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DBL%20Hendrix%20small.png College chemistry, 1983

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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July 9, 2007

Now With Ethyl Mesylate!

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Posted by Derek

One of the stories I missed while on hiatus has been Roche's recall of antiretroviral Viracept (nelfinavir) tablets. As readers may know, a problem with many batches of the drug became known in June. It's a mesylate (aka methanesulfonate) salt, but some of the tablets turned out to have ethyl mesylate in them as well, which is definitely sonething I'd go out of my way to avoid ingesting. A worldwide recall (except for North America, which is on a different supply chain) has been the result.

Methanesulfonate is a very happy anion, which is one of the reasons why methanesulfonic acid is used to make salts of basic drugs. The ions of these formulations tend to not be too tightly bound or paired, making the salt forms generally easier to dissolve. (The stronger the interactions between the ions, the harder it is for water to break up the party and dissolve them). But the contentedness of the sulfonate anion makes it a good leaving group when it's part of a covalent molecule. It would rather be off floating around with a negative charge on it again than be tied up in a regular bond, so sulfonate esters and the like tend to be pretty reactive.

Alkyl mesylate esters, then, are also pretty toxic. Just how toxic is the question, though. The stuff will react with nucleophiles wherever it finds them, and if that's some protein on the surface of a soon-to-be-shed epithelial cell, then no harm done. But there are many other situations that won't work out so well, going all the way up to DNA damage.

So how did this nasty stuff get in there in the first place? When I heard about the contaminant, my first thought was that someone had been washing out the reactors where the salt was formed with ethanol, and that appears to be exactly the case. Alcohol plus free acid under strong acid catalysis will give you ester, in what's literally one of the oldest reactions in the book. Roche appears to have been able to keep the contaminant down below regulatory levels normally, but someone's mind has been wandering over in Switzerland. In consequence, the fearsome Swiss reputation for purity and consistency takes a torpedo below the water line.

Comments (6) + TrackBacks (0) | Category: Infectious Diseases | Why Everyone Loves Us


1. milkshake on July 10, 2007 12:18 AM writes...

I think the worst scenarion for EtOMs formation would be an excess of neat concentrated MsOH coming into contact with straight ethanol in the pipes or MsOH storage reservoir. Once the MsOH is diluted in the crystallization mix there should be no EtOMs formation regardless of ethanol.

It kind of suprises me that they did not catch this - it is a pretty well-known problem.

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2. ZAL on July 10, 2007 2:01 AM writes...

Although this does not seem to be the case, a very common way to get etyhl mesylate in your crude mixture is when you try to mesylate an alcohol with Et3N and MsCl, and use CH2Cl2 as the solvent, which contains EtOH as the stabilizing agent(some of it will still be there even after destillation). This bothered me more than once, as the resulting ester can be quite difficult to separate from your product! So when doing this, always check that you use ethanol-free DCM!

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3. Kramylator on July 10, 2007 7:02 AM writes...

This reminds me of some general concepts I took away from from Trevor Laird's process chemistry course: 1.) when it comes to large-scale or production work, trouble shows up where you least expect it, and 2.) an almost imperceptible variation in an otherwise reliable method can blow you out of the water.
Roche is lucky that they were able to effect some quick damage-control.

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4. Clark Kent on July 11, 2007 3:50 PM writes...

Did you see that Zambia may sue Roche over this? If they go ahead with the suit, it may encourage big pharma to allow generic companies to supply Africa (as no company wants to risk this type of litigation for no profit).
From Reuters: "The drug will not be used in Zambia, and we have launched our independent verification on its effects," said Canicius Banda, spokesman for Zambia's ministry of health. He added that the southern African nation, where 20 percent of its 11.7 million people are infected with HIV, might file claims against Roche on behalf of HIV patients if an investigation determined that the drug had caused harm to them.

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5. Will on July 13, 2007 7:35 AM writes...

I'd like to know how the Zambian government are going to prove the drug did any harm, increased incididence of death in an AIDs group?

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6. Rob on July 27, 2007 10:02 AM writes...

Does anyone know what the levels of ethyl mesylate were in this lot of product? Is there such thing as an acceptable level of ethyl mesylate?

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