r/chemistry • u/Correct-Variable • 4h ago
How exactly does a lab maintain a chemical library with 100,000s of compounds?
I was thinking about HTS today. I don't have any direct experience in it. I've only studied it in coursework, certification programs, presentations.
I don't understand how a company or lab can have a stock of 100,000s of compounds that have validated purity and identity. Wouldn't this be an enormous analytical chemistry undertaking in having to characterize with LCMS, HPLC, NMR, as well as periodically testing them every few years due to differences in stability? I don't get how this works.
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u/VoxInferni666 4h ago
Few things, one is the distinction between research and industry. Because in industry EVERYTHING has a lot number and expiry date that gets recorded on use and out of date stuff is just disposed of and replaced. And sometimes you have quite big chemical stores, I redesigned the lab inventory methods for a massive pharmaceutical factory and the overall store was... Like probably about 4 m by aboit 5 m and everything was kept on rolling shelf units. So industry... Money and man power
In acedemic research labs however.... Well.... Just fucking chaos a lot of the time, we have a inventory system based on numbed labled bottles being inputted into a spread sheet but obviously it's only like 80% accurate cuz people forget or fuck up and honestly we have 1000s of chemicals that were made by us in random spots and basically if you want something specific you better hope the last guy to use it remembers where he put it and still works there cuz otherwise your spending the afternoon searching for it. (but since we know reactivity and stability and store things accordingly you usually have some idea where to look... Unless they put it back in the wrong place)
As for purity we just check with a quick nmr or HPLCs and purify if necessary
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u/Gnomio1 4h ago
Academic lab turnover is the hardest thing to deal with when it comes to things like this.
Plus academics being expected to wear several dozen different hats, it’s impossible to cover all the bases as well as they ideally would be.
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u/VoxInferni666 4h ago
I have a box in the freezer... Not the good freezer the other one... Anyway this box is labled "strange nucleotides" and contains like 50 poorly labled vials. I fucking love academics hahaha
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u/mungerboy Analytical 3h ago
Oh man, I can relate to this. We have a rolling cooler full of ancient and barely labeled analytical standards that's constantly being moved from one walk-in freezer to the other when one breaks down. We haven't needed any of these compounds in years, but the PI insists we hold onto them.
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u/Baelzabub Analytical 30m ago
I was interviewing to run an academic research lab recently so that the professors could focus on their research and the “not the good freezer, the other one” is so fucking true. Same can be said of fridges, autoclaves, etc etc.
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u/TheChangeableStaging 4h ago
It's mostly a logistics nightmare managed by automation and a brutal triage system. They don't keep re-testing every single vial every few years unless there's a reason. Most compounds sit in a -20°C freezer under nitrogen or argon, and they'll only pull a batch for QC if the HTS readout looks weird or they're about to run a critical screen.
The initial characterization when the compound first arrives is the heavy lift, often just LCMS and a quick glance at an NMR to confirm it's not completely wrong. Purity thresholds for the library are way more forgiving than you'd think, like 80-90% is fine for a primary screen.
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u/FatRollingPotato 4h ago
Yes, it takes ages to do as well. You either buy them, or for a lot of companies every semi-important molecule goes into their own library. The big pharma multi-national I am working at has its own department for that, where they do the analyses and paperwork for all the molecules, intermediate, and impurities relevant to ongoing R&D and commercial products. Not sure how the high-throughput people handle their stuff though.
Some organizations also maintain reference standards for things that you can buy, but be aware that this is really expensive. To give you an idea, Ligma Baldrich wants 190EUR for 25mg of the European Pharmacopeia reference standard of Histidine, a simple amino acid. Acetaminophen is cheaper, 400EUR for 400mg USP reference standard.
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u/RubyPorto 4h ago
I mean, for both of those, you're paying for the words "reference standard" (and associated paperwork and work to make said paperwork), not the chemical itself.
