Nonproprietary Names

USP:Aspartame
PhEur:Aspartame USP-NF: Aspartame

Synonyms

(3S)-3-Amino-4-[[(1S)-1-benzyl-2-methoxy-2-oxoethyl]amino]-4oxobutanoic acid; 3-amino-N-(a-carboxyphenethyl)succinamic acid N-methyl ester; 3-amino-N-(a-methoxycarbonylphenethyl)succinamic acid; APM; aspartamum; aspartyl phenylamine methyl ester; Canderel; E951; Equal; methyl N-L-a-aspartyl-L-phenylalaninate; NatraTaste; NutraSweet; Pal Sweet; Pal Sweet Diet; Sanecta; SC-18862; Tri-Sweet.

Chemical Name and CAS Registry Number

N-L-a-Aspartyl-L-phenylalanine 1-methyl ester [22839-47-0]

Empirical Formula and Molecular Weight

C14H18N2O5 294.30

Structural Formula

Functional Category

Sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Technology Aspartame is used as an intense sweetening agent in beverage products, food products, and table-top sweeteners, and in pharmaceutical preparations including tablets,(1,2) powder mixes, and vitamin preparations. It enhances flavor systems and can be used to mask some unpleasant taste characteristics; the approximate sweetening power is 180–200 times that of sucrose. Unlike some other intense sweeteners, aspartame is metabolized in the body and consequently has some nutritive value: 1g provides approximately 17kJ (4kcal). However, in practice, the small quantity of aspartame consumed provides a minimal nutritive effect.

Description

Aspartame occurs as an off white, almost odorless crystalline powder with an intensely sweet taste. 48 SEM 1: Excipient: aspartame; magnification: 70; voltage: 3 kV.

Pharmacopeial Specifications

See Table I. Table I: Pharmacopeial specifications for aspartame. Test PhEur 6.0 USP32–NF27 Identification Characters Appearance of solution Conductivity þ þ 4þ 30 mS/cm þ — — — Specific optical rotation Related substances Heavy metals þ14.58 to þ16.58 4þ 10 ppm þ14.58 to þ16.58 — 40.001% Loss on drying 44.5% 44.5% Residue on ignition — 40.2% Sulfated ash 40.2% — Impurities Transmittance Limit of 5-benzyl-3,6-dioxo-2piperazineacetic acid þ — — — þ 41.5% Chromatographic purity Assay — 98.0–102.0% þ 98.0–102.0%

Typical Properties

Acidity/alkalinity pH = 4.5–6.0 (0.8% w/v aqueous solution) Brittle fracture index 1.05(3) Bonding index 0.8102 (worst case)(3) 2.3102 (best case)(3) Flowability 44% (Carr compressibility index)(3) Density (bulk) 0.5–0.7g/cm3 for granular grade; 0.2–0.4g/cm3 for powder grade; 0.17g/cm3 (Spectrum Quality Products).(3) Density (tapped) 0.29g/cm3 (Spectrum Quality Products)(3) 1100 1300 1500 1700 1900 2100 2300 2500 Wavelength/nm Figure 1: Near-infrared spectrum of aspartame measured by reflectance. Figure 2: Stability profile of aspartame in aqueous buffers at 258C.(8) Density (true) 1.347g/cm3 Effective angle of internal friction 43.08(3) Melting point 246–2478C NIR spectra see Figure 1. Solubility Slightly soluble in ethanol (95%); sparingly soluble in water. At 208C the solubility is 1% w/v at the isoelectric point (pH 5.2). Solubility increases at higher temperature and at more acidic pH, e.g., at pH 2 and 208C solubility is 10% w/v. Specific rotation [a]22D =2.38 in 1N HCl

Stability and Storage Conditions

Aspartame is stable in dry conditions. In the presence of moisture, hydrolysis occurs to form the degradation products L -aspartyl-Lphenylalanine and 3-benzyl-6-carboxymethyl-2,5-diketopiperazine with a resulting loss of sweetness. A third-degradation product is also known, b-L-aspartyl-L-phenylalanine methyl ester. For the stability profile at 258C in aqueous buffers, see Figure 2. Stability in aqueous solutions has been enhanced by the addition of cyclodextrins,(4,5) and by the addition of polyethylene glycol 400 at pH 2.(6) However, at pH 3.5–4.5 stability is not enhanced by the replacement of water with organic solvents.(7) Aspartame degradation also occurs during prolonged heat treatment; losses of aspartame may be minimized by using processes Aspartame that employ high temperatures for a short time followed by rapid cooling. The bulk material should be stored in a well-closed container, in a cool, dry place.

Incompatibilities

Differential scanning calorimetry experiments with some directly compressible tablet excipients suggests that aspartame is incompatible with dibasic calcium phosphate and also with the lubricant magnesium stearate.(9) Reactions between aspartame and sugar alcohols are also known.

Method of Manufacture

Aspartame is produced by coupling together L-phenylalanine (or Lphenylalanine methyl ester) and L-aspartic acid, either chemically or enzymatically. The former procedure yields both the sweet aaspartame and nonsweet b-aspartame from which the a-aspartame has to be separated and purified. The enzymatic process yields only a-aspartame.

