Yiwei+Wang+Final

=**An overview of common non-caloric sweeteners including Stevia, Neotame, Sucralose, Aspartame, Saccharin and Acesulfame Potassium.**=


 * Yiwei Wang**
 * Drexel University**

Abstract
There are several non-caloric sweetener on the market. The most popular sweeteners are stevia, aspartame, neotame, sucralose, saccharin and acesulfame potassium. Only stevia is a natural sweetener while the rest are all artificial ones. They all have the sweet potencies much more higher than that of sucrose. People have claimed that they all have harmful effect on human bodies but a thoroughly overall investigation indicates that they’re all safe by now and is all approved by the food and drug administration. And there are two kind of sweetners that stand out of the rest, stevia and neotame. Stevia has its advantage in controlling diabetes and hypertension and it’s also a natural products. Neotame’s advantage is in its incredibly high sweet potency and could really be cost-effective to companies and consumers.

1.Introduction and History
1.1 Stevia Stevia is originated from South America and is in the Asteraceae family. The name Stevia is from a Spanish botanist and physician Petrus Jacobus Stevus, who first studied the Stevia genus. And people in Paraguay and Brazil have used the Stevia leaves for medicinal use(sweet treat) and as a sweetener(sweeten local teas) for centuries. It’s referred as “the sweet herb of Paraguay”. [1] The Stevia leaves have 30-45 times the sweetness of sucrose. And it’s major components, stevioside and rebaudioside A have up to 300 times the sweetness of sucrose. And it was firstly commercialized by a Japanese company Morita Kagaku Kogyo Co., Ltd. It was also commercialized with Coca-Cola and Pepsi, with the tradename Truvia by Coca-Cola and Cargill, and also PureVia by PepsiCo and Pure Circle. It’s been widely used as a sweetener in east Asia such as Korean and China, and South America area. And Japan has the most consumption of Stevia as sweetener, and 40% of the sweenters in Japanese market is Stevia. Also, China is the largest exported of Stevia in the world.[2] Although people have used Stevia for centuries, but it was until 1899, a Swiss botanist Moisés Santiago Bertoni found and describe the sweet taste of Stevia plant. And in 1931, the sweet components were extracted by two French chemists, and named it stevioside and rebaudioside.[2]

1.2 Aspartame Aspartame is a artificial sweetener and has almost 200 times sweetness of sucrose, it was first discovered by a chemist named James M. Schlatter who worked in G.D. Searle & Company, The discovery was all by accident when he was working on a antiulcer drug project and compound was licked his finger and he tasted sweetness of this compound.[3] Aspartame has different taste of onset and longer duration time with the sucrose. So in order to make it taste more like sugar, it is often blended with acesulfame potassium. [4]But it has peptide characteristic that it breaks when heating. So it cannot be used as a baking sweetener.[5] It was commercialized well by a lot of companies such as NutraSweet Company, Ajinomoto and Holland Sweetener Company. Equal, NutraSweet, and Canderel are all sweetener that uses aspartame.

1.3 Neotame Neotame is also an artificial sweetener with high sweetness potency and could be also used as a flavor enhancer. The sweetness is 7000 to 13000 times of sucrose. And that characteristics make it really cost-effective for company since it requires a small amount of neotame to reach the same sweetness.[6] The discovery of neotame is resulted of a long-term project aimed to get high potency sweetener with optimized performance characteristics. It was first synthesized by two French scientists Claude Nofre and Jean-Marie Tinti from just a N-Alkylation of aspartame. And it was commercialized by NutraSweet Company and it was the major ingredients of NutraSweet. Right now NutraSweet Company holds a lot of patents in neotame.[6] Although chemically, it is pretty similar to aspartame, but it is more stable than aspartame when heating. So it could be also used as baking sweetener. And now, there are over 69 countries are using neotame as a sweetener.[6]

