Some Amphetamine Salts

[GhostChemist]

The following pharmaceutically acceptable salts of A are known in the literature:
2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, aspartate, benzenesulfonate, benzoate, benzylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium salt of ethylenediaminetetraacetic acid, camphorate, camphorsulfonate, camsylate, caronate, citrate, clavulanate, cyclopentanepropionate, digluconate, dodecyl sulfate, edetate, estolate, ezylate, ethanesulfonate, finnarate, gluceptate, glucogeptanate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinat, hydramine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, laurylsulfonate, malate, maleate, mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthylate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, phosphate, phosfatedylphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethyl iodide, undecanoate, valerate, and so forth (Berge et al. (1977) "Pharmaceutical Salts", J Pharm. Sci. 66:1-19).

In this practical work, the synthesis of 16 salts of Amphetamine was carried out.
​

These are:
Saccharinate, Adipate, Phosphate, Aspartate monohydrate, Malate, Citrate, Glutamate, Glutamate hydrochloride, Benzoate, Acetylsalicylate, Tartrate, Succinate, Propionate, Chloride, Bromide, Acetate. ​

Physicochemical and organoleptic parameters were determined for these salts.​

Preparation of Amphetamine free base alcoholic solution with a standard concentration​

Reagents and materials:

• 193 g of Amphetamine sulfate (stored for 1 year)
• 140 g of NaOH in 600 ml of water (the solution should be at room temperature, not hot)
• 800+800 ml DCM
• 200 ml of 20% sulfuric acid
• 1000 ml of distilled water
• 70-100 g of anhydrous sodium sulfate
• 200 ml of 88% ethanol
• pH indicator paper
• Beakers
• Flasks
• Stirrer with heating
• 2000 ml separating funnel
• Funnel
• Filter paper
• Distillation setup
• 250 ml graduated cylinder

Process scheme Scheme 1.

Room temperature of alkali solution added to Amphetamine sulfate. Fig 1.​

If necessary, water can be added to dilute the solution. Fig 2​

The mixture is transferred to a 2000 ml separating funnel. The free base is extracted with a minimum of three portions of DCM (ideally until no odor of the amine remains in a drop of DCM extract). Fig 3​

The amine solution in DCM is transferred to a 2000 ml beaker. 150 ml of water is added, and while stirring, 50 ml of 20% sulfuric acid is gradually added until reaching acidic pH (not use concentrated acid). The mixture is vigorously stirred for 30 minutes. Fig 4​

The mixture is transferred to a 2000 ml separating funnel. The layer of DCM is drained into a 2000 ml beaker, 200 ml of water is added and 25 ml of acid solution is added until reaching acidic pH too. The mixture is vigorously stirred for 30 minutes and then transferred back to the 2000 ml separating funnel. The layer of DCM is again drained into the 2000 ml beaker, 200 ml of water is added and the mixture is vigorously stirred. If the pH is still acidic, no additional acid is added. The mixture is stirred for 30 minutes and then transferred back to the 2000 ml separating funnel. The layer of DCM is separated and discarded. The aqueous acidic layer is filtered through filter paper. Fig 5​

Solution of alkali is prepared. The filtered aqueous solution is mixed with room temperature alkali solution, and the mixture is transferred to a separating funnel and extracted with a minimum of three portions of new DCM. Fig 6​

The obtained amphetamine extract in DCM is dried with anhydrous sodium sulfate. Fig 7​

Next stage, the extract is subjected to distillation at atmospheric pressure at a temperature of 90-110℃ until the DCM stops distilling off. Additionally, the sodium sulfate is further washed with several portions of DCM to ensure complete extraction of the amine. The yield of the amine as a free base is 90 g.
To prepare a solution of the desired concentration, 70 g of the free base amine is used. 88% ethanol is added to the free base amine in several portions to completely transfer the amine from the flask to the cylinder. Fig 8​

In the cylinder, the volume is adjusted with ethanol to 200 ml and thoroughly mixed. The resulting solution is stored in a dark glass container with a ground neck. The amine concentration in the solution is 0.33-0.34 g/ml. Fig 9​

Obtaining saccharin in acidic H+ form​

Reagents and materials:

• 100 g sodium saccharinate
• 400-500 ml of water
• 100 ml of sulfuric acid 40-50%
• Water for rinsing

The process scheme for obtaining saccharin in the H+ form is shown in Scheme 2.

