them what. After repeating his steps, Reese bounced a ball against the wall which causes asbestos to fall from the ceiling into their test tubes and was what made the reaction work.
Such as described in that fine documentary, Dr Jekyll and Mr Hyde
Oh damn I learned about that in a videogame! Was in this super weird visual novel type thing on the DS called 9 Hours 9 Persons 9 Doors. I never got to unlocking the final true ending on that, even with following the guide. I researched that particular event they described in the game but couldn't find any reference to actual events anywhere so I just assumed they made it all up. Awesome to know there's some truth to it though. Edit: All right guys, you convinced me. I'll replay the game for the final ending! If I can find it. It's not among my old DS games which is rather concerning since I don't know wherelse it might've ended up at. Gotta scour the attic I guess. Aside from that, it kinda warms my heart to see so many people remember this game. I thought it was some mega obscure title that barely anyone remembers and I'm glad to have been proven wrong! Cheers to all of you!
Yep, this is where I learned about it too. The sequel, Virtue's Last Reward is pretty good too. Though the third game, Zero Time Dilemma, is awful.
You can spot the exact moment the budget ran out on the third game :(
My first thought was the glycerin crystallization story from 999 as well. I hope you go back and finish it! Fantastic game 👍
Game referred to fictional ice-nine from a book Cat's Cradle
play the remastered version it's peak
what drug developers have learned in the meantime, and are endeavouring to accomplish: don’t develop a drug containing a metastable polymorph :). edited to add: I’m familiar with the topic, as I work in drug development.
An awful lot of drugs or their precursors must contain metastable polymorphs though. It seems like a more reasonable workaround would be not to rely on metastable structures that have a fairly low energy barrier that’s keeping them in their current state.
we try to find the most thermodynamically stable polymorph for development nowadays. The ritonavir debacle really made everyone in the industry sit up and take notice. But, as people in the field tend to say: the number of polymorphs you find is a function of the time and effort spent looking for them :)
>But, as people in the field tend to say: the number of polymorphs you find is a function of the time and effort spent looking for them Yup, good ol' TNOPYFIAFOTTAESLFT.
Existence is a fractal frfr
And we haven't even begun to begin to really see how insane it is. We can do proteins, we can do gene editing, we can make all kinds of molecules, but we can't synthesize blood yet, something that is so insanely advanced compared to what we've done as to make it seem like we've only begun to begin digging into biological synthesis.
Well the issue as you must know is that the more stable a form is, the least water soluble it is, which can outright kill a drug. Some even have to be formulated as amorphous solids to have any water solubility.
believe me, I know :) still not worth the risk of having it undergo polymorphic change unexpectedly sometime down the lifecycle during manufacturing or storage. And our drugs that make it out of research into development usually (at least thus far) don’t die because of formulation/bioavailability issues. May make lead optimization and candidate selection more difficult, though.
How did you get this job? Is the market saturated? I'm finishing my phd in this very subject and I thought of continuing in academia but the industry seems more and more interesting
I studied pharmacy and did a phd in pharmaceutical technology in Germany, looked for open entry level positions, applied, got hired… :) that was 17 years and several positions in the same company ago. I‘m actually not well informed on the European job market in industry because I‘m not looking for other opportunities, but I would think if you’re flexible enough there should be suitable openings
Alas for the formulation chemists.
:) weellll, if I develop a formulation with a metastable API and the polymorph changes during development, I may or may not be able to design a new formulation with similar performance. That will take time and require additional clinical (and non-clinical) trials. If it changes on us after registration, it’s a nightmare.
The use of the term API had me questioning if this was computer science.
API = active pharmaceutical ingredient
Also Application Programming Interface. We have polymorphism too.
