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			{{Short description|Artificial sweetener}}
	{{chembox		{{chembox
			| ImageFile = Neotame.svg
	| verifiedrevid = 444826507
	| ImageFile=Neotame Structural Formulae.png		| ImageFile1 = Neotame zwitterion ball.png
			| ImageAlt1 = Ball-and-stick model of the neotame molecule
	| ImageSize=200px
	| IUPACName= (3''S'')-3-(3,3-Dimethylbutylamino)-4-<nowiki>amino]-4-oxobutanoic acid		| SystematicName = (3''S'')-3--4-{amino}-4-oxobutanoic acid
	| OtherNames=E961; ''N''-(''N''-(3,3-Dimethylbutyl)-<small>L</small>-α-aspartyl)-<small>L</small>-phenylalanine 1-methyl ester		| OtherNames = E961; ''N''-(''N''-(3,3-Dimethylbutyl)-<small>L</small>-α-aspartyl)-<small>L</small>-phenylalanine 1-methyl ester
	| Section1= {{Chembox Identifiers		| Section1 = {{Chembox Identifiers
			| CASNo_Ref = {{cascite|correct|??}}
	| CASNo=165450-17-9		| CASNo=165450-17-9
	| PubChem=9810996		| PubChem=9810996
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	| UNII = VJ597D52EX		| UNII = VJ597D52EX
	| SMILES=CC(C)(C)CCN(CC(=O)O)C(=O)N(CC1=CC=CC=C1)C(=O)OC		| SMILES=CC(C)(C)CCN(CC(=O)O)C(=O)N(CC1=CC=CC=C1)C(=O)OC
			| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
			| ChemSpiderID = 7986751
			| ChEBI_Ref = {{ebicite|changed|EBI}}
			| ChEBI = 83503
			| InChI = 1/C20H30N2O5/c1-20(2,3)10-11-21-15(13-17(23)24)18(25)22-16(19(26)27-4)12-14-8-6-5-7-9-14/h5-9,15-16,21H,10-13H2,1-4H3,(H,22,25)(H,23,24)/t15-,16-/m0/s1
			| InChIKey = HLIAVLHNDJUHFG-HOTGVXAUBG
			| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
			| StdInChI = 1S/C20H30N2O5/c1-20(2,3)10-11-21-15(13-17(23)24)18(25)22-16(19(26)27-4)12-14-8-6-5-7-9-14/h5-9,15-16,21H,10-13H2,1-4H3,(H,22,25)(H,23,24)/t15-,16-/m0/s1
			| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
			| StdInChIKey = HLIAVLHNDJUHFG-HOTGVXAUSA-N
	}}		}}
	| Section2= {{Chembox Properties		| Section2 = {{Chembox Properties
	| C=20|H=30|N=2|O=5		| C=20 | H=30 | N=2 | O=5
	| Appearance=		| Appearance=white powder<ref name=":0"/>
	| Density=		| Density=
			| MeltingPtC=80.9–83.4
	| MeltingPt=
			| MeltingPt_ref=<ref name=":0"/>
	| BoilingPt=		| BoilingPt=
	| Solubility=		| Solubility=12.6 g/kg at 25 °C<ref name=":n"/>
	}}		}}
	| Section3= {{Chembox Hazards		| Section3 = {{Chembox Hazards
			| NFPA-H = 0
			| NFPA-F = 1
			| NFPA-R = 0
	| MainHazards=		| MainHazards=
	| FlashPt=		| FlashPt=
			| AutoignitionPt =
	| Autoignition=
	}}		}}
			| Verifiedfields = changed
			| Watchedfields = changed
			| verifiedrevid = 455127090
	}}		}}
