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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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October 26, 2005

The Latest in Pharmaceutical Technology

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Posted by Derek

I've been spending some time with a batch of compound recently, boiling it in ethyl alcohol all day long. I distill out the ethanol, then add more and boil it up again. And again. Why am I being so darn productive, you ask? Well, this is some material we received from a contract synthesis company, and while it's the right stuff, it came to us with nearly 10% chloroform in it. You find these things out by taking NMR spectra of the outsourced stuff as soon as you get it in, and preferably in more than one solvent. Trust but verify and all that, particularly from the low bidder.

Deuterated chloroform is a common solvent for NMR spectra, and it always shows a greater or lesser peak for the plain stuff. If we'd only run the spectrum in that, we might have just written it off as an ugly bottle of NMR solvent, but it's rather more difficult to explain its presence in a sample run in, say, DMSO. As it turns out, it's a contaminant left over from the last step of the synthesis, and it's the sort of thing you'd think that a day or two on the vacuum pump would take care of. After all, it's pretty volatile stuff, right?

Well, not in this case. This is one of those times when the solvent seems to have decided to work its way into the crystal lattice of a compound, because that chloroform's not going anywhere without a fight. This compound is not the most soluble stuff in the world, but hot ethanol gradually does the trick. Thus the repetitive distillation. Of course, now the compound is cut with ethyl alcohol instead of chloroform, but that's a much more benign thing to feed the rodents come assay time. Drunken mice we can allow for, but not ones that have been chloroformed from the inside out.

Comments (15) + TrackBacks (0) | Category: Life in the Drug Labs


1. Zak on October 27, 2005 1:12 AM writes...

You going to let that shop know that they gave you a contaminated batch, and that you'll be sourcing elsewhere in the future?

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2. Derek Lowe on October 27, 2005 7:16 AM writes...

We have indeed communicated our joy at being charged custom-synthesis prices for solvent. There are plenty of suppliers out there these days. . .

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3. Don Butler on October 27, 2005 9:23 AM writes...


I once had a crystalline compound that held one half of an equivalent of toluene. I removed it by subliming the compound at high vacuum.

I know at least one colleague that claimed that compounds that hold solvents are usually biologically active.

It was true in this case.

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4. daen on October 27, 2005 9:30 AM writes...

Custom oligo synthesis also has its fair share of QA issues (no names though ...). As a matter of routine, we now do MS on all purchased oligos. Better to do an overnight MS run now than find out you've been trying to ligate the unligatable and have just wasted weeks of lab time and a whole bunch of expensive building blocks. Needless to say, we're not too happy at being the QC department for our suppliers, but caveat emptor ...

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5. Marc on October 27, 2005 10:27 AM writes...

Isn`t this work what you pay them to do ?

I understand that this is custom work, and that there could often be reasonably large amounts of solvents or other impurities, but 10% is a large amount of chloroform.
I am not familliar with the whole process, but are 'chloroformed mice' or other solvated rodents common ? could this kind of problem with suppliers ruin a candiate`s chances ?

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6. Petros on October 27, 2005 10:59 AM writes...

A related problem we had some years ago was when we trying to screen for subtype selective ligands using commercially provided recombinant receptor preparations.

After running the assay for 12 to 18 months the supplier found out that two subtypes had been mislabelled. The absence of ligands that clearly distinguished the two subtypes pharmacologically meant that the profile of the subtype supplied appeared to be consistent with the literature and the product spec. It didn't seem necessary to sequence the material provided!

Eventually the supplier agreed to pay for all the wasted consumables (but not manpower) which was a fair bit of cash.

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7. milo on October 27, 2005 11:30 AM writes...

I have found the ethyl acetate is always a nightmare to remove. I recently discovered that a few compounds I have gotten from a major chemical company (Ald... something or other) have been badly contaminated with 1/2 inch stirbars. :-)

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8. Derek Lowe on October 27, 2005 11:45 AM writes...

