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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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October 27, 2011

Fish Nor Fowl

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Posted by Derek

Talking about hydrogenation here the other day brought up another thought: there's a point where lab work becomes quite difficult, and there are not a lot of good options to help with that. I'm talking about scale-up work, the grey zone between benchtop synthesis and production.

The first of those is where I spend my time. I've often said that there are really only two yields to be calculated in medicinal chemistry: enough and not enough. For some cases, "enough" can be two milligrams, if all you need is one assay (although you're not adding to the screening collection that way). Twenty is plenty for a new compound; it'll be in stock for years at the usual rates of screening.

But later on, when you start to get interested in a particular molecule, those numbers inflate quickly. In vivo tests, PK, toxicology - all these can start to chew up much larger amounts of compound. Hundreds of mgs, then grams, tens of grams, hundreds of grams to get through preclinical because it turns out that you need another large-animal run - those of you in the labs will be familiar with the progression. And well downstream of people like me, there's pilot plant work and real commercial production, where things are measured in kilos and up.

Those folks have a tricky job, but they have one advantage: they know what compound they're making, and eventually they've settled on a route that works. (If you can't do that, well, you don't have a drug). And for a real money-making compound, it's worth investing in dedicated equipment, whole dedicated facilities if need be, just to make it correctly. Earlier in the process, though, you have to be ready for all kinds of chemistries to make all kinds of compounds.

The medium-scale is where those two worlds collide. A medicinal chemist can generally make things up to the tens of grams, maybe a hundred or two, using roughly the same techniques that are used on the smaller scale: round-bottom flasks, suction filtration, magnetic stirring, standard-sized rotary evaporators, silica gel columns. Everything gets bigger and more unwieldy, and it always takes more time (and more solvent) than you thought, but it can get done. Some of the more exotic small-scale chemistries do start to break down on you, which also also adds to the time needed when you have to come up with alternatives.

But if you're always having to work on roughly the hundred-gram scale, you're straddling two regimes. The size of the glassware gets hard to manage - things are heavy, they tip over, they crack - and you really have to have more serious capacity for things like solvent evaporation. But this is way too small for industrial-plant equipment, the kind of thing where you design the process to start on the third floor to take advantage of gravity as you pump the contents of the big batch reactor downstairs for the next step. And it's getting too big for scaled-up versions of standard equipment, but at the same time, you need the versatility that general-purpose labware provides.

Some kinds of gear help to bridge this gap - overhead mechanical stirrers, outboard circulating chillers, and large-capacity rota-vaps come to mind. But there are many other cases where something that's neither benchtop nor pilot plant is needed, and doesn't necessarily exist. Hydrogenation is a case in point. It's done on an industrial scale; that's where all that partially hydrogenated vegetable oil comes from, for one thing. And hydrogenation is common on the gram scale or below. But hydrogenating three hundred grams of something can be a real pain in many labs. The common solution is roll-your-eyes-and-split-it-into-batches, but that gets old fast. . .

Comments (22) + TrackBacks (0) | Category: Life in the Drug Labs


1. InfMP on October 27, 2011 8:33 AM writes...

WuXi loves running batches. Send it to them.

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2. simpl on October 27, 2011 8:56 AM writes...

They are also the people who optimise costs. Less a new synthesis, but merging steps, finding better reagents, finding a separation. They save us a lot of money in production.

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3. Ed on October 27, 2011 9:05 AM writes...

On PK/Tox scale you also have to factor in for the dummies in those groups spilling, misformulating and miscalculating quantities of your lovingly prepared sample.

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4. API on October 27, 2011 9:09 AM writes...

Cut out the chromatography

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5. DLIB on October 27, 2011 10:16 AM writes...

invent it!!! It makes me sad to see the people in pharma so spoon-fed these days. You'll take what tools are available and suck it up...

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6. Biotechtranslated on October 27, 2011 10:25 AM writes...

Prior to going back to school, process chemistry is what I used to do.

We had quite a few options for scaling up hydrogenations. We had Buchi hydrogenators, 1 to 2 L in capacity that worked quite well, although you were limited in terms of pressures (a few hundred psi?).

After that, we had hydrogenators that had volumes ranging from 5 to 30L. These were installed units with much higher pressure ratings (up to 1000 psi) and had dedicated operating staff. We did multi-kilo hydrogenations in these quite routinely.

Of course, with the site closures that my company did most of these facilities are gone now, but for a brief while, it was pretty dam easy to scale up hydrogenations.


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7. Chemjobber on October 27, 2011 10:26 AM writes...

But hydrogenating three hundred grams of something can be a real pain in many labs.

I've seen this, but never been involved in it, thank goodness. The hydrogenator sizes start getting bigger and bigger (and harder and harder to roll around on carts, etc.)

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8. See Arr Oh on October 27, 2011 10:29 AM writes...

@Derek - As one of the "medium-scale" chemists you've mentioned, I can tell you that even that space has an upper and lower range. 100 g of a standard med-chem reaction (reductive amination, alkylation, Pd-coupling, etc) can still be accomplished fairly readily using 2-5L flasks, slightly larger joints (29/32 - 45/50) and cooling baths.

Honestly, it's 1-5 kilos where synthesis becomes dodgy. You're still too small for steel-lined multi-gallon reactors, but way too big for standard hoods. We traditionally perform these reactions in multiliter reactors in walk-in hoods, but timelines get tough to predict. For one, just charging reagents into reactors or large-scale hydrogenators can take a few hours. Add to that your friendly exotherms - reactions on this scale tend to provide their own heat - and the fact that you have to use car-sized lab jacks and reactor frames to move everything around, and it becomes a full day of just setting up and maintaining a reaction.

