Nonproprietary Names
USP:Ascorbic Acid JP: Ascorbic Acid
PhEur:Ascorbic Acid
USP:Ascorbic Acid
Synonyms
Acidum ascorbicum; C-97; cevitamic acid; 2,3-didehydro-L-threohexono-1,4-lactone; E300; 3-oxo-L-gulofuranolactone, enol form; vitamin C.
Chemical Name and CAS Registry Number
L-(þ)-Ascorbic acid [50-81-7]
Empirical Formula and Molecular Weight
C6H8O6 176.13
Structural Formula
Functional Category
Antioxidant; therapeutic agent.
Applications in Pharmaceutical Formulation or Technology
Technology Ascorbic acid is used as an antioxidant in aqueous pharmaceutical formulations at a concentration of 0.01–0.1% w/v. Ascorbic acid has been used to adjust the pH of solutions for injection, and as an adjunct for oral liquids. It is also widely used in foods as an antioxidant. Ascorbic acid has also proven useful as a stabilizing agent in mixed micelles containing tetrazepam.(1) 44 Ascorbic Acid SEM 1: Excipient: ascorbic acid usp (fine powder); manufacturer: Pfizer Ltd; lot no.: 9A-3/G92040-CO 146; magnification: 120; voltage: 20 kV. SEM 2: Excipient: ascorbic acid usp (fine powder); manufacturer: Pfizer Ltd; lot no.: 9A-3/G92040-CO 146; magnification: 600; voltage: 20 kV. SEM 3: Excipient: ascorbic acid usp (fine granular); manufacturer: Pfizer Ltd; lot no.: 9A-2/G01280-CO 148; magnification: 120; voltage: 20 kV.
Description
Ascorbic acid occurs as a white to light-yellow-colored, nonhygroscopic, odorless, crystalline powder or colorless crystals with a sharp, acidic taste. It gradually darkens in color upon exposure to light.
Pharmacopeial Specifications
See Table I.
Typical Properties
Acidity/alkalinity pH = 2.1–2.6 (5% w/v aqueous solution) Density (bulk) 0.7–0.9g/cm3 for crystalline material; 0.5–0.7g/cm3 for powder. Density (particle) 1.65g/cm3 Table I: Pharmacopeial specifications for ascorbic acid. Test JP XV PhEur 6.3 USP 32 Identification Characters Specific rotation (10% w/v solution) Residue on ignition þ — þ 20.521.588 to þ40.1% þ þ 20.58 to þ 21.58 þ— þ — þ 20.521.588 to þ40.1% pH 2.2–2.5 2.1–2.6 — Sulfated ash — 40.1% — Copper — 45 ppm — Heavy metals 420 ppm 410 ppm 40.002% Loss on drying 40.20% — — Iron — 42 ppm — Oxalic acid Related substances Appearance of solution — — þ þ þ þ — — — Assay 599.0% 99.0–100.5% 99.0–100.5% Table II: Solubility of ascorbic acid. Solvent Solubility at 208C Chloroform Practically insoluble Ethanol 1 in 50 Ethanol (95%) 1 in 25 Ether Practically insoluble Fixed oils Practically insoluble Glycerin 1 in 1000 Propylene glycol 1 in 20 Water 1 in 3.5 Density (tapped) 1.0–1.2g/cm3 for crystalline material; 0.9–1.1g/cm3 for powder. Density (true) 1.688g/cm3 Dissociation constant pKa1 = 4.17; pKa2 = 11.57. Melting point 1908C (with decomposition) Moisture content 0.1% w/w 1100 1300 1500 1700 1900 2100 2300 2500 Wavelength/nm Figure 1: Near-infrared spectrum of ascorbic acid measured by reflectance. NIR spectra see Figure 1. Solubility see Table II.
Stability and Storage Conditions
In powder form, ascorbic acid is relatively stable in air. In the absence of oxygen and other oxidizing agents it is also heat stable. Ascorbic acid is unstable in solution, especially alkaline solution, readily undergoing oxidation on exposure to the air.(2,3) The oxidation process is accelerated by light and heat and is catalyzed by traces of copper and iron. Ascorbic acid solutions exhibit maximum stability at about pH 5.4. Solutions may be sterilized by filtration. The bulk material should be stored in a well-closed nonmetallic container, protected from light, in a cool, dry place.
Incompatibilities
Incompatible with alkalis, heavy metal ions, especially copper and iron, oxidizing materials, methenamine, phenylephrine hydrochloride, pyrilamine maleate, salicylamide, sodium nitrite, sodium salicylate, theobromine salicylate, and picotamide.(4,5) Additionally, ascorbic acid has been found to interfere with certain colorimetric assays by reducing the intensity of the color produced.(6)
Method of Manufacture
Ascorbic acid is prepared synthetically or extracted from various vegetable sources in which it occurs naturally, such as rose hips, blackcurrants, the juice of citrus fruits, and the ripe fruit of Capsicum annuum L. A common synthetic procedure involves the hydrogenation of D-glucose to D-sorbitol, followed by oxidation using Acetobacter suboxydans to form L-sorbose. A carboxyl group is then added at C1 by air oxidation of the diacetone derivative of Lsorbose and the resulting diacetone-2-keto-L-gulonic acid is converted to L-ascorbic acid by heating with hydrochloric acid.
