Author Topic: Amphetamine monophosphate - the 'ultimate' salt?  (Read 1119 times)

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Antoncho

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Amphetamine monophosphate - the 'ultimate' salt?
« on: November 25, 2003, 09:56:00 AM »
Check this out, bees:

Patent US2507468



Amphetamine monobasic phosphate is practically insoluble in organic solvents and may bee precipitated by adding the calculated amt of 85% phosphoric acid to the freebase's solution in acetone.

Which makes it a perfect alternative to gassing.

Contrary to the situation with sulfuric salts, it can't bee overacidified (although the salt itself might beecome more soluble at lower pH, who knows).

In any case, you can control the addition by the pH - 10% solution has a pH of 5.



But what really blew my mind is the following:





Now ain't that nice? ;D  Just leaves me wonder how could that bee...


Anyone cares to check this out?


Antoncho

Rhodium

  • Guest
Amphetamine Dihydrogen Phosphate
« Reply #1 on: November 25, 2003, 10:50:00 AM »
Monobasic Phosphate Of 1-Phenyl-2-Aminopropane
Theodore V. Goggia
United States

Patent US2907468



My invention relates to a new chemical compound that is especially suited for therapeutic use. More particularly it concerns the monobasic phosphate of 1-phenyl-2-aminopropane, a method of preparing it, and therapeutic compositions containing this salt.

It is known that 1-phenyl-2-aminopropane (commonly referred to as "amphetamine") and certain of its salts have a pronounced therapeutic effect, particularly as stimulants for the central nervous system. This is evidenced by a feeling of well-being and energy, as well as by a reduction of appetite and desire to sleep. The foregoing effects render these compounds of substantial value in the treatment of various pathologic conditions, such as despondency, fatigue, alcoholism, narcolepsy, obesity and the like. Unfortunately, the beneficial effects of these known compounds are accompanied by certain deleterious effects, particularly an undesirable stimulation of the sympathetic nervous system, frequently resulting in uncontrollable jitteriness. Often a cumulative effect of repeated dosages is evidenced by a disagreeable "hang-over." Furthermore, the known compounds leave much to be desired in one or more respects, such as solubility, stability, metabolism, etc.

It is an object of my invention to provide a novel salt of 1-phenyl-2-aminopropane which possesses the above-mentioned beneficial effects to an unusual extent, and which at the same time possesses the deleterious effects referred to previously to a lesser extent than was heretofore deemed possible. A further object is to provide such a salt having improved physical properties, compared to the known salts. and which is subject to more economical utilization by the body.

Another object is to prepare the new salt in a simple, expeditious manner, whereby a high degree of purity, excellent physical form and great stability are assured. A still further object is to make available various therapeutic compositions particularly adapted for the treatment of obesity and of dysmenorrhea, in which my novel salt is combined with other therapeutically active constituents for maximum desired effect. Additional objects will become apparent from a consideration of the following description and claims.

The foregoing objects are accomplished in accordance with my invention which is particularly concerned with the monobasic phosphate salt of 1-phenyl-2-aminopropane. This novel compound will hereinafter sometimes be referred to as "monobasic amphetamine phosphate" or "amphetamine dihydrogen phosphate." Said salt formed by the combination of equimolecular amounts of the amphetamine base and phosphoric acid. It is distinguished from the dibasic (monohydrogen) and tribasic (fully neutralized) forms, since these contain two and three mots, respectively, of amphetamine for each mol of phosphoric acid. My new salt may be represented by the following structural formula:

The novel amphetamine dihydrogen phosphate may exist in the dextro- or levo- rotary forms or as a racemic mixture thereof, depending upon the form of the base from which it is derived. In practice, I prefer to employ the racemic form and the specific data hereinafter given concerning the physical characteristics of the salt apply to this form of the salt.

My monobasic amphetamine phosphate is a white, impalpable powder that is freely soluble in water and sparingly soluble or insoluble in most organic solvents. It is not demonstrably hygroscopic and is completely stable under ordinary conditions of storage. It begins to sinter at 145°C., becomes a clear amorphous mass without liquefaction at 147°C, and retains the latter form up to about 285°C. at which point it begins to decompose with the evolution of a gas (probably CO2). Its melting point could therefore not be determined.

