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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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« Fakery And Its Ends | Main | Hits, Misses, and Some More Misses »

March 7, 2008

Dissolve Your Troubles Away

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Posted by Derek

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.

Comments (17) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. John Johnson on March 7, 2008 10:33 AM writes...

The moral of the story: drug discovery is tricky no matter what solution you come up with.

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2. Analytical Scientist on March 7, 2008 10:38 AM writes...

If you can get solubility without compromising intestinal permeability, though, that's really the brass ring. BCS class I compounds tend to be a joy to develop and their success rates through to market are markedly higher than for other compounds according to retrospective analyses done at several big pharma companies.

The flip side of this is that high intestinal permeability is often the saving grace of some of those marginal solubility compounds that you mention above. If the compound is a greaseball or brick dust without the corresponding virtue of permeability...well, hope is dim for these compounds.

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3. Formulation Sci on March 7, 2008 11:32 AM writes...

A lot of the solubility or lack of solubility of drug molecules may begin with HTS methods used to identify these molecules.

I do not have any concrete evidence for this except some anecdotal ones. Would like comments on this?

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4. Anonymous on March 7, 2008 11:49 AM writes...

Can the soluility issues be solved for ever by using nano technology to deliver the drugs right to the target? Ex: Taxol

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5. CMC guy on March 7, 2008 12:19 PM writes...

I know (and applaud) a number of examples where Formulations groups have successfully overcome difficulties in dissolution or other poor properties for candidates from their bag of tricks/expertise. That said it is so much better to build in molecule up front however functionality that helps solubility can hurt activity, stability or synthesis so most candidates end up compromising factors. Taxol may be example of ultimate compromise because it works and readily sourced but use of (very) undesirable cremophor tolerated.

#3 Form Sci may have a point in that HTS often uses DMSO or DMF that can negate poor solubility and thus hits are not best drugs. In most circumstances med chemists do not have time to make adjustments of leads to more viable molecules because of pressures to progress or cancel project so HTS hit is chosen little or no modification- if additional research done can sometimes result in back ups that are more suitable.

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6. CMC guy on March 7, 2008 12:27 PM writes...

Meant to ask if most people include Log P (or D) either meassured or calculated as part of the selection process? This info can provide much guidance on potential problems but often seen as post evelauate of candidate rather than screen or selection tool.

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7. Enoch on March 7, 2008 2:13 PM writes...

#3 Form Sci -

Chris Lipinski has published and given several talks on the subject. You can Google to your heart's content, but here's one published reference to this work;

http://www.ncbi.nlm.nih.gov/pubmed/11274893

Enjoy

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8. Polymer Bound on March 7, 2008 7:19 PM writes...

#3: The source of the lead could influence solubility but, oddly enough, I think the nature of the target tends to cause these problems. I lack experience in these areas, but most gripes about solubility I've heard come from people working on proteases and kinases. It might just have to do with the nature of their active sites.

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9. NJBiologist on March 7, 2008 9:32 PM writes...

Derek (or anyone else)--Are self-affinity and aqueous affinity essentially the parameters that govern kinetic and equilibrium solubility? How do you predict this sort of thing?

--the guy sitting at his desk, swearing in anticipation of the vial of brick dust which arrives Monday

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10. Morten on March 8, 2008 4:29 AM writes...

Guys remember that taxol is actively transported into the body from the intestine. It's not a good model for anything.

I've heard of using sonication to reach solubility equilibrium faster but does anyone have any other tricks?

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11. weirdo on March 8, 2008 12:05 PM writes...

HTS: HTS is the problem only in that allowing biologists near screening data should never be allowed. They always like the most potent molecule. Seldom, in my experience, are the most potent hits the best starting points for lead optimization. (That's not really fair to biologists, there are plenty of chemists who like to start with good potency, too!). I even know some chemists who complain when they make molecules that have too much water solubility, because they're "hard to isolate". Yikes.

