If you’re a chemist, then you like crystallization. I think that’s pretty much a given; I’ve never met anyone who doesn’t appreciate a good crystal, and watching them form out of a solution never stops feeling a bit like magic. When I was doing a project involving metal-organic frameworks, I had some of the best fun I’ve ever had in the lab making new crystals all the time (and some of the more frustrating times I’ve had while trying to get them to do what I wanted to do afterwards, but that’s another story!)
And of course, many small-molecule pharmaceuticals are produced in some sort of crystalline form, not least because that both helps to purify them and puts them into a defined physical state that we can trust for further formulations. When that solid state changes and a different polymorph forms, chaos can ensue (see the links in that post, and there are plenty more stories besides). One would imagine, since we’ve been crystallizing things for several centuries by now, and since the process is behind the production of hugely important drugs and other substances, that we would have a decent idea of how it happens.
We do not. That link above goes into some of the details, and it’ll show you how tricky the whole process can be when it comes to polymorphs. And even when we’re just talking about one good ol’ crystalline form, the exact process by which those individual molecules come together in solution and start to form orderly lattices is still a matter for hand-waving. This new paper has some details on a molecule that gets crystallized from solution rather often and on a rather large scale: ibuprofen. And the fact that we’re still learning how ibuprofen becomes a solid will tell you all you need to know about where the state of the art is.
As has been seen with some molecules (and often suspected in many more), ibuprofen turns out to go through an interesting liquid-liquid phase separation on the way to becoming a solid. This is “spinodal decomposition“, known to organic chemists as “oiling out” when it happens on a larger scale. You’ll have a solution of some compound, and if you start to adjust the conditions (temperature, salt concentration, addition of another solvent, etc.) you’ll hit a point where suddenly things become cloudy, and that’s usually followed by droplets of a second liquid phase visibly separating as the microscale droplets (which caused the cloudiness) coalesce.
In this work, NMR methods are used to probe the composition of that ibuprofen-rich liquid phase. Molecular dynamics (translational motion and rotation) are slowed compared to the solution phase, which is denser and much more viscous. Intermolecule NOE signals start to show up, indicating close molecular proximity between the ibuprofen molecules that doesn’t exist in the starting solution. In fact, the liquid phase seems to have the molecules about as tightly packed as they are in solid crystalline ibuprofen – they’re just not ordered into a regular lattice, or not yet. This appears to be the first time that anyone’s been able to get such measurements, actually.
It is, in fact, that concentration and reduced motion that allows the crystals to start forming. They don’t nucleate out as tiny solid particles from the initial bulk phase (although this has been demonstrated with other compounds under other conditions). The liquid phase separation is the key, and it’s interesting that there are compounds that can do this without those microdroplets coalescing into a separate oily phase before that crystallization can kick in, and I’m not sure how that works. Perhaps the surfaces of the droplets develop some sort of charge distribution that keeps them from coming together so easily?
The question this paper raises is whether we can exploit this sort of behavior to make new liquid-phase formulations of such drugs, things that are nearly as concentrated as crystals but don’t need to break up a thermodynamically favorable 3D lattice in order to dissolve. Could you really make a gel-cap full of a metastable liquid phase like this (without worrying that they will suddenly solidify into pellets in the bottle?) No one can say it’s impossible, that’s for sure. We just don’t know enough either way!