Edited by

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Typical Properties

Acidity/alkalinity: pH = 5–6 (5% w/v aqueous solution)

D

solution)

Stability and Storage Conditions

Alitame is stable in dry, room temperature conditions but undergoes degradation at elevated temperatures or when in solution at low pH. Alitame can degrade in a one-stage process to aspartic acid and alanine amide (under harsh conditions) or in a slow two-stage process by first degrading to its b-aspartic isomer and then to aspartic acid and alanine amide. At pH 5–8, alitame solutions at 238C have a half-life of approximately 4 years. At pH 2 and 238C the half-life is 1 year.

Alitame should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Alitame may be incompatible with oxidizing and reducing substances or strong acids and bases.

Method of Manufacture

Alitame may be synthesized by a number of routes.(2,3) For example, 3-(D-alaninamido)-2,2,4,4-tetramethylthietane is dis- solved in water and L-aspartic acid N-thiocarboxyanhydride is then added in portions with vigorous stirring, maintaining the pH of 8.5–9.5. The pH is then adjusted to 5.5 and p- toluenesulfonic acid monohydrate is added over a period of one hour. The precipitated crystalline p-toluenesulfonate salt is collected by filtration. To obtain alitame from its salt, a mixture of Amberlite LA-1 (liquid anion exchange resin), dichloro- methane, deionized water, and the salt is stirred for one hour, resulting in two clear layers. The aqueous layer is treated with carbon, clarified by filtration, and cooled to crystallize alitame.

Alternatively, tetramethylthietane amine is condensed with an N-protected form of D-alanine to give alanyl amide. This is then coupled to a protected analogue of L-aspartic acid to give a crude form of alitame. The crude product is then purified.

Alitame 29 

Safety

Alitame is a relatively new intense sweetening agent used primarily in foods and confectionary. It is generally regarded as a relatively nontoxic and nonirritant material.

Chronic animal studies in mice, rats, and dogs carried out for a minimum of 18 months at concentrations >100 mg/kg per day exhibited no toxic or carcinogenic effects. In people, no evidence of untoward effects were observed following ingestion of 15 mg/kg per day for two weeks.

Following oral administration 7–22% of alitame is unab- sorbed and excreted in the feces. The remaining amount is hydrolyzed to aspartic acid and alanine amide. The aspartic acid is metabolized normally and the alanine amide excreted in the urine as a sulfoxide isomer, as the sulfone, or conjugated with glucuronic acid.

The WHO has set an acceptable daily intake of alitame at up to 0.1 mg/kg body-weight.(4)

LD50 (mouse, oral): >5 g/kg LD50 (rabbit, skin): >2 g/kg LD50 (rat, oral): >5 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Alitame should be stored in tightly closed containers, and protected from exposure to direct sunlight and higher than normal room temperatures.

Regulatory Status

Alitame is approved for use in food applications in a number of countries worldwide including Australia, Chile, China, Mex- ico, and New Zealand.

Related Substances

Acesulfame potassium; aspartame; saccharin; saccharin sodium; sodium cyclamate.



Comments

—

Specific References

FAO/WHO. Evaluation of certain food additives and contami- nants. Fifty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 2002; No. 913.

Sklavounos C. Process for preparation, isolation and purification of dipeptide sweeteners. United States Patent No. 4,375,430; 1 Mar, 1983.

Brennan TM, Hendrick ME. Branched amides of L-aspartyl-D- amino acid dipeptides. United States Patent No. 4,411,925; 25 Oct, 1983.

FAO/WHO. Evaluation of certain food additives and contami- nants. Forty-sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1997; No.868.

General References

Anonymous. Use of nutritive and nonnutritive sweeteners—position of ADA. J Am Diet Assoc 1998; 98: 580–587.

Hendrick ME. Alitame. In: Nabors L, Gelardi R, eds. Alternative Sweeteners. New York: Marcel Dekker, 1991: 29–38.

Hendrick ME. In: Grenby TH, ed. Advances in Sweeteners. Glasgow: Blackie, 1996: 226–239.

Authors

LY Galichet.