			'''Neotame''', also known by the ] '''Newtame''',<ref name="fda">{{Cite web|date=14 July 2023|title=Aspartame and Other Sweeteners in Food|url=https://www.fda.gov/food/food-additives-petitions/aspartame-and-other-sweeteners-food|publisher=US Food and Drug Administration|accessdate=30 June 2024}}</ref> is a non-caloric ] and ] ] by ].<ref name=":n">{{Cite book|url=https://books.google.com/books?id=coDPwzFX7rAC|title=Alternative sweeteners|vauthors=Nabors LO|publisher=CRC Press|year=2011|pages=133–150|isbn=978-1439846155|edition=4th|oclc=760056415}}</ref> By ], it is 7,000 to 13,000 times sweeter than ].<ref name=fda/> It has no notable off-flavors when compared to sucrose. It ]. It can be used alone, but is often mixed with other sweeteners to increase their individual sweetness (i.e. ] effect) and decrease their off-flavors (''e.g.'' ]). It is chemically somewhat more stable than aspartame. Its use can be cost effective in comparison to other sweeteners as smaller amounts of neotame are needed.<ref name=":n"/>
	'''Neotame''' is an ] made by ] that is between 7,000 and 13,000 times sweeter than ] (table sugar). In the European Union, it is known by the ] E961.<ref>, ], 26 November 2010</ref> Neotame is moderately heat stable and extremely potent. Neotame is rapidly ] and completely eliminated and does not appear to accumulate in the body.<ref>Dr. Abbott, P.J. , "International Programme on Chemical Safety". Accessed August 31, 2007.</ref>
			It is suitable for use in ] ]s, ]s, ]s, drink powders, and ]s among other foods. It can be used as a table top sweetener for ]s like ]. It covers bitter tastes (e.g. ]).<ref name=":n"/>
	The major metabolic pathway is ] of the ] ] by ]s that are present throughout the body, which yields de-esterified neotame and ]. Because only trace amounts of neotame are needed to sweeten foods, the amount of methanol derived from neotame is much lower than that found in common foods, such as fruit and vegetable juices. It has the characteristic aftertaste common to artificial sweeteners.
			In 2002, ] approved it as a non-nutritive sweetener and flavor enhancer within the ] in foods generally, except meat and poultry.<ref name=fda/> In 2010, it was approved for use in foods within the ] with the ] '''E961'''.<ref>{{Cite web|url=https://www.foodnavigator.com/Article/2010/01/08/Neotame-wins-approval-in-Europe|title=Neotame wins approval in Europe|last=Halliday|first=Jess|website=foodnavigator.com|date=8 January 2010 |access-date=2019-09-15}}</ref> It has also been approved as an additive in many other countries outside US and EU.<ref name=":n"/>
	The product is attractive to food manufacturers as its use greatly lowers the cost of production compared to using sugar or high fructose corn syrup (due to the lower quantities needed to achieve the same sweetening)<ref>Food Navigator, Finance and Industry News. . Accessed August 31, 2007.</ref> while also benefitting the consumer by providing fewer "empty" sugar ] and a lower impact on blood sugar.
