med 5

When mixed in equimolar proportions with a fatty acid, such as stearic acid or oleic acid, triethanolamine forms an anionic soap with a pH of about 8, which may be used as an emulsifying agent to produce fine-grained, stable oil-in-water emulsions. Concentrations that are typically used for emulsi- fication are 2–4% v/v of triethanolamine and 2–5 times that of fatty acids. In the case of mineral oils, 5% v/v of triethanol- amine will be needed, with an appropriate increase in the amount of fatty acid used. Preparations that contain trietha- nolamine soaps tend to darken on storage. However, discolora- tion may be reduced by avoiding exposure to light and contact with metals and metal ions.

Triethanolamine is also used in salt formation for injectable solutions and in topical analgesic preparations. It is also used in sun-screen preparations.(1)

Triethanolamine is used as an intermediate in the manu- facturing of surfactants, textile specialties, waxes, polishes, herbicides, petroleum demulsifiers, toilet goods, cement addi- tives, and cutting oils. Triethanolamine is also claimed to be used for the production of lubricants for the rubber gloves and textile industries. Other general uses are as buffers, solvents, and polymer plasticizers, and as a humectant.

See also Section 18.

Description

Triethanolamine is a clear, colorless to pale yellow-colored viscous liquid having a slight ammoniacal odor. It is a mixture of bases, mainly 2,2',2''-nitrilotriethanol although it also contains 2,2'-iminobisethanol (diethanolamine) and smaller amounts of 2-aminoethanol (monoethanolamine).

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for triethanolamine.

Test PhEur 2005 USPNF 23

Characters + —

Identification + +

Appearance of solution + —

Related substances + —

Heavy metals 410 ppm —

Water 41.0% 40.5%

Sulfated ash 40.1% 40.05%

Impurities + —

Organic volatile impurities — +

Specific gravity — 1.120–1.128

Refractive index — 1.481–1.486

Assay 99.0–103.0% 99.0–107.4%

Typical Properties

Acidity/alkalinity: pH = 10.5 (0.1 N solution)

Boiling point: 3358C Flash point: 2088C Freezing point: 21.68C

Hygroscopicity: very hygroscopic.

Melting point: 20–218C Moisture content: 0.09% Solubility: see Table II.

Table II: Solubility of triethanolamine.

Solvent Solubility at 208C

Acetone Miscible

Benzene 1 in 24

Carbon tetrachloride Miscible

Ethyl ether 1 in 63

Methanol Miscible

Water Miscible

Surface tension: 48.9 mN/m (48.9 dynes/cm) at 258C

Viscosity (dynamic): 590 mPa s (590 cP) at 308C

Triethanolamine 795

Stability and Storage Conditions

Triethanolamine may turn brown on exposure to air and light. The 85% grade of triethanolamine tends to stratify below 158C; homegeneity can be restored by warming and mixing

before use.

Triethanolamine should be stored in an airtight container protected from light, in a cool, dry place.

See Monoethanolamine for further information.

Incompatibilities

Triethanolamine is a tertiary amine that contains hydroxy groups; it is capable of undergoing reactions typical of tertiary amines and alcohols. Triethanolamine will react with mineral acids to form crystalline salts and esters. With the higher fatty acids, triethanolamine forms salts that are soluble in water and have characteristics of soaps. Triethanolamine will also react with copper to form complex salts. Discoloration and precipitation can take place in the presence of heavy metal salts. Triethanolamine can react with reagents such as thionyl chloride to replace the hydroxy groups with halogens. The products of these reactions are very toxic, resembling other

nitrogen mustards.

Method of Manufacture

Triethanolamine is prepared commercially by the ammonolysis of ethylene oxide. The reaction yields a mixture of mono- ethanolamine, diethanolamine, and triethanolamine, which are separated to obtain the pure products.

Safety

Triethanolamine is used primarily as an emulsifying agent in a variety of topical pharmaceutical preparations. Although generally regarded as a nontoxic material,(2) triethanolamine may cause hypersensitivity or be irritant to the skin when present in formulated products. The lethal human oral dose of triethanolamine is estimated to be 5–15 g/kg body-weight.