Date of Revision

17 August 2005.

Almond Oil

Nonproprietary Names

BP: Almond oil

PhEur: Amygdalae oleum virginum USPNF: Almond oil

Synonyms

Almond oil, bitter; artificial almond oil; bitter almond oil; expressed almond oil; huile d’amande; oleo de ameˆndoas; olio di mandorla; sweet almond oil; virgin almond oil.

Chemical Name and CAS Registry Number

Almond oil [8007-69-0]

Empirical Formula and Molecular Weight

Almond oil consists chiefly of glycerides of oleic acid, with smaller amounts of linoleic and palmitic acids. The PhEur 2005 describes almond oil as the fatty oil obtained by cold expression from the ripe seeds of Prunus dulcis (Miller) DA Webb var. dulcis or Prunus dulcis (Miller) DA Webb var. amara (DC) Buchheim or a mixture of both varieties. A suitable antioxidant may be added.

The USPNF 23 describes almond oil as the fixed oil obtained by expression from the kernels of varieties of Prunus amygdalus Batsch (Fam. Rosaceae).

Structural Formula

See above.

Functional Category

Emollient; oleaginous vehicle; solvent.

Applications in Pharmaceutical Formulation or Technology

Almond oil is used therapeutically as an emollient(1) and to soften ear wax. As a pharmaceutical excipient it is employed as a vehicle in parenteral preparations,(2) such as oily phenol injection. It is also used in nasal spray,(3) and topical preparations.(4)Almond oil is also consumed as a food substance, see Section 18.

Description

A clear, colorless, or pale-yellow colored oil with a bland, nutty taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for almond oil.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Absorbance + —    

Acid value 42.0 —    

Characters + —    

Cottonseed oil — +    

Foreign kernel oils — +    

Foreign oils — +    

Iodine value — 95–105    

Mineral oil and fatty oils — +    

Peroxide value 415.0 —    

Saponification value — 190–200    

Sesame oil — +    

Specific gravity — 0.910–0.915    

Unsaponifiable matter 40.7% —    

Free fatty acids + +    

Saturated fatty acids < C16 40.1% —    

Arachidic acid 40.2% —    

Behenic acid 40.2% —    

Eicosenoic acid 40.3% —    

Erucic acid 40.1% —    

Linoleic acid 20.0–30.0% —    

Linolenic acid 40.4% —    

Margaric acid 40.2% —    

Oleic acid 62.0–86.0% —    

Palmitic acid 4.0–9.0% —    

Palmitoleic acid 40.6% —    

Stearic acid 43.0% —    

Sterols + —    

∆5-Avenasterol 510.0% —    

∆7-Avenasterol 43.0% —    

Brassicasterol 40.3% —    

Cholesterol 40.7% —    

Campesterol 44.0% —    

Stigmasterol 43.0% —    

b-Sitosterol 73.0–87.0% —    

∆7-Stigmasterol 43.0% —  

Typical Properties

Flash point: 3208C

Melting point: —188C

Refractive index: n40 = 1.4630–1.4650

Smoke point: 2208C

Solubility: miscible with chloroform, and ether; slightly soluble in ethanol (95%).

Stability and Storage Conditions

Almond oil should be stored in a well-closed container in a cool, dry place away from direct sunlight and odors. It may be sterilized by heating at 1508C for 1 hour. Almond oil does not easily turn rancid.

Almond Oil 31 

Incompatibilities

—

Method of Manufacture

Almond oil is expressed from the seeds of the bitter or sweet almond, Prunus dulcis (Prunus amygdalus; Amygdalus com- munis) var. amara or var. dulcis (Rosaceae).(5) See also Section 4.

Safety

Almond oil is widely consumed as a food and is used both therapeutically and as an excipient in topical and parenteral pharmaceutical formulations, where it is generally regarded as a nontoxic and nonirritant material. However, there has been a single case reported of a 5-month-old child developing allergic dermatitis attributed to the application of almond oil for 2 months to the cheeks and buttocks.(6)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Regulatory Status

Included in nonparenteral and parenteral medicines licensed in the UK. Widely used as an edible oil.

