Hang around any drug discovery organization and you’ll hear complaints about how the drug candidates don’t dissolve well. The people who test the compounds on cells and proteins complain a bit about this, and the ones who test on mice and rats complain even more. Traditionally, the problem eventually lands on the lab benches of the people who work out formulations, who complain that by the time it gets to them that there’s only so much than can be done. So over the years, it’s become more of a concern for the chemists who make the things in the first place, as I guess it should.
Solubility isn’t the single most important factor in making drug candidates, but you can’t ignore it, either. Having a drug that dissolves well frees you up during development. Whenever you get low or variable blood levels while testing a new compound in animals, you always wonder if the compound was dissolving in the gut properly. If the answer is already known to be “Yes”, then you can concentrate on the other potential problems. (That said, solubility doesn’t correlate with good blood levels as well as you might imagine, because of those other factors. Awful solubility correlates pretty well with awful blood levels, though).
There are other virtues: a soluble compound is also a lot easier to dose i.v., which is a valuable stage in figuring out how it’s being distributed in whole animals. And getting into the clinic is hard enough without having to worry about how you’re going to dose the first human volunteers, and whether a temporary fix for the problem (a “service formulation”) will provide relevant data or hold up at all as you go on into Phase II. There are, to be sure, some valuable drugs with absolutely horrible solubility problems (taxol comes immediately to mind), but you'd rather not find yourself competing with it for the title.
But solubility, as a word, conceals several different behaviors. It comes down to how much the compound likes to associate with itself versus how much it likes to associate with solvent. Those two values can vary pretty independently, and you get different situations as they slide up and down. In the case of a drug formulation, that solvent is going to be as watery as feasible, so here’s how things break down:
Low self-affinity and low aqueous affinity: the first value will give you an oil or a low-melting solid, and the second will give you trouble going into solution. We try to avoid this category if possible, although you can always formuate as some sort of oil-filled gel cap if you’re really up for it, as with Vitamin E.
Lower self-affinity and higher aqueous affinity: Depending on the absolute values here, this could be low-melting again. But this time it’ll hop right into water, because it’s actually happier there than it is in its own crystal form. Formulation should be a breeze, but the problem with these guys is that they’ll soak water right out of the air and turn into goo if you don’t watch out.
High self-affinity and lower aqueous affinity: here’s where you run into trouble, and here, unfortunately, is where a lot of med-chem drug candidates land. The first value will give you a high melting point – the crystal’s very happy the way it is, thanks, and would rather not give up its structure. And water has a hard time competing. This is where the formulations people really get a workout – in a future post we’ll talk about some of the tricks used in this situation. Sometimes the chemists can fix things by making one part of the molecule lumpier – literally – so that the structure doesn’t pack so well into a crystal form.
High self-affinity and high aqueous affinity: depending on the absolute values again, this could be tricky. There are some high-melting solids that dissolve in water just fine: ionic substances like table salt make great crystals, but their interactions with water are even more favorable. But you can also end up with a compound that will stay in water, but has trouble going into water. Once the molecules are surrounded by water, they’re happy, but those first few water molecules have a tough time pulling each drug molecule out of the crystal surface. If you grind one of these guys up really fine and stir it for three days, you’ll probably get a reasonable solution, but at first glance you’d take it for a compound from the previous class. All the more reason to make sure you're at equilibrium before drawing any conclusions.
So that’s a quick look at solubility, and a quick look at the range that a medicinal chemist has to think about: from picturing molecules stacking one by one into a crystal, to picturing a drug candidate gumming up a syringe held by a muttering, red-faced pharmacologist.