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November 17, 2002
New! Improved! Now With Stickier Lumps!
An evergreen struggle inside a drug research company goes on between the chemists and the people who have to formulate their compounds. (By "formulate," for those outside the business, I mean "put them into something that'll allow them to be reproducibly given to animals." This can be a pill, but in research it's more typically a liquid dose of some sort.) Sometimes the chemists deal with the same biology-side lab that doses the animals, sometimes with a separate formulations group - but the interaction doesn't change much.
"Stop giving us these insoluble gumballs!"
"Well, stop trying to make everything go into water! It's an organic compound, y'know."
"Water? What's that? We haven't been able to take anything up in water around here since 1982! We're lucky if your stuff goes into boiling DMSO!"
"That wouldn't be much worse than that last vehicle you came up with - remember, that brew that killed the entire control group? You might as well have used drain cleaner."
"Hah! Even drain cleaner wouldn't dissolve that brick dust you guys keep turning out."
And so on. . .I've had quite a few conversations like this, mostly in fun. But it's not always that we chemists make a compound that the formulations people can live with, that's for sure. In the best possible case, your compound just goes into solution. Solutions are reproducible; something's either dissolved or it's not. A solution in plain water would be ideal, but nothing in the projects I've worked on has ever done that, or even come reasonably close. More often, there's something more organic-compound-friendly like polyethylene glycol (PEG) in there with the water. You can half-and-half those just fine for most animals, and a lot of compounds will stay in solution that way.
As folks get more and more desperate, there are additives that can help to keep a compound from crashing out. Various detergents, polysaccharides, and long-chain goos are out there, and finding the right gemisch is like working on a bake-off recipe. Some of these extras aren't tolerated well in specific animal models, though, so there are always constraints. And if you're dosing intravenously rather than orally (which at some point all projects need to do, to get some crucial data,) then the list of acceptable vehicles shortens dramatically.
The next stop for the difficult ones is a suspension. (This is only an oral dosing problem, of course: injecting a suspension into a vein is a reliable way to kill an animal, or a person.) These formulations get trickier to work with, because suspensions come in all sort of guises: from pearly stuff that looks like shampoo to things that look like chicken noodle soup, complete with the noodles. The best way to handle these things is find something that your compound will dissolve in, then add a defined amount of water to crash it out. That gives you the best shot at getting the same thing every time, although you have to be careful to add things in the right order, with similar stirring technique, and so on.
Starting from a powder and suspending that in some vehicle is much more troublesome. Particle size can vary widely between batches, unless you're being picky about it (which at the early research stage of things we rarely are.) You could even have made totally different solid forms of the compound in different batches, which phenomenon (polymorphism) can really induce migraines. And the time one of these suspensions sits around can really affect its behavior, as the particles start to dissolve a bit around the edges and re-precipitate, or clump together and drift down to the bottom of the vial.
If your compound works well when dosed as a suspension, though, you're still in better shape in the long term. That's a better predictor of how it'll behave as a pill or tablet (which are, after all, lumps of finely milled powder.) On the other hand, if your compound works when given as a solution but not as a suspension, then you have some serious problems that you'd better start worrying about.
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