Advantame is a non-caloric

artificial sweetener A sugar substitute or artificial sweetener, is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie () or low-calorie sweetener. Arti ...

and

aspartame Aspartame is an artificial non-saccharide sweetener commonly used as a sugar substitute in foods and beverages. 200 times sweeter than sucrose, it is a methyl ester of the aspartic acid/phenylalanine dipeptide with brand names NutraSwe ...

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

Ajinomoto is a Japanese multinational food and biotechnology corporation which produces seasonings, cooking oils, frozen food Freezing food Food preservation, preserves it from the time it is prepared to the time it is eaten. Since early times, farm ...

. By

mass Mass is an Intrinsic and extrinsic properties, intrinsic property of a physical body, body. It was traditionally believed to be related to the physical quantity, quantity of matter in a body, until the discovery of the atom and particle physi ...

, it is about 20,000 times sweeter than

sucrose Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

and about 110 times sweeter than aspartame. It has no notable off-flavors when compared to sucrose and tastes sweet a bit longer than aspartame and is chemically more stable. It can be blended with many other natural and artificial sweeteners.Nabors 2012, p. 31–44 Advantame can be used as a table top sweetener and in certain

bubblegum Bubble gum (or bubblegum) is a type of chewing gum, designed to be inflated out of the mouth as a bubble. Composition In modern chewing gum, if natural rubber such as chicle is used, it must pass several purity and cleanliness tests. However, ...

s, flavored drinks,

milk product Dairy products or milk products are food products made from (or containing) milk. The most common dairy animals are cow, water buffalo, nanny goat, and ewe. Dairy products include common grocery store food around the world such as yogurt, chee ...

jam Fruit preserves are preparations of fruits whose main preserving agent is sugar and sometimes acid, often stored in glass jars and used as a condiment or spread. There are many varieties of fruit preserves globally, distinguished by the meth ...

s and

confectionery Confectionery is the Art (skill), art of making confections, or sweet foods. Confections are items that are rich in sugar and carbohydrates, although exact definitions are difficult. In general, however, confections are divided into two bro ...

among other things. In 2013, it was approved for use in foods within EU with the

E number E numbers, short for Europe numbers, are codes for substances used as food additives, including those found naturally in many foods, such as vitamin C, for use within the European Union (EU) and European Free Trade Association (EFTA). Commonly ...

E969. In 2014,

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approved advantame as a non-nutritive sweetener and flavor enhancer within

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in foods generally, except meat and poultry.

Safety

The

acceptable daily intake Acceptable daily intake or ADI is a measure of the amount of a specific substance (originally applied for a food additive, later also for a residue of a veterinary drug or pesticide) in food or drinking water that can be ingested (orally) daily ove ...

of advantame for humans is 32.8 mg per kg of bodyweight (mg/kg bw), while according to

EFSA The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002 ...

it is 5 mg per kg of bodyweight (mg/kg bw). Estimated possible daily intakes from foods are well below these levels.

NOAEL The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effe ...

for humans is 500 mg/kg bw in EU. Ingested advantame can form

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...

, but normal use of advantame is not significant to those with

phenylketonuria Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also r ...

. It also has no adverse effects in type 2 diabetics. It is not considered to be

carcinogenic A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

mutagenic In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...

. The

Center for Science in the Public Interest The Center for Science in the Public Interest (CSPI) is a Washington, D.C.–based non-profit watchdog and consumer advocacy group. History and funding CSPI is a consumer advocacy organization. Its focus is nutrition and health, food safety ...

ranks advantame as safe and as

generally recognized as safe Generally recognized as safe (GRAS) is a United States Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts under the conditions of its intended use. An ingredient with a GRAS d ...

Sweetness

Relative sweetness of advantame varies. It depends on the concentration and food/matrix in which it is used. In water solutions of advantame, that are equivalently sweet to water solutions of 3–14 percentage sucrose by weight (wt%), advantame is 7000–47700 times sweeter. Relative sweetness of advantame increases

logarithmically In mathematics, the logarithm of a number is the exponent by which another fixed value, the base, must be raised to produce that number. For example, the logarithm of to base is , because is to the rd power: . More generally, if , then ...

as the sucrose concentration of a comparably sweet sucrose solution increases, but eventually reaches a plateau. By

extrapolation In mathematics Mathematics is a field of study that discovers and organizes methods, Mathematical theory, theories and theorems that are developed and Mathematical proof, proved for the needs of empirical sciences and mathematics itself. ...

, sweetness of an advantame water solution is estimated to reach a maximum at a concentration that is equivalent to a 15.8 wt% sucrose water solution.