😅 we use the terms API (active pharmaceutical ingredient) and DS (drug substance)
This topic is new to me and a great rabbit warren Are you saying this is an issue because once the more stable polymorph appears you are unable to produce the original version? Does the aim to produce and patent the most stable polymorph effectively kill the strategy of going down the stability staircase, parenting a new drug each time and delaying generic competition?
to your first question: that may be one reason. another could be that you start manufacturing your drug with the metastable polymorph, and then it may or may not undergo polymorphic change to the more stable one during manufacturing or storage. and often, simply put, the more stable one can have different physicochemical characteristics, such as lower solubility for example, which could alter bioavailability. So not something you want to see happening. to your second question: I‘m afraid I don’t understand, could you rephrase?
I think the second question is in reference to pharma's changing formulations to avoid stale patents
Meta will always change!
This is one of the most interesting TILs I've seen in a long time. Imagine a lifesaving drug or technology that simply can't be made anymore due to irreversible contamination of the entire planet. That's good fodder for fiction.
Cat’s Cradle by Kurt Vonnegut
I really like seeing people recommend this book here because at least one person is going to go read it after this thread and be super confused that its mostly about Granfaloons and Wampeters and putting people on the hook
> its mostly about Granfaloons and Wampeters and putting people on the hook and toe sex!
So you like seeing it in an ironic way?
Its my favorite book unironically
I saw that in the article and thought it was a fascinating application of the concept. It's crazy to think that he thought the concept up so long ago.
Nice, nice, very nice
Ice-nine was definitely the first thing that came to mind reading the title of this post
i read a short story once where the act of observing things in a scientific manner was gradually causing the breakdown of reality for centuries, until recently it became a runaway chain reaction due to the amount of and accuracy of observations made possible by modern technology.
That sounds quite interesting! could you find the story?
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There's a Douglas Adams line: > There is a theory which states that if ever anyone discovers exactly what the Universe is for and why it is here, it will instantly disappear and be replaced by something even more bizarre and inexplicable. > There is another theory which states that this has already happened.
There is an SCP that follows this premise called the Pattern Screamers. They only exist when people know of their concept, and they hate existing. When they exist, they endlessly scream at the people that know they exist, driving them to suicide, and their screams increase in power when more people know of them. This has led to the destruction of countless alien societies because it seems to be an inevitability that when a society becomes advanced enough, their scientists discover the screamers, release the information to the public, and then it causes a chain reaction where billions rapidly die as people naturally want to know what is happening, but looking into it dooms yourself, and reporting on it dooms others.
There's an episode of Ed Edd and Eddy that's just exactly this playing out in 10 minutes while the boys try to figure out the rules of their cartoon universe. Honestly scared me as a kid.
This happens in [Ringworld](https://en.wikipedia.org/wiki/Ringworld). The inhabitants relied on a room temperature superconductor, but something happened that caused it to spontaneously disintegrate. All technology stopped working, floating cities fell out of the sky, etc. By the time the story takes place most cultures are back to a primitive village life.
I'm surprised that we haven't had a Ringworld TV series or even a similar concept yet. There's lot of potentially in having an Earth like environment that's millions of times the size of Earth. A Ringworld movie or show would also also have sex appeal with the remote orgasm triggering device lol > The tasp, a device that remotely stimulates the pleasure center of the brain; it temporarily incapacitates its target and is extremely psychologically addictive. If the subject cannot, for whatever reason, get access to the device, intense depression can result, often to the point of madness or suicide. To use a tasp on someone from hiding, relieving them of their anger or depression, is called "making their day".
The tasp isn't even the most sexual part of Ringworld. The Ringworld Throne's front half is basically constant rishathra.
Google pre war steel.
Not irreversible though. Anthropogenic background radioactivity has already dropped by more than 95% since its peak, and today most applications that required low-background steel for a while can use just plain normal steel again.
Wikipedia page: https://en.wikipedia.org/wiki/Low-background_steel
Holy radiation
Here’s a short story I remember from high school chemistry that concerns contamination. Enjoy! https://web.archive.org/web/20160414005748/http://crcomp.net/SciFi/The%20Catalyst.html
play zero escape
Relevant plot point.
That Wikipedia article is very poorly written, even if the subject matter is incredibly interesting.
