Choosing a salt

[haribo1]

Most drugs are presented in their salt forms. HCl, HBr, HSO4 and so on. Now, here is my dumbness. Why is it, for example, that morphine comes as a sulfate whereas codeine comes as a phosphate?

On a related note, using an organic salt such as citrate, will the drug & salt dissociate when heated sufficiently? I mean, if you made diamorphine acetate, will it form acetic acid and freebase heroin as it's heated. I'm sure shelf-life is impared, but it would sure be convenient.

On one post, pseudotrophyl 4-fluoro benzoate was shown to not readily form salts like a hydrochloride. I know a lot of the cocaine analogs like CTF are usually presented as the naphthalene-1,5-disulfonate (Armstrongs acid?).

Sorry for this sad, sad, untutored question, but I've only ever worked with HCl, HBr & H2SO4 salts.

 

[fastandbulbous]

Generally a mixture of reasons, but mostly solubility & stability (which includes a tendancy to suck water out of the air). Both morphine & codeine come as a tartrate, there's also morphine acetate (very soluble) etc

 

[haribo1]

So, with those cocaine analogs, the napthaline-1,5 disulfonate is the most soluable that they could come up with?

 

[Bondmaker]

i once had..

.. a booklet prepared by the chemists in the company that i worked for. It was one of these in-house things, not widely published. Basically it gave all the common and some useful uncommon salts to make for drug formulations. Some of the reasons for making a particular salt had to do with solubility, color, ability to flow well, non-hygroscopicity, dead on stoichiometry, so thet you had a repeatable number of counterions in a perfect cystal lattice, and hence when you diluted and mixed the inert ingredients, each tab or capsule contained exactly Xg of compound, sometiimes the counterion salt was the last salt made that gave total stereochemical-purity (other enantiomers or diastereomers from an enriched mixture salted out pure leaving unwanted material in the mother liquors. Even slightly toxic salts like fumarates could be pharmacologically acceptable if they imparted better characteristics to the final formulation, simply because so little is used in the process.
Hydrochlorides are the most common, but sometimes a molecule will just bunk out of solution as the hydrochloride because it takes up excess hydrogen chloride, which is hygroscopic, but the material can be a white, free flowing, non-hygrosopic, stable, monohydrochloride after one or two recrystallizations. It all depends on both the molecule and the pharmacodynamics. Some salts form tighter ion pairs, which affects things like volume and solubility, but basically, all salts become hydrochlorides when they hit the stomach acid. The bowel is a slightly basic environment, like cytosol, so dissociation to the freebase often occurs here, whence absorption into the hepatic artery occurs for first pass hepatic metabolism in the liver, before it hits the general bloodtream (PNS) and on to the CNS. One other reason is finished molecular weight. If you sell your compound by weight, you can essentially "dilute" it by using a high molecular weight counterion, less compound weight per unit weight because the counterion weighs more.
Also Haribo-1 when preparing a series of analogs to be tested in-vitro they often come upon a particular salt that seems to be easy recrystallizable in a common solvent for recystallization, and makes trouble-free salts throughout the compound series. Things like not taking on a molecule of solvent or water from the atmosphere after final recryst. and drying are important for consistently easy calculations for the biologists.

 

[Bondmaker]

i once had..

.. a booklet prepared by the chemists in the company that i worked for. It was one of these in-house things, not widely published. Basically it gave all the common and some useful uncommon salts to make for drug formulations. Some of the reasons for making a particular salt had to do with solubility, color, ability to flow well, non-hygroscopicity, dead on stoichiometry, so thet you had a repeatable number of counterions in a perfect cystal lattice, and hence when you diluted and mixed the inert ingredients, each tab or capsule contained exactly Xg of compound, sometiimes the counterion salt was the last salt made that gave total stereochemical-purity (other enantiomers or diastereomers from an enriched mixture salted out pure leaving unwanted material in the mother liquors. Even slightly toxic salts like fumarates could be pharmacologically acceptable if they imparted better characteristics to the final formulation, simply because so little is used in the process.
Hydrochlorides are the most common, but sometimes a molecule will just bunk out of solution as the hydrochloride because it takes up excess hydrogen chloride, which is hygroscopic, but the material can be a white, free flowing, non-hygrosopic, stable, monohydrochloride after one or two recrystallizations. It all depends on both the molecule and the pharmacodynamics. Some salts form tighter ion pairs, which affects things like volume and solubility, but basically, all salts become hydrochlorides when they hit the stomach acid. The bowel is a slightly basic environment, like cytosol, so dissociation to the freebase often occurs here, whence absorption into the hepatic artery occurs for first pass hepatic metabolism in the liver, before it hits the general bloodtream (PNS) and on to the CNS. One other reason is finished molecular weight. If you sell your compound by weight, you can essentially "dilute" it by using a high molecular weight counterion, less compound weight per unit weight because the counterion weighs more.