			Its ] is fast and is not retained in the body. ] forms in its metabolism. Only trace amounts of neotame are added to foods, so the amount of methanol is insignificant for health. It is safe for ] and those with ].<ref name=":4"/><ref name=":0"/>
	== Chemistry ==
	It is chemically similar to the artificial sweetener ] but is used at vastly lower levels and is more stable {{citation needed|date=February 2011}}. Chemically, it has a 3,3-dimethylbutyl group attached to the ] of the ] portion of the molecule. ]s, which would typically break the peptide bond between the aspartic acid and phenylalanine moieties, are effectively blocked by the presence of the 3,3-dimethylbutyl moiety, thus reducing the production of ], thereby making its consumption by those who suffer from ] safe.<ref>Science Toys, Ingredient Listings. . Accessed August 31, 2007.</ref> Neotame, simply a modified version of aspartame, contains all the same elements found in aspartame and more: the amino acids L-aspartic acid and L-phenylalanine, plus two organic groups, one known as a methyl ester group and the other as a neohexyl group. <ref>Dr. Janet Starr Hull. </ref>
			French scientists Claude Nofre and Jean-Marie Tinti invented neotame.<ref name=":n"/> In 1992, they filed a United States ], which was granted in 1996.<ref name=":2">{{Cite web|title=US 5,480,668|url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5480668.PN.&OS=PN/5480668&RS=PN/5480668|access-date=2019-09-15}}</ref>
	== Approval ==
	Neotame was approved by the ] (FDA) for general use in July 2002, and has now been approved by the EU to become a classified E number (E961) however not yet widely used in food products. Neotame also is approved for use in Australia and New Zealand. Neotame is assigned the ] (INS) food additive code 961.<ref>International Life Sciences Institute, Summary of evaluations performed by JECFA. . Accessed April 16, 2008.</ref>
			==Safety==
	Although over 100 corporate-sponsored studies were conducted on neotame to prove its safety prior to FDA approval,<ref></ref> the controversy relating to a related sweetener, aspartame, has caused a stir among opponents of that additive. However, neotame and ] are the only two artificial sweeteners ranked as "safe" by the consumer advocacy group ].<ref>'''', ]</ref>
			In US and EU, the ] (ADI) of neotame for humans is 0.3 and 2&nbsp;mg per kg of bodyweight (mg/kg&nbsp;bw), respectively. ] for humans is 200&nbsp;mg/kg&nbsp;bw per day within EU.<ref name=fda/><ref name=":0"/> Estimated possible daily intakes from foods are well below ADI levels. Ingested neotame can form ], but in normal use of neotame, this is not significant to those with ]. It also has no adverse effects in ]. It is not considered to be ] or ].<ref name=":4">{{Cite journal|date=2002|title=Food additives permitted for direct addition to food for human consumption; neotame|url=https://www.govinfo.gov/content/pkg/FR-2002-07-09/pdf/02-17202.pdf|journal=Federal Register|volume=67|issue=131|pages=45300–45310}}</ref><ref name=":0"/> The ] has ranked neotame as safe.<ref>{{Cite web|url=https://cspinet.org/eating-healthy/chemical-cuisine|title=Chemical Cuisine {{!}} Center for Science in the Public Interest|website=cspinet.org|date=25 February 2016|access-date=2019-09-15}}</ref>
			==Sweetness==
	Consumer reports show that the taste of neotame, in comparison to natural sucrose, is extremely noticeable and is often described as bitter.
			Water solutions of neotame that are equivalent in ] to ] water solutions increase ] in relative sweetness as the sucrose concentration of a comparably sweet sucrose solution increases until a plateau is reached. Maximum sweetness is reached at neotame solution concentrations that are relatively as sweet as a water solution that is 15.1 percentage sucrose by weight, i.e., at 15.1 sucrose equivalence % (SE%). For comparison, ], ] and ] reach their maximum sweetness at 11.6&nbsp;SE%, 11.3&nbsp;SE% and 9&nbsp;SE%, respectively.<ref name=":n"/>
	== References ==
	{{Reflist}}
			Neotame is a high-potency sweetener, and it is 7,000 to 13,000 times sweeter than table sugar.<ref name=fda/> Neotame contains flavor-enhancing properties, and compared to sucrose or aspartame, it has a relatively lower cost per sweetness factor.<ref>{{cite journal |last1=Nofre |first1=C |last2=Tinti |first2=Jean-Marie |title=Neotame: discovery, properties, utility |journal=Food Chemistry |date=15 May 2000 |volume=69 |issue=3 |pages=245–257 |doi=10.1016/S0308-8146(99)00254-X |url=https://reader.elsevier.com/reader/sd/pii/S030881469900254X?token=94BD3C2662EF3EFCFB126841D82A6ED5DDDADEFA522206B4B4A9C8F64B58CFE6A9CCF4D8A3D20891264742DB94F07CE1&originRegion=us-east-1&originCreation=20211112232110 |access-date=12 November 2021}}</ref>
	== External links ==
	* , Sweeteners Holdings, Inc.