My new salt may be prepared by adding to amphetamine an equimolecular amount of phosphoric acid. The amount of phosphoric acid required may either be calculated beforehand or else controlled by observing the pH of the reaction mixture and discontinuing the addition as soon as the desired pH value is reached. The pH of a 10% solution of my new salt at a temperature of 25°C is 4.95-5.00 determined colorimetrically and electrometrically. The neutralization reaction is strongly exothermic and, unless modified and controlled in a manner such as will be hereinafter described, results only in a chemical mass consisting of varying proportions of the three possible phosphates with, under certain circumstances, an excess of base or of acid intermingled.

I have found that the necessary control of the reaction may be achieved by having present a substantial amount of a solvent for the amphetamine. One may employ a solution of the amphetamine in water or in an organic solvent such as carbon tetrachloride, ethylene glycol, propyl alcohol, chloroform, acetone and the like. The organic solvents, particularly acetone, are preferred. The phosphoric acid is slowly added to such an amphetamine solution under constant agitation. . After the precise amount required to form the monobasic salt has been added, agitation is continued for up to a half hour or more to insure complete conversion of the base to the desired salt. When an organic solvent such as acetone is employed, the salt separates in the form of a fine, white, flocculent precipitate that becomes more and more dense and abundant as the reaction proceeds. The precipitate may be separated by filtration and, when dried, is in a very suitable form for compounding in various therapeutic preparations.

The following example will serve to illustrate the preparation of my new salt. The invention is, of course, not limited, to the details given therein.

Example

135 grams (1 mol) of amphetamine (1-phenyl-2-aminopropane) were stirred into 300 mL of acetone in a stainless-steel vessel. To the resultant solution there were slowly added under constant agitation 115.3 grams of 85% phosphoric acid (containing 1 mol of H3PO4), care being taken to avoid any sudden rise in temperature or local overheating due to the considerable amount of heat that is evolved. During the addition of the phosphoric acid a fine white, flocculent precipitate appears which becomes more and more dense and abundant, as the quantity of added acid increases.

When the entire quantity of the phosphoric acid has thus been added, agitation of the mixture is continued for about a half hour or more to insure complete conversion. The precipitate is then allowed to settle, the supernatant liquid is drawn off, and the residue is filtered. The precipitate thus separated may, if desired, be washed with acetone and is then dried by evaporation to constant weight. It forms a fine, white, impalpable powder consisting of pure monobasic amphetamine phosphate. When employing the racemic amphetamine, a racemic salt is formed having the physical characteristics hereinbefore described.


My new salt, obtained as described above, may, if desired, be ground to such a fineness that it will pass through a 100 mesh sieve. It is then ready for compounding into various forms and preparations for therapeutic use. For example, it may be incorporated in the customary extenders or excipients, such as milk sugar, and made into tablets, each containing a predetermined dosage of the salt, such as 5 or 10 mg. Another convenient and desirable form for oral administration is obtained by incorporating my new salt in the coating of a standard form of chicle chewing gum. In such case the entire dosage of the salt is preferably incorporated in an intermediate layer of the coating, so that it will be quickly available and yet protected by an outer layer.

An important advantage of my new salt lies in its ready solubility in water. It is about six times as soluble as either the dibasic phosphate or the dibasic sulfate. Thus a quicker and more intense therapeutic action is assured. The action is also less persistent from the standpoint of cumulation that may result in a "hang-over" feeling.

Based upon extensive experience in human therapy, I have determined that the monobasic amphetamine phosphate is more effective, dose for dose, than is the dibasic amphetamine sulfate, which is the best known of the amphetamine salts. This is indeed surprising, because my new salt contains less of the amphetamine base than does an equal quantity of the dibasic sulfate. It follows that the amphetamine is far more potent in the form of the monobasic phosphate, than in the form of the salt most widely used today.

While my salt is more. effective, dose for dose, than the dibasic sulfate, insofar as the desired stimulation of the central nervous system is concerned, it produces less undesirable side-effects attributable to stimulation of the sympathetic nervous system. This may be due to the fact that it contains less of the amphetamine base. However, that does not explain why the desired therapeutic effects are not similarly diminished, but rather substantially enhanced. It appears that the undesirable side-effects are distinct from the desired effects of these salts, insofar as dosage is concerned, and it is probable that the desired effects are favorably influenced by the presence of phosphoric acid. It is well known that phosphates in general are metabolized more readily than are the sulfates which are foreign to the physiologic processes of the body. Regardless of what may be the true explanation, the, fact remains that the desired effects can be produced with my new salt, while greatly diminishing or completely eliminating the undesired effects that were heretofore considered inevitable in the therapeutic use of amphetamine salts.


