Development of a New, No Calorie Commercial Sweetener Neotame

Chapter 32

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Development of a New, No Calorie Commercial Sweetener Neotame 1

2

IndraPrakash andIhabE.Bishay 1

2

The Coca-Cola Company, One Coca-Cola Plaza, Atlanta,GA30313 The NutraSweet Company, 222 Merchandise Mart Plaza, Suite 936, Chicago, IL 60654

Neotame, a new high potency sweetener and flavor enhancer, is derived from aspartame and is 8000 times sweeter than sucrose. It provides zero calories and has clean, sweet sugar-like taste with no undesirable taste characteristics. It is functional in a wide array of beverages and foods and can be used with other high potency or carbohydrate sweeteners. It is stable under dry conditions, and has comparable stability to aspartame in aqueous food systems. It is safe for use by general population and has been approved byU.S.FDAand several other countries around the world. Development of neotame i.e. discovery, manufacture, physical and chemical characteristics, taste profile, blends, stability and applications will be reviewed.

492

© 2008 American Chemical Society

In Sweetness and Sweeteners; Weerasinghe, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.


493 Neotame is a new high-intensity sweetener and flavor enhancer developed by The NutraSweet Company. It is a derivative of the dipeptide composed of the amino acids aspartic acid and phenylalanine and is approximately 7,000 13,000 times sweeter than sugar (30 - 60 times sweeter than aspartame). Neotame provides zero calories and has a clean sweet sugar-like taste with no undesirable taste characteristics. It is functional in a wide array of beverages and foods and is well suited for blending with other high-intensity or carbohydrate sweeteners. Neotame is stable under dry conditions and in aqueous food systems its stability is similar to aspartame with greater stability in neutral p H conditions and/or at higher temperatures (e. g., heat processing, baking and yogurt). The results of numerous safety studies confirm that neotame is safe for use by the general population, including children, pregnant women, and people with diabetes. In addition, no special labeling for phenylketonuric (PKU) individuals is required. Neotame has been approved for general use as a sweetener and flavor enhancer in the United States, Mexico, China, Australia and New Zealand and in many other countries. Its unique properties will provide the food technologist with another tool to produce innovative new foods and beverages to meet the demand of consumers to have available great tasting foods without all of the calories of sugar.

Discovery of Neotame Neotame was the result of a long-term research program to discover new high-intensity sweeteners with desirable taste characteristics. French scientists Claude Nofre and Jean-Marie Tinti invented neotame by substitution of the N terminus of aspartame. The chemical structures of aspartame and neotame are compared in Figure 1. Nofre and Tinti prepared a series of N-substituted aspartame derivatives that are listed in Table 2 along with their corresponding sweetness potencies

Aspartame

Neotame

Figure 1. Comparison of the chemical structures of aspartame and neotame


494 Table 1. Approximate sweetener indices of some of the common high-intensity sweeteners Approximate sweetness index

Sweetener


Sucrose

a

1.0

8

Acesulfame-K

200

Aspartame

200

Neotame

8000

Saccharin

300

Sucralose

600

Included for reference.

relative to a 2% solution of sucrose. As noted in Table 2, aspartame substituted with a 3,3-dimethylbutyl group results in the sweetest of the compounds tested. 12

Sweetness Potency of Neotame In sweetener research sucrose is the standard against which other compounds are compared. "Sucrose equivalence" or " % S E " is the standardized sweetness intensity scale established for comparing sweet compounds. A n x% SE is equivalent in sweetness to an x% sucrose in water solution. Neotame is 7,000 to 13,000 times sweeter than sucrose and is more potent than the high-intensity sweeteners currently marketed in the U.S. (Table 1). Though it is a derivative of aspartame, neotame is 30 to 60 times sweeter than aspartame. The actual sweetness potency is dependent on the neotame concentration required in various food or beverage products. Because of its remarkable sweetness potency, neotame is used in food and beverage products at considerably lower concentrations than other high-intensity sweeteners. In fact, consumer exposure to neotame will be much lower than that from flavoring ingredients such as vanillin, cinnamon, and menthol that are commonly used in food and beverages. The concentration-response curve for neotame was established using a trained sensory panel to evaluate the sweetness intensity of five solutions of neotame at increasing concentrations. The results are presented in Figure 2. Based on these data, neotame can reach an extrapolated maximum sweetness intensity (plateau) of 15.1% SE in water. Sweeteners such as aspartame, acesulfame-K, sodium cyclamate, and sodium saccharin attain their maximum sweetness intensity in water at approximately 16.0% SE, 11.6% SE, 11.3% SE, and 9.0% SE, respectively. 3


