Aspartame

Background

Aspartame is an artificial sweetener used in reduced calorie foods. It is derived primarily from two naturally occurring amino acids chemically combined and designated by the chemical name N-L-aaspartyl-L-phenylalanine-l-methyl ester (APM). Discovered inadvertently in 1965, it was later patented and is currently the most utilized artificial sweetener in the United States.

Aspartame is a white, odorless, crystalline powder. It is about 200 times sweeter than sugar and is readily dissolvable in water. It has a sweet taste without the bitter chemical or metallic aftertaste reported in other artificial sweeteners. These properties make it a good ingredient to use as a sugar replacement in many food recipes. However, aspartame does tend to interact with other food flavors, so it cannot perfectly replace sugar. Recipes for baked goods, candies, and other products must be modified if aspartame is utilized. Although aspartame can be used in microwave recipes, it is sensitive to extensive heating, which makes it unsuitable for baking.

The fact that aspartame provides sweetness and flavor without imparting other physical characteristics such as bulk or calories like other sweeteners makes it unique. Another useful trait is that it has a synergistic effect with other sweeteners, making it possible to use less total sweetener. In addition to sweetening foods, aspartame is used to reduce calories, and intensify and extend fruit flavors.

History

Humans have desired foods with a sweet taste for thousands of years. Ancient cave paintings at Arana in Spain show a neolithic man taking honey from a wild bee's nest. It has been suggested that early humans might have used the sweet taste of foods to tell them which ones would be safe to eat. It is even thought that the desire for sweet taste might be an innate human trait. Unfortunately, many of the foods that are naturally sweet contain relatively large amounts of calories and carbohydrates.

Alternative sweeteners were developed to provide the sweet taste without the unnecessary calories. They also provide the additional benefits of enhancing the palatability of pharmaceuticals, aiding in the management of diabetes, and providing a cost-effective source where sugar is not available. The first one, saccharin, was discovered in 1879 and has been used in products such as toothpaste, mouthwash, and sugarless gum.

The sugarlike taste of aspartame was discovered accidentally by James Schlatter, an American drug researcher at G.D. Searle and Co. in 1965. While working on an antiulcer drug, he inadvertently spilled some APM on his hand. Figuring that the material was not toxic, he went about his work without washing it off. He discovered APM's sweet taste when he licked his finger to pick up a piece of weighing paper. This initial breakthrough then led the company to screen hundreds of modified versions of APM. However, none of these materials offered all of the advantages found in the original compound, including economical manufacturing, excellent taste quality and potency, natural metabolic pathways for digestion, excellent stability, and very low toxicity. Consequently, the company pursued and was granted United States patent 3,492,131 and various international patents, and the initial discovery was commercialized. The U.S. patent expired in 1992, and the technology is now available to any company who wants to use it.

After many years of toxicity testing, the FDA initially approved aspartame's use as a sweetener in 1980. However, a hallmark of synthetic chemicals used in food products is that their safety is under constant scrutiny. Aspartame is no exception and has been surrounded by some controversy concerning its safety since its introduction. Most of these concerns were put to rest in late 1984, when after investigating various aspartame-related complaints, the FDA and the Centers for Disease Control concluded that the substance is safe and does not represent a widespread health risk. This conclusion was further supported by the American Medical Association in 1985, and aspartame has been gaining market share ever since. In addition to its use in the United States, aspartame has also been approved for use in over 93 foreign countries.

Aspartame has been marketed since 1983 by Searle under the brand names NutraSweet' and Equal'. Currently, NutraSweet' is a very popular ingredient and is used in more than 4,000 products, including chewing gum, yogurt, diet soft drinks, fruit-juices, puddings, cereals, and powdered beverage mixes. In the U.S. alone, NutraSweet®'s sales topped $705 million in 1993, according to the company.

