14 ms·

Disappearing Polymorphs

173 points by josephcsible 3y ago

cvoss 3y ago
> a phenomenon in which a seemingly stable crystal structure is suddenly unable to be produced The whole intro to this article really undersold to me how significant a phenomenon this is describing. My jaw dropped when I got into the Case Studies section. Apparently there are certain drugs which are nigh impossible to make today because a more stable (but medically ineffective (or still patented)) version of the crystal was once created and now contaminates the atmosphere in microscopic quantities.
- eru 3y ago
  The article also mentions the same in reverse: > It is hypothesized that "unintentional seeding" may also be responsible for the phenomenon in which it often becomes easier to crystallize synthetic compounds over time. (Well, to be fair, the only thing that's reversed is the human value judgement. The proposed mechanism is the same.)
r0ckarong 3y ago
Stupid sophons at it again.
swarthout 3y ago
It is wild to see disappearing polymorphism appear on the front page of HN! My company, Lavo Life Sciences (W23) is building software to predict polymorphism in drug molecules, happy to answer any questions on this thread :)
- xvedejas 3y ago
  Are there any promising paths towards preventing this? Seeding clean rooms with other chiral molecules that can encourage the lost higher energy form of a crystal, maybe?
  - izme 3y ago
    It also makes you wonder if novel crystal forms could be discovered by purposely seeding the process with other arbitrary seeds.
  - greggsy 3y ago
    I wonder if you could also detect it using some other harmless but otherwise volatile material?
- Izkata 3y ago
  I think there was another post about this a few days ago. IIRC the title was about a specific drug affected by it.
colanderman 3y ago
> Form II was of sufficiently lower energy that it became impossible to produce Form I in any laboratory where Form II was introduced, even indirectly. Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants by their presence, probably because they carried over microscopic seed crystals of the new polymorph. If someone told me this entire article was fabricated I would believe them. I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go. Chemistry is wild.
- uoaei 3y ago
  Just wait til you hear about car tires and microplastics!
  - deleted 3y ago
    [deleted]
  - greggsy 3y ago
    Not really relevant?
    - uoaei 3y ago
      The relevant part: > I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go. Everywhere you drive, you leave behind microplastics as particulate. These are washed into waterways and end up in aquatic ecosystems, including the seafood you eat. There's also some small enough to be airborne, thus prone to inhalation by humans and other animals.[1] Particulate production from road wear increases with the fourth power of the weight of the vehicle.[2] One has to assume by Newton's third law that the same is true of tires. Tires and roads are made of petroleum-based materials, i.e., they produce microplastics. This means a car twice as heavy (e.g. EVs vs ICE cars in the same form factor) produces sixteen times as much particulate matter. This also means that typical cars emit a minimum of four million times as much particulate as bicycles. E-bikes emit 10 times as much particulate as bicycles. Microplastics cling to everything, that's just the nature of particulate. So they follow you everywhere. [1] https://www.wbcsd.org/Sector-Projects/Tire-Industry-Project/Resources/Tire-Road-Wear-Particles-Papers https://www.wbcsd.org/Sector-Projects/Tire-Industry-Project/... [2] https://en.wikipedia.org/wiki/Fourth_power_law https://en.wikipedia.org/wiki/Fourth_power_law
izme 3y ago
This is fascinating, such that I went looking for more information on this phenomenon and found an interesting preprint regarding the polymorphism of ritonavir suggesting that specific milling processes are able to reliably produce each form. At least I think that's what it says, I'm definitely not a chemist! https://chemrxiv.org/engage/chemrxiv/article-details/645112f307c3f0293717c139 https://chemrxiv.org/engage/chemrxiv/article-details/645112f...
gundmc 3y ago
The article says this is of particular concern to Pharmaceuticals and Computer Hardware industries, but all of the case studies are from pharmaceuticals and food products. I can imagine how this could present an issue for hardware manufacturing, but are there examples of this occurring in that industry?