The appearance of sodium saccharinate is a white crystalline powder. Fig 10

The sodium salt of saccharin is completely dissolved in water, and then a solution of sulfuric acid is added until the acidic pH. Fig 11​

The precipitated saccharin in the H+ form is filtered off and dried in the air. Fig 12​

Obtaining Amphetamine salts​

Information on the composition of some amphetamine salts with references to databases:

Amphetamine saccharinate

Amphetamine phosphate
https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4890764.htm
https://pubchem.ncbi.nlm.nih.gov/compound/Amphetamine phosphate
https://www.chemspider.com/Chemical-Structure.56613.html?rid=d886c5ea-1182-4a55-939f-63b31f4f7778
Amphetamine phosphate C9H16NO4P
Molecular Weight: 233.20 g/mol

Amphetamine adipate
https://go.drugbank.com/salts/DBSALT001323
https://www.chemspider.com/Chemical-Structure.15186703.html
https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL1200387/
C15H23NO4
Molecular Weight: 281.35
Water Solubility 32.2 mg/mL

Amphetamine aspartate
https://go.drugbank.com/salts/DBSALT001345
https://www.chemspider.com/Chemical-Structure.7977072.html
C22H33N3O4
Average mass: 403.523
Water Solubility1.74 mg/mL
CAS Number 25333-81-7

Salt with malic acid
(2S)-2-Hydroxysuccinic acid - (2R)-2-phenyl-1-propanamine (1:2)
https://www.chemspider.com/Chemical-Structure.44209557.html

Benzoate
https://pubchem.ncbi.nlm.nih.gov/compound/49805693

Adderall is available in the form of fast-release tablets, as well as in two different extended-release versions. Adderall XR is a medication with a duration of action of 10-12 hours.

Mydayis
https://www.drugs.com/mydayis.html
https://www.drugs.com/medical-answers/mydayis-different-adderall-xr-3331573/
Active ingredients: dextroamphetamine sulfate and amphetamine sulfate, dextroamphetamine saccharate and amphetamine aspartate monohydrate
Inactive ingredients: hard gelatin capsules, ethylcellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer, methyl acrylate, methyl methacrylate, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain gelatin, titanium dioxide, yellow iron oxide and edible inks. The 12.5 mg and 25 mg capsules also contain FD&C Blue #2.
The 37.5 mg also contains red iron oxide. The 50 mg capsule also contains D&C Red #28, D&C Red #33, and FD&C Blue #1.
Mydayis contains similar active ingredients as Adderall XR but is formulated to last up to 16 hours for the treatment of ADHD. Adderall XR lasts up to 12 hours, and is given once daily. Adderall XR capsules can be used in patients 6 years of age and older, while Mydayis capsules are used in patients 13 years and older. Adderall XR is now available in a generic option.

Common schemes for the processes of obtaining amphetamine salts​

The production of saccharinate, adipate, monophosphate and aspartate monohydrate is carried out according to Scheme 3.

The production of malate, citrate, glutamate and glutamate hydrochloride is carried out according to Scheme 4.

The production of benzoate, acetylsalicylate and tartrate is carried out according to Scheme 5.

The production of succinate, propionate, hydrochloride and hydrobromide is carried out according to Scheme 6.

The production of acetate is carried out according to Scheme 7.

The calculations of the amount of acids and the theoretical yield of salts are provided in Table 1.

Table 1. The quantity of acids (1-12) per 15 ml of amine solution in ethanol and (13-14) per 10 ml containing approximately 5 and 3.4 g of free base, respectively.​

The amphetamine salt with corresponding acid​	The quantity of acid, g​	The quantity of salt (theory), g​	Solvent​
Saccharinate​	6.8​	11.7​	EtOH​
Adipate​	5.4​	10.4​	EtOH​
Monophosphate​	4.36 g (85%)​	8.6​	EtOH​
Aspartate monohydrate​	2.5​	7.7​	EtOH​
Malate​	2.5​	7.4​	EtOH​
Citrate​	2.6​	7.3​	EtOH​
Glutamate and Glutamate hydrochloride​	2.7 +1 ml 14% HCl​	8.3 (HCl)​	EtOH​
Benzoate​	4.6​	9.5​	Bnzene, EtOH, DCM​
Acetylsalicylate​	6.7​	11.6​	EtOH​
Tartrate​	2.8​	7.7​	EtOH+T℃​
Succinate​	2.2​	7.1​	EtOH​
Propionate​	2.7​	7.7​	-​
Hydrochloride​	1​	4.3​	Н2О​
Hydrobromide​	2.1​	5.4​	Н2О​
Acetate (11 ml)​	1.6​	5​	-​

The appearance of the acids is presented in the following photos.