Raw Materials

Aspartame is primarily derived from compounds called amino acids. These are chemicals which are used by plants and animals to create proteins that are essential for life. Of the 20 naturally occurring amino acids, two of them, aspartic acid and phenylalanine, are used in the manufacture of aspartame.

All amino acids molecules have some common characteristics. They are composed of an amino group, a carboxyl group, and a side chain. The chemical nature of the side chain is what differentiates the various amino acids. Another characteristic of amino acids is the ability to form different molecular configurations known as isomers. These isomers are designated by the letters L and D. Aspartame is composed of only L, L isomers; none of the other isomer combinations taste sweet. The sweet taste of aspartame could not have been predicted by looking at the two amino acids that it is derived from. L-aspartic acid has a flat taste and L-phenylalanine tastes bitter. However, when the two compounds are chemically combined and the L-phenylalanine is slightly modified, a sweet taste is achieved.

Aspartic acid is one of five amino acids that have a "charged" side group. The charged side group on aspartic acid is (-CH₂-COOH). When put in water, this material ionizes and becomes negatively charged. Phenylalanine has a nonpolar, hydrophobic side group which is not compatible with water. It is made up of a six carbon ring and is attached to the main amino acid backbone via a methyl (-CH₂) group. Prior to synthesis into aspartame, it is reacted with methanol. This adds a methyl group which is linked to the molecule by an oxygen, and the compound is converted to a methyl ester. The methanol required for the synthesis of aspartame has the chemical structure (CH₃-OH). This is a very common material and is used extensively by organic chemists for various chemical syntheses.

The Manufacturing
Process

Although its components—aspartic acid, phenylalanine, and methanol—occur naturally in foods, aspartame itself does not and must be manufactured. NutraSweet' (aspartame) is made through fermentation and synthesis processes.

Fermentation

Direct fermentation produces the starting amino acids needed for the manufacture of aspartame. In this process, specific types of bacteria which have the ability to produce certain amino acids are raised in large quantities. Over the course of about three days, the amino acids are harvested and the bacteria are destroyed.

• 1 To start the fermentation process, a sample from a pure culture of bacteria is put into a test tube containing the nutrients necessary for its growth. After this initial inoculation the bacteria begin to multiply. When their population is large enough, they are transferred to a seed tank. The bacterial strains used to make L-aspartic acid and L-phenylalanine are B. flavum and C. glutamicum respectively.
• 2 The seed tank provides an ideal environment for growing more bacteria. It is filled with the things bacteria need to thrive, including warm water and carbohydrate foods like cane molasses, glucose, or sucrose. It also has carbon sources like acetic acid, alcohols or hydrocarbons, and nitrogen sources such as liquid ammonia or urea. These are required for the bacteria to synthesize large quantities of the desired amino acid. Other growth factors such as vitamins, amino acids, and minor nutrients round out seed tank contents. The seed tank is equipped with a mixer, which keeps the growth medium moving, and a pump, which delivers filtered, compressed air. When enough bacterial growth is present, the contents from the seed tank are pumped to the fermentation tank.
• 3 The fermentation tank is essentially a larger version of the seed tank. It is filled with the same growth media found in the seed tank and also provides a perfect environment for bacterial growth. Here the bacteria are allowed to grow and produce large quantities of amino acids. Since pH control is vital for optimal growth, ammonia water is added to the tank as necessary.
• 4 When enough amino acid is present, the contents of the fermentation tank are transferred out so isolation can begin. This process starts with a centrifugal separator, which isolates a large portion of the bacterial amino acids. The desired amino acid is further segregated and purified in an ion-exchange column. From this column, the amino acids are pumped to a crystallizing tank and then to a crystal separator. They are then dried and readied for the synthesis phase of aspartame production.

Synthesis

Aspartame can be made by various synthetic chemical pathways. In general, phenylalanine is modified by a reaction with methanol and then combined with a slightly modified aspartic acid which eventually forms aspartame.

