Nonproprietary Names

USP-NF: Acetyltributyl Citrate
PhEur:Tributyl Acetylcitrate

Synonyms

Acetylbutyl citrate; acetylcitric acid, tributyl ester; ATBC; Citroflex A-4; tributyl acetylcitrate; tributylis acetylcitras; tributyl Oacetylcitrate; tributyl citrate acetate.

Chemical Name and CAS Registry Number

1,2,3-Propanetricarboxylic acid, 2-acetyloxy, tributyl ester [77-907]

Empirical Formula and Molecular Weight

C20H34O8 402.5

Structural Formula

Functional Category

Plasticizer.

Applications in Pharmaceutical Formulation or Technology

Technology Acetyltributyl citrate is used to plasticize polymers in formulated pharmaceutical coatings,(1–5) including capsules, tablets, beads, and granules for taste masking, immediate release, sustained-release and enteric formulations.

Description

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

Pharmacopeial Specifications

See Table I.

Typical Properties

Acid value 0.02 Boiling point 3268C (decomposes) Flash point 2048C Pour point 598C Solubility Miscible with acetone, ethanol, and vegetable oil; practically insoluble in water. Viscosity (dynamic) 33mPas (33cP) at 258C Table I: Pharmacopeial specifications for acetyltributyl citrate. Test PhEur 6.3 USP32–NF27 Identification Appearance Characters Specific gravity þ þ þ— þ— — 1.045–1.055 Refractive index 1.442–1.445 1.4410–1.4425 Sulfated ash 40.1% — Acidity Water þ40.25% þ40.25% Heavy metals 410 ppm 40.001% Related substances Assay (anhydrous basis) þ99.0–101.0% — 599.0% Acetyltributyl Citrate 9

Stability and Storage Conditions

Acetyltributyl citrate should be stored in a well-closed container in a cool, dry location at temperatures not exceeding 388C. When stored in accordance with these conditions, acetyltributyl citrate is a stable product.

Incompatibilities

Acetyltributyl citrate is incompatible with strong alkalis and oxidizing materials.

Method of Manufacture

Acetyltributyl citrate is prepared by the esterification of citric acid with butanol followed by acylation with acetic anhydride.

Safety

Acetyltributyl citrate is used in oral pharmaceutical formulations and films intended for direct food contact. It is also used in selfadhesive thin films used for topical delivery systems.(6) It is generally regarded as a relatively nontoxic and nonirritating material. However, ingestion of large quantities may be harmful. LD50 (cat, oral): >50mL/kg(7) LD50 (mouse, IP): >4g/kg LD50 (rat, oral): >31.5g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Acetyltributyl citrate is slightly irritating to the eyes and may be irritating to the respiratory system as a mist or at elevated temperatures. Gloves and eye protection are recommended for normal handling, and a respirator is recommended when using acetyltributyl citrate at elevated temperatures.

Regulatory Status

Included in FDA Inactive Ingredients Database (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Approved in the USA for direct food contact in food films. 17 Related Substances Acetyltriethyl citrate; tributyl citrate; triethyl citrate.

Comments

Acetyltributyl citrate is used as a plasticizer in food contact films, although it has been known to migrate from food-grade PVC films into high-fat foods such as olive oil.(8) Polylactide plasticized with acetyltributyl citrate has been investigated as a biodegradable barrier for use in guided-tissue regeneration therapy.(9) The EINECS number for acetyltributyl citrate is 201-067-0. The PubChem Compound ID (CID) for acetyltributyl citrate is 6505. 19 Specific References 1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizer on the physical and mechanical properties of acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. 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– 245. 3 Steurnagel CR. Latex emulsions for controlled drug delivery. McGinity 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 physicalmechanical properties of acrylic resin films cast from aqueous dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19(3): 315–332. 5 Repka MA et al. Influence of plasticisers and drugs on the physicalmechanical properties of hydroxypropylcellulose films prepared by hot melt extrusion. Drug Dev Ind Pharm 1999; 25(5): 625–633. 6 Lieb S et al. Self-adhesive thin films for topical delivery of 5aminolevulinic acid. Eur J Pharm Biopharm 2002; 53(1): 99–106. 7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 3512. 8 Goulas AE et al. Effect of high-dose electron beam irradiation on the migration of DOA and ATBC plasticizers from food-grade PVC and PVDC/PVC films, respectively, into olive oil. J Food Prot 1998; 61(6): 720–724. 9 Dorfer CE et al. Regenerative periodontal surgery in interproximal intrabony defects with biodegradable barriers. J Clin Peridontol 2000; 27(3): 162–168.

General References

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Author

s ME Quinn, PJ Sheskey.

Date of Revision

18 February 2009.