Nonproprietary Names
PhEur:Adipic Acid USP-NF: Adipic Acid
Synonyms
Acidum adipicum; acifloctin; acinetten; adilactetten; asapic; 1,4butanedicarboxylic acid; E355; 1,6-hexanedioic acid; Inipol DS.
Chemical Name and CAS Registry Number
Hexanedioic acid [124-04-9]
Empirical Formula and Molecular Weight
C6H10O4 146.14
Structural Formula
Functional Category
Acidifying agent; buffering agent; flavoring agent.
Applications in Pharmaceutical Formulation or Technology
Technology Adipic acid is used as an acidifying and buffering agent in intramuscular, intravenous and vaginal formulations. It is also used in food products as a leavening, pH-controlling, or flavoring agent. Adipic acid has been incorporated into controlled-release formulation matrix tablets to obtain pH-independent release for both weakly basic(1,2) and weakly acidic drugs.(3,4) It has also been incorporated into the polymeric coating of hydrophilic monolithic systems to modulate the intragel pH, resulting in zero-order release of a hydrophilic drug.(5) The disintegration at intestinal pH of the enteric polymer shellac has been reported to improve when adipic acid was used as a pore-forming agent without affecting release in the acidic media.(6) Other controlled-release formulations have included adipic acid with the intention of obtaining a late-burst release profile.(7)
Description
Adipic acid occurs as a white or almost white, odorless nonhygroscopic crystalline powder. The crystal structure of adipic acid is monoclinic holohedral.
Pharmacopeial Specifications
See Table I. Table I: Pharmacopeial specifications for adipic acid. Test PhEur 6.0 USP32–NF27 Identification Characters Melting range þ þ151–1548C þ— 151–1548C Appearance of solution Loss on drying þ 40.2% — 40.2% Residue on ignition — 40.1% Sulfated ash 40.1% — Chlorides 4200 ppm 40.02% Nitrates 430 ppm 40.003% Sulfates 4500 ppm 40.05% Iron 410 ppm 40.001% Heavy metals 410 ppm 40.001% Related substances Assay (anhydrous) þ99.0–101.0% — 99.0–101.0%
Typical Properties
Acidity/alkalinity pH = 2.7 (saturated solution at 258C); pH = 3.2 (0.1% w/v aqueous solution at 258C) Boiling point 337.58C Dissociation constant pKa1: 4.418 at 258C; pKa2: 5.412 at 258C. Density 1.360g/cm3 Flash point 1968C (closed cup) Adipic Acid Heat of combustion 17653.9kJ/mol (4219.28kcal/mol) at 258C Heat of solution 33.193kJ/mol (7.9kcal/mol) at 258C Melting point 152.18C Solubility see Table II. Vapor pressure 133.3Pa (1mmHg) at 159.58C Viscosity (dynamic) 4.54mPas (4.54cP) at 1608C for molten adipic acid. Table II: Solubility of adipic acid. Solvent Solubility at 208C unless otherwise stated Acetone Soluble Benzene Practically insoluble Cyclohexane Slightly soluble Ethanol (95%) Freely soluble Ether 1 in 157.8 at 198C Ethyl acetate Soluble Methanol Freely soluble Petroleum ether Practically insoluble Water 1 in 71.4 1 in 0.6 at 1008C
Stability and Storage Conditions
Adipic acid is normally stable but decomposes above boiling point. It should be stored in a tightly closed container in a cool, dry place, and should be kept away from heat, sparks, and open flame.
Incompatibilities
Adipic acid is incompatible with strong oxidizing agents as well as strong bases and reducing agents. Contact with alcohols, glycols, aldehydes, epoxides, or other polymerizing compounds can result in violent reactions.
Method of Manufacture
Adipic acid is prepared by nitric acid oxidation of cyclohexanol or cyclohexanone or a mixture of the two compounds. Recently, oxidation of cyclohexene with 30% aqueous hydrogen peroxide under organic solvent- and halide-free conditions has been proposed as an environmentally friendly alternative for obtaining colorless crystalline adipic acid.(8)
Safety
Adipic acid is used in pharmaceutical formulations and food products. The pure form of adipic acid is toxic by the IP route, and moderately toxic by other routes. It is a severe eye irritant, and may cause occupational asthma. LD50 (mouse, IP): 0.28g/kg(9) LD50 (mouse, IV): 0.68g/kg LD50 (mouse, oral): 1.9g/kg LD50 (rat, IP): 0.28g/kg LD50 (rat, oral): >11g/kg
Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity of the material handled. Adipic acid is combustible and can react with oxidizing materials when exposed to heat and flame. It emits acrid smoke and fumes when heated to decomposition. Dust explosion is possible if in powder or granular form, mixed with air. Adipic acid irritates the eyes and respiratory tract. Protective equipment such as respirators, safety goggles, and heavy rubber gloves should be worn when handling adipic acid.
Regulatory Status
GRAS listed. Included in the FDA Inactive Ingredients Database (IM, IV, and vaginal preparations). Accepted for use as a food additive in Europe. Included in an oral pastille formulation available in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances —
Comments
A specification for adipic acid is contained in the Food Chemicals Codex (FCC).(10) The EINECS number for adipic acid is 204-673-3. The PubChem Compound ID (CID) for adipic acid is 196. 19 Specific References 1 Guthmann C et al. Development of a multiple unit pellet formulation for a weakly basic drug. Drug Dev Ind Pharm 2007; 33(3): 341–349. 2 Streubel A et al. pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets. J Control Release 2000; 67(1): 101–110. 3 Pillay V, Fassihi R. In situ electrolyte interactions in a disk-compressed configuration system for up-curving and constant drug delivery. J Control Release 2000; 67(1): 55–65. 4 Merkli A et al. The use of acidic and basic excipients in the release of 5fluorouracil and mitomycin C from a semi-solid bioerodible poly(ortho ester). J Control Release 1995; 33(3): 415–421. 5 Pillay V, Fassihi R. Electrolyte-induced compositional heterogeneity: a novel approach for rate-controlled oral drug delivery. J Pharm Sci 1999; 88(11): 1140–1148. 6 Pearnchob N et al. Improvement in the disintegration of shellac-coated soft gelatin capsules in simulated intestinal fluid. J Control Release 2004; 94(2–3): 313–321. 7 Freichel OL, Lippold BC. A new oral erosion controlled drug delivery system with a late burst in the release profile. Eur J Pharm Biopharm 2000; 50(3): 345–351. 8 Sato K et al. A ‘green’ route to adipic acid: direct oxidation of cyclohexenes with 30 percent hydrogen peroxide. Science 1998; 281: 1646–1647. 9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 83–84. 10 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 26.
General References
Grant DJW, York P. A disruption index for quantifying the solid state disorder induced by additives or impurities. II. Evaluation from heat of solution. Int J Pharm 1986; 28(2–3): 103–112.
Author
D Law.
Date of Revision
27 February 2009.