Related Substances

Canola oil; corn oil; cottonseed oil; peanut oil; refined almond oil; sesame oil; soybean oil.

Refined almond oil

Synonyms: amygdalae oleum raffinatum.

Comments: refined almond oil is defined in some pharmaco- peias such as the PhEur 2005. Refined almond oil is a clear, pale yellow colored oil with virtually no taste or odor. It is obtained by expression of almond seeds followed by subsequent refining. It may contain a suitable antioxidant.

Comments

A 100 g quantity of almond oil has a nutritional energy value of 3700 kJ (900 kcal) and contains 100 g of fat of which 28% is polyunsaturated, 64% is monounsaturated and 8% is satu- rated fat.



Studies have suggested that almond consumption is associated with health benefits, including a decreased risk of colon cancer.(7)

A specification for bitter almond oil is contained in the Food Chemicals Codex (FCC).

Specific References

Pesko LJ. Peanut recipe softens brittle, split nails. Am Drug 1997;

214(Dec): 48.

Van Hoogmoed LM, Agnew DW, Whitcomb M, et al. Ultrasono- graphic and histologic evaluation of medial and middle patellar ligaments in exercised horses following injection with ethanola- mine oleate and 2% iodine in almond oil. Am J Vet Res 2002; 63(5): 738–743.

Cicinelli E, Savino F, Cagnazzo I, et al. Progesterone administra- tion by nasal spray in menopausal women: comparison between two different spray formulations. Gynecol Endocrinol 1992; 6(4): 247–251.

Christen P, Kloeti F, Gander B. Stability of prednisolone and prednisolone acetate in various vehicles used in semi-solid topical preparations. J Clin Pharm Ther 1990; 15(5): 325–329.

Evans WC. Trease and Evans’ Pharmacognosy, 14th edn. London: WB Saunders, 1996: 184.

Guillet G, Guillet M-H. Percutaneous sensitization to almond in infancy and study of ointments in 27 children with food allergy. Allerg Immunol 2000; 32(8): 309–311.

Davis PA, Iwahashi CK. Whole almonds and almond fractions reduce aberrant crypt foci in a rat model of colon carcinogenesis. Cancer Lett 2001; 165(1): 27–33.

General References

Allen LV. Oleaginous vehicles. Int J Pharm Compound 2000; 4(6): 470–

472.

Anonymous. Iodine 2% in oil injection. Int J Pharm Compound 2001;

5(2): 131.

Brown JH, Arquette DJ, Kleiman R, et al. Oxidative stability of botanical emollients. Cosmet Toilet 1997; 112(Jul): 87–90, 92, 94,

96–98.

Shaath NA, Benveniste B. Natural oil of bitter almond. Perfum Flavor

1991; 16(Nov–Dec): 17, 19–24.

Authors

SA Shah, D Thassu.

Date of Revision

15 August 2005.

Alpha Tocopherol

Nonproprietary Names

BP: Alpha tocopherol JP: Tocopherol

PhEur: RRR-a-Tocopherolum USP: Vitamin E

See also Sections 3, 9, and 17.

Synonyms

Copherol F1300; ( )-3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; E307; East- man Vitamin E TPGS; synthetic alpha tocopherol; all-rac-a- tocopherol; dl-a-tocopherol; 5,7,8-trimethyltocol.

Chemical Name and CAS Registry Number

(  )-(2RS,4'RS,8'RS)-2,5,7,8-Tetramethyl-2-(4',8',12'-tri-

methyltridecyl)-6-chromanol [10191-41-0]

Note that alpha tocopherol has three chiral centers, giving rise to eight isomeric forms. The naturally occurring form is known as d-alpha tocopherol or (2R,4'R,8'R)-alpha-toco- pherol. The synthetic form, dl-alpha tocopherol or simply alpha tocopherol, occurs as a racemic mixture containing equimolar quantities of all the isomers.

Similar considerations apply to beta, delta, and gamma tocopherol and tocopherol esters.

See Section 17 for further information.

Empirical Formula and Molecular Weight

C29H50O2 430.72