Advantame is a non-caloric

artificial sweetener A sugar substitute 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. Artificial sweeteners may be d ...

and

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

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, interlayer insulating materials for semiconductor packages for use in personal computers, cooking oils, frozen foods, beverages, sweeteners, amino acids, ...

. By

mass Mass is an intrinsic property of a body. It was traditionally believed to be related to the quantity of matter in a physical body, until the discovery of the atom and particle physics. It was found that different atoms and different elementar ...

, 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 bubblegums, flavored drinks, milk products, jams and

confectionery Confectionery is the art of making confections, which are food items that are rich in sugar and carbohydrates. Exact definitions are difficult. In general, however, confectionery is divided into two broad and somewhat overlapping categories ...

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

E number E numbers ("E" stands for "Europe") 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 (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...

in foods generally, except meat and poultry.

Safety

The

acceptable daily intake 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 effec ...

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 formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

, 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 re ...

. It also has no adverse effects in

type 2 diabetics Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

. It is not considered to be

carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...

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 i ...

. 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 that advocates for safer and healthier foods. History and funding CSPI is a consumer advocacy organization. Its f ...

ranks advantame as safe and as generally recognized as safe.

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 is the inverse function to exponentiation. That means the logarithm of a number to the base is the exponent to which must be raised, to produce . For example, since , the ''logarithm base'' 10 o ...

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

extrapolation In mathematics, extrapolation is a type of estimation, beyond the original observation range, of the value of a variable on the basis of its relationship with another variable. It is similar to interpolation, which produces estimates between know ...

, 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 compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

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

phyllodulcin Phyllodulcin is a dihydroisocoumarin found in ''Hydrangea macrophylla'' and ''Hydrangea serrata''.Accumulation of phyllodulcin in sweet-leaf plants of Hydrangea serrata and its neutrality in the defence against a specialist leafmining herbivore. M ...

. 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 c ...

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 in ...

. 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 extract of the vanilla bean. Synthetic vanillin is now used ...

. 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 organic ...

with

palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself na ...

on aluminium oxide and

platinum on carbon Platinum on carbon, often referred to as Pt/C, is a form of platinum used as a catalyst. The metal is supported on activated carbon in order to maximize its surface area and activity. Uses Catalytic hydrogenation Platinum on carbon is used for c ...

in one step to advantame in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

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 (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

and 1.65 g/L in

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

. 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, dew, or fog to be present. Humidity depe ...

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 drink that usually contains water (often carbonated), a sweetener, and a natural and/or artificial flavoring. The sweetener may be a sugar, high-fructose corn syrup, fruit juice, a s ...

. 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 a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

by the

vanillyl In organic chemistry, the vanillyl group (also known as vanilloyl) is a functional group. Compounds containing a vanillyl group are called vanilloids, and include vanillin, vanillic acid, capsaicin, vanillylmandelic acid Vanillylmandelic acid (VMA ...

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 and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

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 200 times sweeter than sucrose and is commonly used as a sugar substitute in foods and beverages. It is a methyl ester of the aspartic acid/phenylalanine dipeptide with the trade names ...

neotame Neotame, also known by the trade name Newtame, is a non-caloric artificial sweetener and aspartame analog by NutraSweet. By mass, it is 8000 times sweeter than sucrose. It has no notable off-flavors when compared to sucrose. It enhances origina ...

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 compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

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 pharmacology, pharmacological or biological activity likely to be therapeutical ...

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