• 5 The amino acids derived from the fermentation process are initially modified to produce aspartame. Phenylalanine is reacted with methanol resulting in a compound called L-phenylalanine methyl ester. Aspartic acid is also modified in such a way to shield various portions of the molecule from the effects of further reactions. One method is by reacting the aspartic acid with substances that result in added benzyl rings to protect these sites. This ensures that further chemical reactions will occur only on specific parts of the aspartic acid molecule.
• 6 After the amino acids are appropriately modified, they are pumped into a reactor tank, where they are allowed to mix at room temperature for 24 hours. The temperature is then increased to approximately 149°F (65 °C) and maintained for another 24 hours. The reaction is then cooled to room temperature. It is diluted with an appropriate solvent and cooled to about 0°F (-18°C), causing crystallization. The crystals are then isolated by filtration and dried. These crystals are an intermediate of aspartame which must be further modified.
• 7 The intermediate is converted to aspartame by reacting it with acetic acid. This reaction is performed in a large tank filled with an aqueous acid solution, a palladium metal catalyst, and hydrogen. It is thoroughly mixed and allowed to react for about 12 hours.

Purification

• 8 The metal catalyst is removed by filtration, and the solvent is distilled, leaving a solid residue. This residue is purified by dissolving it in an aqueous ethanol solution and recrystallizing. These crystals are filtered and dried to provide the finished, powder aspartame.

Quality Control

The quality of the compounds is checked regularly during the manufacturing process. Of particular importance are frequent checks of the bacterial culture during fermentation. Also, various physical and chemical properties of the finished product are checked, such as pH level, melting point, and moisture content.

The Future

Currently, there are only three alternative sweeteners in the United States that can be used in food products. While aspartame is perhaps one of the best available, scientists are looking for new ways to make these sweeteners taste as much like sugar as possible. Their research has been focused in three areas, including finding new derivatives, blending sweeteners, and enhancing the efficiency of aspartame.

Most of the chemical derivative work has centered on finding compounds which will fit into the taste bud receptors better than traditional aspartame. Using aspartame as the model, researchers believe they will be able to improve various characteristics by making slight modifications. For example, they have found that when L-aspartic acid alone is modified in a certain way, it gives products that have a sweet taste. Future research will likely focus on these kinds of derivatives.

Another area of research focuses on improving the heat stability of aspartame. Using encapsulation technology, aspartame has been developed which can be used in baked goods and baking mixes. Initial test results are positive, and FDA approval has been granted for bakery applications.

Since only three synthetic sugar substitutes are currently approved for use in food in the U.S., combining artificial sweeteners in products is becoming an important technological advance. Here, scientists combine two or three sweeteners in an effort to make the product taste more sugarlike.

Where to Learn More

Books

Nabors, Lyn, and Robert Gelardi. Alternative Sweeteners. Marcel Dekker, Inc., 1986.

Periodicals

Best, Daniel and Lisa Nelson. "Low-calorie foods and sweeteners." Prepared Foods, June 1993, p. 47.

Tomasula, Dean. "Sweet as sugar: artificial sweetener producers are blending products, in search of a market winning combination." Chemical Marketing Reporter, June 27, 1994, p. S22.

—PerryRomanowski

Artificial Sweeteners

There are presently four artificial, or synthetic, sweeteners that have been approved by the U.S. Food and Drug Administration (FDA): saccharin, aspartame, acesulfame-K, and sucralose. People use artificial sweeteners because they suffer from diseases such as diabetes mellitus, because they are concerned about dental caries and periodontal disease, or because they wish to lose or to avoid gaining weight. Artificial sweeteners in very small quantities give foods sweetness, and most are not metabolized, meaning that the artificial sweeteners themselves furnish zero dietary calories.

