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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Should Genentech Be a Part of Roche? | Main | Iloperidone: A Schizophrenia Drug Goes Down For the Last Time »

July 28, 2008

Questions You Don't Necessarily Want the Answers To . . .

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Posted by Derek

1. “Hey, who dropped that condenser out on the floor in front of my hood? That looks just like the one I had on my reaction flask. . .”

2. “How come the toxicology people haven’t called me about our lead compound yet? Two-week tox finished a while ago, and usually they’re a lot faster than this. . . “

3. “Is there any active aluminum compound left in this reaction or what? I keep dripping methanol into it to quench it, and nothing’s going on at all so far. . .”

4. “Who’s going to scale up our candidate compound, anyway? We need 300 grams of the stuff, and the scale-up group is booked solid. . .”

5. “So, is this the high-pressure hydrogen line or the low-pressure one that I’m opening?”

6. “I wonder what the error bars are on that behavioral assay. . .”

Comments (30) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. yttrai on July 28, 2008 8:30 AM writes...

“Who’s going to scale up our candidate compound, anyway? We need 300 grams of the stuff, and the scale-up group is booked solid. . .”

Bwahahahahahahaha.

And the problem is, if you accomplish something like this once, on time, your fate is more or less sealed for the remainder of your days.....

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2. Lethe on July 28, 2008 8:52 AM writes...

"This data can't be right, can it? That would mean I don't understand what's going on here at all..."

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3. Still Scared of Dinosaurs on July 28, 2008 8:52 AM writes...

"Ya think senior management is still OK with the timelines?"

"Any body know if their drug is better than ours?"

"Will the job cuts to affect our group?"

And my favorite...

"Any chance that marginally significant p-value is due to the fact that we ran an open-label study and all the placebo patients dropped out?"

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4. daen on July 28, 2008 9:30 AM writes...

Chemists and software development:

"Hmmm ... how hard could it be to make it handle two orders of magnitude more compounds and get it to run an order of magnitude faster on my three year old laptop?"

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5. Anonymous on July 28, 2008 10:15 AM writes...

Number 1:

I tell my group that we can expect to make the first 100 g of any compound for which we need that much. Our scaleup group NEVER has time for it.

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6. Retread on July 28, 2008 10:17 AM writes...

Why is the US National Institute of Mental Health attempting to run a trial of chelation therapy (dimercaptosuccinic acid) on autistic children? [ Nature vol. 454 p. 259 '08 (17 July) ]

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7. processchemist on July 28, 2008 10:39 AM writes...

"This chinese company sent a 10g sample of their product with a 99% HPLC grade. What will be the grade for the first 5 Kg ordered?"

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8. Ambrose on July 28, 2008 10:45 AM writes...

We can treat you like a customer should be treated and can give your scale-up project the attention it needs.

I worked in API manufacturing and sourcing for years and recently went into the contract process development and manufacturing business with some partners. Our company is Apicore LLC. We're located in the US.
Check out our site www.apicore.com

You can reach me at ambrose@apicore.com

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9. weirdo on July 28, 2008 11:20 AM writes...

Oh, good, Derek gets SPAM now! Great!

Another good question: "If your material is pure, what's that peak right there?"

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10. Yancey Ward on July 28, 2008 11:28 AM writes...

Number 3 reminds of a reaction I scaled up in which I was reducing a nitro-pyridine N-oxide with iron powder and acetic acid. The procedure said that the reaction would warm as I slowly added the iron powder. After I had added the first 40 grams, the reaction mixture was still at room temperature, the iron appeared to be unreacted at the bottom of the flask, and I walked away, scratching my head. When I returned 10 minutes later, the entire contents of the flask were all over the inside walls of the hood and dripping onto the floor.

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11. CMC guy on July 28, 2008 11:58 AM writes...

#4 from the other side of the aisle:
You want 300g by this route they used in med chem? And material is needed by when...

Note most small companies don't even have scale-up groups and process groups are rare.

#6 Would expand to include any animal and most bioassays.

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12. Hap on July 28, 2008 12:33 PM writes...

#6: Maybe they're as tired of the antiimmunization meme ("vaccines cause autism") as almost everyone else is, and they have an oversupply of wooden stakes.

#9: Well, Derek has trolls (drive-by trolls, trolls with google-fu, trolls with racism...), so why not spam? It's not like spammers care...although a spammer selling Kevin Trudeau's miracle weight-loss and wallet-gain cures would be frickin' hilarious...

"Are you sure the product of this reaction is supposed to be (black/fluorescent/a brick)?"

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13. NH_chem on July 28, 2008 12:45 PM writes...

My favorites:

"I know the hood was on fire while I was eating lunch but why didn't you try to save my reaction and not use the fire extinguisher?"

AND

"Are you sure that you want to quench old LAH with ether and toluene?"

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14. Yancey Ward on July 28, 2008 1:03 PM writes...

"If we place the drying oven next to the lab refrigerator, do you think anyone will put the n-butyllithium in the wrong place?"

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15. Chrispy on July 28, 2008 2:27 PM writes...