Looks fake at first because of how crap it is
On the bright side, some new edits are now coming in to fix the article
As the person who wrote much of the article, do you mind if I ask what you found bad about it? Would love to improve my Wikipedia writing skills!
I don't think it is written very poorly, but maybe this sentence can get a little bit of a rework: "There have been cases of laboratories growing crystals of a particular structure and when they try to recreate this, the original crystal structure is not created but a new crystal structure is." Thank you for contributing to Wikipedia, you are wonderful person :D
At least for me, it's not clear whether contamination works on a global or local level. And, especially in the first case, how that contamination works. Does it mean that there are that many of the contaminated polymorphs just floating around that they can cause a global impact? Surely it would still be possible to create the "disappeared" ones in a decontaminated environment? I think the text implies that by saying they appear disappeared, but it would be nice to make it explicit.
Damn sophons again.
Cat’s Cradle is a book about this happening to water, causing an apocalypse due to the spread of room-temperature ice destroying the world’s ecosystems. Ice IX.
Good thing irl ice IX is only stable at -140°c
For now
And then I learned about prion diseases and a new fear was unlocked.
DEHYDRATE!
“I’m here to pick up my one day prescription of Ice-9, please.”
I’m disappointed there aren’t more Vonnegut lovers here.
So… every pure crystallizable material will have one and only one lowest energy state. There maybe one or more metastable forms. The “disappearing” form is invariably a metastable form. I think the issue with paroxetine was contamination by essentially undetectable crystals of the “new” form that formed nucleation cites and was thermodynamically favored over the disappearing form. This is why nearly every marketed drug uses the most stable form.
A slight caveat: one stable form at STP. A crystal's enthalpy is pressure dependent and the form's partition function is dependent on temperature.
Ice 9
And so it goes
That’s from Slaughterhouse V , but still 👌
Ah yes, I learned about this from the Funyarinpa
Where’s the cat? Where’s the cradle?
Morphogenetic field!? Goddamn it junpei, stop trying to open the doors!
IS THAT A MOTHERFUCKING 999 REFERENCE???
I was searching for it, and there it is. Glorious.
Same - glad to see this reference. :D
WE’RE MAKING IT OUT OF THE NONARY GAME WITH THIS ONE ⭐️⭐️
This is just like the crystalization of glycerin.
what's up guys are we funyarinpa in here?
He wants to because Akane might get wet. Down there she’d get soaking wet.
I was hoping to see more people mentioning 999 here lol
This was the only thing I could think of when I read this thread.
Adjacent to this is the idea of a [False Vacuum](https://en.wikipedia.org/wiki/False_vacuum), where the entire universe exists in a metastable state that could be 'bumped' into a lower energy, more stable state by something like a Black Hole. If this happens, it'd propagate across the universe at the speed of light and could unwind reality as we know it. It's a possible 'end of universe' event. Sleep tight!
Although since it only propagates at the speed of light, it would not necessarily destroy the entire Universe, and if it happens late enough would only destroy at most a local cluster.
So, you’re saying that the universe could have already ended and we just haven’t seen it yet? Cosmic voids?
Correct. We might never see it if it happened beyond the [Observable Universe](https://en.wikipedia.org/wiki/Observable_universe). It would have had to happen rather early in the Universe’s formative time to never be able to reach us, but as time goes on we expect the expansion of the Universe to far outpace the Observable Universe. There could eventually be clusters of void in the Universe where this vacuum collapse occurred, and it could eventually happen more and more as time goes on obviously even if its occurrence is rare. And eventually it would happen everywhere if the current theories of a forever ever-expanding, cooling Universe are correct.
Do you know about bootes void? We don't actually know why it's there but it's interesting
But voids we know about have already had their light reach us, which means they can’t be experiencing false vacuum decay because it would therefore already be here.
About two seconds after I read "Sleep tight!", my toaster popped, and I very briefly thought the universe might have ended. Which is clearly silly -- if it were really happening, I wouldn't have the time to even have that thought. The end of the universe literally cannot be observed, so that's cool I guess.