- greggsy 3y ago
  While the semiconductor industry does deal in the use of some specialised materials, and do require ultra clean room conditions, I believe their structure is an order of magnitude simpler than those used in the pharmaceutical. It’s the process that is difficult. I’m just an armchair observer though, and I’m sure something like this has cropped up in some unpublished paper.
deleted 3y ago
[deleted]
CamperBob2 3y ago
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 Nobody else's bullshit alarm is going off here? Just mine? Seriously?
- vjk800 3y ago
  I was wondering about this too. I get that it's a commonly used drug, but the entire earth's atmosphere? How many molecules per cubic meter of air is that plant letting out? How are the particles travelling around the world exactly?
  - wizzard0 3y ago
    I don’t think it’s the plants, the fine dust of the pills being _consumed_ all over the world should be enougg
- wizzard0 3y ago
  The words “entire athmosphere” and the “plants” might be an exaggregation, but 1) I can readily imagine the _labs_ being contaminated by the reference samples. 2) If the compound is stable, not clumping and not hygroscopic - yes, certainly. “Microscopic” doesn’t do it justice, as there doesn’t seem to be any limit to how small the seed crystals can get. Since we’re manufacturing literally tons of pharmaceuticals, and carefully manually spreading them over the Earth surface to the pharmacies, so for stable substances it doesn’t seem such an exaggregation to me.
  - hoseja 3y ago
    Well there is a limit, one unit cell.
- ale42 3y ago
  Sounds like science-fiction or some conspiracy theories indeed... but the phenomenon seems to be scientifically well-described. I'm just wondering, wouldn't a clean room be able to keep out those micro-seeds?
woopsn 3y ago
[flagged]
plutonorm 3y ago
The morphic resonance guys claim this is proof. And I for one do find it a little unbelievable that these seeds are travelling the world, such that for any cubic foot of air you find a seed. Show me the math on that.
- ndsipa_pomu 3y ago
  The fact that they can make the metastable crystals when they isolate them suggests that contamination is more likely than morphic resonance (which doesn't have any solid evidence going for it). I don't know if the theory behind morphic resonance suggests the mechanism, but if so, would that mechanism be blocked in a similar fashion?
- russdill 3y ago
  Anyone who's ever had seasonal allergies will quickly and fully understand the implications. And allergens are absolutely enormous. Heck, there's a species of plankton that float through the air, with on average 1 million cells per cubic meter.
  - ndsipa_pomu 3y ago
    I did not know that https://en.wikipedia.org/wiki/Aeroplankton https://en.wikipedia.org/wiki/Aeroplankton
wildermuthn 3y ago
This feels to me like a repeated “oh, that’s odd” moment. Perhaps this isn’t as simple as “the seed crystals are just everywhere now”, and maybe the explanation is something fundamental about our universe that remains undiscovered.
- ndsipa_pomu 3y ago
  Reminds me of Rupert Sheldrake's Morphic fields which aren't generally thought to exist https://en.wikipedia.org/wiki/Rupert_Sheldrake https://en.wikipedia.org/wiki/Rupert_Sheldrake
cyberax 3y ago
The ritonavir story is super-interesting. It's also interesting how the problem got worked around. Initially, ritonavir had to be shipped as a frozen gel, to slow down the conversion. But this was not optimal at all. The ultimate solution was hot extrusion: molten ritonavir is dispersed in an inert carrier, and then left to cool. The carrier insulates the droplets from outside contact, so it can't get contaminated with the more stable polymorph. This idea itself is completely obvious. But like pretty much everything in engineering, it took a decade to perfect the process. If you have a misfortune to get prescribed Paxlovid for COVID, break a tablet and look at it in a microscope. You'll clearly see the ritonavir droplets embedded inside the carrier material. It's super-cool. (Ritonavir is used in Paxlovid not because of its antiviral properties, but because it inhibits some liver enzymes, thus slowing down the metabolism of the active ingredient)
lawlessone 3y ago
This sounds a lot like prion diseases.