"That FDA decision/trial data/expiring patent will mean we sell a lot less of our drug. I wonder how we'll make up the difference?"

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16. Anonymous on July 28, 2008 2:47 PM writes...

How about:

"Do you think anyone will have emptied the solvent waste on the HPLC?"

or

"The clogP of my compound is 5.2, I wonder how soluble it will be?"

and

"This must be a mistake, none of my colleagues would take the last one and leave the empty box behind - would they?"

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17. Hap on July 28, 2008 3:44 PM writes...

What is the (in)correct answer for #2, anyway? I would have figured if it simply failed, they would have told you, right? If figured you would have heard if the tox labs had to be decontaminated, or something similar.

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18. Athabascan Ranger on July 28, 2008 3:59 PM writes...

How about:

‘are you certain those dead animals in the mid and high dose groups are due to drug administration?’

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19. psi*psi on July 28, 2008 4:13 PM writes...

LMAO at #14! My lab DOES have a small refrigerator next to the oven. Can't count the many times I nearly placed NMR tubes in the fridge or solutions for crystal growth in the oven, though I've never actually been distracted enough to miss catching the mistake.

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20. RTW on July 28, 2008 4:36 PM writes...

Hap - Having been accused of being a Troll - I assure you I am a Yooper and only live below the bridge because thats where the jobs are.

Maybe you can figure that one out.

But no I don't troll around here to attempt to get a rise out of people. I was truly a 20 year veteran of the industry that enjoyed what I was doing. That is until that last 5 years. I actually thought what I did made a difference until then. My often caustic remarks have much to do with scientific observation. I am afterall trained to be observant and so are a lot of the other folks here I presume.

And daen - sounds like you are in cheminformatics now? I feel for you a great deal because thats where I have landed.

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21. Hap on July 28, 2008 5:00 PM writes...

#20: Huh? I was thinking of Srikanth, or the "Actual Chemist" bitching about Derek's competence, as the canonical trolls here. I assure that I wasn't thinking of you with #9.

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22. NJBiologist on July 28, 2008 9:08 PM writes...

"Is this stuff soluble in anything that *won't* make the rats scream bloody murder when we dose it?"

---

@20: Since when do they allow snowmobiles on the bridge? Everybody knows that Yoopers can't get around without them....

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23. Don B. on July 29, 2008 7:07 AM writes...

No results from pharmacology on compound # 9 in a month. ergo it must be active so start making analogs!

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24. DrSnowboard on July 29, 2008 7:21 AM writes...

"What's the activity of the NH2 precursor to this library plate of compounds? Are you sure you got rid of it all...?"

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25. enzgrrl on July 29, 2008 10:00 AM writes...

"Just how pure is this enzyme, anyway? I got it from Sigma..."

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26. vasili on July 29, 2008 3:48 PM writes...

CMC guy:
“Who’s going to scale up our candidate compound, anyway? We need 300 grams of the stuff, and the scale-up group is booked solid. . .”

This is the 10% yield crappy route you medchems used to make 100 mg from a 1000€ 5g starting material, using MW, purified via chiral HPLC and you want 300g of product in 2 weeks >97% purity??.
Let me think...

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27. Jose on July 29, 2008 5:04 PM writes...

"Your ordered from Strem and not Aldrich, right??"

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28. CMC guy on July 29, 2008 5:28 PM writes...

#26 vasili although appreciate your elaboration, having been there-done that many times, I would not wish to sound overly critical of the medchemists (although if can't tease them some life would be less fun). Their mission is to make that 100 mg and likely numerous other analogs under similar oppressive timelines too (agree would be nice if the best candidate was not from the most expensive/hardest to source starting materials but Murphy's law often enforced). They try to make sense out all the bio/assay data that rarely follow straight lines. As the original question implies if the compound has promise the medchemist frequently get the unpleasant task of banging out more ASAP so can continue evaluation. Until they are successful not much of a role for all the downstream people.

We also are exercising exaggeration here I think. I have only been involved in a couple projects that required more than about 120g to run complete pre-IND studies and the ones that needed more used larger animals (dogs) that consumed several gms/animal. Usually could step up gradually and do 30-50g scales on bench with easy patches then consolidate/crystallize to single batch. I will add if you do actually need 300g likely should consider some pretty quick process smoothing just to make manageable (i.e. based on lab notebook calc 100 Gal of solvent for this one reaction?).

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29. Norepi on July 29, 2008 6:50 PM writes...

#20-Howdy, from one Yooper to another.

"Are you sure these two assays are actually part of the same project?"

and from the synthesis side:

"Did they really have to recrystallize it from carbon tetrachloride?!?

"Just how old is this bottle of [insert feisty organometallic reagnet here] anyway? D'ya think it's still good?"

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30. toxicologist on July 30, 2008 2:43 AM writes...

"We've changed the synthesis route and we don't know what the impurities will be in the final material; that won't affect the currently running 2-year rat study, will it?"

"Has anyone told you yet about the [insert tox study here] results yet?"

"Didn't an analog of this compound just have registration denied?"

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