Following concern about the possible production of nitrosamines in the stomach, the Swiss authorities have restricted the use of triethanolamine to preparations intended for external use.(3)

LD50 (guinea pig, oral): 5.3 g/kg(4) LD50 (mouse, IP): 1.45 g/kg

LD50 (mouse, oral): 7.4 g/kg LD50 (rat, oral): 8 g/kg

Handling Precautions

Triethanolamine may be irritant to the skin, eyes, and mucous membranes. Inhalation of vapor may be harmful. Protective clothing, gloves, eye protection, and a respirator are recom- mended. Ideally, triethanolamine should be handled in a fume cupboard. On heating, triethanolamine forms highly toxic nitrous fumes. Triethanolamine is combustible.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (rectal, topical, and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Diethanolamine; monoethanolamine.

Comments

Various grades of triethanolamine are available. The standard commercial grade contains 85% triethanolamine. The superior grade contains 98–99% triethanolamine.

One volume part of triethanolamine with 5–7 parts of a mixture of CaO2 and ZnO2 is used as a filling material that enhances the restorative process in periodontal tissues. Triethanolamine is recommended as the preferred stabilizer to be used in latex polymerization because of its weak mutagenic effect in the Ames tests.

The EINECS number for triethanolamine is 203-049-8.

Specific References

Turkoglu M, Yener S. Design and in vivo evaluation of ultrafine inorganic-oxide-containing-sunscreen formulations. Int J Cosmet Sci 1997; 19(4): 193–201.

Maekawa A, Onodera H, Tanigawa H, et al. Lack of carcinogeni- city of triethanolamine in F344 rats. J Toxicol Environ Health 1986; 19(3): 345–357.

Anonymous. Trolamine: concerns regarding potential carcinogeni- city. WHO Drug Inf 1991; 5: 9.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3568.

General References

Friberg SE, Wohn CS, Lockwood FE. The influence of solvent on nonaqueous lyotropic liquid crystalline phase formed by triethan- olamine oleate. J Pharm Sci 1985; 74(7): 771–773.

Ramsay B, Lawrence CM, Bruce JM, Shuster S. The effect of triethanolamine application on anthralin-induced inflammation and therapeutic effect in psoriasis. J Am Acad Dermatol 1990; 23: 73–76.

Yano H, Noda A, Hukuhara T, Miyazawa K. Generation of maillard- type compounds from triethanolamine alone. J Am Oil Chem Soc 1997; 74(7): 891–893.

BP: Triethyl citrate PhEur: Triethylis citras USPNF: Triethyl citrate

Synonyms

Citric acid, ethyl ester; Citroflex 2; Citrofol AI; E1505;

Hydagen CAT; TEC.

Chemical Name and CAS Registry Number

Hydroxy-1,2,3-propanetricarboxylic acid, triethyl ester [77- 93-0]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Triethyl citrate and the related esters acetyltriethyl citrate, tributyl citrate, and acetyltributyl are used to plasticize polymers in formulated pharmaceutical coatings.(1–5) The coating applications include capsules, tablets, beads, and granules for taste masking, immediate release, sustained- release, and enteric formulations.

Triethyl citrate is also used as a direct food additive for flavoring, for solvency, and as a surface active agent.

Description

Triethyl citrate is a clear, odorless, practically colorless, oily liquid.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for triethyl citrate.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance + —

Specific gravity — 1.135–1.139

Refractive index 1.440–1.446 1.439–1.441

Acidity + +

Related substances + —

Sulfated ash 40.1% —

Heavy metals 45 ppm 40.001%

Water 40.25% 40.25%

Assay (anhydrous basis) 98.5–101.0% 99.0–100.5%

Typical Properties

Acid value: 0.02

Boiling point: 2888C (decomposes)

Flash point: 1558C

Pour point: —458C

Solubility: soluble 1 in 125 of peanut oil, 1 in 15 of water.

Miscible with ethanol (95%), acetone, and propan-2-ol.

Viscosity (dynamic): 35.2 mPa s (35.2 cP) at 258C

Stability and Storage Conditions

Triethyl citrate should be stored in a closed container in a cool, dry location. When stored in accordance with these conditions, triethyl citrate is a stable product.

Incompatibilities

Triethyl citrate is incompatible with strong alkalis and oxidizing materials.