Adipic acid. Fig 13​

Orthophosphoric acid. Fig 14​

Acetylsalicylic acid. Fig 15​

Aspartic acid. Fig 16​

Benzoic acid. Fig 17​

Citric acid. Fig 18​

Glutamic acid. Fig 19​

Hydrobromic acid. Fig 20​

Malic acid (Apple acid). Fig 21​

Propionic acid. Fig 22​

Succinic acid. Fig 23​

Tartaric acid. Fig 24​

Salts 12-15 are obtained by adding the corresponding acid dropwise to a solution of the free base in ethanol until a slightly acidic reaction is achieved (chloride, bromide) and in the case of propionate and acetate, until neutral pH. Fig 25​

The process of obtaining salts (1-11) is the same in all cases. It involves placing a portion of the acid into a flask with a stirrer, followed by the addition of 30 ml of 88% ethanol. Fig 26​

Next stage, 15 ml of the amine solution is added and with stirring, the mixture is heated to 100°C under a reflux condenser until a homogeneous solution is obtained. The pH of the solution should be neutral or slightly acidic, without the smell of the free amine. Fig 27​

If necessary, the solution is filtered and then evaporated to crystallization at a temperature not exceeding 100°C. If the solution crystallizes poorly, a small excess of the corresponding acid can be added. Fig 28​

The crystals are washed with 30-40 ml of one of the listed solvents (ethyl acetate, diethyl ether, petroleum ether, benzene, toluene) or their mixture with a small volume (5-15 ml) of acetone. Fig 29​

The precipitated salt was filtered or the solvent was decanted. Fig 30​

The salts are dried in air or in a desiccator over alkali for at least 24 hours. The yields of the salts are nearly quantitative, with a difference of 3-4% from the theoretical yield.
The appearance of the obtained salts is shown in the following photos.

Acetylsalicylate after drying in a desiccator for 48 hours. Fig 31​

The salt with adipic acid. Fig 32​

The salt with aspartic acid. Fig 33​

Benzoate. Fig 34​

Citrate after drying in a desiccator for 6 days. Fig 35​

Hydrochloride after drying in a desiccator for 24 hours. Fig 36​

Hydrobromide after drying in a desiccator for 24 hours. Fig 37​

Glutamate after drying in a desiccator for 2 days. Fig 38​

Glutamate hydrochloride. Fig 39​

Malate after drying for 4 days. Fig 40​

Monophosphate. Fig 41​

Propionate after drying in a desiccator for 4 days. Fig 42​

The amphetamine saccharinate salt after drying for 7 days. Fig 43​

Succinate after drying for 24 hours. Fig 44​

Tartrate. Fig 45​

Acetate after drying for 4 days. Fig 46​

The appearance and organoleptic properties (taste) of the obtained salts are presented in Table 2.​

Amphetamine salts of the corresponding acids​	Physical properties​	Organoleptic evaluation (Taste)​
1. Saccharinate​	Syrup or highly hygroscopic crystals, with a caramel-like consistency even after drying in a desiccator, and has a yellowish tint	Sweet​
2. Adipate​	Crystals, non-hygroscopic, white in color, should not oxidize upon storage	Bitter​
3. Monophosphate​	Crystals with a yellowish tint, tend to be hygroscopic and prone to oxidation in the air	Sour, bitter​
4. Aspartate monohydrate​	Crystalline non-hygroscopic powder with a creamy hue	Sour, bitter​
5. Malate (Apple acid)​	The powder, after drying in the desiccator, is cream-colored and tends to be hygroscopic	Pleasantly sour​
6. Citrate​	Hygroscopic syrup even after drying, yellow in color​	Sour, with a faint sweetish-etheric odor​
7. Glutamate (I) and Glutamate hydrochloride (II)​	Syrup, after drying in the desiccator, becomes a cream-colored powder. (I) Crystals (II)​	Pleasantly bitter with a slight numbing sensation. Hydrochloride - Acidic with a meaty taste​
8. Benzoate​	Syrup or hygroscopic mass of amber color. After drying, sticky crystals	Bitter, pungent​
9. Acetylsalicylate​	Syrup in amber color​	It's possible that the salt is a mixture of salicylate and amphetamine acetate. Taste: sour, bitter, pungent, with slight anesthetic properties. Smell: ethyl acetate​
10. Tartrate​	Crystals of white or cream color	Sour​
11. Succinate​	Crystalline powder of cream color	Sour, bitter​
12. Propionate​	Syrup in amber color	Very mild bitterness, 'refreshing'​
13. Hydrochloride​	White crystalline powder. After drying in the desiccator	Bitter​
14. Hydrobromide​	Syrup, hygroscopic crystals. After drying in the desiccator, it becomes a hygroscopic mass	Mildly bitter and not unpleasant​
15. Acetate​	Crystalline, poorly suited for drying	Slightly acidic​

Table 3. Conversion of the amount of salts corresponding to acids to a standard dose of 50-200 mg of amphetamine sulfate, which contains 0.0367-0.1468 g of amphetamine free base.​