Sweetener Molecules and Sweetness

Sucrose and most artificial sweeteners are chemically quite dissimilar. Sucrose (C₁₂H₂₂O₁₁), the most common "natural" sweetener, is a disaccharide composed of the monosaccharides glucose and fructose. Saccharin has the formula C₇H₅O₃NS. Aspartame (C₁₃H₁₈O₅N₂), L-aspartyl-L-phenylalanine methyl ester , is the methyl ester of a dipeptide. Acesulfame-K has the formula C₅H₆O₃NS. Sucralose (C₁₁H₁₉O₈Cl₃) is prepared from sucrose via the substitution of three chloride groups for three hydroxyl groups. The molecular structures of sucrose, saccharin, aspartame, acesulfame-K, and sucralose are shown in Figure 1.

A sweetener must be soluble in water and the molecule must bind readily to a specific kind of receptor molecule at the surface of the tongue. The receptor is coupled to a G-protein, which dissociates when the sweetener binds to the receptor, activating a nearby enzyme, and triggering a sequence of events resulting in signals that are carried to and interpreted by the brain. The sweetness "signal" depends on this interaction between receptor and sweetener. The importance of molecular shape to sweetness is illustrated by the case of aspartame, as its stereo isomer , L-aspartyl-D-phenylalanine methyl ester, has a bitter, not a sweet, taste.

Discovery, Sweetness, and Metabolic Products

Saccharin was the first artificial sweetener, discovered in 1879 by Constantin Fahlberg at Johns Hopkins University. The Monsanto Chemical Works was incorporated in 1901 to produce saccharin in the United States. Saccharin is easy to make, stable when heated, and is approximately 300 times sweeter than sucrose when equal quantities are compared. One common saccharin product is Sweet and Low.

Saccharin does not accumulate in body tissues. Controversy over the use of saccharin has existed for over a century. In the 1960s and early 1970s saccharin and/or its impurities were shown to cause bladder cancer in rats.

In 1977 a Canadian study concluded that saccharin was the causative agent. Saccharin was banned in Canada. At about the same time the FDA proposed to limit the use of saccharin, but public outcry was so great that the U.S. Congress placed a moratorium on bans of saccharin until further studies were completed. The original moratorium was in effect for two years but has been continually extended to the present day.

Aspartame was discovered in 1965 by James Schlatter at G.D. Searle & Company. Aspartame is relatively easy to make and is approximately 200 times sweeter than sucrose. It is most commonly sold as Nutra Sweet and Equal. It is less stable than saccharin and breaks down above 29.44°C (85°F). In the body, aspartame is broken down into/absorbed as products that include aspartate, phenylalanine, and methanol. Phenylalanine is toxic to individuals who are homozygous (having identical genes in homologous chromosomes) for phenylketonuria, a genetic disease wherein individuals cannot catabolize phenylalanine. Phenylketonuria causes mental retardation. Products containing aspartame must therefore be labeled for phenylalanine. The FDA considers aspartame to be one of the most thoroughly studied and tested food additives and has judged it to be safe. Controversy still lingers with respect to the effects of aspartame's breakdown products—phenylalanine and aspartate, as well as methanol and its breakdown products formaldehyde and formate.

Acesulfame-K was discovered in 1967 by scientists working at Hoechst AG. It is also called Sunett. It is approximately 200 times sweeter than sugar. It has a long shelf life and does not break down in foods that are cooked or

baked. Over ninety studies have been completed that have concluded that acesulfame-K is safe.

Sucralose was discovered in 1976 by researchers at Tate & Lyle PLC. It is also called Splenda. Sucralose is approximately 600 times sweeter than sugar and is stable at high temperatures. It was approved by the FDA in 1998–1999, and it is supported by a safety database of more than 110 studies. Concerns persist, including concerns over possible side effects associated with breakdown products (which include chlorine and 1,6-dichlorofructose), shrunken thymus glands (and their impacts on the immune system), and unanticipated effects that may not have manifested during the short time that sucralose has been used.

see also Toxicity.

Vivienne A. Whitworth

Bibliography

Henkel, John (1999). "Sugar Substitutes: Americans Opt for Sweetness and Lite." FDA Consumer Magazine 33(6):12–16.