Method of Manufacture

Triethyl citrate is prepared by the esterification of citric acid and ethanol in the presence of a catalyst.

Safety

Triethyl citrate is used in oral pharmaceutical formulations and as a direct food additive. It is generally regarded as a nontoxic and nonirritant material. However, ingestion of large quantities may be harmful.

LD50 (mouse, IP): 1.75 g/kg(6) LD50 (rat, IP): 4 g/kg

LD50 (rat, oral): 5.9 g/kg LD50 (rat, SC): 6.6 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Triethyl citrate is irritating to the eyes and may irritate the skin. Irritating to the respiratory

Triethyl Citrate 797

system as a mist or at elevated temperatures. Gloves, eye protection, and a respirator are recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Acetyltributyl citrate; acetyltriethyl citrate; tributyl citrate.

Comments

A specification for triethyl citrate is contained in the Food Chemicals Codex (FCC). The EINECS number for triethyl citrate is 201-070-7.

Specific References

Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizers on the physical and mechanical properties of acrylic resin copolymers. Int J Pharm 1994; 103: 293–301.

Lehmann K. Chemistry and application properties of polymetha- crylate coating systems. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989: 153–245.

Steurnagel CR. Latex emulsions for controlled drug delivery. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989: 1–61.

Gutierrez-Rocca JC, McGinity JW. Influence of aging on the physical–mechanical properties of acrylic resin films cast from aqueous dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19(3): 315–332.

Liu J, Williams R. Properties of heat-humidity cured cellulose acetate phthalate free films. Eur J Pharm Sci 2002; 17(1–2): 31–41.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3546.

BP: Vanillin PhEur: Vanillinum USPNF: Vanillin

Synonyms

4-Hydroxy-m-anisaldehyde; p-hydroxy-m-methoxybenz- aldehyde; 3-methoxy-4-hydroxybenzaldehyde; methylproto- catechuic aldehyde; Rhovanil; vanillic aldehyde.

Chemical Name and CAS Registry Number

4-Hydroxy-3-methoxybenzaldehyde [121-33-5]

Empirical Formula and Molecular Weight

Vanillin has also been investigated as a photostabilizer in furosemide 1% w/v injection, haloperidol 0.5% w/v injection, and thiothixene 0.2% w/v injection.(5)

Description

White or cream, crystalline needles or powder with character- istic vanilla odor and sweet taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for vanillin.

Applications in Pharmaceutical Formulation or Technology

Vanillin is widely used as a flavor in pharmaceuticals, foods, beverages, and confectionery products, to which it imparts a characteristic taste and odor of natural vanilla. It is also used in perfumes, as an analytical reagent and as an intermediate in the synthesis of a number of pharmaceuticals, particularly methyl- dopa. Additionally, it has been investigated as a potential therapeutic agent in sickle cell anemia(1) and is claimed to have some antifungal properties.(2)

In food applications, vanillin has been investigated as a preservative.(3,4)

As a pharmaceutical excipient, vanillin is used in tablets, solutions (0.01–0.02% w/v), syrups, and powders to mask the unpleasant taste and odor characteristics of certain formula- tions, such as caffeine tablets and polythiazide tablets. It is similarly used in film coatings to mask the taste and odor of vitamin tablets.

Typical Properties

Acidity/alkalinity: aqueous solutions are acid to litmus. Boiling point: 284–2858C (with decomposition) Density (bulk): 0.6 g/cm3

Flash point: 1538C (closed cup) Melting point: 81–838C Solubility: see Table II.

Specific gravity: 1.056 (liquid)

Table II: Solubility of vanillin.

Solvent Solubility at 208C

unless otherwise stated

Acetone Soluble

Alkali hydroxide solutions Soluble

Stability and Storage Conditions

Vanillin oxidizes slowly in moist air and is affected by light.

Solutions of vanillin in ethanol decompose rapidly in light to give a yellow-colored, slightly bitter tasting solution of 6,6'- dihydroxy-5,5'-dimethoxy-1,1'-biphenyl-3,3'-dicarbaldehyde. Alkaline solutions also decompose rapidly to give a brown- colored solution. However, solutions stable for several months may be produced by adding sodium metabisulfite 0.2% w/v as an antioxidant.(6)

The bulk material should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

Incompatible with acetone, forming a brightly colored com- pound.(7) A compound practically insoluble in ethanol is formed with glycerin.