Yep, this is indeed what we're supposedly paying them to do.

As several comments here have noted, solvents can sometimes really hang on to solid material. And these solvates, if they're really in the crystal lattice, have different properties (melting point, solubility) than the parent compound.

This can be innocuous (as it often is when the solvent is water), or bearable (when it's, say, ethanol), or a real problem. Dosing orally with a chloroform contamination is bound to raise doubts about the efficacy and side effects of the compound. But this isn't one of our own drug candidates - it's someone else's, for a reference standard. That's often the way that contract synthesis houses are used.

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9. Drew on October 27, 2005 12:01 PM writes...

Milo- speaking of that specific "artsy" supplier, I recently had a boronic acid that was a 1:1 mixture of regioisomers. Called, complained, was told "It meets our purity specs.", while staring an an NMR that was far, far from pure!

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10. milo on October 27, 2005 1:21 PM writes...

Derek, your comment about solvates having different properties etc... got me thinking (while waiting for toluene to come off on the rotovap): When in the drug discovery process do you start thinking about the physical properties of a compound? Do you try for solids from the start? High melting or low melting ones? are oils shunned due to problem in making them pills? When do you start looking at morphology of a solid and looking at kinetics of dissolution etc...

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11. bronxite on October 27, 2005 1:42 PM writes...

There's a joke that floats around Hollywood that goes something like:
a writer is a frustrated producer
a producer is a frustrated director
a director is a frustrated actor
an actor is a frustrated person

perhaps a synthetic chemist at a contract synthesis outfit is a frustrated medicinal chemist.

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12. SRC on October 27, 2005 9:14 PM writes...

A couple thoughts:

Recrystallize the compound from chloroform or a chloroform/something else mixture and see if it retains chloroform stoichiometrically. If so, metathesis to a different salt (assuming the compound is a salt, of course) will do the trick. The chances of another salt packing in such a similar fashion are minimal.

If the adduct is not stoichiometric, then perform differential scanning calorimetry, thermogravimetry, or similar technique to find out quantitatively what it takes to remove the chloroform.

Alternatively, in the worst case, take the compound up in methylene chloride and isolate it again. If chloroform packs nicely into the lattice, methylene chloride won't pack as well, and of course is a lot more volatile. Naturally, if the original material crystallized with stoichiometric chloroform, the stuff from methylene chloride probably won't crystallize nearly as well, but of course that's the whole idea.

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13. M on October 28, 2005 4:23 AM writes...

Well, as someone who used to work at a contract research company in Oxford, UK I can tell you they pay these guys absolute peanuts (£24k for PhD) and work them 50hrs+ a week with constant bullying. If they tell you, the customer, they're putting 6 FTEs on a project they'll put 3 and work them like dogs. If the customer comes round to visit the team as they often do, they'll stick more chemists in there so it looks there is the corrent amount of FTEs. The problem is, the better these poor overworked guys do, the more big pharma will outsource to them. That is unti big pharma start going to China and India. Don't even start me on health and safety at CROs!!!

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14. Derek Lowe on October 28, 2005 7:54 AM writes...

SRC, I only wish this stuff were soluble in methylene chloride. It doesn't even go into refluxing ethanol - heck, I have to roll it around for a while in the NMR tube before I take the spectrum in DMSO. It's a pig. It's not a salt, either, worse luck. Fortunately, the brute-force treatment I'm giving it seems to do the trick.

And M's comments on contract houses are right on the mark. They're notorious low-margin sweatshops, and have gotten sweatier in recent years as offshore competition has seriously entered the field.

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15. SRC on October 28, 2005 3:17 PM writes...


My condolences. The stuff does indeed sound like a pig; even brick dust dissolves a bit in DMSO.

Do the lousy solubility properties arise from extensive hydrogen-bonding (the "tetraglycine effect"), from extensive planar bits of the molecule that stack like quarters, or is it something else?

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