The free acid corresponding to amphetamine salt​	Conversion to the standard dose of amphetamine sulfate corresponding to 50-200 mg.​
Saccharinate​	86-345.7​
Adipate​	76.4-305.5​
Monophosphate​	63.3-253.2​
Aspartate monohydrate​	57.2-228.8​
Malate​	54.9-219.6​
Citrate​	54.1-216.3​
Glutamate (I) and Glutamate hydrochloride (II)​	56.7-226.7 (I) 61.6-246.5 (II)​
Benzoate​	69.9-279.4​
Acetylsalicylate​	85.6-342.4​
Tartrate​	57.1-228.3​
Succinate​	52.7-210.9​
Propionate​	56.8-227.2​
Hydrochloride​	46.6-186.4​
Hydrobromide​	58.7-234.7​

Table 4. Dosages of free acids or their salts for food use​

Free acid or its sodium salt​	Dosage​	Additional information​
Saccharinate​	1 kg instead of 200 kg of sugar. Mixture of cyclamate and saccharin 10:1​	The permissible daily dose is 5 mg per 1 kg of body weight​
Adipates​	Up to 10 g/kg of the product​	​
Phosphates​	Up to 20 g/kg of the product​	​
Aspartates​	3-6 g of acid per day​	Aspartate acts as a transporter of ions (such as magnesium and potassium in the drug Asparkam) through cellular membranes..​
Malate​	Up to 20 g/kg of the product​	​
Citrate or citric acid​	Up to 20 g/kg of the product​	​
Sodium glutamate or glutamic acid​	For acid, 120 mg/kg of body weight per day. Up to 10 g/kg of products​	The acid is used in pharmaceuticals to treat some mental and nervous disorders, as well as to regulate protein metabolism.​
Benzoate​	For acid, 5 mg/kg of body weight per day. Up to 2 g/kg of production​	Preservative Has antimicrobial activity​
Acetylsalicylate​	Up to 4 g per day​	Analgesic​
Tartrate​	30 mg/kg of body weight per day. Up to 5 g/kg of products​	acidifier​
Succinate​	3-6 g/kg of product​	acidifier In pharmacy - an anti-stress medication​
Propionic acid and sodium propionate​	Up to 3 g/kg of products​	Preservative​

​

Conclusions

• The best crystal salts without dried in desiccator are Adipate, Aspartate, Glutamate hydrochloride, Monophosphate and Tartrate. These amphetamine salts washed solvent and dry on air after synthesis. These salts haven’t hygroscopic properties.
• The perspective salts with good structure after dried in desiccator are Hydrochloride, Hydrobromide, Glutamate, Malate, Succinate, Benzoate and Acetate. Malate has good stable properties for storage as powder, but has hygroscopic properties.
• Amphetamine salt with Saccharin has interesting caramel-form and sweet taste.
• All salts very soluble in water and alcohols. Non soluble in diethylether, benzol, toluol, petroleum ether, dry cold aceton.

 

[lemon]

This is something sooo rare and valuable, thanks for the effort!

 

[HIGGS BOSSON]

Very good job

 

[hacke8]

Thank you for sharing, very comprehensive knowledge, I hope the BB forum will become more and more wonderful.

 

[Mo0odi]

Thanks for all this effort

 

[bigbadbear]

thank you so much for all this efforts and hard work

 

[Melv99]

If you add approx half the amount per mol of L-Malic acid to DL-Amphetamine FB in a NP then added DH20. Wouldn't the aqueous layer contain mostly D-Amp Malate with the L mostly stay in the NP?

Lastly! Thanks! Very interesting post. Finally someone did the work and answerws the questions we all have had. Nice work

 

[GhostChemist]

about Malic acid and isomers we haven`t now experimental information
May be later

 

[Pororo]

you did great work bro many thanks

but you forgot to mention an important salt - lactate. It may be useful if such amph class derivatives used for vape liquids.

amph class lactates form of ionic liquids (liquid form salt).

 

[GhostChemist]

Interesting, we are working in the vape liquids too

 

[Pororo]

what is best drying route for the such ionic salt liquids?
dissolve it in acetone, dry with magnesium, then evaporate acetone?

 

[Papasandalus]

Great job, would you be able to post photos of these salts under uv light?

 

[Mo0odi]

Why wasn't fenethylline mentioned? It's a combination between amphetamine and theophylline

 

[G.Patton]

Hi, there is separated topic about fenethylline (Captagon).

 

[Pororo]

Malate is also suitable for the vape systems. Has anybody tried to vape amphetamine malate?

 

[cokemuffin]

Can someone crystallize them with dextro amphetamine base to look if some salts form crystals

 

[cokemuffin]

In the scheme adipate is mentioned in a 2 to 1 molar ration of amphetamine and adipic acid, but the actual process shows a 1 to 1 ratio?