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QSAR of protonated ionic salt forms on base drug-like molecules & their differences

Nagelfar

Nagelfar

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QSAR of protonated ionic salt forms on base drug-like molecules & their differences

This has been a topic of interest to me since my inception into chemistry knowledge of any type.

Most abuseable drugs are hydrochlorides (HCl), whether street drugs or pharmaceuticals (though non-commonly abused / non-abuseable pharmaceuticals run the whole gamut). Notable exceptions exist.

It seems that research chemicals vary quite a bit more (you get bigger names like naphthalenedisulfonate, methanesulfonate, etc). Due to acids in plants, so do whole herbal preparations (Morphine meconate is an example that comes to mind.)

The salt form in question seems to alter its solubility & conversion ratio quite a bit.

Besides its isometry, adderall is split between three salt forms of its amphetamine ingredient: aspartate-monohydrate, saccharide & sulfate. Tartrate also seem to be more prevalent among amphetamine type chemicals. Yet street amphetamine is frequently a hydrochloride.

Also of interest, is when the salt is active in itself. There were barbiturate salts of morphine used for their doubly sedating effect, while being a vehicle for the base of the morphine molecule to pass the cell membrane at once.

Is there any information to be had, on specific drugs for instance, on novel QSAR between a single drug molecule and its alternate salt form's affects? Tables, lists, anything of that nature would be of interest to me here.
 
Yet street amphetamine is frequently a hydrochloride.
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Is it? I thought it was mostly a sulphate.

Is there any information to be had, on specific drugs for instance, on novel QSAR between a single drug molecule and its alternate salt form's affects?
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As far as I know many salt drugs are converted to the HCl form upon treatment with stomach acid, so the difference in salts are mostly to retain stability and sometimes to deter injection by removing water solubility. This last example is seen in e.g. the use of napthalienedisuphonate for ... I think it was dextropropoxyphene, as opposed to the water-sol HCl.
 
sekio said:
Is it? I thought it was mostly a sulphate.
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I suppose I am thinking of N-methylated

Isn't adderall's formulation, for example, a way to make it an extended onset of effects without a de-facto continuous release binder?

Speaking of stomach acid, even uric acid could theoretically be used (in a pinch with base and haven't any citric or ascorbic?)
 
Nagelfar said:
I suppose I am thinking of N-methylated

Isn't adderall's formulation, for example, a way to make it an extended onset of effects without a de-facto continuous release binder?
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I believe that is Vyvanse. Adderall XR uses that waxy bead shit... (Don't know what it is called.)
 
Isn't adderall's formulation, for example, a way to make it an extended onset of effects without a de-facto continuous release binder?
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I think that was the intention. But most of the XR comes from the polymer matrix as others have noted.
 
Psychedelic Jay said:
I believe that is to balance out the Dopamine and Norepinephrine effects of those different salts to equate to a better "formula."
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Psychedelic Jay? Are you trying a new chemistry 'random response generator' bot?

hehe, no sorry. I didn't think the salts contributed to the dopaminergic or monoamine effects of the actual molecular structure of the drug at all. Do you have any source? That would be highly interesting.
 
Nagelfar said:
Psychedelic Jay? Are you trying a new chemistry 'random response generator' bot?

hehe, no sorry. I didn't think the salts contributed to the dopaminergic or monoamine effects of the actual molecular structure of the drug at all. Do you have any source? That would be highly interesting.
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"Manufacturers claim that the mixture of salts in Adderall XR makes its effects smoother (that is, makes softer highs and lows)."

Reynolds, Cecil R; Fletcher-Janzen, Elaine (2009). Handbook of Clinical Child Neuropsychology (3rd, revised ed.). Springer. p. 531. ISBN 978-0-387-70708-2. Retrieved 2009-06-23.

That's what I found. It seems that the different salts are in place to make a less severe comedown...
 
That would just be reasoned (to me) to be a form of extended release from the only possible (to my knowledge) pharmacology to it, as an explanation as why that would be. Not anything to do with DA or NE affinity.

I was speaking to another that was of the opinion that the manufacturer simply keeps that formulation as a vestigial and a marketing ploy that it is somehow more thoroughly processed as to be less abuseable than others on the market (e.g. Dexedrine). I'm still open to other lines of thinking.
 
just one question: is the salt form of a drug not always transferred to the freebase / neutral form prior to membrane passage? if so, and if the counterion is not biologically active in any form, what other parameter than the solubility of the precipitated drug would it control?
 
For pharmaceuticals it is not only solubility that is a key issue but also thermal stability, hygroscopicity and tendency to form polymorphs and hydrates. For example hydrochlorides of weak bases have a tendency to lose HCl over time and revert to the freebase form. Amphetamine is commonly marketed as the sulfate because the hydrochloride is very hygroscopic.
 
Nagelfar said:
I was speaking to another that was of the opinion that the manufacturer simply keeps that formulation as a vestigial and a marketing ploy that it is somehow more thoroughly processed as to be less abuseable than others on the market (e.g. Dexedrine). I'm still open to other lines of thinking.
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I think this is probably close to the truth - maybe there were patent issues as well?
 
With adderall in particular I think that a lot of it has to do with patent issues b/c different salts of the same drug molecule are considered "new chemical entities." So if you change from a sulphate to saccharate its considered a completely different and patent-able drug.The salt form of alkaloids also has an impact on the pharmacokinetics due to differing ionization rates.
 
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