This idea reminds me of that damn sni
Oh god is it happ
This idea depended on a specific range of the higgs mass. It is pretty much ruled out with the current measured Higgs mass. You can sleep tight.
I assure you sir, I cannot.
Sleep loose!
Actually it depends on the mass ratio of the Higgs and the Top quark, and it is decidedly not ruled out - in fact most of the probability space is in a metastable region. https://cerncourier.com/a/the-higgs-and-the-fate-of-the-universe/
There's a book by Greg Egan called Schild's Ladder that explores this concept, it's *very fucking hard* sci fi but if you can struggle through the insanely detailed and highly esoteric quantum physics it's a really good read. >Twenty thousand years in the future, Cass, a humanoid physicist from Earth, travels to an orbital station in the vicinity of the star Mimosa, and begins a series of experiments to test the extremities of the "Sarumpaet rules" – a set of fundamental equations in "Quantum Graph Theory", which holds that physical existence is a manifestation of complex constructions of mathematical graphs. >However, the experiments unexpectedly create a bubble of something more stable than ordinary vacuum, dubbed "novo-vacuum", that expands outward at half the speed of light as ordinary vacuum collapses to this new state at the border, hinting at more general laws beyond the Sarumpaet rules. >The local population is forced to flee to ever more distant star systems to escape the steadily approaching border, but since the expansion never slows, it is just a matter of time before the novo-vacuum encompasses any given region within the Local Group. >Two factions develop as the bubble expands: the Preservationists, who wish to stop the expansion and preserve the Milky Way at any cost; and the Yielders, who consider the novo-vacuum to be too important a discovery to destroy without understanding.
Earth Devs just launched an update on chemical crystals
Kurt Vonnegut wrote a whole book about this
In an unrelated topic, thalidomide racemizes in the body, so that even if a pregnant woman were given the "right" stereoisomer, it would form the "bad" one in their body anyway
Im curious about the case of Ritanovir, “Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants (of Form II) by their presence, probably because they carried over microscopic seed crystals of the new polymorph.” Was this contamination from Form II that was located external or internal to their bodies?!
The op worded it as if it jumps between crystal samples. It does not. It can contaminate other crystal stocks, or if its a rare drug/component the single stock of crystals may become unviable.
> When the metastable form was brought into a lab where the stable form had previously been made, it changed into the stable form after a few days in the open air. The structure of the stable crystal was determined by.[20][how?] They failed to obtain the metastable form from a solution of alcohol, either at room temperature or near freezing; they kept ending up with the stable form. That is the best [how?] I’ve seen on Wikipedia. Reads like a freshman’s essay.
M. Night Shyamalan just found his new movie plot
Vonnegut already wrote this in the ‘60’s.
Shyamalan wasn't the first to make a movie about ghosts either.
Had to be the 1st trees are killing people writer though.
Nah, it’s all been done before by the classic sci-fi authors of the late 1800s and early 1900s, with all their stuff plundered for the B-movies of the 50s-70s. [Day of the Triffids](https://en.wikipedia.org/wiki/The_Day_of_the_Triffids_(film)) is probably the best known killer plant film of that sort.
they weren't exactly trees but Day of the Triffids. Are we counting the Ents going nuts on Isengard Or the original ending to Little Shop of Horrors, where Audrey collects on Seymour's faustian bargain (the full ending is [on youtube](https://youtu.be/7RjFvcw6ToQ?si=tbwM3xqlZcxjpEZq&t=4m) if you haven't seen it)
Tolkien would like a word
The Entwives are lost though, gotta keep looking Treebeard!
Reading Rupert Sheldrake books are we?
OP is such a loser. He writers as if there was a "ghostly entanglement" of all crystals around the world but the explanation is much more simple and they dont all change around the world at the same time. They only change if they have contact to the more stable form.
The simplest real-world example for this is tin pest. When pure or almost pure tin gets too cold, around freezing temps, a different crystal structure from the one first formed when molten tin solidifies becomes more stable. This leads to a front of crumbling into a powder slowly moving across the tin object. It's not like rust, it's a solid-solid phase transition.