495 Table 2. Hydrophobic groups substituted on the terminal nitrogen of aspartame and the corresponding sweetening potencies of the resulting compounds XOOH

/

N

v

R-HN Y -^" OCH

No.

3


° Sh

Relative sweetener potency"

R = ( hydrophobic group) 1

CH3CH2CH2CH2

400

2

(CH ) CHCH

500

3

(CH ) CHCH CH

4

(R,S>CH CH CH(CH )CH

5

(CH CH ) CHCH

6

(CH ) CCH CH

7

Cyclohexyl

800

8

Cycloheptyl

900

9

Cyclooctyl

1000

10

Cyclopentylmethyl

1500

11

Cyclohexylmethyl

800

12

C6HsCH CH CH

13

(R,S)-C H CH(CH )CH CH

14

3,3-Dimethylcyclopentyl

15

(R,S)-3-Methylcyclohexyl

1000

16

3,3,5,5-Tetramethylcyclohexyl

1000

17

(R,S)-2-Hydroxycyclohexyl

18

(3-OCH 4-OH)C H CH CH CH

19

(3-OCH ,4-OH)C H CH=CHCH

20

(R,S)-(3-OCH ,4OH)CeH CH CH CH(CH ) (R,S)-(3-OCH ,4OH)C H CH=CHCH(CH )

3

3

2

2

2

3

3

3

2

2

2

2

2000

1500

2

3

6

3

2

3

6

2

1200

2

150

2

800 2

3

3

2,500

2

2

2,000 500

3

3

3

10,000

= (neotame)

5

2

900

2

2

2

3)

6

a

3

2

6

1300

2

2

3

3

21

2

500

3

Sweetener potency is given on a molar basis relative to a 2% sucrose solution.



496 —

Predicted

•

Observed

*

} η y

1

•

~7'> α Υ Concentration (ppm)

Figure 2. Neotame concentration response curve in water

Manufacture of Neotame Neotame can be made in one step by the reaction of aspartame with 3,3dimethylbutyraldehyde in methanol using hydrogen and a catalyst (palladium or platinum) under mild conditions (Figure 3). ' Other possible methods of preparation are from aspartame precursors, aspartic acid derivatives via anhydride or other peptide coupling methods, and by the aminolysis of substituted oxazolidinone derivatives. 4

^

C

0

0

COOH

H 0

ο

-

>

h

3,3-Dimethyl-

.

butyraldehyde

Aspartame

ch oh 3

η

η

Neotame

Figure 3. Manufacture of neotame


497

Properties of Neotame Chemical Neotame is N-[N-(33-dimethylbulyl)-L-a-aspartyl]-L-phenylalanine 1- methyl ester (CAS registry number 165450-17-9, INS number 961). It is a derivative of a dipeptide composed of the amino acids aspartic acid and phenylalanine. Neotame contains both a carboxylic acid and a secondary amino group, with pK values of 3.03 and 8.08, respectively. It is capable of forming both acidic and basic salts, as well as complexes with various metals,feusaffording unique delivery forms having improved solubility and other characteristics. The two amino acids in neotame, aspartic acid and phenylalanine, are the natural L-configuration. The other three possible isomers, L,D-, D,D-, and D,L-, lack the sweet taste of neotame.


a

9

Physical Neotame is a fairly low-melting hydrate (m.p. 80.9 - 83.4 °C). It is a white to off-white crystalline powder with 4.5% water of hydration, the empirical formula C20H30N2O5 • H 0 , and a molecular weight of 396.48. Neotame has similar solubility in water as aspartame (12.6 g/L vs 10 g/L at 25 °C) but is more readily soluble compared to aspartame in some solvents that are typically used in food systems and pharmaceuticals. For example, neotame is more readily soluble in ethanol compared to aspartame (Table 3). The solubility of neotame in water and ethyl acetate increases with increasing temperature (Table 4). Using neotame in a salt form (e.g., as a phosphate salt) significantly increases the rate of dissolution. 2

