Aspartam production

Numerous naturally occurring chemicals have a sweet taste. Man, too, can create chemicals which have a sweet taste. Examples of artificial sweeteners include saccharin and aspartame— products of the laboratory. Generally, artificial sweeteners impart sweetness without adding calories. 

There are thousands of breweries worldwide. However, the number of companies using fermentation to produce therapeutic substances and/or fine chemicals number well over 150, and those that grow microorganisms for food and feed number nearly 100. Lists of representative fermentation products produced commercially and the corresponding companies are available (1). Numerous other companies practice fermentation in some small capacity because it is often the only route to synthesize biochemical intermediates, enzymes, and many fine chemicals used in minor quantities. The large volume of L-phenylalanine is mainly used in the manufacture of the artificial dipeptide sweetener known as aspartame [22389-47-0]. Prior to the early 1980s there was httle demand for L-phenyl alanine, most of which was obtained by extraction from human hair and other nonmicrobiological sources. 

USP grade. Estimated production cost. Majority is used to make aspartame. ... 

Formic acid is used as an intermediate in the production of a number of dmgs, dyes, flavors, and perfume components. It is used, for example, in the synthesis of aspartame and in the manufacture of formate esters for flavor and fragrance appHcations. 

Fumaric acid and malic acid [6915-15-7] are produced from maleic anhydride. The primary use for fumaric acid is in the manufacture of paper siting products (see Papermaking additives). Fumaric acid is also used to acidify food as is malic acid. Malic acid is a particularly desirable acidulant in certain beverage selections, specifically those sweetened with the artificial sweetener aspartame [22839-47-0]. 

There are numerous further appHcations for which maleic anhydride serves as a raw material. These appHcations prove the versatiHty of this molecule. The popular artificial sweetener aspartame [22839-47-0] is a dipeptide with one amino acid (l-aspartic acid [56-84-8]) which is produced from maleic anhydride as the starting material. Processes have been reported for production of poly(aspartic acid) [26063-13-8] (184—186) with appHcations for this biodegradable polymer aimed at detergent builders, water treatment, and poly(acryHc acid) [9003-01-4] replacement (184,187,188) (see Detergency). 

An estimation of the amount of amino acid production and the production methods are shown ia Table 11. About 340,000 t/yr of L-glutamic acid, principally as its monosodium salt, are manufactured ia the world, about 85% ia the Asian area. The demand for DL-methionine and L-lysiae as feed supplements varies considerably depending on such factors as the soybean harvest ia the United States and the anchovy catch ia Pern. Because of the actions of D-amiao acid oxidase and i.-amino acid transamiaase ia the animal body (156), the D-form of methionine is as equally nutritive as the L-form, so that DL-methionine which is iaexpensively produced by chemical synthesis is primarily used as a feed supplement. In the United States the methionine hydroxy analogue is partially used ia place of methionine. The consumption of L-lysiae has iacreased ia recent years. The world consumption tripled from 35,000 t ia 1982 to 100,000 t ia 1987 (214). Current world consumption of L-tryptophan and i.-threonine are several tens to hundreds of tons. The demand for L-phenylalanine as the raw material for the synthesis of aspartame has been increasing markedly. 

Sucrose occupies a unique position in the sweetener market (Table 3). The total market share of sucrose as a sweetener is 85%, compared to other sweeteners such as high fmctose com symp (HFCS) at 7%, alditols at 4%, and synthetic sweeteners (aspartame, acesulfame-K, saccharin, and cyclamate) at 4%. The world consumption of sugar has kept pace with the production. The rapid rise in the synthetic sweetener market during 1975—1995 appears to have reached a maximum. 

The safety of aspartame for human consumption has been studied extensively. The results of these studies have satisfied the FDA. However, because phenylalanine is a metaboUte of aspartame, people who lack the abiUty to metabolize this amino acid should refrain from using aspartame. Any aspartame-containing diet food must indicate that the product contains phenylalanine. 

