Nonproprietary Names

None adopted.

Synonyms

Aclame; L-aspartyl-D-alanine-N-(2,2,4,4-tetramethylthietan-3-yl)amide; 3-(L-aspartyl-D-alaninamido)-2,2,4,4-tetramethylthietane.

Chemical Name and CAS Registry Number

L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide anhydrous [80863-62-3] L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate [99016-42-9]

Empirical Formula and Molecular Weight

C14H25N3O4S 331.44 (for anhydrous) C14H25N3O4S21=2H2O 376.50 (for hydrate)

Structural Formula

Functional Category

Sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Technology Alitame is an intense sweetening agent developed in the early 1980s and is approximately 2000 times sweeter than sucrose. It has an insignificant energy contribution of 6kJ (1.4kcal) per gram of alitame. Alitame is currently primarily used in a wide range of foods and beverages at a maximum level of 40–300mg/kg.(1)

Description

Alitame is a white nonhygroscopic crystalline powder; odorless or having a slight characteristic odor.

Pharmacopeial Specifications

—

Typical Properties

Acidity/alkalinity pH = 5–6 (5% w/v aqueous solution) Isoelectric point pH 5.6 Melting point 136–1478C Solubility see Table I. Table I: Solubility of alitame. Solvent Solubility at 208C unless otherwise stated Chloroform 1 in 5000 at 258C Ethanol 1 in 1.6 at 258C n-Heptane Practically insoluble Methanol 1 in 2.4 at 258C Propylene glycol 1 in 1.9 at 258C Water 1 in 8.3 at 58C 1 in 7.6 at 258C 1 in 3.3 at 408C 1 in 2.0 at 508C Specific rotation [a]25D = þ408 to þ508 (1% w/v aqueous solution)

Stability and Storage Conditions

Alitame is stable in dry, room temperature conditions but undergoes degradation at elevated temperatures or when in solution at low pH. Alitame can degrade in a one-stage process to aspartic acid and alanine amide (under harsh conditions) or in a slow two-stage process by first degrading to its b-aspartic isomer and then to aspartic acid and alanine amide. At pH 5–8, alitame solutions at 238C have a half-life of approximately 4 years. At pH 2 and 238C the half-life is 1 year. Alitame should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Alitame may be incompatible with oxidizing and reducing substances or strong acids and bases.

Method of Manufacture

Alitame may be synthesized by a number of routes.(2,3) For example, 3-(D-alaninamido)-2,2,4,4-tetramethylthietane is dissolved in water and L-aspartic acid N-thiocarboxyanhydride is then added in portions with vigorous stirring, maintaining the pH of 8.5–9.5. The pH is then adjusted to 5.5 and p-toluenesulfonic acid monohydrate is added over a period of one hour. The precipitated crystalline p-toluenesulfonate salt is collected by filtration. To obtain alitame from its salt, a mixture of Amberlite LA-1 (liquid anion exchange resin), dichloromethane, deionized water, and the salt is stirred for one hour, resulting in two clear layers. The aqueous layer is treated with carbon, clarified by filtration, and cooled to crystallize alitame. Alternatively, tetramethylthietane amine is condensed with an Nprotected form of D-alanine to give alanyl amide. This is then coupled to a protected analogue of L-aspartic acid to give a crude form of alitame. The crude product is then purified.

Safety

Alitame is a relatively new intense sweetening agent used primarily in foods and confectionary. It is generally regarded as a relatively nontoxic and nonirritant material. Chronic animal studies in mice, rats, and dogs carried out for a minimum of 18 months at concentrations >100mg/kg per day exhibited no toxic or carcinogenic effects. In people, no evidence of untoward effects were observed following ingestion of 15mg/kg per day for two weeks. Following oral administration 7–22% of alitame is unabsorbed and excreted in the feces. The remaining amount is hydrolyzed to aspartic acid and alanine amide. The aspartic acid is metabolized normally and the alanine amide excreted in the urine as a sulfoxide isomer, as the sulfone, or conjugated with glucuronic acid. The WHO has set an acceptable daily intake of alitame at up to 0.1mg/kg body-weight.(4) LD50 (mouse, oral): >5g/kg LD50 (rabbit, skin): >2g/kg LD50 (rat, oral): >5g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Alitame should be stored in tightly closed containers, and protected from exposure to direct sunlight and higher than normal room temperatures. Almond Oil

Regulatory Status

Alitame is approved for use in food applications in a number of countries worldwide including Australia, Chile, China, Mexico, and New Zealand. 17 Related Substances Acesulfame potassium; aspartame; saccharin; saccharin sodium; sodium cyclamate.

Comments

The PubChem Compound ID (CID) for alitame is 64763. 19 Specific References 1 FAO/WHO. Evaluation of certain food additives and contaminants. Fifty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 2002; No. 913. 2 Sklavounos C. Process for preparation, isolation and purification of dipeptide sweeteners. United States Patent No. 4,375,430; 1 Mar, 1983. 3 Brennan TM, Hendrick ME. Branched amides of L-aspartyl-D-amino acid dipeptides. United States Patent No. 4,411,925; 25 Oct, 1983. 4 FAO/WHO. Evaluation of certain food additives and contaminants. Forty-sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1997; No. 868.

General References

Anonymous. Use of nutritive and nonnutritive sweeteners—position of ADA. J Am Diet Assoc 1998; 98: 580–587. Hendrick ME. Alitame. Nabors L, Gelardi R, eds. Alternative Sweeteners. New York: Marcel Dekker, 1991; 29–38. Hendrick ME. Grenby TH, ed. Advances in Sweeteners. Glasgow: Blackie, 1996; 226–239. Renwick AG. The intake of intense sweeteners – an update review. Food Addit Contam 2006; 23: 327–338.

Author

LY Galichet.

Date of Revision

5 August 2008.