 

[haribo1]

Now, that booklet is something I would like to read

I noticed that clomethiazole infusion comes as the edisylate (ethane disulfonate). The compound isn't to study so the capsules come as freebase.

On reflection, HOW does clomethiazole form a salt? You can't salt an imine can you?

 

[neuwelt]

Imines have severly reduced basicity due to sp2 hybridization which withdraws the non-bonding electron par to the nuclues. This however doesn't necessarily mean that they won't form salts with acids. It all depends on what imine we're looking at. Pyridine for example has an pKa around 5 and readily forms a salt with hydrochloric acid. Ethanedisulfonate has a pKa of -2 and is a very strong acid, used most likely for the very low basicity of clomethiazole.

The choise of salts has as said much to do with stability and solubility but it also may affect bioavailability etc so it's important that pharmaceutical compositions are well studied to improve a drugs effects.

 

[haribo1]

Wow, I'm learning a lot from this thread.

There is clomethiazole. Why the ethane DIsulfonate? Is that to leave a free hydrogen or is it to salt 2 molecules?

 

[UnfortunateSquid]

Yes it protonates at the thiazole nitrogen, it's better considered an azole than an imine.

God damn my internet sucks today.

Neuwelt answered your question, it's because ethane disulfonate has a low enough pKa to protonate the ring nitrogen, which dosn't really want to be protonated, as per your first thoughts!

 

[neuwelt]

Ethanesulfonate is a much weaker acid (pKa circa 1.5-1.6). Too weak for clomethiazole is my late night tired guess.

 

[haribo1]

Yes it protonates at the thiazole nitrogen, it's better considered an azole than an imine.

God damn my internet sucks today.

Neuwelt answered your question, it's because ethane disulfonate has a low enough pKa to protonate the ring nitrogen, which dosn't really want to be protonated, as per your first thoughts!

Of course! Thats why it's called clomethiAZOLE I really need to get these ring systems down pat.

 

[leungkachong]

Has anyone wondered why no-one has considered the use of acids (even if it slightly raises production cost), which have activity in themselves. For example, MAPS might be able to get a couple hypochondriac scientists off their backs if they were working with MDMA alpha-lipoate as their psychotherapeutic adjuvant.

It might be a lil' too much to ask of black market buddies though.

 

[ralf2]

Has anyone wondered why no-one has considered the use of acids (even if it slightly raises production cost), which have activity in themselves.

There is a compound known as Barbexaclone which is propylhexedrine with a salt of an barbituric acid. I think there has been other barbiturates with a salt of amphetamine instead. (Yes, I know about Dexamyl, but I think that was just a mixture and not a true salt.)

 

[Pomzazed]

Has anyone wondered why no-one has considered the use of acids (even if it slightly raises production cost), which have activity in themselves.

Another example is Dimenhydrinate, although its conjugate stimulant properties wont do anything much.

 

[fastandbulbous]

Even slightly toxic salts like fumarates could be pharmacologically acceptable if they imparted better characteristics to the final formulation, simply because so little is used in the process.

I once used to own one of those 'psychedelic drug synthesis' handy lirttle paperbacks, to which Uncle Fester was the main contributor and the synthesis of MDA was eventually finalized by the production of the oxalate salt of MDA. NOW that's something that just screams NOOOOO!