173 points by josephcsible 3y ago

> a phenomenon in which a seemingly stable crystal structure is suddenly unable to be produced The whole intro to this article really undersold to me how significant a phenomenon this is describing. My jaw dropped when I got into the Case Studies section. Apparently there are certain drugs which are nigh impossible to make today because a more stable (but medically ineffective (or still patented)) version of the crystal was once created and now contaminates the atmosphere in microscopic quantities.

eru 3y ago
The article also mentions the same in reverse: > It is hypothesized that "unintentional seeding" may also be responsible for the phenomenon in which it often becomes easier to crystallize synthetic compounds over time. (Well, to be fair, the only thing that's reversed is the human value judgement. The proposed mechanism is the same.)

r0ckarong 3y ago

Stupid sophons at it again.

swarthout 3y ago

It is wild to see disappearing polymorphism appear on the front page of HN! My company, Lavo Life Sciences (W23) is building software to predict polymorphism in drug molecules, happy to answer any questions on this thread :)

xvedejas 3y ago
Are there any promising paths towards preventing this? Seeding clean rooms with other chiral molecules that can encourage the lost higher energy form of a crystal, maybe?
- izme 3y ago
  It also makes you wonder if novel crystal forms could be discovered by purposely seeding the process with other arbitrary seeds.
- greggsy 3y ago
  I wonder if you could also detect it using some other harmless but otherwise volatile material?
Izkata 3y ago
I think there was another post about this a few days ago. IIRC the title was about a specific drug affected by it.

colanderman 3y ago

> Form II was of sufficiently lower energy that it became impossible to produce Form I in any laboratory where Form II was introduced, even indirectly. Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants by their presence, probably because they carried over microscopic seed crystals of the new polymorph. If someone told me this entire article was fabricated I would believe them. I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go. Chemistry is wild.

uoaei 3y ago
Just wait til you hear about car tires and microplastics!
- deleted 3y ago
  [deleted]
- greggsy 3y ago
  Not really relevant?
  - uoaei 3y ago
    The relevant part: > I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go. Everywhere you drive, you leave behind microplastics as particulate. These are washed into waterways and end up in aquatic ecosystems, including the seafood you eat. There's also some small enough to be airborne, thus prone to inhalation by humans and other animals.[1] Particulate production from road wear increases with the fourth power of the weight of the vehicle.[2] One has to assume by Newton's third law that the same is true of tires. Tires and roads are made of petroleum-based materials, i.e., they produce microplastics. This means a car twice as heavy (e.g. EVs vs ICE cars in the same form factor) produces sixteen times as much particulate matter. This also means that typical cars emit a minimum of four million times as much particulate as bicycles. E-bikes emit 10 times as much particulate as bicycles. Microplastics cling to everything, that's just the nature of particulate. So they follow you everywhere. [1] https://www.wbcsd.org/Sector-Projects/Tire-Industry-Project/Resources/Tire-Road-Wear-Particles-Papers https://www.wbcsd.org/Sector-Projects/Tire-Industry-Project/... [2] https://en.wikipedia.org/wiki/Fourth_power_law https://en.wikipedia.org/wiki/Fourth_power_law

izme 3y ago

This is fascinating, such that I went looking for more information on this phenomenon and found an interesting preprint regarding the polymorphism of ritonavir suggesting that specific milling processes are able to reliably produce each form. At least I think that's what it says, I'm definitely not a chemist! https://chemrxiv.org/engage/chemrxiv/article-details/645112f307c3f0293717c139 https://chemrxiv.org/engage/chemrxiv/article-details/645112f...

gundmc 3y ago

The article says this is of particular concern to Pharmaceuticals and Computer Hardware industries, but all of the case studies are from pharmaceuticals and food products. I can imagine how this could present an issue for hardware manufacturing, but are there examples of this occurring in that industry?