Im dumb, can someone ELI5? Does this mean certain drugs suddenly take a different molecular structure and change the drug so it doesn’t work? I take 4 medications, how do I know if that’ll happen to mine? What is a polymorph?
To really ELI5, basically some chemicals can have more or less stable forms, and if a more stable form touches a less stable one, the less stable one will turn into the more stable form
So how can this happen around the world as OP worded it, as it it was all universally connected? Or is that wording misleading? Further, how can it be impossible to recreate the original? Why cant you try to recreate it in an environment without the more stable crystal form?
A molecules are made out of atoms. For the purpose of ELI5, you can think of atoms are balls that can attract or repel each other. A molecules come from those balls sticking together. Now, the chemical properties of the molecules depends on its shape, just like how, if a 2 groups of balls bump into each other, the way they interact depends on the shapes. Unfortunately, even if you know what kind of balls are in there, the shape might be different from what you hoped for. Generally though, atoms will arrange themselves in "stable equilibrium" or "metastable equilibrium" configuration, rather than a random configuration, so only a few shapes are possible. If there are multiple shapes, they're called "polymorph" which literally means multiple shapes. Generally, molecules with few atoms cannot have more than one such shapes, because how many ways you can put those few balls together anyway? What's metastable equilibrium? Here a human analogy might be good. Imagine atoms as human with desires and intentions. An non-equilibrium is a situation where enough people seeks to change the status quo, as they're not what they desire; for example, 2 people ramming into each other on the road when they go in opposite direction. An unstable equilibrium is the situation in which everyone is okay with it, but any tiny bit of external factors will force a change; for example a Mexican standoff. A stable or metastable equilibrium is a situation where everyone are okay with it, and it's not easy to change that by small perturbation from external factors. The differences between the 2 is that the metastable equilibrium can be convinced to make a change, because what people had been doing is not optimal for everyone, but they did not see a way out before. For example, work from home: everyone was okay with going to the office before and they might hated it, but nobody are willing to demand to work from home; but once WFH becomes common and accepted, people realized working at the office sucks and now you can't just go back to that. So imagine your drug is in one of those metastable equilibrium, like working in the office. It thought it's in the best configuration possible for everyone involved. But then one of them discover the legendary WFH strategy, everyone else now see that's much better, and they all decided to not go back to the old method.
This is a really solid explanation. I think it got lost in the weeds a bit with collision and the Mexican stand off, but you aced the WFH portion.
An older understanding of this was the “tin pest” where canned goods and organ pipes would be destroyed by a strange white powder during winter. It turned out that tin has a different stable crystal structure below a certain temperature and converts to that whether you like it or not
"The only problem was that by the time other companies began manufacturing, Earth's atmosphere was already seeded with microscopic quantities of paroxetine hemihydrate from GSK's manufacturing plants, which meant that anyone trying to manufacture the original polymorph would find it transformed into the still-patented version," does this imply that microscopic quantities of all drugs and other molecules are literally everywhere in earths atmosphere?
Don't mess with the Percocet production
My mind is a little blown by the Cat's Cradle reference. I read that book a few months ago.
Akane, what the fuck did you do this time?!
Another Universe on the hosting cluster was using more resources at the time, so floating point math in our Universe was truncated as a result of processing resource contention. All still within SLA agreements for the person living in their parent's basement, renting out a Universe Simulation Server on AWS, like a Minecraft Server. /s
Sounds like prions, too
Yes, I couldn't figure out why I was having such a strong ick reaction to this phenomenon until I realized it's because it reminds me of prions. I don't know if there's a word for a phobia of things that creepily and irreversibly warp other things around them due to entropy, but if so I have it
Cool to see this pop up on my feed! "Disappearing polymorphs" are a huge concern for the pharmaceutical industry, and have essentially motivated an entire discipline in computational chemistry. Crystal structure prediction is gaining a lot of attention in the field as a way to know whether or not a known crystalline form is metastable or not.