Kretchmer, Norman, and Hollenbeck, Claire B., eds. (1991). Sugars and Sweeteners. Boca Raton, FL: CRC Press.

Smith, David V., and Margolskee, Robert F. (2001). "Making Sense of Taste." Scientific American 284(3):32–39.

Internet Resources

Hodgin, Greg. "The History, Synthesis, Metabolism, and Uses of Artificial Sweeteners." Available from <http://www.ecit.emory.edu/ecit>.

Kitts, David D. "Sweetness Chemistry." Available from <http://www.agsci.ubc.ca/courses>.

Lok, Corie. "Sweet Tooth Gene Found." Available from <http://www.nature.com/nsu/>.

Tate & Lyle PLC. "Sucralose—Technical Information." Available from <http://www.officialsucralosesite.com>.

Aspartame

Definition

Aspartame, an artificial sweetener that is used as a substitute for sugar in many foods and beverages, is considered by some scientists to be a neurotoxin, a substance that is detrimental to the nervous system. This allegation remains controversial.

Description

Aspartame was introduced as an artificial sweetener by the Monsanto Company in the 1970s. For much of the intervening time, individuals and special interest groups have maintained that aspartame damages the nervous system. Given the number and popularity of the items that are sweetened using aspartame (i.e., yogurts, soft drinks), the special interest groups assert that the general population is at risk for neurological damage caused by the ingestion of aspartame.

Alleged harmful effects of aspartame ingestion include seizures and a change in the level of dopamine, a brain neurotransmitter. Symptoms associated with lupus , multiple sclerosis , and Alzheimer's disease have been claimed to result from an excess intake of aspartame. As well, aspartame consumption is claimed to increase the difficulty of diet-dependent diabetics in regulating their blood glucose level.

One peer-reviewed scientific study has documented an improvement in fibromyalgia symptoms (pain in the muscles, ligaments, and tendons) following the elimination of monosodium glutamate and aspartame from the diet. The influence of aspartame alone, however, was not assessed. Studies conducted prior to the marketing of aspartame and following its introduction have failed to demonstrate these claimed negative effects. The U.S. Food and Drug Administration (FDA) maintains that aspartame is not a health threat to the general population, although individuals who are sensitive to the compound can develop headaches and feel fatigued. Currently, there is no evidence directly linking aspartame with diseases such as lupus, multiple sclerosis, and Alzheimer's.

Demographics

As the association of aspartame with neurological disorders is not proven, statistics relating to how often and how many individuals suffer ill effects from aspartame are unavailable. If the claim of a general population effect is true, and that the effect is cumulative (builds up over time), then aspartame would affect older people more than younger people. There has been no evidence or suggestion of any gender, race, or cultural predilection to negative effects from aspartame.

If, however, only certain people are predisposed to be more sensitive to the presence of aspartame, then the demographics would include this subpopulation. The characteristics of such a group have not been defined.

Causes and symptoms

At elevated temperatures of about 90° Fahrenheit, a component of aspartame can convert to formaldehyde. High concentrations of formaldehyde can kill cells and tissues. Furthermore, formaldehyde can, in turn, be converted to formic acid, which can cause metabolic acidosis. Whether these changes are detrimental to the nervous system is not known.

One research paper published in 2001 reported one patient in whom aspartame exacerbated an ongoing migraine attack. Whether this occurrence is more widespread among the general public is unknown.

Diagnosis

Currently, any symptoms that are directly attributable to aspartame excess have not been conclusively identified. The suspected symptoms such as fibromyalgia and changes in dopamine levels are associated with other maladies including lupus, multiple sclerosis, or Alzheimer's disease. Factors that may trigger migraine headache vary among individuals, and physicians may suggest that those suffering from migraine lower their consumption of aspartame.

Treatment

Symptoms may disappear when the use of aspartame is discontinued.