greggsy 3y ago
While the semiconductor industry does deal in the use of some specialised materials, and do require ultra clean room conditions, I believe their structure is an order of magnitude simpler than those used in the pharmaceutical. It’s the process that is difficult. I’m just an armchair observer though, and I’m sure something like this has cropped up in some unpublished paper.

deleted 3y ago

[deleted]

CamperBob2 3y ago

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 Nobody else's bullshit alarm is going off here? Just mine? Seriously?

vjk800 3y ago
I was wondering about this too. I get that it's a commonly used drug, but the entire earth's atmosphere? How many molecules per cubic meter of air is that plant letting out? How are the particles travelling around the world exactly?
- wizzard0 3y ago
  I don’t think it’s the plants, the fine dust of the pills being _consumed_ all over the world should be enougg
wizzard0 3y ago
The words “entire athmosphere” and the “plants” might be an exaggregation, but 1) I can readily imagine the _labs_ being contaminated by the reference samples. 2) If the compound is stable, not clumping and not hygroscopic - yes, certainly. “Microscopic” doesn’t do it justice, as there doesn’t seem to be any limit to how small the seed crystals can get. Since we’re manufacturing literally tons of pharmaceuticals, and carefully manually spreading them over the Earth surface to the pharmacies, so for stable substances it doesn’t seem such an exaggregation to me.
- hoseja 3y ago
  Well there is a limit, one unit cell.
ale42 3y ago
Sounds like science-fiction or some conspiracy theories indeed... but the phenomenon seems to be scientifically well-described. I'm just wondering, wouldn't a clean room be able to keep out those micro-seeds?

woopsn 3y ago

[flagged]

plutonorm 3y ago

The morphic resonance guys claim this is proof. And I for one do find it a little unbelievable that these seeds are travelling the world, such that for any cubic foot of air you find a seed. Show me the math on that.

ndsipa_pomu 3y ago
The fact that they can make the metastable crystals when they isolate them suggests that contamination is more likely than morphic resonance (which doesn't have any solid evidence going for it). I don't know if the theory behind morphic resonance suggests the mechanism, but if so, would that mechanism be blocked in a similar fashion?
russdill 3y ago
Anyone who's ever had seasonal allergies will quickly and fully understand the implications. And allergens are absolutely enormous. Heck, there's a species of plankton that float through the air, with on average 1 million cells per cubic meter.
- ndsipa_pomu 3y ago
  I did not know that https://en.wikipedia.org/wiki/Aeroplankton https://en.wikipedia.org/wiki/Aeroplankton

wildermuthn 3y ago

This feels to me like a repeated “oh, that’s odd” moment. Perhaps this isn’t as simple as “the seed crystals are just everywhere now”, and maybe the explanation is something fundamental about our universe that remains undiscovered.

ndsipa_pomu 3y ago
Reminds me of Rupert Sheldrake's Morphic fields which aren't generally thought to exist https://en.wikipedia.org/wiki/Rupert_Sheldrake https://en.wikipedia.org/wiki/Rupert_Sheldrake

cyberax 3y ago

The ritonavir story is super-interesting. It's also interesting how the problem got worked around. Initially, ritonavir had to be shipped as a frozen gel, to slow down the conversion. But this was not optimal at all. The ultimate solution was hot extrusion: molten ritonavir is dispersed in an inert carrier, and then left to cool. The carrier insulates the droplets from outside contact, so it can't get contaminated with the more stable polymorph. This idea itself is completely obvious. But like pretty much everything in engineering, it took a decade to perfect the process. If you have a misfortune to get prescribed Paxlovid for COVID, break a tablet and look at it in a microscope. You'll clearly see the ritonavir droplets embedded inside the carrier material. It's super-cool. (Ritonavir is used in Paxlovid not because of its antiviral properties, but because it inhibits some liver enzymes, thus slowing down the metabolism of the active ingredient)

lawlessone 3y ago

This sounds a lot like prion diseases.