	*
	*
			==Chemistry==
			===Structure===
			Neotame is formally a ] of 3,3-dimethylbutanal and aspartame. The latter is a ] of ] and ]. Neotame has 2 ]s and 4 ]. Sweetness is due to the (2''S''),(3''S'')-stereoisomer.<ref name=":3">{{Cite journal|vauthors=Bathinapatla A|date=2014|title=Determination of Neotame by High-Performance Capillary Electrophoresis Using β-cyclodextrin as a Chiral Selector|url=https://www.researchgate.net/publication/265390621|journal=Analytical Letters|volume=47|issue=17|pages=2795–2812|doi=10.1080/00032719.2014.924008|s2cid=93160173|issn=0003-2719|display-authors=etal}}</ref>
			===Spectroscopy===
	]
			Neotame ] identifies its structure with a peak at 0.84 ppm indicating the three methyl groups on the carbon chain bonded to the nitrogen.<ref name="garbow">{{cite journal |last1=Garbow |first1=Joel R. |last2=Likos |first2=John J. |last3=Schroeder |first3=Stephen A. |title=Structure, dynamics, and stability of β-cyclodextrin inclusion complexes of aspartame and neotame |journal=Journal of Agricultural and Food Chemistry |date=1 April 2001 |volume=49 |issue=4 |pages=2053–2060 |doi=10.1021/jf001122d |pmid=11308366 |url=https://pubs.acs.org/doi/pdf/10.1021/jf001122d |access-date=12 November 2021}}</ref>
	]
			]
			===Synthesis===
	]
			Neotame is synthesized from aspartame through a reductive ] with ] in a ] catalyst with methanol.<ref name="prakash">{{cite journal |last1=Prakash |first1=Indra |last2=Bishay |first2=Ihab |last3=Schroeder |first3=Steve |title=Neotame: Synthesis, Stereochemistry and Sweetness |journal=Synthetic Communications |date=1 December 1999 |volume=29 |issue=24 |page=4461-4467 |doi=10.1080/00397919908086610 |access-date=12 November 2021 |url=https://www.tandfonline.com/doi/pdf/10.1080/00397919908086610}}</ref> The stereochemistry of aspartame is conserved during the synthesis and therefore, neotame and aspartame have the same stereochemistry. (2''S''),(3''S'')-stereoisomer of aspartame is needed to synthesize the (2''S''),(3''S'')-stereoisomer of neotame.<ref name=prakash/>
	]
	]
			===Properties and reactivity===
	]
			]
	]
			Neotame has similar stability as aspartame, but has greater stability especially in heated and dairy foods.<ref name=fda/> Increased temperature, moisture or ] increase losses, and are the main relevant properties of a food when considering the stability of neotame. For example, about 90% of original neotame remains after 8&nbsp;weeks of storage in pH&nbsp;3.2 beverages. Neotame is especially stable as a dry powder at room temperature and ] even if mixed with ] or ], and is relatively inert in foods with ]s like ].<ref name=":n"/>
	]
	]
			Unlike aspartame, neotame doesn't form ]s via ] cyclization due to its N-alkyl substitution with 3,3-dimethylbutyl. This increases its heat stability.<ref name=fda/>
	]
	]
			Over 1000&nbsp;g of neotame dissolves in 1&nbsp;kg of ethanol at 15&nbsp;°C. At 15&nbsp;°C the solubility of neotame is 10.6&nbsp;g/kg in water and 43.6&nbsp;g/kg in ]. At 25&nbsp;°C the solubilities are 12.6&nbsp;g/kg and 77.0&nbsp;g/kg, respectively. At 40&nbsp;°C the solubilities are 18.0&nbsp;g/kg and 238&nbsp;g/kg, respectively. At 50&nbsp;°C the solubilities are 25.2&nbsp;g/kg and 872&nbsp;g/kg, respectively.<ref name=":n"/> Neotame is ] and its 0.5&nbsp;] solution has a pH of 5.80.<ref name=":0"/>
			===Manufacture===
			]
			Industrially neotame is made from 3,3-dimethylbutanal and aspartame via ].<ref name=":n"/> They are dissolved in ], ] ] is added, air is replaced with ] and the reaction is carried out in room temperature under pressure for a few hours. Catalyst is filtered out. This can be aided with ]. Methanol is ] followed by addition of water. The mixture is cooled for a few hours, neotame is isolated via ], washed with water and ]. Neotame is milled to suitable size.<ref name=":0"/>
			==Metabolism==
			]. CH<sub>3</sub>OH is methanol.]]