Method of Manufacture

Vanillin occurs naturally in many essential oils and particularly in the pods of Vanilla planifolia and Vanilla tahitensis. Industrially, vanillin is prepared from lignin, which is obtained from the sulfite wastes produced during paper manufacture. Lignin is treated with alkali at elevated temperature and pressure, in the presence of a catalyst, to form a complex mixture of products from which vanillin is isolated. Vanillin is then purified by successive recrystallizations.

Vanillin may also be prepared synthetically by condensa- tion, in weak alkali, of a slight excess of guaiacol with glyoxylic acid at room temperature. The resultant alkaline solution, containing 4-hydroxy-3-methoxymandelic acid is oxidized in air, in the presence of a catalyst, and vanillin is obtained by acidification and simultaneous decarboxylation. Vanillin is then purified by successive recrystallizations.

Safety

There have been few reports of adverse reactions to vanillin, although it has been speculated that cross-sensitization with other structurally similar molecules, such as benzoic acid, may occur.(8) Adverse reactions that have been reported include contact dermatitis(9) and bronchospasm caused by hypersensi- tivity.(10)

The WHO has allocated an estimated acceptable daily intake for vanillin of up to 10 mg/kg body-weight.(11)

LD50 (guinea pig, IP): 1.19 g/kg(12) LD50 (guinea pig, oral): 1.4 g/kg LD50 (mouse, IP): 0.48 g/kg

LD50 (rat, IP): 1.16 g/kg LD50 (rat, oral): 1.58 g/kg LD50 (rat, SC): 1.5 g/kg

Handling Precautions

Observe normal precautions appropriate to the quantity of material handled. Eye protection is recommended. Heavy airborne concentrations of dust may present an explosion hazard.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral solutions, suspensions, syrups, and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Ethyl vanillin.

Comments

One part of synthetic vanillin is equivalent to 400 parts of vanilla pods. The EINECS number for vanillin is 204-465-2.

Specific References

Abraham DJ, Mehanna AS, Wireko FC, et al. Vanillin, a potential agent for the treatment of sickle cell anemia. Blood 1991; 77: 1334–1341.

Lisa´ M, Leifertova´ I, Baloun J. A contribution to the antifungal effect of propolis [in German]. Folia Pharm 1989; 13(1): 29–44.

Fitzgerald DJ, Stratford M, Narbad A. Analysis of the inhibition of food spoilage yeasts by vanillin. Int J Food Microbiol 2003; 86(1–2): 113–122.

Fitzgerald DJ, Stratford M, Gasson MJ, Narbad A. The potential application of vanillin in preventing yeast spoilage of soft drinks and fruit juices. J Food Prot 2004; 67(2): 391–395.

Thoma K, Klimek R. Photostabilization of drugs in dosage forms without protection from packaging materials. Int J Pharm 1991; 67: 169–175.

Jethwa SA, Stanford JB, Sugden JK. Light stability of vanillin solutions in ethanol. Drug Dev Ind Pharm 1979; 5: 79–85.

Thakur AB, Dayal S. Schiff base formation with nitrogen of a sulfonamido group. J Pharm Sci 1982; 71: 1422.

Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989: 238–239.

Wang X-S, Xue Y-S, Jiang Y, et al. Occupational contact dermatitis in manufacture of vanillin. Chin Med J 1987; 100: 250–254.

Van Assendelft AHW. Bronchospasm induced by vanillin and lactose. Eur J Respir Dis 1984; 65: 468–472.

FAO/WHO. Specifications for the identity and purity of food additives and their toxicological evaluation: some flavouring substances and non-nutritive sweetening agents. Eleventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1968; No. 383.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 3661–3662.

General References

Clark GS. Vanillin. Perfum Flavor 1990; 15(Mar/Apr): 45–54. Rhodia Inc. Technical literature: Rhovanil. 2001.

Rees DI. Determination of vanillin and ehtyl vanillin in food products.

Chem Ind 1965; 1: 16–17.

Vegetable Oil, Hydrogenated

Nonproprietary Names

BP: Hydrogenated vegetable oil JP: Hydrogenated oil

USPNF: Hydrogenated vegetable oil

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