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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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« The Life of a Paper | Main | Snow and Chance Happeneth To Them All »

January 12, 2011

Gassing Your Crystals

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Posted by Derek

Now, this is a pretty neat trick. One of the things that drug development people have to worry about a lot is the crystal forms of the new compound. You might imagine (if you haven't had to do this stuff) that if a compound is crystalline, then that's that - you've got the solid form now, and full speed ahead.

But many substances can crystallize in all sorts of forms - here's one with at least seven different solved crystal structures (and it has more that haven't yielded an X-ray structure yet). By the time you bring in solvates, where the molecule crystallizes along with the solvent it was last in, or with water dragged in from the air, or what have you, you can go well up into the double digits, and we haven't even begun talking about salt forms yet. Each one of those starts the whole counter running all over again. These polymorphs have different melting points, different rates of dissolution, and different behavior when they hit the stomach, and these are all things that you have to worry about.

There have been several real holdups in the drug industry, where a compound that had been developed as one form suddenly decided that it would rather be another one when the chemistry was scaled up. That blows out all the blood levels and dosing protocols that were worked out before. Sometimes the new form can be used, once all the data are re-acquired, but sometimes it turns out to be unusably worse than the old form. The challenge then is: how do you get it to be one rather than the other? And how can you be sure that it'll happen every time?

So we're always interested in ways to make molecules take on different crystal forms, and in ways to make them switch from one to another. That's where this latest paper comes in. They've found that you can expose solvated crystals to pressurized carbon dioxide gas and alter the crystalline forms. The gas molecules work their way into the crystal lattice, displace the solvate molecules, and then when the pressure is taken off, they work their way back out again (or can be persuaded to with a little heat). It's an ingenious idea, and you can bet that development scientists all over the industry have saved copies of this paper already. We need all the help we can get!

Comments (17) + TrackBacks (0) | Category: Drug Development


1. anchor on January 12, 2011 12:15 PM writes...

Derek: Is there is any scientific find that you know out in the literature, suggesting different poly-morphs with different efficacy?

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2. processchemist on January 12, 2011 12:22 PM writes...

Interesting paper. A lot of work to do to explore the real utility and industrial applicability of this trick. They're using "fixed bed" apparatus of 15 ml and obtain notable results with 500 psi of CO2. They noticed some behaviours related to particle size, but they don't quantify it (no psd analysis of the samples) - quite obvious, because this is an eterogeneous reaction. I'm curious to see some prices of dryers rated for 500 psi... Since when you talk about prevacid it's only a cost issue, I suspect that the current process is the most economically viable route, but in the last two years some polymorphs I worked on were needing totally original approches, so...

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3. MattW on January 12, 2011 12:43 PM writes...

No snow day Derek? Open for work @ hyaluron-amri in Burlington

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4. A Nonny Mouse on January 12, 2011 1:09 PM writes...


There is the "famous" incident of the Abbott anti-HIV (can't remember the name at the moment) which changed forms in the formulation they were using so that it lost its efficacy. It was withdrawn for quite some time until they sorted the problem.

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5. Bluto Blutarsky on January 12, 2011 1:24 PM writes...

@4 - A Nonny Mouse

The Abbott compound in question is Ritonavir. The Abbott team involved in understanding and fixing this issue published two papers on the formation of the new polymorph which began appearing soon after launch of the drug. Crystallization of a new form appeared in the formulated product. For more info, please see the following:

The latter paper identified that the API possesses conformational polymorphism and suggests that the crystallization of the new, less soluble form was promoted by a degradation product in the process.

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6. barry on January 12, 2011 1:31 PM writes...

the most famous (and best-studied) case of polymorphism affecting dissolution rate, solubility and system exposure to an oral dose was ritonavir

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7. Pharmaheretic on January 12, 2011 2:08 PM writes...

The full MMR-Autism Scam Article. Read about the role of pharma in promoting that scam.
BMJ 2011; 342:c5258 doi: 10.1136/bmj.c5258(Published 11 January 2011)

..To facilitate negotiations, letters and draft contracts went back and forth to the Royal Free. A principal document was finished in the autumn of 1999, naming Wakefield, Pounder, Carmel, Immunospecifics Biotechnologies (IB Ltd), the medical school, Freemedic, an American foundation called Neuro Immuno Therapeutics, and its head, Hugh Fudenberg, an immunologist...

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8. MiseryChemist on January 12, 2011 2:36 PM writes...

Back in my earlier years when I worked at Pfizer, there was one of their high profile compounds (now on the market) that was approaching 150 known XRPD patterns. Granted many were various mixtures of previously discovered polymorphs and/or solvates from different solvents, but as Derek said, this is no easy matter.

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9. Jeffrey Soreff on January 12, 2011 8:12 PM writes...

Let me apologize in advance for the dumb comment:
Why isn't it possible to use an amorphous solid
solution? Perhaps a mix of mono or disaccharides in
the case of sufficiently polar medications? There
are plenty of mixtures which are infamously hard to
crystallize. I would have thought there should be
a wide enough range of potential solid solutions
to find a glassy solid solution for most medications?
Why doesn't this work?

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10. OldLabRat on January 13, 2011 8:54 AM writes...

@ 9
Not a dumb idea at all. This is done for high value compounds that usually have low solubility. However, the issues are very much the same as with polymorphs: different matrixes and drug particle sizes still affect absorption rates, etc. One company of which I'm aware that works in this area is Bend Research; there are likely others.

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11. Jeffrey Soreff on January 13, 2011 9:31 AM writes...

Many Thanks!

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12. Anonymous on January 13, 2011 10:50 AM writes...

I've never seen the particular type of ball and stick structure shown in the New Polymorphs of ROY paper. Are the atoms modeled that way for a reason?

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13. barry on January 13, 2011 1:20 PM writes...

re #9:

any time you dose an amorphous solid, you worry about reproducibility. If the material dissolves in the gut but then sometimes crystallizes, the bioavailability will be much reduced in those individuals.
If crystallization in the gut is impeded by an excipient, you may still get crystallization in the kidney (as with the sulfa drugs)

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14. Bored on January 13, 2011 10:35 PM writes...

#13 Barry
You inspired the following Haiku:

Amorphous solid
Now crystal in my stomach
So much for working.

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15. simpl on January 14, 2011 11:49 AM writes...

@ anchor: see for example It is so common that I'd guess all the large firms have seen it in research and in development. The main worry is that different solubility can affect absorption in the body.
@ barry: I recall that early studies with ciclosporin were done in cognac to get around the low solubility. It was later found to crystallise out in the gut, and formulations switched to more mundane fat solubilisers.

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16. GladToMoveToProcess on January 15, 2011 7:51 AM writes...

@13: We had a compound that was active (dogs) with the first oral dose, but nearly inactive on later doses unless quite some time passed. Bottom line was the stuff was protonated in the stomach, but some of the poorly soluble free base precipitated in the gut. That provided seed crystals for the next dose, when nearly all would crystallize. Ended up going to a prodrug that avoided this problem.

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17. anonymous on October 22, 2014 11:41 AM writes...

#12, it's an ORTEP type figure, they're common for displaying X-ray crystal structures. It includes some information about thermal motion/uncertainty in atomic positions.

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