Aspartame^[1]

Names
IUPAC names N-(L-α-Aspartyl)-L-phenylalanine, 1-methyl ester
Identifiers
CAS Number	22839-47-0 Y
3D model (JSmol)	Interactive image
ChemSpider	118630 Y
ECHA InfoCard	100.041.132
E number	E951 (glazing agents, ...)
UNII	Z0H242BBR1 Y
CompTox Dashboard (EPA)	DTXSID0020107
InChI InChI=1S/C14H18N2O5/c1-21-14(20)11(7-9-5-3-2-4-6-9)16-13(19)10(15)8-12(17)18/h2-6,10-11H,7-8,15H2,1H3,(H,16,19)(H,17,18)/t10-,11-/m0/s1 Key: IAOZJIPTCAWIRG-QWRGUYRKSA-N InChI=1/C14H18N2O5/c1-21-14(20)11(7-9-5-3-2-4-6-9)16-13(19)10(15)8-12(17)18/h2-6,10-11H,7-8,15H2,1H3,(H,16,19)(H,17,18)/t10-,11-/m0/s1 Key: IAOZJIPTCAWIRG-QWRGUYRKBV
SMILES O=C(O)C[C@H](N)C(=O)N[C@H](C(=O)OC)Cc1ccccc1
Properties
Chemical formula	C14H18N2O5
Molar mass	294.307 g·mol−1
Density	1.347 g/cm3
Melting point	246–247 °C
Boiling point	decomposes
Solubility in water	sparingly soluble
Solubility	slightly soluble in ethanol
Acidity (pKa)	4.5-6.0 [2]
Hazards
NFPA 704 (fire diamond)	1 1 0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

Aspartame (or APM) (Template:PronEng or /əˈspɑrteɪm/) is an artificial, non-saccharide sweetener used as a sugar substitute in some foods and beverages. The most notable name brand of aspartame is Nutra-sweet.^{[citation needed]} In the European Union, it is codified as E951. Aspartame is a methyl ester of the aspartic acid/phenylalanine dipeptide. It was first synthesized in 1965.

The safety of aspartame has been the subject of several political and medical controversies, Congressional hearings and internet hoaxes since its initial approval for use in food products by the U.S. Food and Drug Administration (FDA) in 1974. A 2007 medical review on the subject concluded that "the weight of existing scientific evidence indicates that aspartame is safe at current levels of consumption as a non-nutritive sweetener".^[3] However, because its breakdown products include phenylalanine, aspartame must be avoided by people with the genetic condition phenylketonuria (PKU).

Chemistry

Aspartame is a methyl ester of the dipeptide of the natural amino acids L-aspartic acid and L-phenylalanine. Under strongly acidic or alkaline conditions, aspartame may generate methanol by hydrolysis. Under more severe conditions, the peptide bonds are also hydrolyzed, resulting in the free amino acids.^[4]

There are two approaches to synthesis which are used commercially. In the chemical synthesis, the two carboxyl groups of aspartic acid are joined into an anhydride and the amino group is protected by a compound that will prevent further reactions of that group. Phenylalanine is methylated and combined with the N-protected aspartic anhydride, then the blocking group is removed from aspartic acid by acid hydrolysis. The drawback of this technique is that a byproduct, the bitter tasting β-form, is produced when the wrong carboxyl group from aspartic acid links to phenylalanine. A process using an enzyme from Bacillus thermoproteolyticus to catalyze the condensation of the chemically altered amino acids will produce high yields without the β-form byproduct. A variant of this method, which has not been used commercially, uses unmodified aspartic acid, but produces low yields. Methods for directly producing aspartyl-phenylalanine by enzymatic means, followed by chemical methylation, have also been tried but not scaled for industrial production.^[5]

Properties and use

Aspartame is an artificial sweetener and is approximately 200 times sweeter than sucrose, or table sugar. Due to this property, though aspartame upon metabolism produces 4 kilocalories of energy per gram, the quantity of aspartame needed to produce a sweet taste is so small that its caloric contribution is negligible.^[3] The taste of aspartame and other artificial sweeteners differ from that of table sugar in the times of onset and how long the sweetness lasts, though aspartame comes closest amongst artificial sweeteners to sugar's taste profile. The sweetness of aspartame lasts longer than sucrose, so it is often blended with other artificial sweeteners like acesulfame potassium to produce an overall taste more like sugar.^[6] Aspartame can be synthesized from its constituent amino acids, L-phenylalanine and L-aspartate.