In the first publication describing the preparative use of an enzymatic reaction in ionic liquids, Erbeldinger et al. reported the use of the protease thermolysin for the synthesis of the dipeptide Z-aspartame (Entry 6) [34]. The reaction rates were comparable to those found in conventional organic solvents such as ethyl acetate. Additionally, the enzyme stability was increased in the ionic liquid. The ionic liquid was recycled several times after the removal of non-converted substrates by extraction with water and product precipitation. Recycling of the enzyme has not been reported. It should be noted, however, that according to the log P concept described in the previous section, ethyl acetate - with a value of 0.68 - may interfere with the pro-... 

Neotame does not break down with the heat of cooking, another drawback to aspartame. It is also thirty times sweeter than aspartame, so less is needed to sweeten a product. 

Aspartame is made from two amino acids and methanol. When it is digested, it breaks down into these three parts. Amino acids are the normal breakdown products of proteins. 

Aspartame is a low-calorie sweetener used in many foods and drinks. Because it is between 160 and 200 times sweeter than sugar, only very small amounts are needed to sweeten a product. A typical 12-ounce low-calorie soft drink will have 180 milligrams of aspartame in it. 

Caramel color interacts with other food components. As an example, a concentration higher than 700 ppm caramel in cola increased the rate of hydrolysis of the aspartame, forming alpha-L-aspartyl-L-phenylalanine. Caramelization products inhibited enzymic browning by 85.8 and 72.2% when heated at pH 4 and 6, respectively, for 90 min. The highest inhibitory activity was found for the fraction with molecular weight of 1000 to 3000. Caramel is often used for adulteration of juices and other foods like honey or coffee. It can be determined by quantification of marker molecules such as 5-HMF, 4-Mel, and DFAs. ... 

Another advantage of biocatalysis is that chemo-, regio-, and stereoselectivities are attainable that are difficult or impossible to achieve by chemical means. A pertinent example is the production of the artificial sweetener, aspartame, which has become somewhat of an industrial commodity. The enzymatic process (Fig. 2.31), operated by the Holland Sweetener Company (a joint venture of DSM and Tosoh), is completely regio- and enantiospecific (Oyama, 1992). 

Because of the high incidence of lactose intolerance in the general population, lactose is not recommended as a sweetener for pediatric populations [70]. Aspartame, a phenylalanine derivative, is incorporated in many chewable tablets and sugar-free dosage forms. Aspartame-containing products should be avoided in children with autosomal recessive phenylketonuria [54]. 

The production process for (S)-phenylalanine as an intermediate in aspartame perpetuates the principle of reracemization of the nondesired enantiomer (Figure 4.5) in a hollow fiber/ liquid membrane reactor. Asymmetric hydrolysis of the racemic phenylalanine isopropylester at pH 7.5 leads to enantiopure phenylalanine applying subtilisin Carlsberg. The unconverted enantiomer is continuously extracted via a supported liquid membrane [31] that is immobilized in a microporous membrane into an aqueous solution of pH 3.5. The desired hydrolysis product is charged at high pH and cannot, therefore, be extracted into the acidic solution [32]. 

Figure 4.12 Precipitation of product synthesis of aspartame from phenylalanine methylester applying a batch process in combination with two filtration steps...

The commercially available form of Aspartame is hemihydrate Form II, which transforms into hemihydrate Form I when milled, and a 2.5-hydrate species is also known [57,58]. XRPD has been used to study the desolvation and ultimate decomposition of the various hydrates. When heated to 150°C, both hemihydrate forms dehydrate into the same anhydrous phase, which then cyclizes into 3-(carboxymethyl)-6-benzyl-2, 5-dioxopiperazine if heated to 200°C. The 2.5-hydrate was shown to dehydrate into hemihydrate Form II when heated to 70°C, and this product was then shown to undergo the same decomposition sequence as directly crystallized hemihydrate Form II. 

Where a foodstuff contains a sweetener or sweeteners, as allowed, the statement with sweetener/s must accompany the name of the product. Where a foodstuff contains both added sugar and sweeteners, as allowed, the statement with sugar/s and sweetener/s must accompany the name of the product. Foodstuffs that contain aspartame must bear the statement contains a source of phenylalanine . Foodstuffs that contain more than 10% added polyols must bear the statement excessive consumption may produce laxative effects . 