1.4 Sucralose Sucralose is an artificial sweetener which tastes 600 times sweetness of sucrose. And it is also a non-caloric sweetener because most of the sucralose cannot be broke down by human body. And there is a interesting story in discovery of sucralose. It was first discovered by scientists from Tate&Lyle Company and Leslie Hough and Shashikant Phadnis from Queen Elizabeth College as well. At that time, they were working on a sucrose project, Phadnis was asked to test a chlorinated sugar compound but he thought Hough was asked him to taste. And then, he found it to be greatly sweet than sucrose.[5] Tate & Lyle patented this compound and we can find many products that contains sucralose such as Splenda, Sukrana, SucraPlus, Candys, Cukren and Nevella. And now, over 80 countries approved it for use as sweetener. Sucralose is a very stable sweetener under heating or over a broad range of pH. And it could be used in baking products as well as cooking material instead of sugar. [5]

1.5 Saccharin Saccharin is also an artificial sweetener with more sweetness than sucrose. But the downside of it is that it has a bitter or metallic after state, especially under higher concentration. So it is often used to compensate for other sweetener's weaknesses and disadvantages. The most well-known blend of saccharin is its blend with aspartame in carbonated soft drinks, which compensate for aspartame’s short period of storage time but still remain the same syrup. [7] There is also a story in the discovery of it. It was found by Constantin Fahlberg, a chemist who was working in Ira Remsen's laboratory at the Johns Hopkins University. And one day, Fahlberg the sweet taste on his hand and related to the compound he had been working on. Then he patented it and named it saccharin and soon grew wealthy without any mentioning of Ira Remsen, while Remsen believed that he deserved credit for substances produced in his laboratory. But no matter how the story went, it was still an important discovery.[5] It was commercialized not long after the discovery and the most famous product now is “Sweet'N Low". People began to use it vastly as a sweetener is in the World War I times when there was a large sugar shortage.

1.6 Acesulfame Potassium Acesulfame Potassium is also a artificial non-caloric sweetener and it has 180-200 times sweetness of sucrose. Pretty much like saccharin, it has a slightly bitter aftertaste, especially under high concentration. So it is always blend with other sweetener in order to get a more sugar-like flavor. Like most of the artificial sweetener, acesulfame potassium’s discovery is also by accident when Karl Clauss and Harald Jensen were working on a similar compound (5,6-dimethyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide) in 1967. And one day, Clauss licked the chemical that was accidentally dipping on his finger and noticed the sweetness. After that, further research showed that compounds with the similar ring structure had different sweetness with the slight structural difference.[8] And then, they singled out the compound 6-methyl-1,2,3-oxathiazine-4(3H)-one 2,2-dioxide has the most favorable sweetness and WHO setting the name acesulfame potassium to this compound in 1978. Now, the products Sunett and Sweet One are the major acesulfame potassium sweetener.

2.Structure
2.1 Stevia The main sweet components in Stevia are stevioside and rebaudioside A, which are the most commonly used stevia sweeteners. Both of them are constructed by replacing the carboxyl H-atom of their aglycone stevio with glucose while stevioside has two linked glucose molecules at the H site and rebaudioside A has three as showed in the Fig.1 below.[1] Fig.1 The structure of steviol and the major sweet components of stevia

2.2 Aspartame It’s a methyl ester of a dipeptide composed of aspartic acid and phenylalanine. There are two forms of it, alpha and beta forms. But only the alpha-aspartame is sweet and “aspartame” is always refer to alpha-aspartame unless specified[5].(Fig.2) Fig.2 The structure of alpha-aspartame(left) and beta-aspartame(right)

2.3 Neotame. Neotam (N- [N- (3,3-dimethylbutyl)-L- -aspartyl]-L-phenylalanine 1-methyl ester) is a derivative of the dipeptide composed of the amino acids, aspartic acid and phenylalanine as shown in the figure below.(Fig.3) Fig.3 The structure of neotame

2.4 Sucralose Sucralose is generated by replacing at three of the primary hydroxyl groups of sucrose with chlorine, and also the inversion of configuration at carbon-4, from the gluco- to the galactoanalogue.(Fig.4) Fig.4 The structure of sucralose

2.5 Saccharin Saccharin (1,2-benzoisothiazol-3(2H)-on-1,1-dioxide, 2), the structure is shown below.(Fig.5) Fig.5 The structure of saccharin