Like many other peptides, aspartame may hydrolyze (break down) into its constituent amino acids under conditions of elevated temperature or high pH. This makes aspartame undesirable as a baking sweetener, and prone to degradation in products hosting a high-pH, as required for a long shelf life. The stability of aspartame under heating can be improved to some extent by encasing it in fats or in maltodextrin. The stability when dissolved in water depends markedly on pH. At room temperature, it is most stable at pH 4.3, where its half-life is nearly 300 days. At pH 7, however, its half-life is only a few days. Most soft-drinks have a pH between 3 and 5, where aspartame is reasonably stable. In products that may require a longer shelf life, such as syrups for fountain beverages, aspartame is sometimes blended with a more stable sweetener, such as saccharin.^[7]

Aspartame's major decomposition products are its cyclic dipeptide (diketopiperazine form), the de-esterified dipeptide (aspartyl-phenylalanine), and its constituent components, phenylalanine,^[8] aspartic acid,^[9] and methanol.^[10] At 180° C, aspartame undergoes decomposition to form a diketopiperazine (DKP) derivative.^[11]

In products such as powdered beverages, the amine in aspartame can undergo a Maillard reaction with the aldehyde groups present in certain aroma compounds. The ensuing loss of both flavor and sweetness can be prevented by protecting the aldehyde as an acetal.

Descriptive analyses of solutions containing aspartame report a sweet aftertaste as well as bitter and off-flavour aftertastes.^[12]

Discovery and approval

Aspartame was discovered in 1965 by James M. Schlatter, a chemist working for G.D. Searle & Company. Schlatter had synthesized aspartame in the course of producing an antiulcer drug candidate. He accidentally discovered its sweet taste when he licked his finger, which had become contaminated with aspartame, to lift up a piece of paper.^[13][14]

In 1975, prompted by issues regarding Flagyl and Aldactone, a U.S. FDA task force team reviewed 25 studies submitted by the manufacturer, including 11 on aspartame. The team reported “serious deficiencies in Searle’s operations and practices".^[15] The FDA sought to authenticate 15 of the submitted studies against the supporting data, in 1979 the Center for Food Safety and Applied Nutrition (CFSAN) concluded that, as any problems with the aspartame studies were minor and did not affect the conclusions, the studies could be used to assess aspartame's safety.^[15]

In 1980, the FDA convened a Public Board of Inquiry (PBOI) consisting of independent advisors charged with examining the purported relationship between aspartame and brain cancer. The PBOI concluded that aspartame does not cause brain damage, but it recommended against approving aspartame at that time, citing unanswered questions about cancer in laboratory rats.^[15][16]

Citing data from a Japanese study that had not been available to the members of the PBOI,^[17] and after seeking advice from an expert panel that found fault with statistical analyses underlying the PBOI's hesitation, yet argued against approval,^[18] FDA commissioner Hayes approved aspartame for use in dry goods.^[19] In 1983, the FDA further approved aspartame for use in carbonated beverages, and for use in other beverages, baked goods, and confections in 1993. In 1996, the FDA removed all restrictions from aspartame, allowing it to be used in all foods.

In 1984, Monsanto Company bought G.D. Searle—and the aspartame business became a separate Monsanto subsidiary, the NutraSweet Company. On May 25, 2000, Monsanto sold it to J.W. Childs Equity Partners II L.P.^[20] The U.S. patent on aspartame expired in 1992. Since then, the company has competed for market share with other manufacturers, including Ajinomoto, Merisant and the Holland Sweetener Company. The latter stopped making the chemical in late 2006 because "global aspartame markets are facing structural oversupply, which has caused worldwide strong price erosion over the last five years", making the business "persistently unprofitable".^[21]

Several European Union countries approved aspartame in the 1980s, with EU-wide approval in 1994. The European Commission Scientific Committee on Food reviewed subsequent safety studies and reaffirmed the approval in 2002. The European Food Safety Authority reported in 2006 that the previously established Acceptable Daily Intake was appropriate, after reviewing yet another set of studies.^[22]

