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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.
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.
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
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.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 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 |
| 6.8 | 11.7 | EtOH |
| 5.4 | 10.4 | EtOH |
| 4.36 g (85%) | 8.6 | EtOH |
| 2.5 | 7.7 | EtOH |
| 2.5 | 7.4 | EtOH |
| 2.6 | 7.3 | EtOH |
| 2.7 +1 ml 14% HCl | 8.3 (HCl) | EtOH |
| 4.6 | 9.5 | Bnzene, EtOH, DCM |
| 6.7 | 11.6 | EtOH |
| 2.8 | 7.7 | EtOH+T℃ |
| 2.2 | 7.1 | EtOH |
| 2.7 | 7.7 | - |
| 1 | 4.3 | Н2О |
| 2.1 | 5.4 | Н2О |
| 1.6 | 5 | - |
The appearance of the acids is presented in the following photos.
Adipic acid. Fig 13
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 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 |
| 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. |
| 86-345.7 |
| 76.4-305.5 |
| 63.3-253.2 |
| 57.2-228.8 |
| 54.9-219.6 |
| 54.1-216.3 |
| 56.7-226.7 (I) 61.6-246.5 (II) |
| 69.9-279.4 |
| 85.6-342.4 |
| 57.1-228.3 |
| 52.7-210.9 |
| 56.8-227.2 |
| 46.6-186.4 |
| 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.
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