Table 3. Comparison of the solubility of neotame and aspartame in water and some typical solvents at 25 °C Will

Soybean oil Water Ethyl acetate Glycerin Propylene glycol Ethanol

Solubility of neotame (g/100g of solvent) 0.03 1.26 7.7 10.29 21.20 > 100

Solubility of aspartame (g/100g of solvent) 0.01 1.02 100

Stability of neotame The stability of neotame is dependent upon pH, moisture, and temperature. Dry powder is stable for at least five years under proper storage conditions (Figure 4). In aqueous systems p H stability follows a bell-shaped curve at a given temperature. The optimum p H for neotame's maximum stability is about 4.5. As expected, stability decreases with increasing temperature. In aqueous systems (pH 2 - 8 ) the major decomposition pathway of neotame is through the hydrolysis o f the methyl ester forming de-esterified neotame (Figure 5), also the major metabolite of neotame in humans. (25 °C, 60% RH) 100 80

2

'to

z

Φ 40 as* 20 0

20

40

60

80

100

120 140

160

180 200

220 240

260

Time (weeks) Figure 4. Stability ofNeotame in the Dry Form (Reproduced with permission from Food Technol, July 2002, 56(7), 36 Copyright 2002.)


499


De-esterified Neotame

Figures. Major pathway of degradation of neotame under hydrolytic condition (Reproduced with permission from Food Technol, July 2002, 56(7), 36. Copyright 2002.)

De-esterified neotame is not sweet Under conditions of use neotame does not degrade to phenylalanine. Unlike aspartame, neotame does not form a diketopiperazine (DKP) derivative (Figure 6). Neotame is compatible with reducing sugars and will not participate in Maillard browning reactions and is compatible with many aldehyde or ketone-based flavoring agents, Neotame has similar stability to aspartame in many applications at low p H and temperature, stability improves at higher pH's & temperatures. For example in cola beverage neotame shows similar stability at the lower temperatures, but shows slightly better stability at the higher temperatures (Figure 7).

(OOCHX

DKP

Figure 6. Major pathways of degradation of aspartame under hydrolytic conditions (Reproduced with permission from Food Technol, July 2002, 56(7), 36. Copyright 2002.)



500

Figure 7. Stability of Neotame and Aspartame in Cola (pH 3.1) (Reproduced with permissionfromFood Technol, July 2002, 56(7), 36. Copyright 2002.) (See color insert in this chapter.) In heat-processed beverages, such as lemon tea, both neotame and aspartame show good stability after High Temperature-Short Time (HTST) heat processing and during the beverage's shelf life (Figure 8). Unlike aspartame, neotame is not digested by the cultures found in yogurt, therefore neotame can be added before the incubation stage without loosing a significant amount of the sweetness (Figure 9). Since neotame is more heat stable than aspartame, it may not need to be encapsulated in application where aspartame requires encapsulation, such as in baking goods (Figure 10).

Figure 8. Stability of Neotame and Aspartame in Lemon Tea (Reproduced with permissionfromFood Technol, July 2002, 56(7), 36. Copyright 2002.)



501

Figure 9. Stability ofNeotame and Aspartame in Yogurt

Figure 10. Stability of Neotame and Aspartame in Yellow Cake


502

Sensory properties of Neotame


Taste profile Neotame exhibits a clean sweet taste profile at use levels in product applications. A trained descriptive panel evaluated neotame and sucrose at comparable sweetness levels in water. The taste profile of neotame is very similar to that of sucrose, with the predominant sensory characteristic of neotame being a very clean sweet taste. The sweetness of neotame increases as the concentration in water increases but taste attributes such as bitterness, sourness, and metallic taste are undetectable (Figure 11). In a similar study with neotame in a cola drink, increasing the sweetener concentration from 9 to 46 ppm improved the desirable flavor attributes (cola flavor, sweet taste, and mouthfeel) but not the undesirable notes (Figure 12).

