Benzdiazepines water solubility

[jasoncrest]

BENZODIAZEPINES SOLUBILITY

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#1. Salts

#1.a. Why some benzos can be converted into a salt and not others?

#1.b. Which benzos can be converted into a salt?
(besides Midazolam Maleate/Hydrochloride, Loprazolam Mesylate, Flurazepam Dihydrochloride and Chlordiazepoxide Hydrochloride)

#1.c. Are Clorazepate Dipotassium and Ethyl Loflazepate water-soluble benzos because they are carboxylate salts?

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#2. Esters

#2.a. Are all benzodiazepines esters water-soluble?

#2.b. Is Oxazepam Dipropylacetate an ester of Oxazepam? Is it water-soluble?

#2.c. Pivoxazepam is another ester of Oxazepam, is it water-soluble?

#2.d. Which other benzodiazepines can be converted into an ester besides Oxazepam?

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#3. Substitution

Fosazepam is a water-soluble analogue of Diazepam, it is water soluble, but it is not a salt; what makes it soluble is the substitution with a dimethylphosphoryl/dimethylphosphinyl group.

#3.a. Can other benzos be substituted with a dimethylphosphoryl/dimethylphosphinyl group to enhance solubility?

#3.b. Can other groups be substituted to common benzodiazepines to make them water soluble?

Réf:
http://en.wikipedia.org/wiki/Fosazepam
http://www.psychotropics.dk/usr_vie...e=All&backurlname=Search+Result&Catalogtype=A

 

[jasoncrest]

I already answered one of my question:
#2.d. There are also esters of Lorazepam: Lorazepam Acetate and Lorazepam Pivalate (= Pivazepam)
But are they water-soluble?

 

[mad_scientist]

I would imagine that any benzo could be made to form a salt under the right conditions, just pharmaceutical companies wouldn't bother when its being formulated into pills for oral administration.

The fact that flurazepam is available as the dihydrochloride means that two of its nitrogens have been converted into a charged form with a Cl- counterion, and at least one of those must be one of the heterocyclic nitrogens from the diazepine ring, which suggests that any benzo could be made into a water soluble salt if you tried hard enough.

Not all benzo esters will be water soluble, succinate is a special case because it has a super water soluble COOH group at the other end which drags the lipophillic benzo molecule into solution. Other esters like acetate and pivalate (2,2-dimethylpropanoate) will be much less water soluble. I would imagine a phosphate ester would be even better than succinate, but might not detach so quickly once it was inside the body.

Any benzo which has a free OH group could be converted into an ester, this includes oxazepam, temazepam, lorazepam and lormetazepam, there may be other ones I'm not familiar with as well.

Any benzo with an N1-methyl could have it replaced by a dimethylphosphorylmethyl to make a water soluble equivalent, but fosazepam is a pretty crappy benzo I think, basically just a delayed release version of nordazepam which isn't that great itself. The nitrazepam equivalent might be better though.

 

[jasoncrest]

Any benzo with an N1-methyl could have it replaced by a dimethylphosphorylmethyl to make a water soluble equivalent

Is it a hard procedure?
Benzos are so easy to get (OTC in so many 3d world countries), if dimethylphosphorylmethyl substitution is as easy as Amphetamine synthesis or Opium conversion to Heroin, that could make a great new generation of street drugs, the best after Opiates; some clandestine chemists should get into it.......

 

[Ham-milton]

I don't know if I'd agree "the best after opiates"- but I'd love to live somewhere with easy benzo access.


Is the fosazepam drawing a mistake or does it actually have an 8 sided ring, instead of the typical 7 for benzos. I don't think I've ever seen a "benzo" with an 8 sided ring.

 

[Reminisant B]

Since the only real benefit of water soluble benzo's is their ability to be injected the result would not be a good recreational drug.

midazolam in clinical settings can cause serious blackouts, respiratory problems let alone some unknown benzo salt from the street. It also wouldn't be necessarily euphoric or happy for some people and instead just cause amnesia.

 

[mad_scientist]

Is the fosazepam drawing a mistake or does it actually have an 8 sided ring, instead of the typical 7 for benzos. I don't think I've ever seen a "benzo" with an 8 sided ring.

Its a mistake according to PubChem. Not that PubChem's structures are 100% reliable either, but the literature says fosazepam is a prodrug for nordazepam so the structures must be similar.

Not sure how easy it would be converting benzos into the dimethylphosphorylmethyl derivative, I dunno that the precursors would be that easy to get, and I'd be worried about the toxicity of the dimethylphosphorylmethyl moeity after its come off the benzo.

I'd say if you just want to prep water-insoluble benzos for injection it would be easier just trying to make them into a salt form.

 

[jasoncrest]

Is the fosazepam drawing a mistake or does it actually have an 8 sided ring, instead of the typical 7 for benzos. I don't think I've ever seen a "benzo" with an 8 sided ring.

It's the drawing that's inaccurate, the image comes from www.psychotropics.dk; see on wikipedia.org, it has a 7 sided ring.

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Can someone answer my questions?
I'm REALLY interested in this (water-soluble benzos are my favorite drugs after Opiates)

 

[Ham-milton]

what hasn't been answered? I think it all comes down to the last sentence of Mad_Scientist's last post.

does anyone think that it would remain active as a depressant as drawn?

 

[jasoncrest]

I imagine is a little more difficult than shaking Diazepam in a solution of hydrochloride acid to make Diazepam Hydrochloride, right?

Are non water-soluble benzos in their base form?

 

[johanneschimpo]

If its not a two-word name, its in its base form (fuck me because there's probably one fucked up exception I can't think of)

cheat sheet, which I'm sure you already knew:
1 word: base
2 words: salt

ex.

_______pam <--- base (ex. diazepam)

_______pam __________ <--- salt (ex. midazolam hydrochloride)


I can't imagine any benzo in base form being water soluble, unless it had some sort of wild water-soluble chain branching off it, but none spring to mind. And even then, probably none in existence due to issues with activity.

 

[haribo1]

To form a salt with an organic compound, the compound must either have an amine group (so add acid to form salt) or a carboxylic acid (so add base to form salt). Most benzo's don't have these feature.

 

[mad_scientist]

Most benzos do have at least one amine group, the N1 nitrogen in the diazepine ring is a tertiary amine.

You can definately form salts of tertiary amines, I'm just not sure how favourable it would be, and if you needed really acidic conditions it might decompose.

But like I said above, it obviously can be done with at least some benzos, because flurazepam is available as the dihydrochloride salt, which means that two of its nitrogens have reacted with HCl to form NH+Cl-

I'm not sure if it would be as simple as shaking it with HCl because obviously if the benzo base isn't water soluble then it won't be soluble in the aqueous HCl solution, but if you dissolved the benzo in non-polar solvent and bubbled HCl gas through it, like how people salt freebases of other drugs, I would imagine that at least some of the benzo would get converted to the HCl salt.

Only problems I could foresee is that maybe if its not very favourable for the tertiary nitrogen in the diazepine ring to get hydrogenated then the conversion rate might be quite low, and also if the benzo is lipophillic enough then it might stay dissolved in the non-polar solvent even after conversion to the salt form rather than precipitating out.

 

[haribo1]

^That's an AMIDE...

 

[mad_scientist]

Hmm thats true. What about the other nitrogen then, the N4? Can nitrogens with double bonds form salts? I don't see why not, but its not really my area. And with flurazepam dihydrochloride one of those heterocyclic nitrogens has formed a salt at any rate, doesn't really matter which one...

 

[haribo1]

^Thats an IMINE.