Chemistry

Advantame is formally a

secondary amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

and 3-(3-hydroxy-4-methoxyphenyl)propanal (HMPA). Structurally advantame resembles a combination of aspartame and phyllodulcin. Advantame has 2

stereocenter In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

s and 4

stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...

. Advantame can be made from aspartame and

vanillin Vanillin is an organic compound with the molecular formula . It is a phenolic aldehyde. Its functional groups include aldehyde, hydroxyl, and ether. It is the primary component of the ethanolic extract of the vanilla bean. Synthetic vanillin ...

. Vanillin is transformed to HMPA in 4 steps. 3-hydroxy-4-methoxycinnamaldehyde (HMCA) is formed in the third step. HMCA is hydrogenated to HMPA in the final step. HMPA is selectively

hydrogenated Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organi ...

with

palladium Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), ...

aluminium oxide Aluminium oxide (or aluminium(III) oxide) is a chemical compound of aluminium and oxygen with the chemical formula . It is the most commonly occurring of several Aluminium oxide (compounds), aluminium oxides, and specifically identified as alum ...

and platinum on carbon in one step to advantame in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

with aspartame. Product is crystallized. Crude crystals are washed, recrystallized, washed and dried. At 15 °C the solubility of advantame is 0.76 g/L in water, 7.98 g/L in

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

and 1.65 g/L in

ethyl acetate Ethyl acetate commonly abbreviated EtOAc, ETAC or EA) is the organic compound with the formula , simplified to . This flammable, colorless liquid has a characteristic sweet smell (similar to pear drops) and is used in glues, nail polish removers, ...

. At 25 °C the solubilities are 0.99 g/L, 13.58 g/L and 2.79 g/L, respectively. At 40 °C the solubilities are 2.10 g/L, 38.27 g/L and 7.96 g/L, respectively. At 50 °C the solubilities are 3.10 g/L, 98.68 g/L and 16.00 g/L, respectively. Advantame as a dry powder degrades very slowly at 25 °C and 60%

relative humidity Humidity is the concentration of water vapor present in the air. Water vapor, the gaseous state of water, is generally invisible to the human eye. Humidity indicates the likelihood for precipitation (meteorology), precipitation, dew, or fog t ...

and can last for years under such conditions. It can last for more than a year in aqueous solutions at pH 3.2. This corresponds to the typical pH of

soft drinks A soft drink (see § Terminology for other names) is a class of non-alcoholic drink, usually (but not necessarily) carbonated, and typically including added sweetener. Flavors used to be natural, but now can also be artificial. The sweet ...

. It degrades faster at higher temperatures and humidity, but is generally more stable than aspartame. Unlike aspartame, advantame doesn't form a

diketopiperazine A diketopiperazine (DKP), also known as a ''dioxopiperazine'' or ''piperazinedione'', is a class of organic compounds related to piperazine but containing two amide linkages. DKP's are the smallest known class of cyclic peptide. Despite their name ...

via intra-molecular cyclization due to

steric hindrance Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...

by the vanillyl group.

Metabolism

In humans, 89% of the ingested advantame is excreted in feces and 6.2% in urine. Some is excreted unchanged, but most as

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s. Advantame is poorly absorbed, rapidly metabolized and only small amounts of it and its metabolites can be detected in blood shortly after ingestion. 52% of the ingested dose is excreted in feces as de-esterified advantame and 30% as ''N''-(3-(3-hydroxy-4-methoxyphenyl))propyl-L-aspartic acid and as an equivalent molar amount of

. 1% of the ingested dose is excreted in urine as the aforementioned aspartic acid analog, 1.9% as 5-(3-aminopropyl)-2-methoxyphenyl and 2.3% as de-esterified advantame.

Methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

forms in de-esterification, but this is considered insignificant at advantame concentrations intended to be used in foods, and in comparison to methanol naturally formed in body and to methanol naturally found in foods.

History

developed advantame and announced its structure publicly in print in 2008. At first advantame was identified by the laboratory code ANS9801.

Aspartame Aspartame is an artificial non-saccharide sweetener commonly used as a sugar substitute in foods and beverages. 200 times sweeter than sucrose, it is a methyl ester of the aspartic acid/phenylalanine dipeptide with brand names NutraSwe ...

, neotame and aspartame N-substituted with

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

via

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

bond (covered in US patent 5,286,509) were selected as the

lead compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but ...

s for research that lead to advantame.

Notes

References

External links

*{{Commonscatinline Sugar substitutes Methyl esters Phenols Phenol ethers Dipeptides Carboxamides E-number additives Phenethylamines