References Cited

The following references are of record in the file of this patent:

Patents

Patent US2358582

Haffner et al., Aug. 22, 1944

Patent US2361373

Alles, Oct. 31, 1944

Patent AU117996

July 10, 1943

Patent AU119265

Nov. 21, 1944

Other References
Bakas, "Zentralblatt für Gynokologie," vol. 34, pages 1893-1898 (1938).
Chinoin, "Klinische Wochenschrift" vol. 13, page 483 (April 1939).
Stepan, "Chemical Abstracts," vol. 37, page 3565 (1943).
Torok, "Chemical Abstracts," vol. 32, page 2211 (1938).
Degering, "An Outline of Organic Nitrogen Compounds," (Univ. Lithoprinters, 1945) page 304.
Hygiea Medicinsk Tidskrift, Vol. 102, pages 1635-1642 (1940).
Decision of District CL N. J. Septi. 1, 190, 66 USPQ 440,463, 467,469,

silenziox

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Wait a minute Rhod, hasn't this thing allready
« Reply #2 on: November 25, 2003, 01:14:00 PM »
Wait a minute Rhod, hasn't this thing allready been on your website for quite a long time?

https://www.thevespiary.org/rhodium/Rhodium/chemistry/amphetamine.phosphate.html




Vitus_Verdegast

  • Guest
only the preparation is described
« Reply #3 on: November 25, 2003, 02:29:00 PM »
The patent Antoncho found is still a very interesting read! I would very much like to compare both amphetamine sulfate and monophosphate by bioassaying, when I get my permission from the DEA  ;) .

The Pharmaceutical Manufacturing encyclopedia (1988) article on Rhodium's page probably took the experimental part from the patent.


Rhodium

  • Guest
The general idea
« Reply #4 on: November 25, 2003, 02:30:00 PM »
The general idea about making the phosphate salt was there all the time, but not all these details about differing pharmacology etc. I'll add this patent right away at the end of the doc you linked.

Nicodem

  • Guest
I would not trust a claim of greater activity...
« Reply #5 on: November 26, 2003, 01:46:00 AM »
I would not trust a claim of greater activity of the phosphate salt. I don't trust scientific articles so I trust patents even less (they have more interests to tell crap - money). Even in the best looking articles they often on purpose omit some really important fact and I know this from experience.
It is however known in the general pharmacology that the form of application (type of salt and crystal size) causes some differences in the absorption rate in the stomach. This means that the phosphate salt would be slightly more active (on molarity not mass relation as it is suggested in the patent) only if the phosphate is much more rapidly dissolved (could be). Their reasoning about the metabolisms of sulphate/phosphate is totally unreliable since the fate of the anionic part does nothing to influence the activity of the cationic part (when in solution anions and cations don’t “posses” each other). Besides the “desired therapeutic effects” could also be the anorexic activity or who knows what since if you read the first sentence (of the 2nd part) word by word it could also mean that the side effects are the CNS effects interpreted as the “stimulation of the sympathetic nervous system”  (this is quite common in older literature). Even psylocibine/psylocine don’t differentiate in activity by molar relation and they are not phosphate salts but phosphate esters!
Anyway I wish to thank Antocho very much for the idea. I was tormenting myself with the conc. HCl salting of some amines from acetone solutions. Because of the water in muriatic acid some salts don’t precipitate. I will try the phosphoric acid next time. Any idea on how to precipitate a salt out of toluene without using HCl gas? Acetates precipitate only in very, very few cases, so do the citrates, maybe tartrates or benzoates? I would appreciate some help on this.

Rhodium

  • Guest
salts
« Reply #6 on: November 26, 2003, 10:07:00 AM »
Oxalates have a high tendency to crystallize from THF or alcohol solutions, but I don't know about how well it would go with toluene, as I don't know if the acid is soluble in that solvent - a prequisite for good crystallization is that both the free acid and the free base is soluble in the crystallization solvent, this while the salt should not be soluble.

I have heard reports of 2C-B hydrobromide (water soluble) coming on significantly faster than 2C-B hydrochloride (very sparingly soluble in water), so solubility differences might definitely play a role here.

suttleila

  • Guest
methamphetamine
« Reply #7 on: November 28, 2003, 12:48:00 AM »
can the samething be done with methamphetamine to get more euphoric highs or a better feel from the salt?

Rhodium

  • Guest
the usual salt is already soluble
« Reply #8 on: November 28, 2003, 01:17:00 PM »
As methamphetamine hydrochloride is pretty soluble as is, I find it doubtful that any other salt would have significantly different effects.