Figure 11. Descriptive taste profile of neotame at various concentrations in water (See color insert in this chapter.)

Sweetness temporal profile The temporal profile of sweeteners demonstrates the changes in the perception of sweetness over time. This property is a key to the functionality of a sweetener and is complementary to its taste profile. Every sweetener exhibits a characteristic onset or response time and an extinction time. Most highintensity sweeteners, in contrast to sugar, display a prolonged extinction time. As shown in Figure 13, the sweetness temporal profile of neotame in water is close to that of aspartame, with a slightly slower onset and slightly longer extinction time. A longer extinction time can be beneficial in some products such as chewing gum where prolonged sweetness is a desirable quality. The sweetness temporal profile of neotame may also be modified by the addition of hydrophobic organic acids (e.g., cinnamic acid) and certain amino



503

Figure 12. Taste profile of neotame at various concentrations in cola (See color insert in this chapter.)

Figure 13. Comparative temporal profile of neotame vs sucrose and aspartame at isosweet concentrations in water (See color insert in this chapter.)


504 101112

acids (e.g., serine and tyrosine). Taste modifiers may be used in concentrations necessary to achieve the desired taste profile of a product for a desired application.

Blending Blending of sweeteners (nutritive as well as non-nutritive) is well known in the literature to improve the taste characteristics, stability, and synergy. A blend of neotame and saccharin shows sweetness synergy and provides 14 to 24% greater sweetness than would be predicted by adding together the sweetness intensities of the individual sweeteners. Such synergistic blends offer cost savings by decreasing the total amount of sweetener needed. Neotame can be blended with nutritive sweeteners as well as other high-intensity sweeteners such as aspartame, acesulfame salts, cyclamate, sucralose, saccharin, etc. Furthermore, the clean sweetness of neotame permits its substitution for substantial amounts of carbohydrate sweeteners without altering the flavor of the product. Because time-intensity and taste profiles of each sweetener is different and are also different from sucrose, the resulting profiles in blends combine properties of the different sweeteners and reduce the negative characteristics such as bitterness, metallic, etc. For example, the sweetness of acesulfame-K is generally perceived fairly quickly, it therefore, provides a quick impact sweetness, but often fades fairly quickly. Acesulfame-K also has a bittermetallic taste that limits it use in many applications. Therefore, acesulfame-K combines particularly well with sweeteners having a more delayed onset of sweetness and a longer lasting sweetness, such as aspartame or neotame. So for example a blend that has neotame or aspartame contributing 70% of the sweetness and acesulfame-K contributing 30% of the sweetness, has a sweetness profile much closer to sugar with a quick onset, significantly reduced lingering sweetness, and no bitterness or metallic off-taste. Neotame has also been shown to be very effective at replacing up to 50% of the sucralose in a beverage sweetened with 100% sucralose or a sucralose/acesulfame-K blend. Triangle taste tests have shown that consumers cannot differentiate between the sucralose sweetened beverage and beverage containing sucralose and neotame. Because of neotame's attractive cost position, replacing sucralose with neotame can yield significant economic benefits.


13,14,15,16,17,18

19

1

20

Sugar substitution Neotame's clean sweet taste is well suited for substitution of a portion of a carbohydrate sweetener while maintaining a taste that is indistinguishable from


§05 the 100% carbohydrate product. For example, studies have shown that 20% of the carbohydrate sweetener such as high fructose corn syrup (HFCS) can be replaced with 2.1 ppm of neotame in a cola carbonated soft drink and the taste is indistinguishable from the 100% HFCS-sweetened cola beverage (Figure 14). Because neotame is 1/5 the cost of HFCS and 1/10 the cost of sugar, it can offer a significant economic benefit and, because neotame has no calories, offers a positive caloric benefit. Downloaded by NANYANG TECHNOLOGICAL UNIV on August 20, 2015 | http://pubs.acs.org Publication Date: March 4, 2008 | doi: 10.1021/bk-2008-0979.ch032

Λ

th

Figure 14. Descriptive test results of cola beverages -100% High Fructose Corn Syrup (See color insert in this chapter.)