Metabolism and phenylketonuria

Upon ingestion, aspartame breaks down into natural residual components, including aspartic acid, phenylalanine, methanol,^[23] and further breakdown products including formaldehyde^[24] and formic acid, accumulation of the latter being suspected as the major cause of injury in methanol poisoning. Human studies show that formic acid is excreted faster than it is formed after ingestion of aspartate. In some fruit juices, higher concentrations of methanol can be found than the amount produced from aspartame in beverages.^[9]

High levels of the naturally-occurring essential amino acid phenylalanine are a health hazard to those born with phenylketonuria (PKU), a rare inherited disease that prevents phenylalanine from being properly metabolized. Since individuals with PKU must consider aspartame as an additional source of phenylalanine, foods containing aspartame sold in the United States must state "Phenylketonurics: Contains Phenylalanine" on their product labels.^[25]

In the UK, foods that contain aspartame are legally required by the country's Food Standards Agency to list the chemical among the product's ingredients and carry the warning "Contains a source of phenylalanine" – this is usually at the foot of the list of ingredients. Manufacturers are also required to print '"with sweetener(s)" on the label close to the main product name' on foods that contain "sweeteners such as aspartame" or "with sugar and sweetener(s)" on "foods that contain both sugar and sweetener".^[26]

Marketing

Equal, NutraSweet, and Canderel are ingredients of approximately 6,000 consumer foods and beverages sold worldwide, including (but not limited to) diet sodas and other soft drinks, instant breakfasts, breath mints, cereals, sugar-free chewing gum, cocoa mixes, frozen desserts, gelatin desserts, juices, laxatives, chewable vitamins supplements, milk drinks, pharmaceutical drugs and supplements, shake mixes, tabletop sweeteners, teas, instant coffees, topping mixes, wine coolers and yogurt. It is provided as a table condiment in some countries. Aspartame is less suitable for baking than other sweeteners, because it breaks down when heated and loses much of its sweetness. Aspartame is also one of the main sugar substitutes used by people with diabetes.

Ajinomoto

In 2004 the market for aspartame, in which the company Ajinomoto, the world's largest aspartame manufacturer, had a 40 percent share, was 14,000 metric tons a year, and consumption of the product was rising by 2 percent a year.^[27] Ajinomoto acquired its aspartame business in 2000 from Monsanto for $67M.^[28]

In 2008, Ajinomoto sued British supermarket chain Asda, part of Wal-Mart, for a malicious falsehood action concerning its aspartame product when the chemical was listed as excluded from the chain's product line, along with other "nasties".^[29] In July 2009, a British court found in favour of Asda.^[30] In June 2010, an appeal court reversed the decision, allowing Ajinomoto to pursue a case against Asda to protect aspartame's reputation.^[31] Asda said that it would continue to use the term "no nasties" on its own-label products.^[32]

In November 2009, Ajinomoto announced a new brand name for its aspartame sweetener — AminoSweet.^[33][34]

Competition

Because sucralose, unlike aspartame, retains its sweetness after being heated, and has at least twice the shelf life of aspartame, it has become more popular as an ingredient.^[35] This, along with differences in marketing and changing consumer preferences, caused aspartame to lose market share to sucralose.^[36][37] In 2004, aspartame traded at about $30/kg and sucralose, which is roughly three times sweeter by weight, at around $300/kg.^[38]

Safety controversy

Aspartame has been the subject of several controversies and hoaxes since its initial approval by the U.S. Food and Drug Administration (FDA) in 1974. Critics allege that conflicts of interest marred the FDA's approval of aspartame, question the quality of the initial research supporting its safety,^[39][40][41] and postulate that numerous health risks may be associated with aspartame.

The validity of these claims has been examined and dismissed.^[39][3][42] In 1987, the U.S. Government Accountability Office concluded that the food additive approval process had been followed properly for aspartame.^[39][43] Aspartame has been found to be safe for human consumption by more than ninety countries worldwide,^[44][45] with FDA officials describing aspartame as "one of the most thoroughly tested and studied food additives the agency has ever approved" and its safety as "clear cut".^[46] The weight of existing scientific evidence indicates that aspartame is safe at current levels of consumption as a non-nutritive sweetener.^[3]

Compendial status

• British Pharmacopoeia ^[47]
• United States Pharmacopeia ^[48]

References