2.6 Acesulfame Potassium Acesulfame potassium is the potassium salt of a ring structure compound 6-methyl-1,2,3-oxathiazine-4(3H)-one 2,2-dioxide. The structure is shown below.(Fig.6) Fig.6 The acesulfame potassium structure

3. Synthesis 3.1 Stevia This in the Synthesis category but technically it is called extraction rather than synthesis since Stevia is the only natural sweetener in this paper. The extraction method of sweet components of Stevia was patented by The National Research Council of Canada. In this method, stevia was first treated with column extraction under 0-25°C, then the extracts underwent a purification process with microfiltration, nanofiltration and ultrafiltration.[9]

3.2 Aspartame Nowadays, there are two synthetic method of aspartame commercially. The first method is by the coupling of amino acids L-phenylalanine methyl ester and L-aspartic acid, and therefore generated the dipeptide methyl ester. But there is a drawback that it will produce both sweet alpha-aspartame and nonsweet beta-aspartame, and further separation of these two forms is required. [10] The other method is by a enzymatic selection process. The main idea is to let the esterified L-phenylalanine couple with N-protected L-aspartic anhydride and form N-protected alpha-aspartame. Then with the series of protection removal, crystallization, decolorization,filtration and etc., alpha-aspartame could be generated. [10]

3.3 Neotame Neotame is just a modified structure of aspartame. Once aspartame is obtained, get aspartame to react with 3,3-dimethylbutyraldehyde by a reductive alkylation process followed by purification, drying and milling. And then neotame could be generated. [6]

3.4 Sucralose The synthesis of sucralose is generally by the selective chlorination of sucrose with a series of protection and deprotection. Specifically,it undergoes a selective protection of the the primary alcohol groups, then it goes through the acetylation and deprotection of the primary alcohol groups process. After that, an induced acetyl migration takes place on one of the hydroxyl groups, the partially acetylated sugar is then chlorinated with a chlorinating agent such as phosphorus oxychloride, finally after removing the acetyl groups, sucralose is obtained. [11]The process diagram is shown below. (Fig.7) Fig.7 The sucralose synthesis scheme

3.5 Saccharin Saccharin could also be obtained by several method. The original method invented by Remsen & Fahlberg starts with toluene. First get the chlorosulfonic acid sulfonated and obtain the ortho and para substituted chlorosulfonic acid. Then separated out the ortho products and get para-chlorosulfonic acid oxidized and generated the carboxylic acid. The synthetic route is shown below. (Fig.8) [12] Fig.8 The original method to obtain saccharin

The another method is actually a improved one by Maumee Chemical Company of Toledo, Ohio. In this process, anthranilic acid successively reacts with nitrous acid (from sodium nitrite and hydrochloric acid, sulfur dioxide, chlorine, and then ammonia to yield saccharin(as showed in Fig.9). [12] Fig.9 An alternative saccharin synthesis scheme

3.6 Acesulfame Potassium Earliest method that Clauss and Jensen use to obtain acesulfame potassium is by using chlorosulfonyl or fluorosulfonyl isocyanate as the starting material. And then the starting material could react with propyne, acetone, acetoacetic acid, tbutyl acetoacetate or acetylacetone and obtain N-chloro or N-(fluorosulfonyl)acetoacetamide followed by cyclized by methanolic potassium hydroxide to give Ace-K(Fig.10). [8] Fig.10 The Clauss and Jensen method

There is also a alternative method in obtaining acesulfame potassium with higher yields. The reaction uses acetoacetamide as the starting material and reacts with sulfur trioxide followed by dehydrated with sulfur trioxide and neutralization with potassium hydroxide, then Acesulfame potassium is obtained. (Fig.11) [5] Fig.11 The evolved acesulfame potassium synthesis method