SPISSHAK

  • Guest
I read somewhere
« Reply #9 on: November 29, 2003, 08:50:00 AM »
that it is more bio avaialable and therefore more potent on a mole for mole basis.
have to try this one and confirm.

hest

  • Guest
Methamphetaminephosphate
« Reply #10 on: December 25, 2003, 10:34:00 AM »
Just made a shot with methamphetamine, not good.
0,3mole Methamphetamine freebase was disolved into 300mL acetone, then 0,3mole 85% H3PO4 disolved in 100mL acetone was added over 15min with external icecooling. A semisolid pasta did precipitate, but deff. not a powder. Hygroscopic ?? dont, know but i stic to the hydrochloride from now on.

GC_MS

  • Guest
amphetamine
« Reply #11 on: December 25, 2003, 11:49:00 AM »
I have done the same for amphetamine. It forms a sort of paste, which you can ground to some sort of powder. It indeed doesn't look like a powder though. Rather different...


cublium

  • Guest
Ever tried filtering that paste?
« Reply #12 on: December 25, 2003, 11:17:00 PM »
Ever tried filtering that paste?

Zero_To_Nine

  • Guest
Mono vs Di vs Triphosphate ?
« Reply #13 on: December 29, 2003, 04:37:00 AM »
When crystallising MDMA freebase I use 85% phosphoric acid in acetone. This works well for me and in this way I don´t have to gas with HCl. Recently Rhodium supplied me with an article from some Hong Kong group in which they identified MDMA monophospate in tablets (see Forensic Articles digest). I was surpised to read that a monophosphate salt is formed since I always assumed that a triphosphate salt would be formed (just like a disulphate is formed from amphetamine and sulfuric acid). Is this due to the weaker acidity of the phosphoric acid ?

josef_k

  • Guest
That depends on how much acid you drip in.
« Reply #14 on: December 30, 2003, 02:31:00 PM »
That depends on how much acid you drip in. If you drip in equal mols of acid as you have mols of freebase you will get the monophosphate, just as you can get the monosulphate if you drip in enough acid (but it will redissolve in the alcohol so noone does that).

Zero_To_Nine

  • Guest
OK, so once one phosphate is attached to the...
« Reply #15 on: January 03, 2004, 06:31:00 AM »
OK, so once one phosphate is attached to the MDMA/amph. molecule there is decreased affinity for the second phosphate group. I tried using higher molar ratios of phosphoric acid when precipitating the MDMA freebase, e.g. 1 mol freebase to 3 mol acid, but I ended up with an viscous oily substance. However, when adding more of the freebase a whitish precipitate was formed.

terbium

  • Guest
Monobasic phosphate
« Reply #16 on: January 03, 2004, 02:47:00 PM »
OK, so once one phosphate is attached to the MDMA/amph. molecule there is decreased affinity for the second phosphate group. I tried using higher molar ratios of phosphoric acid when precipitating the MDMA freebase, e.g. 1 mol freebase to 3 mol acid,

No, you have it backwards. 1 mole of phosphoric acid can react with 1, 2 or 3 moles of amphetamine. When 1 mole of amphetamine reacts with 1 mole of phosphoric acid you get  monobasic amphetamine phosphate. When 2 moles of amphetamine reacts with 1 mole of phosphoric acid you get dibasic amphetamine phosphate and with 3 moles of amphetamine to 1 mole of phosphoric acid you would get tribasic amphetamine phosphate.


cell

  • Guest
this discussion is interesting from a chemical
« Reply #17 on: February 06, 2004, 03:43:00 PM »
This discussion is interesting from a chemical pow, but when it comes to practice it has been my experience that freebase absorbed on some kind of powder gives people fare more the best results.

Shelf time is limited thought, eaven in the fridge.
No more than than 3 month and you can fell decrease in potensety. On the other side when doing fresh freebase meth I can assure you: you will never sleep.

I have seen people do 25% freebase meth absorbed on kreatine powder jump around on the tables for eight houers, and after that they were doing everything to organice an afterparty.


When entering the party people were yelling MORE MORE MORE.

Zamboni

  • Guest
Its mentioned here, too. Post 76431
« Reply #18 on: February 08, 2004, 05:53:00 PM »
Its mentioned here, too.

Post 76431 (missing)

(PolytheneSam: "Re: Amphetamine phosphate", Methods Discourse)