Add to this the complexities of shipping "medium" sizes of chemicals (1-25 kg, often can't be sent next day or by air), and the physical constraints of the chemistry (usually have to be able to lift 40+ lbs and be flexible enough to work with the larger glassware) and it becomes a completely different working experience.

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9. agogmagog on October 27, 2011 10:46 AM writes...

This is where I work. Currently about half way through the synthesis of 1.6kg of prostaglandin X. Broken into 4 batches of ~400g. Fourteen steps including a lithiation, DIBAL reduction, Hydrogentation and two (count 'em) chromatography steps. All under bloody GMP. This is our fourth campaign.
Reactors, 5, 10 and 20L RBF's, storage vessels 5, 10 and 15L duran bottles. 20L rotovaps.
Chemists have to be strong. Chemists have to be careful. Things are big enough to be very dangerous, but small enough to be close and personal.

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10. Chemjobber on October 27, 2011 10:56 AM writes...

Chemists have to be strong. Chemists have to be careful. Things are big enough to be very dangerous, but small enough to be close and personal.

God, this is so true.

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11. really? on October 27, 2011 11:07 AM writes...

R&D groups that are working in high volume industries routinely do things at the 200-500g scale. A 300 g hydrogenation in my lab is routine. We use an autoclave, a 1,2 or 4L depending on the conditions needed. Solvent evaporation? We distill under vacuum, not via rotavop mind you…. Good old fashioned bulb to bulb.

It is amazing the types of chemistry and techniques that are available in the not-fancy world of commodity chemicals.

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12. MTK on October 27, 2011 11:25 AM writes...

@9 and 10,

I'll agree with the careful part, but the strong part? No. If you need brute strength to run a reaction than you've got a problem. That is not being careful. It's an accident waiting to happen.

Ask for and get the proper equipment to help you do the job safely.

"Hey, let's be careful out there"

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13. Chemjobber on October 27, 2011 11:31 AM writes...

"Hey, let's be careful out there"

Thanks, sarge (in all sincerity).

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14. coprolite on October 27, 2011 11:36 AM writes...

Enough, not enough, and cheez-wiz

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15. SP on October 27, 2011 11:43 AM writes...

I'd say 2 mg is plenty to put into an HTS deck- @500 MW, that's 400 uL of 10 mM stock, a set of screening plates for 6 months will use 50 uL of that, figure 20 uL each time you cherry pick- that's a couple years of HTS. Minus whatever you needed for the original assay- if that's also in 384 or 1536 it's the equivalent of a cherry pick.

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16. okemist on October 27, 2011 11:45 AM writes...

I used to run the H2 room at Derek's last place, and the large shaker had a 2.5 L bottle. We could fit almost 2 L of reaction solution into it. After that i had no problem running reactions with bubbling hydrogen right into a reaction without pressure, and currently do this on 8 kg in a 100 L Buchi.

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17. AlChemie on October 27, 2011 1:00 PM writes...

BTDT subsurface works and transfer hydrog. sometimes slurry works, last place I was at, if over 1g, time for process to take over, it was too hard was the reason

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18. processchemist on October 27, 2011 3:19 PM writes...

I've spent most of my time between classic bench operations, kilo scale operations (10-22 l flasks, 20-100 l glass reactors) and small pilot plants. Mid scale hydrogenations are a pain where sun does not shine. Hydrogenators in the range from 10 to 50 l are not common (and not cheap, at all). And laws and safety guidelines can be tricky, in my country. I usually explore the possibility of hydrogen transfer, for reactions with a possible projection of a future 20-50 l scale, but obviously this option can be excluded by regulatory constraints (an INDA filed with a standard hydrogenation in the description of the process can be one).

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19. bcpmoon on October 28, 2011 2:05 AM writes...

I used to work a company like agogmagog above, reactors 10-160L / 630L with suitable downstream work-up units. Add some 1-5 / 50L autoclaves and you´re there. I really liked the Buchi glassware autoclaves / reactors, you can see what happens which gives you a heads-up on many problems. (PARR systems are also nice but were mostly SS then)
Nowadays I am more upscale (16 cbm), but for development we can use a small (50L) development lab, enough for most purposes.
May I also recommend a good cat screening? If you are depending on 40bar you severely limit your options. (And don´t forget to clean up your starting material. Really.)

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20. petros on October 28, 2011 7:59 AM writes...

I remember when we had to scale up the prep of our candidate for early tox because insufficient capacity was available in the WDF's development labs.

Step 2 of the prep was a Rosemund reduction, and the product had a tendency to polymerise.

It also involved running the same Wittig reaction ca.50 times to try and find conditions that gave >90%Z product.

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21. A Nonny Mouse on October 28, 2011 5:06 PM writes...

Just completed the 100g synthesis of a ferrocene containing drug (Google it).

First attempt from 100g SM, 6 weeks and 15g (it was only documented on 50mg scale with lots of columns)

Second attempt 40g and 4 weeks.

Third attempt, with everything that had been learned, 75g and 3 days.

Like everything else, it's a matter of a learning curve with scale up, especially when taking an undeveloped literature procedure.

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22. Tyrosine on October 30, 2011 12:24 AM writes...

Timelines are often what makes this mid-scale tough. We were handed an unoptimised 14 step, 8% overall, synthesis with lots of chromatography (the chemists notes actually read "careful chromatography is necessary or the next step fails" ! *groan*). The request was for 150 grams in three months. Not enough time to reinvent and test a new process unless we are lucky, but grinding through the bench synthesis on scale will be a nightmare.

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