4. Safety and Health effect
4.1 Stevia Steviol, the aglycone of the stevio glycosides is once reported to be mutagenic in 1985[13], but it is soon be reputed by another paper indicating that the 1985 paper mishandled the data they collected and in that case even water could be mutagenic [14]. Although recently, several studies shows that the steviol and stevioside has weak mutagenic effect[15, 16], but overall study showed that the usage of steviol or stevioside could cause cancer or birth defects nor the use of stevia has any harmful effects on human bodies[1, 17]. In a word, stevia and its extracts is safe. Besides the fact that it has no harmful effect on human bodies, stevia is also pretty effective in controlling diabetes and hypertensions. In the controlling diabetes aspect, several paper has pointed out that the stevia could revitalize the β-cells of pancreas[18], make insulin respond more faster in rats[19] and also stimulating insulin production to lower the blood sugar level[20]. And even one report concluded that consumption of stevia could reverse diabetes and metabolic syndrome, which is pretty beneficial for diabetic patients[21]. Also, stevia could reduce the hypertension is reported in a clinical paper by a two-year study with humans[22]. Although there is another paper indicating that it has no effect with hypertension[23]. But generally it has no harmful effect.

4.2 Aspartame There is safety controversies regarding with aspartame. A lot of people has reported aspartame is related with cancer, hair loss, depression, dementia, behavioural disturbances and etc. But there is no any scientific evidence to support that. However, in 1987, the U.S. Government Accountability Office stated that they handled a proper process for approval of aspartame as the food additive. What’s more, the 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".[24] Although from the evidence right now, there is no correlation between aspartame and cancer, Phenylalanine, which is hazard to people born with phenylketonuria (PKU), is produced when aspartame dipeptides break down. So in the US, the foods containing aspartame must put “Phenylketonurics: Contains Phenylalanine” on the product label.

4.3 Neotame Neotame also underwent an extensive safety investigation by FDA, and the results should that it has no toxicity at any dosage by experiments carried on rats, mice and dogs. And besides, neotame and sucralose are the only two artificial sweeteners ranked as "safe" by the consumer advocacy group Center for Science in the Public Interest.[6]

4.4 Sucralose Sucralose is another artificial sweeteners ranked as "safe" by the consumer advocacy group Center for Science in the Public Interest along with neotame. Besides, a lot of paper reported that sucralose has no harmful effect by experiments carried on over 100 animal and clinical studies in the FDA approval process unanimously.[25, 26] It’s safe to say that sucralose is no risk to human bodies. However, there is an experiment by the Swedish Environmental Research Institute stated that wastewater treatment has very little effect on sucralose. Although the amount level of sucralose in wastewater is low, but it’s still be noticed that it’ll continous increase.

4.5 Saccharin People’s understanding in saccharin evolves with the time. Before the year 2000, all the food containing saccharin must include a warning label because results from experiments relate saccharin with the development of bladder cancer in rodents. And it was until 2000, when people finally realized that the rodents are different from human, they have high protein level and more calcium phosphate in their urines and that excessive protein and calcium phosphate combine together and form microcrystals. And those microcrystals would damage the bladder. And then, the over-production of cells in order to repair the damage could increase the risk for tumor formation.[7, 27] However, in human’s urines don’t have that environment and therefore it could not be relevant to human carcinogenesis. After that, the warning label was removed by the order of the FDA. And in 2010, the EPA made a statement that saccharin is no longer considered a potential hazard to human health.

4.6 Acesulfame Potassium FDA approves to use acesulfame potassium as a food additive. But people still concern that it would be carcinogenic because acesulfame potassium has not been investigated thoroughly. In all, acesulfame potassium should still be questioned and further safety investigation is recommended.

5. Conclusion In all, through out the investigation of different sources and papers. I found stevia could be a ideal sugar substitutes compared to other non-caloric sweetener. Since it is the only natural sweeteners in this paper, it has no harmful effects to human bodies and also it might help with controlling of diabetes and hypertension while other artificial sweetener couldn’t do that. And the reason why stevia has not been used as sweetener vastly in US is just a political thing. The artificial sweetener companies were worried that stevia could harm their business, so they pressured the FDA to label it as “unsafe” in 1991. However, the objection is removed in 2008 and I really think stevia could have a great success in US market as a non-caloric sweetener. The other sweetener that I am impressed is neotame. It has incredibly higher sweet potency which make it a really cost-effective sweetener and unlike other artificial sweetener, quite a lot of reports show it has no toxicity. Plus the fact that it is pretty stable and could be using in several different food. Therefore, from the overview paper, I would say neotame is an ideal artificial sweetener.[6]