			In humans and many other animals like dogs, rats and rabbits, neotame is rapidly but incompletely absorbed. Its ] are not retained or concentrated in specific tissues.<ref name=":0">{{Cite journal|date=2007|title=Neotame as a sweetener and flavour enhancer - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food|journal=EFSA Journal|volume=5|issue=11|pages=581|doi=10.2903/j.efsa.2007.581|issn=1831-4732|doi-access=free}}</ref>
			In humans at oral doses of about 0.25&nbsp;mg per kg of bodyweight (mg/kg&nbsp;bw), about 34% is absorbed into blood. ] of oral doses of 0.1–0.5&nbsp;mg/kg&nbsp;bw are somewhat linear, and at such doses, maximum neotame concentration in ] is reached after about 0.5&nbsp;hours with a ] of about 0.75&nbsp;hours. In blood and in body in general, non-specific ]s degrade neotame to de-esterified neotame and ], which is the main metabolic pathway in humans. De-esterified neotame has a plasma half-life of about 2&nbsp;hours, and is the main metabolite in plasma.<ref name=":0"/>
			In humans, over 80% of the original oral dose is excreted in feces and urine within 48 hours and the rest later. About 64% of the original dose is excreted in feces mostly as metabolites. Major metabolite in feces is the de-esterified neotame. Over 1% of the original dose is excreted in feces as ''N''-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine. Over 1% is excreted in urine as ] conjugate of ]. Other minor metabolites form.<ref name=":0"/>
			The major metabolic pathway leads to ''N''-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine with a side product of methanol, and the minor pathway happens when the ''N''-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine is oxidized into 3,3-dimethylbutyric acid. The side products for the minor pathway is methanol, aspartic acid and phenylalanine.<ref>{{cite journal |last1=Nofre |first1=C |last2=Tinti |first2=Jean-Marie |title=Neotame: discovery, properties, utility |journal=Food Chemistry |date=15 May 2000 |volume=69 |issue=3 |pages=245–257 |doi=10.1016/S0308-8146(99)00254-X |url=https://reader.elsevier.com/reader/sd/pii/S030881469900254X?token=94BD3C2662EF3EFCFB126841D82A6ED5DDDADEFA522206B4B4A9C8F64B58CFE6A9CCF4D8A3D20891264742DB94F07CE1&originRegion=us-east-1&originCreation=20211112232110 |access-date=12 November 2021}}</ref>
			Methanol from neotame metabolism is insignificant at regulated levels used in foods and in comparison to methanol naturally found in foods.<ref name=":0"/>
			==Patent==
			The ] covering the neotame molecule in the US, 5,480,668,<ref name=":2"/> was originally set to expire 7 November 2012, but was extended for 973 days by the ]. The patent expired on 8 July 2015.<ref>{{cite web|url=http://www.uspto.gov/patents/resources/terms/156.jsp|title=USPTO extension of 5,480,668|access-date=2012-09-21}}</ref>
			==References==
			{{Reflist}}
			==External links==
			*{{Commons category-inline}}
			*
			]
			]
			]
			]
			]