Flavor Modification and Enhancement Flavor modifiers are substances that are added to enhance or modify a product's flavor, which includes the combined perception of taste, smell, and aroma. Products containing vitamins, nutraceuticals, pharmaceuticals, salt substitutes, and soy in various applications are often either bitter or harsh in flavor. The addition o f neotame at a subsweetening level modifies or masks undesirable notes/qualities such as bitterness, astringency, and burning or cooling sensations. Undesirable attributes such as the potential bitterness of caffeine, cocoa, and potassium chloride and the harsh notes of medicinals and plant extracts can be modified or masked. Neotame reduces the bitter taste of potassium chloride in salt substitutes, thereby providing a cleaner salty taste. In soy products neotame reduces or


506 eliminates "beany" flavor notes. Neotame modifies or enhances the attributes of many flavoring chemicals, including essential oils, oleoresins, plant extracts, reaction flavors, and mixtures thereof 21


Food Applications and Functionality Historically, the stability and functionality of a new sweetener or an ingredient was determined for each food product before the sweetener was approved. This process generated redundant data. This redundancy could be avoided i f products with similar ingredients and processing conditions could be reduced to representative test products for evaluation. The functionality of neotame was demonstrated with a three-dimensional food matrix model representing the intended conditions of use in foods. Based on experience with aspartame and the structural similarities of neotame and aspartame, product moisture, process temperature, and product p H were considered to be the key factors responsible for neotame stability and were selected to represent the three_dimensions of the matrix. These products were prepared according to standard formulas, then packaged appropriately, stored at room temperature conditions (25 °C and 60% relative humidity) , and evaluated for stability at appropriate intervals. Neotame concentrations were determined using validated H P L C methods. Functionality (sweetness) of the test products was determined using panels consisting of 35 to 50 persons. Samples were appropriately prepared, served, and evaluated using a five-point scale of categories ranging from 5 (much too sweet) to 1 (not at all sweet). The samples were considered functional i f no more than 75% of the panelists rated the sweetness in categories 2 (not quite sweet enough) and 1. The evaluations of the test products are presented below: 22

23

1)

Carbonated soft drink: Neotame remained functional as a sweetener in cola flavored carbonated soft drink through at least 16 weeks, consistent with currently marketed low-calorie carbonated soft drinks. Hot pack lemon tea: Neotame remained functional as a sweetener in hot pack lemon tea for approximately 25 weeks. Powdered soft drink: A t each evaluation the sweetness of the reconstituted drink received a rating of just about right, indicating that the product was stable and functional as a sweetener during 52-weeks of storage at 25 °C and 60% relative humidity. Tabletop product: Neotame was considered stable and functional in tabletop products for 156 weeks when stored at 25 °C and 60% relative humidity. ' Chewing gum: Using neotame that was double encapsulated with modified starch and hydroxypropyl methyl cellulose (HPMC) resulted in a 52 weeks shelf-life. Subsequent work has shown that in some formulations, encapsulation is not needed for neotame stability in chewing gum. 24

2) 3)

4)

25 26

5)

27


507 6)

Dairy products/ strawberry yogurt: At the end of a 6-week period, the typical shelf life of these products, about 98% of the initial neotame remained. Sensory results showed that neotame had excellent functionality as a sweetener m yogurt. 7) Bakery products/ yellow cake: Neotame was functional as a sweetener in yellow cake with 82% remaining after baking at 350 °F. After storage for five days, which is longer than cakes are commercially held for optimum freshness, there was only a 4% loss of neotame. The combined losses of less than 20% did not affect sweetener functionality. 8) Other products: Functionality of neotame has been demonstrated in cereals and cereal-based foods , nutraceuticals , pharmaceuticals , edible gels , and confectionery products .