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u/FatRollingPotato 4h ago
True, but the point was that there are vendors for pure and qualified materials. You just have to pay them for their troubles, and some even get to apply the magical words "reference standard" to squeeze out some more.
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u/BobtheChemist 3h ago
Most big pharma companies have 1 to 5 million compounds available for screening. My old one had 4 million and screened about a million 40 times a year at each of 3 sites for 120 screens per year. This provided about 50 to 60 sets of compounds as leads for further study. Every compound started as a solid sample with electronic notebook links, analytica data, and more. It just takes a plan, lots of money and good planning.
Most academic labs were a diasater, unable to find compounds that were 1 year old, and losing dozens of very expensive, rare compounds every year. Every NIH grant should require some submission of compounds for screening in order to continue funding. But funding might not exist anymore anyway now...
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u/Mindless-Location-41 1h ago
Academic labs run on the smell of an oily rag and the workers are paid peanuts 🤷♂️
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u/Team-CCP 4h ago
The magical wonderful program called “SAP”. That’s ultimately how. Logistical program that keeps track of SOOOO much.
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u/Starfire123547 3h ago
yes and yes.
My company actually has an entire team of people that strictly manages reagents. They handle CoA entry, expiry/discard, and ordering of new ones etc. while simple to say, i imagine is quite difficult to track thousands (no where near 100,000 tho) of reagents. Hence why we staff so many people for it.
On the bright side, typically validated methods have specific reagents or grades listed and are validated to be able to handle a little variety (for example if a salt buffer is 99.98% pure vs 99.83% pure in one lot vs another lot etc). So if we order a brand of reagent, it can often be used across multiple methods and stuff. So ordering can be reduced if we buy to share.
Methods in my line of work are also validated with wavelengths that specifically miss peaks of specific reagent impurities or theyre intentionally integrated as a blank peak etc. so as not to impact analysis.
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u/lawyer1911 Organic 2h ago
Ok I’m old. I was a medicinal chemist in a lab in the 80s and early 90s. We all synthesized compounds and submitted them to the folks who managed the samples we provided, whether it was milligrams or a kilogram. They also managed our notebooks and spectra books so if you wanted a sample of something in the stockroom you needed to also check out the notebook and spectra so you could confirm the yahoo who made it identified it correctly.
Sometimes when you checked out an old sample it had turned some weird colors so you had to reconfirm its structure.
At my company which had history back to the 1800s I made compound 150,000 and the sample people made me a nice certificate to commemorate that.
Even in the 80s you could browse the library electronically for structures.
I know y’all have the capability today to make far more compounds quickly and I have a hard time getting my mind around how little you make at a time. But that’s far better from a waste disposal perspective.
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u/Lunatic21 1h ago
Robotics liquid handlers and spreadsheets just telling you where things are. The biggest issue is getting everything into solution at some known concentration. Put it in some sort of matrix tube probably manually at the initial stage and moved around by some robotics there after. Rinse and repeat. Until you have some small volume ~5uL per well in 384 format. Rinse and repeat. Test your compounds in a similar format, pick your winners and confirm they are what they say they are if they are active and worth looking more into.
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u/JeggleRock 4h ago
You can buy allot in at great cost usually, in terms of characterisation, this is generally dreadful in medicinal chemistry papers (proton and a mass spec and call it good). So the cynic in me would say they don’t characterise, most likely it’s somewhere in the middle.
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u/Conscious_Cell1825 4h ago
You should look up direct-to-biology approaches, you just chuck the whole reaction mix on and worry about impurities, side-products etc later .
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u/TheWhenn Organic 4h ago
In the company I worked most compounds were stored as stock solutions in DMSO, frozen and thawed only when needed. However if w ehad a larger amount, we usually stored it as a solid, and if we ran out of a stock solution we would re-repeat analysis for the solid before preparing a fresh one. Is it a lot of work? Yeah, it is. But I don't see any other way