Special concerns

Aspartame poisoning is a contentious issue. Scientific peer-reviewed papers have reported on research performed at companies that have a vested interest in sales of aspartame. While the quality of the scientific data contained in these studies may be sound, other scientists criticize that the evidence presented is difficult to evaluate in light of possible conflicting interests. By the same token, the claims made by special interest groups concerning the dangers of aspartame should be viewed cautiously, as little or no data is presented to support their claims.

Resources

BOOKS

Blaylock, R. L. Excitotoxins. Santa Fe, NM: Health Press. 1996.

Roberts, H. J. Aspartame (Nutrasweet): Is It Safe? Philadelphia: The Charles Press, 1992.

PERIODICALS

Butchko, H. H., et al. "Aspartame: Review of Safety." Regulatory Toxicology and Pharmacology (April 2002): S1–93.

Newman, L. C., and R. B. Lipton. "Migraine MLT-down: An Unusual Presentation of Migraine in Patients with Aspartame-triggered Headaches." Headache (October 2001): 899–901.

Smith, J. D., C. M. Terpening, S. O. Schmidt, and J. G. Gums. "Relief of Fibromyalgia Symptoms following Discontinuation of Dietary Excitotoxins." Annals of Pharmacotherapy (June 2001): 702–706.

OTHER

"Aspartame Information Page." National Institute of Neurological Disorders and Stroke. January 21, 2004 (May 17, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/aspartame.htm>.

ORGANIZATIONS

Food and Drug Administration. 5600 Fishers Lane, CDER

HFD-210, Rockville, MD 20857. (301) 827-4573 or (888) 463-6332. <http://www.fda.gov>.

Brian Douglas Hoyle, PhD

artificial sweetener substance used as a low-calorie sugar substitute. Saccharin , cyclamates , and aspartame have been the most commonly used artificial sweeteners. Saccharin, a coal-tar derivative three hundred times as sweet as sugar, was discovered in 1879. Cyclamates were approved for consumer use in 1951; they are 30 times sweet as sugar and, unlike saccharin. have no bitter aftertaste at high concentration. They were banned in 1969 because of suspected carcinogenic properties. Aspartame, an amino-acid compound that is about 160 times as sweet as sugar, was discovered in 1965 and is a widely used low-calorie sweetener. It cannot be used in cooking because it is destroyed on boiling in water. People who are sensitive to the amino acid phenylalanine should not use aspartame. Neotame, an aspartame analog, is 30 to 60 times sweeter than aspartame, more stable at high temperatures, and far less likely to pose a risk to people sensitive to phenylalanine. Sucralose, which is manufactured by adding chlorine to sugar, is not destroyed by heat and is widely used as a sweetener in packaged foods that have been baked or otherwise heated during their processing. About 600 times sweeter than sugar, it was first synthesized in 1976. Stevioside, which is 300 times as sweet as sucrose, is a terpene derivative and is available in several countries.

aspartame An artificial sweetener, aspartyl‐phenylalanine methyl ester, some 200 times as sweet as sucrose. Stable for a limited time (a few months) in solution, when it gradually breaks down. Used in soft drinks, dessert mixes, and as a ‘table top sweetener’. The major trade names are Canderel, Equal, Nutrasweet, and Sanecta.

Because aspartame contains phenylalanine, it is specifically recommended that children with phenylketonuria avoid consuming it, although the amounts that would normally be consumed are small.

as·par·tame / ˈaspärˌtām/ • n. a very sweet substance used as an artificial sweetener, chiefly in low-calorie products.

artificial sweetener see sweetener, artificial .

sweeteners, artificial See sweeteners, intense.

artificial sweeteners See sweeteners, intense.

aspartame see sweetener, artificial .

aspartame •acclaim, aflame, aim, became, blame, came, claim, dame, exclaim, fame, flame, frame, game, lame, maim, misname, name, proclaim, same, shame, tame •endgame • counterclaim • nickname •byname • filename • forename •surname • airframe • mainframe •Ephraim • doorframe • subframe •underframe • aspartame