2529

30

31

32

33

34

Benefits of Neotame Neotame provides several benefits as a sweetener and/or flavor enhancer in food and beverage systemSo Some of these benefits are reviewed below. • 8,000 times more potent than sugar • Because of its high potency, the quantity of neotame required to sweeten a product is about 1/30 to 1/60 of the amount of aspartame required and 1 /12 to 1 /15 of the amount of sucralose required. • Has a clean, sweet taste, like that of sugar • Neotame is non-caloric. • Neotame requires no P K U labeling. • Based on its chemistry, neotame is not likely to react with aldehydes and, consequently, may be compatible with flavors containing aldehydes. • Neotame enhances the flavor of some ingredients such as mint, citrus, and fruit flavors in various food and beverage systems. • Neotame is very cost effective

Regulatory Status of Neotame Safety of neotame The results of extensive research done in animals and humans using amounts of neotame that far exceed expected consumption levels clearly confirm the safety of neotame for the general population including children, pregnant women, and people with diabetes. Neotame is not mutagenic, teratogenic, carcinogenic and has no effect on reproduction. In addition, no special labeling for phenylketonuric individuals is required. The major route of metabolism of neotame is de-esterification. Both neotame and de-esterified neotame have short plasma half-lives with rapid and complete elimination. ' 25 35


508 United States regulatory status The United States Food and Drug Administration has approved of neotame for general use in food as a sweetener and flavor enhancer under G M P .


International regulatory status The NutraSweet Company has fded for regulatory approval in a number of foreign countries. Approval has already been received from Mexico, China, Philippines, Indonesia, Australia and New Zealand and in over 20 other countries for use of neotame as a sweetener and flavor enhancer.

References 1. 2. 3.

4. 5. 6.

7.

8.

9.

Nofre, C. and Tinti, J.-M. N-Substituted derivatives of aspartame useful as sweetening agents.U.S.patent 5,480,668. 1996. Nofre, C. and Tinti, J.-M. Neotame: discovery, properties, utility. Food Chem. 2000, 69, 245-297. DuBois, G., Walters, D, Schiffman, S., Warwick, Z., Booth, B., Pecore, S., Gibes, K., Carr, B., and Brands, L. Concentration-response relationships of sweeteners. in Sweeteners Discovery, Molecular Design, and Chemoreception, D.E. Walters, F.T. Orthoefer, and G.E. DuBois eds., American Chemical Society, Washington, DC. 1991, Chapter 20, pp 261276. Nofre, C. and Tinti, J.-M. Method of preparing a compound derived from aspartame, useful as a sweetening agent.U.S.patent 5,510,508. 1996. Prakash, I., Method for preparing and purifying an N-alkylated aspartame derivative.U.S.patent 5,728,862. 1998. Prakash, I., Synthesis of N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-Lphenylalanine l-methyl ester using oxazolidinone derivatives.U.S.patent 6,852,875. 2005. Prakash, I. and Chapeau, M . - C . N-3,3-Dimethylbutyl-L-aspartic acid and esters thereof, the process of preparing the same, and the process for preparing N-(N-(3,3-dimethylbutyl)-αL-aspartyl)-L-phenylalanine 1methyl ester therefrom.U.S.patent 6,077,962. 2000. Orlovski, V . , Prakash, I., Scaros, M . and Moore, C. A method for the preparation of N-neohexyl-α-aspartyl-L-phenylalanine methyl ester from imidazolidin-4-one intermediates. U.S. patent 6,465,677. 2002. Prakash, I., Bishay, I., and Schroeder, S. Neotame: synthesis, stereochemistry and sweetness. Synthetic Communications, 1999, 29(24), 4461-4467.



