Triethyl Citrate

1 Nonproprietary Names Table I: Pharmacopeial specifications for triethyl citrate. BP: Triethyl Citrate Test PhEur 6.0 USP32–NF27 PhEur: Triethyl Citrate þþ USP-NF: Triethyl Citrate Identification Characters þ — Appearance þ — Specific gravity — 1.135–1.139 2 Synonyms Refractive index 1.440–1.446 1.439–1.441 Acidity þþ Citric acid ethyl ester; Citroflex 2; Citrofol AI; E1505; ethyl citrate; Related substances þ — Hydagen CAT; 1,2,3-propanetricarboxylic acid, 2-hydroxy-, Sulfated ash 40.1% — triethyl ester (9CI); TEC; triethylis citras. Heavy metals 45 ppm 40.001% Water 40.25% 40.25% Assay (anhydrous basis) 98.5–101.0% 99.0–100.5% 3 Chemical Name and CAS Registry Number 2-Hydroxy-1,2,3-propanetricarboxylic acid triethyl ester [77-93- 0] 10 Typical Properties Acid value 0.02 Boiling point 2948C Flash point 1558C 4 Empirical Formula and Molecular Weight Pour point 458C C12H20O7 276.29 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 5 Structural Formula 11 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.

12 Incompatibilities Triethyl citrate is incompatible with strong alkalis and oxidizing materials.

13 Method of Manufacture Triethyl citrate is prepared by the esterification of citric acid and 6 Functional Category ethanol in the presence of a catalyst. Plasticizer; solvent. T 14 Safety Triethyl citrate is used in oral pharmaceutical formulations and as a 7 Applications in Pharmaceutical Formulation or direct food additive. It is generally regarded as a nontoxic and Technology nonirritant material. However, ingestion of large quantities may be harmful. Triethyl citrate and the related esters acetyltriethyl citrate, tributyl (6) citrate, and acetyltributyl citrate are used to plasticize polymers in LD50 (mouse, IP): 1.75 g/kg (1–5) formulated pharmaceutical coatings. The coating applications LD50 (rat, IP): 4 g/kg include capsules, tablets, beads, and granules for taste masking, LD50 (rat, oral): 5.9 g/kg immediate release, sustained-release, and enteric formulations. LD (rat, SC): 6.6 g/kg Triethyl citrate is also used as a direct food additive for flavoring, 50 for solvency, and as a surface active agent. 15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. Triethyl citrate is irritating to the eyes 8 Description and may irritate the skin. It is irritating to the respiratory system as a Triethyl citrate is a clear, viscous, odorless, and practically colorless, mist or at elevated temperatures. Gloves, eye protection, and a hygroscopic liquid. respirator are recommended.

16 Regulatory Status 9 Pharmacopeial Specifications GRAS listed. Accepted for use as a food additive in Europe. See Table I. Included in the FDA Inactive Ingredients Database (oral capsules

756 Triolein 757 and tablets). Included in the Canadian List of Acceptable Non- 3 Steurnagel CR. Latex emulsions for controlled drug delivery. McGinity medicinal Ingredients. JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989; 1–61. 4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the physical– 17 Related Substances mechanical properties of acrylic resin films cast from aqueous Acetyltributyl citrate; acetyltriethyl citrate; tributyl citrate. dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19(3): 315–332. 5 Liu J, Williams R. Properties of heat-humidity cured cellulose acetate 18 Comments phthalate free films. Eur J Pharm Sci 2002; 17(1–2): 31–41. 6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th A specification for triethyl citrate is contained in the Food (7) edn. New York: Wiley, 2004; 3546. Chemicals Codex (FCC). 7 Food Chemicals Codex, 6th edn. Bethesda, MD: United States The EINECS number for triethyl citrate is 201-070-7. The Pharmacopeia, 2008; 988. PubChem Compound ID (CID) for triethyl citrate is 6506. 20 General References 19 Specific References Vertellus Specialties Inc. Technical data sheet: Citroflex 2, 2007. 1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizers on the physical and mechanical properties of 21 Author acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. J Teckoe. 2 Lehmann K. Chemistry and application properties of polymethacrylate coating systems. McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989; 153– 22 Date of Revision 245. 24 February 2009.

Triolein

1 Nonproprietary Names 6 Functional Category None adopted. Emollient; penetration enhancer; solubilizing agent; solvent.

2 Synonyms 7 Applications in Pharmaceutical Formulation or Captex GTO; glycerol trielaidate; glyceryl trioleate; 9-octadecenoic Technology acid-1,2,3-propanetriyl ester; olein; 1,2,3-propanetriyl tris((E)-9- Triolein is used as a solubilizer and solvent in injectable prepara- octadecenoate); trielaidin; trielaidoylglycerol; 1,2,3-tri(cis-9-octa- tions. It has been used in marketed preparations of sustained-release decenoyl)glycerol. injections of cytarabine and multivesicular liposomal injections of morphine sulfate. It has also been used in enteric coatings for oral preparations in combination with other enteric coating excipients to 3 Chemical Name and CAS Registry Number protect against degradation by pancreatic lipase.(1) 2,3-bis[[(Z)-octadec-9-enoyl]oxy]propyl (Z)-octadec-9-eno- Triolen is used in personal care products as a skin-conditioning T ate [122-32-7] and viscosity-controlling agent.

4 Empirical Formula and Molecular Weight 8 Description

C57H104O6 885.43 Triolein occurs as a clear, colorless to yellowish oily liquid, and is tasteless and odorless. 5 Structural Formula 9 Pharmacopeial Specifications —

10 Typical Properties Boiling point 235–2408C Density 0.915 g/cm3 Flash point 3308C Free fatty acids 40.1% Iodine value 80–100 Melting point 5to48C Peroxide value 42 Refractive index 20 nD = 1.4676; 60 nD = 1.4561.