Safety
Ascorbic acid is an essential part of the human diet, with 40 mg being the recommended daily dose in the UK(7) and 60mg in the USA.(8) However, these figures are controversial, with some advocating doses of 150 or 250mg daily. Megadoses of 10g daily have also been suggested to prevent illness although such large doses are now generally considered to be potentially harmful.(9–11) The body can absorb about 500mg of ascorbic acid daily with any excess immediately excreted by the kidneys. Large doses may cause diarrhea or other gastrointestinal disturbances. Damage to the teeth has also been reported.(12) However, no adverse effects have been reported at the levels employed as an antioxidant in foods, beverages,(13) and pharmaceuticals. The WHO has set an Ascorbic Acid acceptable daily intake of ascorbic acid, potassium ascorbate, and sodium ascorbate, as antioxidants in food, at up to 15mg/kg bodyweight in addition to that naturally present in food.(14) LD50 (mouse, IV): 0.52g/kg(15) LD50 (mouse, oral): 3.37g/kg LD50 (rat, oral): 11.9g/kg
Handling Precautions
Ascorbic acid may be harmful if ingested in large quantities and may be irritating to the eyes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and rubber or plastic gloves are recommended.
Regulatory Status
GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (inhalations, injections, oral capsules, suspensions, tablets, topical preparations, and suppositories). Included in medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances Ascorbyl palmitate; erythorbic acid; sodium ascorbate.
Comments
Many dosage forms for ascorbic acid have been developed for its administration to patients, including microencapsulation.(16) A specification for ascorbic acid is contained in the Food Chemicals Codex (FCC).(17) The EINECS number for ascorbic acid is 200-066-2. The PubChem Compound ID (CID) for ascorbic acid is 5785. 19 Specific References 1 Hammad MA, Muller BW. Solubility and stability of tetrazepam in mixed micelles. Eur J Pharm Sci 1998; 7: 49–55. 2 Hajratwala BR. Stability of ascorbic acid. STP Pharma 1985; 1: 281– 286. 3 Touitou E et al. Ascorbic acid in aqueous solution: bathochromic shift in dilution and degradation. Int J Pharm 1992; 78: 85–87. 4 Botha SA et al. DSC screening for drug–drug interactions in polypharmaceuticals intended for the alleviation of the symptoms of colds and flu. Drug Dev Ind Pharm 1987; 13: 345–354. 5 Mura P et al. Differential scanning calorimetry in compatibility testing of picotamide with pharmaceutical excipients. Thermochim Acta 1998; 321: 59–65. 6 Krishnan G et al. Estimation of phenylephrine hydrochloride in multicomponent pharmaceutical preparations. Eastern Pharmacist 1990; 33: 143–145. 7 Department of Health. Dietary reference values for food energy and nutrients for the United Kingdom: report of the panel on dietary reference values of the committee on medical aspects of food policy. Report on Health and Social Subjects 41. London: HMSO, 1991. 8 Subcommittee on the tenth edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences. National Research Council. Recommended Dietary Allowances, 10th edn. Washington, DC: National Academy Press, 1989. 9 Ovesen L. Vitamin therapy in the absence of obvious deficiency: what is the evidence? Drugs 1984; 27: 148–170. 10 Bates CJ. Is there a maximum safe dose of vitamin C (ascorbic acid)? Br Med J 1992; 305: 32. 11 Mason P. Vitamin C.Dietary Supplements, 2nd edn. London: Pharmaceutical Press, 2001; 227–233. 12 Giunta JL. Dental erosion resulting from chewable vitamin C tablets. J Am Dent Assoc 1983; 107: 253–256. 13 Food and Drug Administration. CFSAN/Office of Food Additives Safety. Data on benzene in soft drinks and other beverages, May 2007. 14 FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of 46 Ascorbyl Palmitate the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539. 15 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 309–310. 16 Esposito E et al. Spray-dried Eudragit microparticles as encapsulation devices for vitamin C. Int J Pharm 2002; 242: 329–334. 17 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 67.
General References
Abramovici B et al. [Comparative study of the tabletability of different grades of vitamin C.] STP Pharma 1987; 3: 16–22[in French]. Allwood MC. Factors influencing the stability of ascorbic acid in total parenteral nutrition infusions. J Clin Hosp Pharm 1984; 9: 75–85. Bhagavan HN, Wolkoff BI. Correlation between the disintegration time and the bioavailability of vitamin C tablets. Pharm Res 1993; 10: 239–242. Davies MB et al. Vitamin C—Its Chemistry and Biochemistry. London: Royal Society of Chemistry, 1991. Hu F et al. Effects of different adhesives on the stability of vitamin C buccal tablets. Zhejiang Yike Daxue Xuebao 1997; 26: 108–110. Krishna G et al. Development of a parenteral formulation of an investigational anticancer drug, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. Pharm Dev Technol 1999; 4: 71–80. Nebuloni M et al. Thermal analysis in preformulation studies of a lyophilized form of an antibiotic. Boll Chim Farm 1996; 135: 94–100. Pinsuwan S et al. Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions. Int J Pharm 1999; 181: 31– 40. Saleh SI, Stamm A. Evaluation of some directly compressible L-ascorbic acid forms. STP Pharma 1988; 4: 10–14. Saleh SI, Stamm A. Contribution to the preparation of a directly compressible L-ascorbic acid granular form: comparison of granules prepared by three granulation methods and evaluation of their corresponding tablets. STP Pharma 1988; 4: 182–187. Seta Y et al. Preparation and pharmacological evaluation of Captopril sustained-release dosage forms using oily semisolid matrix. Int J Pharm 1988; 41: 255–262.
Author
AH Kibbe.