509 10. Bishay, I., Prakash, I., Desai, N., and Gelman, Y. Modification of the taste and physicochemical properties of neotame using hydrophobic additives. PCT International application W O 00/69282. 2000. 11. Gerlat, P., Hatchwell, L., Walters, G., Miragilo, Α., and Sawyer, H . Use of N-neohexyl-α-aspartyl-L-phenylalanine methyl ester as flavor modifier. U.S. patent application No. 09/465,837. 2000. 12. Prakash, I., Bishay, I., Desai, N., and Walters, D. Modifying the temporal profile of the high-potency sweetener neotame. J. Agric. Food Chem. 2001, 49(2), 786-778. 13. Lavia, A. and Hill, J. Sweeteners with masked saccharin aftertaste. French patent 2,087,843. 1972. 14. Paul, T. Chem. Zeit. 1921, 45, 38-39. 15. Schiffman, S., Booth, B . , Carr, B . , Losee, M., Sattely-Miller, E., and Graham, B . Investigation of synergism in binary mixtures of sweeteners. Brain Research Bulletin, 1995, 38(2), 105-120, 16. Scott, D . Saccharin-dipeptide sweetening compositions. British patent 1,256,995. 1971. 17. Verdi, R. and Hood, L . Food Technol. 1993, 47, 94-102. 18. Walters, E. High intensity sweetener blends. Food Product Design. Weeks Publishing Co. Northbrook, IL. 1993. 19. Pajor, L . and Gibes, K . N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-Lphenylalanine 1-methyl ester synergistic sweetener blends. U.S. patent 6,048,999. 2000. 20. Northland Laboratories Report. NutraSweet Triangle Discrimination Study, Mixed Berry Flavored Beverage. Northland Laboratories, Northbrook, IL July 11, 2005. 21. Gerlat, P., Walters, G., Bishay, I., Prakash, I., Jarrett, T., Desai, N., Sawyer, H., and Bechert, C.-L. Use of additives to modify the taste characteristics of N-neohexyl-α-aspartyl-L-phenylalanine methyl ester. U.S. patent 6,368,651. 2002. 22. Pariza, M . , Ponakala, S., Gerlat, P., and Andress, S. Predicting the functionality of direct food additives. Food Technol. 1998, 52(11), 56-60. 23. F D A . International conference on harmonization; guidelines for room temperature storage. Fed. Reg. 1994, 59(183), 48754-48759. 24. Gerlat, P., Milovanovic, S., Ponakala, S., Ziegler, J., Sawyer, H . , and Walters, G. Neotame-based sweeteners for beverages. P C T International application W O 99/30576. 1999. 25. F A P . Monsanto Co.: Filing a food additive petition. F A P 8A4580. Food and Drug Admin., Fed. Reg. 1998, 63(27), 6762. 26. Towb, Α., Dron, Α., and Walters, G . Drying of neotame with co-agents. P C T International application W O 02/05660. 2002. Ponakala, S. V . , Gerlat, P. Α., Ziegler, J. G., Jarrett, T. N. and Cheng, J. Tabletop sweetener compositions comprising sweetener with extremely high potency. P C T International application W O 99/30577. 1999.



510 27. Roefer, W. Unpublished data. Dept. of Analytical Chemistry, The NutraSweet Company, Mt. Prospect, Ill. 2002. 28. Gaughan, W., Gerlat, P., Ziegler, J., Walters, G., Logli, L., Corliss, G., and Finley, J. Neotame sweetener for dairy products and dairy product substitutes. P C T International application W O 99/30578. 1999. 29. Chinn, B . , Solter, S., Ponakala, S., Ziegler, J., Bakhoum, M., Jarrett, T., Paeschke, T., and Corliss, G . Use of N-[N-(3,3-dimethylbutyl)-L-αaspartyl]-L-phenylalanine 1-methyl ester in baked goods, frostings and bakery fillings. P C T International application W O 99/30566. 1999. 30. Ponakala, S. and Corliss, G . Cereals and cereal-based food sweetened with neotame. P C T International application W O 00/056175. 2000. 31. Ponakala, S., Walters, G., Gerlat, P., and Hatchwell, L . Nutraceuticals having N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester. P C T International application W O 00/057726. 2000. 32. Ponakala, S. Pharmaceutical compositions containing neotame. PCT International application W O 01/028590. 2001. 33. Ponakala, S., Walters, G . , and Schroeder, S. Manufacture of edible gels sweetened with neotame. P C T International application W O 00/056176. 2000. 34. Jarrett, T. Confectionery food products sweetened with N-[N-(3,3dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester. P C T International application W O 01/010236. 2001. 35. F A P . Monsanto Co.: Filing a food additive petition. F A P 9A4643. Food and Drug Admin., Fed. Reg. 1999, 64(25), 6100.


Development of a New, No Calorie Commercial Sweetener Neotame

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