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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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July 29, 2004

Down in the Salt Mine

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Posted by Derek

As I mentioned yesterday, I've been spending the last couple of days working on salt forms of one of our compounds. Even folks who slept through one semester of general chemistry may remember that an acid plus a base gives you a salt, which is just what I've been doing. Most of the compounds we work with have a basic nitrogen atom in them somewhere - medicinal chemistry would grind to a halt without basic nitrogens - so to form a salt you add an equivalent amount of some acid.

Once or twice in my career I've batted from the other side of the plate, working with acidic compounds and making a salt by adding a base. There are some therapeutic targets where only acidic compounds seem to work, but I haven't spent as much time on those. Actually, acidic compounds aren't as much trouble. They seem to behave a little better in their original form than the strongly basic ones do, partly because they're not suddenly being jerked over to the other end of the pH scale when they hit the stomach, and partly because they can deal with a whole different set of uptake and transport systems.

The reason you go to all this salt trouble is because the salts are often easier to dissolve and dose than the free bases. Often the situation is even worse than that: the free base is nearly impossible to dose, and a salt form is your only way out. There are a limited number of things you can dissolve your compound in if you're giving it to a mouse or rat every day. (The rats are a bit more resilient, as a rule.) Water would be ideal, but I'm not sure if I've made half a dozen things in the last fifteen years that would just dissolve in straight water.

A common (and reasonably innocuous) additive is polyethylene glycol, known in the trade just as "peg." (I often come away from formulation discussion humming Steely Dan.) I'm trying to get these compounds into half-and-half PEG/water, and anything will be an improvement over the lumpy-gravy suspensions that we're getting now. Suspensions aren't bad per se: a good one, which has the pearly look of an opaque shampoo, is a fine dosing method. But they're not all created equal, and they're harder to generate reproducibly. The problem with dosing the oatmealy ones is that they give you lower blood levels than you expect for a given amount of compound, and the levels tend to vary along with the (unreproducible) size of the lumps. The experiments are nearly worthless.

So what sorts of acids do we use? The most popular is good ol' hydrochloric. At least half the pharmaceutical salts on the market are HCl-derived. Then there are salts from organic acids (maleate, citrate, fumarate, gluconate), other mineral acids (sulfate, phosphate), and some mixed breeds like methanesulfonate. Those probably cover 95% of what's out there.

The ideal salt is stable, powdery, free-flowing, and doesn't turn into a goo by soaking up water from the air. You find that elegant substance in the least elegant way possible, because there is absolutely no way to tell which of these is going to be the best. There are some rank-order decision tree charts that people use, but they're departed from as often as they're honored. My chosen field, once you get the gift wrap off of it, is about as empirical as they come.

Comments (2) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. John J. Coupal on July 31, 2004 12:10 PM writes...

Your comments about drug suspensions not being bad per se brings something to mind. Motrin oral suspension for kids contains no alcohol, but contains cornstarch as a suspending agent for the ibuprofen. It has the pearly look of an opaque shampoo, that you describe. Our daughter had been giving several doses to our grandson for fever. I asked her if she had inverted the bottle several times before doling out the dose. She said, no. The labeling states: "shake well before using". Of course, that's ridiculous advice because of resulting air bubbles forming in the dose, reducing the drug dose and possibly degrading the drug. FDA approves such nonsense in patient labeling, because it's a well-worn phrase. But, wrong. The public - probably correctly - thinks that any liquid in a bottle is a true solution, because no-one tells them that it may not be.

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2. Rich Younger on August 3, 2004 12:24 PM writes...

I had been wondering why lots of boxes say " x mg of drug name as x+y mg of drug name hydrochloride". Now I know.

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