Pressures of short lead times: I hear this all the time, and it's a cop-out. Who forces those short lead times? Managers who were once (at many companies) or still are (at my company) drug discovery scientists? I think it's the teams themselves that make bad decisions, rather than so-called "managers". But it's a lot easier to blame your boss for doing a poor job, than admitting something could have been done differently earlier in the project. If you find yourself at a company that forces bad scientific decisions to meet artificial timelines, go to another one. There are plenty of pharma companies, big and small, that don't reward bad decisions.

Philosophy of drug design: Clearly an important factor, as Lipinski's article elegantly shows. Overreliance on potency leads to low solubility, if one does not analyze HOW that potency is achieved. Take a look at how the appropriate placement of an adamantyl group can lead to a log-improvement in "affinity". Duh, make a molecule with good affinity want to get out of water and into grease as quickly as possible, and all of a sudden you have great affinity. Not exactly the path to happiness, however.

PolymerBound: I think you're absolutely correct. But this only points out how project teams need to do a better job at selecting targets!

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12. milkshake on March 9, 2008 4:37 AM writes...

Weirdo: It is pretty easy to grab a HTS hit and run with it. You optimise the hell out of it and within a year you get a low-nanomolar undruggable compound. But the management flowchart checkpoints are met and the pencil-pushers look more dynamic as they seriously chew around on their endless project meetings

I have been on a project that suffered an embarassment of riches. First the people working on this target re-synthesized couple of literature compounds, made hybrids and came up with two patentable leads - one ho-hum, one pretty decent one. Meanwhile our HTS group kicked in and we got at least five more dissimilar very promising-looking drug-like hit classes. (Each structural class showed in screening several times, you could almost build a SAR starting point from the HTS data alone). Now with a small academic group - with only few people in chemistry and biology - how do you work on seven dissimilar molecules all at the same time? It took us quite some time to narrow it down to only two or three most promissing leads that we pursue full time - but after a year you suddenly reach the stage in SAR where the each class diverges into two so you have again four lead substructures... It has been a strange situation, but comparing different kinds of molecules for the same target lets us to appreciate the different properties of these leads (and rather tired when thinking how much work remains to be done, to get a good PK and cell potency and selectivity, all at the same time). We are lucky to have a grant so that we can go on like this for couple of years. Our top management are scientists so no-one is forcing us to pick one particular lead and "make a candidate from it by the end of year"

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13. Great Molecular Crapshoot on March 9, 2008 4:45 PM writes...

A quick comment because the last one I made didn't get thru. Nobody seems to have said much about ionisation (apart from CMC Guy's query about logD) and this is a very important determinant of solubility. Here's a review article that may be of interest:

http://www.ingentaconnect.com/content/ben/ctmc/2001/00000001/00000004/art00005


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14. weirdo on March 10, 2008 10:44 AM writes...

milkshake: It is also pretty easy to blame bad decisions on "management pressure". Too easy, unfortunately.

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15. Kay on March 10, 2008 1:08 PM writes...

Morten: since taxol is not oral, I am confused by your comment.

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16. Morten on March 10, 2008 6:33 PM writes...

Freg... what drug was I thinking of then... I'm blank.

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17. markm on March 18, 2008 8:12 AM writes...

A discussion of solubility reminds me of the sulfa drugs discoverd by Bayer (IIRC) in the 1920's (the first effective antibiotics, based on sulfonamide). Sulfonamide was soluble enough to be readily absorbed in therapeutic concentrations from a pill, but often patients with sore throats and children had difficulty swallowing the pills, so oral liquid and injectable formulations were greatly desired - and it simply would not dissolve in high enough concentrations for these purposes.

In the 1930's one small American drug company finally found a solvent - ethylene glycol. Somehow they didn't do any toxicity testing, and marketed the sweet-tasting solution primarily as a children's medicine. To their credit, they reacted to the first reports of poisonings by immediately doing all they could to recall the drug, including publicity and asking the FDA to get their entire (rather small) staff out to help track down every bottle, but there were over 100 fatalities before all the shipments were accounted for. It was after this incident that Congress gave the FDA the powers to require drug testing, approve drugs before they were marketed, and to order recalls.

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