Sweeteners can be roughly divided into two groups bulk and intense sweeteners. Prodolliet (1996) and Gloria (2000) reviewed thoroughly the analysis and properties of intense sweeteners acesulfame-K, alitame, cyclamate, aspartame, glycyrrhizin, neohesperidin DC, saccharin, stevioside, sucralose and thaumatin. They are generally used in low calorie products such as diet... 

Chen et al. (1997a) analysed sodium saccharin in soft drinks, orange juice and lemon tea after filtration by injection into an ion-exclusion column with detection at 202 nm. Recoveries of 98-104% were obtained. They reported that common organic acids like citric and malic and other sweeteners did not interfere. Qu et al. (1999) determined aspartame in fruit juices, after degassing and dilution in water, by IC-PAD. The decomposition products of aspartame, aspartic acid and phenylanaline were separated and other sweeteners did not interfere. The recoveries of added aspartame were 77-94%. Chen et al. (1997b) separated and determined four artificial sweeteners and citric acid. 

There is a recent trend towards simultaneous CE separations of several classes of food additives. This has so far been applied to soft drinks and preserved fruits, but could also be used for other food products. An MEKC method was published (Lin et al., 2000) for simultaneous separation of intense sweeteners (dulcin, aspartame, saccharin and acesulfame K) and some preservatives (sorbic and benzoic acids, sodium dehydroacetate, methyl-, ethyl-, propyl- and isopropyl- p-hydroxybenzoates) in preserved fruits. Ion pair extraction and SPE cleanup were used prior to CE analysis. The average recovery of these various additives was 90% with good within-laboratory reproducibility of results. Another procedure was described by Frazier et al. (2000b) for separation of intense sweeteners, preservatives and colours as well as caffeine and caramel in soft drinks. Using the MEKC mode, separation was obtained in 15 min. The aqueous phase was 20 mM carbonate buffer at pH 9.5 and the micellar phase was 62 mM sodium dodecyl sulphate. A diode array detector was used for quantification in the range 190-600 nm, and limits of quantification of 0.01 mg/1 per analyte were reported. The authors observed that their procedure requires further validation for quantitative analysis. 

In fact, the results of nearly 200 toxicological and clinical studies have demonstrated the safety of aspartame. Its use has been endorsed by the Joint FAO/WHO Expert Committee on Food Additives, American Medical Association, American Heart Association, and numerous other health agencies. It is consumed in more than 90 countries worldwide and is an ingredient in over 1,000 products. Nevertheless, perhaps because of its widespread use (half the US population regularly consumes products sweetened with aspartame) or negative publicity, it is second only to olestra in the number of adverse reaction complaints it has generated through ARMS (Table 7.1). 

Approved in 1981 as a table top sweetener and for dry foods, aspartame was permitted in carbonated soft drinks in 1983, and in 1996 its approval was extended to all foods and beverages. There has been controversy over the role a Public Board of Inquiry played in the approval process, but this has been discounted in reports by the American Medical Association (Council of Scientific Affairs, 1985) and Stegink (1987). Reports of adverse reactions began almost immediately after approval in the 1980s, and by mid-1984 more than 600 complaints had been received by the FDA. Reports of adverse reactions peaked in 1985, when over 1,500 complaints were received by ARMS, and have been declining since then. As of June 2000, ARMS had received a total of 7,335 complaints about aspartame, with 47% of complaints linked to diet soft drinks, followed by 27% of complaints attributed to table top sweeteners. All other product categories were mentioned in fewer than 10% of complaints. 

Special attention was paid to the potential influence on phenylketonurics (PKU), as aspartame contains phenylalanine. As persons suffering from PKU should avoid uncontrolled intake of phenylalanine-containing food constituents or food additives, most countries require a warning on aspartame-sweetened products unless the aspartame level brought about by constituents of these products will exceed the aspartame levels.1314 Evaluations of aspartame were carried out by JECFA, and an ADI of 0-40mg/kg of body weight was allocated.15 The SCF allocated the same level,10 whereas the FDA published a value of 50 mg/kg.16... 

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