Gassing your crystals

Gassing Your Crystals

By Derek Lowe 12 January, 2011

“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!”

https://pubs.acs.org/doi/abs/10.1021/ja107617m

A New Strategy of Transforming Pharmaceutical Crystal Forms

The robust nature of network materials allows them to (for example) respond to external stimuli such as pressure, temperature, light, or gas/solvent adsorption and desorption. There is difficulty in retaining long-range order in purely molecular organic solids, due to weak intermolecular interactions such as van der Waals forces. Here, we show gas-induced transformations of the well-known pharmaceuticals clarithromycin and lansoprazole. For clarithromycin, the stimulus is capable of converting the kinetic solvate and guest-free crystal forms to the commercial thermodynamically stable polymorph with a huge saving in energy cost relative to industrially employed methods. The synthesis of the marketing form of lansoprazole involves a solvate that readily decomposes and that is stirred in water, filtered, and dried intensively. Our method readily circumvents such synthetic problems and transforms the sensitive solvate to the marketed drug substance with ease. Such expedient transformations hold great implications for the pharmaceutical industry in general when considering the ease of transformation and mild conditions employed.

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This reminds me of vapor diffusion anti-solvent method of crystallization. What if you were to steam out ethanol from a high-THCa solution, for example? CO2 sounds like more fun and the pressure changes could obviously be way more drastic. Super nice find.

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THCA crashes so easy from butane extracts there’s no need for any other method, imo.

However for slippery cannabinoids likes CBN I think it could be very helpful

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Choice of solvents would affect the crystal formations. My implication is with purity, I guess.

The idea here is that additional gasses(not the solvent) will affect crystal morphology? That will play somewhat into purity but the main thing it seems useful for is find new stable crystal forms

Crystal morphologies are patentable even if the the compound itself is public knowledge

Moreso that the solvent will affect morphology. The anti-solvent is just there for miscibility and THCa’s lack of solubility - though it probably plays at least some role.

Regardless - more interesting than the patentability is how human delivery may be affected.

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We can use the recrystallization solvent as a major variable to influence the crystal habit. If we can influence a more polar crystal morphology that would make the isolate harder to dissolve in non polar solvents, which could be beneficial if you wanted to rinse your isolate with an alkane.

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Yes solvents, antisolvents, water in the air, etc affect morphology. This is specifically referring to gasses themselves can affect lattice structures and growth rates.

Utilizing CO2 for crystallization reactions can speed up the process to take hours instead of days, but this method is utilizing gaseous CO2. The real magic happens with CO2 in it’s liquid form. It’s a beautiful concept because as you said there is little to no work when removing the CO2 from your crystals.

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Seems there could be potential to end up with CBD “pop-rocks” ?

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The process is not the same as CO2 extraction, but is more in line with commonly known crystallization reactions; saturate, hold, crash. The “popping” is contained in the same fashion that the solvent is held. This one “melts in the container, not in your hand”.