Safety

Aspartame is widely used in oral pharmaceutical formulations, beverages, and food products as an intense sweetener, and is generally regarded as a nontoxic material. However, the use of aspartame has been of some concern owing to the formation of the potentially toxic metabolites methanol, aspartic acid, and phenylalanine. Of these materials, only phenylalanine is produced in sufficient quantities, at normal aspartame intake levels, to cause concern. In the normal healthy individual any phenylalanine produced is harmless; however, it is recommended that aspartame be avoided or its intake restricted by those persons with phenylketonuria.(10) The WHO has set an acceptable daily intake for aspartame at up to 40mg/kg body-weight.(11) Additionally, the acceptable daily intake of diketopiperazine (an impurity found in aspartame) has been set by the WHO at up to 7.5mg/kg body-weight.(12) A number of adverse effects have been reported following the consumption of aspartame,(10,12) particularly in individuals who drink large quantities (up to 8 liters per day in one case) of aspartame-sweetened beverages. Reported adverse effects include: headaches;(13) grand mal seizure;(14) memory loss;(15) gastrointestinal symptoms; and dermatological symptoms. However, scientifically controlled peer-reviewed studies have consistently failed to produce evidence of a causal effect between aspartame consumption and adverse health events.(16,17) Controlled and thorough studies have confirmed aspartame’s safety and found no credible link between consumption of aspartame at levels found in the human diet and conditions related to the nervous system and behavior, nor any other symptom or illness. Aspartame is well documented to be nongenotoxic and there is no credible evidence that aspartame is carcinogenic.(18) Although aspartame has been reported to cause hyperactivity and behavioral problems in children, a double-blind controlled trial of 48 preschool-age children fed diets containing a daily intake of 38 13mg/kg body-weight of aspartame for 3 weeks showed no adverse effects attributable to aspartame, or dietary sucrose, on children’s behavior or cognitive function.(19)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Measures should be taken to minimize the potential for dust explosion. Eye protection is recommended. Aspartame

Regulatory Status

Accepted for use as a food additive in Europe and in the USA. Included in the FDA Inactive Ingredients Database (oral powder for reconstitution, buccal patch, granules, syrups, and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances Alitame; aspartame acesulfame; neotame. Aspartame acesulfame Empirical formula C18H23O9N3S Molecular weight 457.46 CAS number 106372-55-8 Comments A compound of aspartame and acesulfame approx. 350 times sweeter than sucrose. Aspartame acesulfame is listed in the USP32–NF27.

Comments

The intensity of sweeteners relative to sucrose depends upon their concentration, temperature of tasting, and pH, and on the flavor and texture of the product concerned. Intense sweetening agents will not replace the bulk, textural, or preservative characteristics of sugar, if sugar is removed from a formulation. Synergistic effects for combinations of sweeteners have been reported, e.g. aspartame with acesulfame potassium. Aspartame can cause browning when used at high temperatures. A specification for aspartame is contained in the Food Chemicals Codex (FCC).(20) The PubChem Compound ID (CID) for aspartame includes 2242 and 21462246. 19 Specific References 1 Joachim J et al. [The compression of effervescent aspartame tablets: the influence of particle size on the strain applied on the punches during compression.] J Pharm Belg 1987; 42: 17–28[in French]. 2 Joachim J et al. [The compression of effervescent aspartame tablets: the influence of particle size and temperature on the effervescence time and carbon dioxide liberation kinetics.] J Pharm Belg 1987; 42: 303–314[in French]. 3 Mullarney MP et al. The powder flow and compact mechanical properties of sucrose and three high-intensity sweeteners used in chewable tablets. Int J Pharm 2003; 257(1–2): 227–236. 4 Brewster ME et al. Stabilization of aspartame by cyclodextrins. Int J Pharm 1991; 75: R5–R8. 5 Prankerd RJ et al. Degradation of aspartame in acidic aqueous media and its stabilization by complexation with cyclodextrins or modified cyclodextrins. Int J Pharm 1992; 88: 189–199. 6 Yalkowsky SH et al. Stabilization of aspartame by polyethylene glycol 400. J Pharm Sci 1993; 82: 978. 7 Sanyude S et al. Stability of aspartame in water: organic solvent mixtures with different dielectric constants. J Pharm Sci 1991; 80: 674– 676. 8 The NutraSweet Company. Technical literature: NutraSweet technical bulletin, 1991. 9 El-Shattawy HE et al. Aspartame-direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7: 605–619. 10 Golightly LK et al. Pharmaceutical excipients: adverse effects associated with inactive ingredients in drug products (part II). Med Toxicol 1988; 3: 209–240. 11 FAO/WHO. Evaluation of certain food additives and contaminants. Twenty-fifth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1981; No. 669. 12 Butchko HH, Kotsonis FN. Aspartame: review of recent research. CommentsToxicol 1989; 3(4): 253–278. 13 Schiffman SS et al. Aspartame and susceptibility to headache. N Engl J Med 1987; 317: 1181–1185. 14 Wurtman RJ. Aspartame: possible effect on seizure susceptibility [letter]. Lancet 1985; ii: 1060. 15 Anonymous. Sweetener blamed for mental illnesses. New Scientist 1988; February 18: 33. 16 O’Donnell K. Aspartame and neotame. Mitchell H, ed. Sweeteners and Sugar Alternatives in Food Technology. Oxford, UK: Blackwell Publishing, 2006; 86–102. 17 European Commission. Opinion of the Scientific Committee on Food: update on the safety of aspartame, 2002. Available at: http:// europa.eu.int/comm/food/fs/sc/scf/out155_en.pdf (accessed 18 February 2009). 18 Magnuson BA et al. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol 2007; 37: 629–727. 19 Wolraich ML et al. Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. N Engl J Med 1994; 330: 301–307. 20 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 69.

General References

Marie S. Sweeteners. Smith J, ed. Food Additives User’s Handbook. Glasgow: Blackie, 1991; 47–74. Roy GM. Taste masking in oral pharmaceuticals. Pharm Technol Eur 1994; 6(6): 24, 26–2830–3234, 35. Stegink LD, Filer LJ, eds. Aspartame, Physiology and Biochemistry. New York: Marcel Dekker, 1984.

Author

A Cram.

Date of Revision

18 February 2009.