627

Iida S et al. Stable ascorbic acid solutions. Japanese Patent No. 61,130,205; 21 Author 1986. Pfeifer HJ, Webb JW. Compatibility of penicillin and ascorbic acid injection. CP McCoy. Am J Hosp Pharm 1976; 33: 448–450. Sekine K et al. Powdery pharmaceutical compositions containing ascorbic acids for intranasal administration. Japanese Patent No. 63,115,820; 1988. 22 Date of Revision Thielemann AM et al. Biopharmaceutical study of a controlled- release formulation. Farmaco (Prat) 1988; 43: 387–395. 20 January 2009.

Sodium Benzoate

1 Nonproprietary Names administered, orally or intravenously, in order to determine liver BP: Sodium Benzoate function. JP: Sodium Benzoate PhEur: Sodium Benzoate 8 Description USP-NF: Sodium Benzoate Sodium benzoate occurs as a white granular or crystalline, slightly hygroscopic powder. It is odorless, or with faint odor of benzoin and has an unpleasant sweet and saline taste. 2 Synonyms sodium ; benzoate of soda; E211; natrii benzoas; 9 Pharmacopeial Specifications natrium benzoicum; sobenate; sodii benzoas; sodium benzoic acid. See Table I. 3 Chemical Name and CAS Registry Number Table I: Pharmacopeial specifications for sodium benzoate. Sodium benzoate [532-32-1] Test JP XV PhEur 6.0 USP32–NF27 4 Empirical Formula and Molecular Weight Identification þþþ þþ C H NaO 144.11 Characters — 7 5 2 Acidity or alkalinity þþþ Appearance of þþ— 5 Structural Formula solution Arsenic 42 ppm — — Chloride þ 4200 ppm — Heavy metals 420 ppm 410 ppm 40.001% Loss on drying 41.5% 42.0% 41.5% S Phthalic acid þ —— Sulfate 40.120% — — Total chlorine — 4300 ppm — Assay (dried basis) 599.0% 99.0–100.5% 99.0–100.5%

10 Typical Properties 6 Functional Category Acidity/alkalinity pH = 8.0 (saturated aqueous solution at 258C). Antimicrobial ; tablet and capsule lubricant. It is relatively inactive above approximately pH 5. Antimicrobial activity Sodium benzoate has both bacteriostatic 7 Applications in Pharmaceutical Formulation or and antifungal properties attributed to undissociated benzoic Technology acid; hence preservative efficacy is best seen in acidic solutions Sodium benzoate is used primarily as an antimicrobial preservative (pH 2–5). In alkaline conditions it is almost without effect. Density 1.497–1.527 g/cm3 at 248C in cosmetics, foods, and pharmaceuticals. It is used in concentra- 8 tions of 0.02–0.5% in oral medicines, 0.5% in parenteral products, Freezing point depression 0.24 C (1.0% w/v) NIR spectra see Figure 1. and 0.1–0.5% in cosmetics. The usefulness of sodium benzoate as a Osmolarity A 2.25% w/v aqueous solution is iso-osmotic with preservative is limited by its effectiveness over a narrow pH range; serum. see Section 10. Partition coefficients Vegetable oil : water = 3–6 Sodium benzoate is used in preference to benzoic acid in some see Table II. circumstances, owing to its greater solubility. However, in some applications it may impart an unpleasant flavor to a product. Sodium benzoate has also been used as a tablet lubricant(1) at 2–5% 11 Stability and Storage Conditions w/w concentrations. Solutions of sodium benzoate have also been Aqueous solutions may be sterilized by autoclaving or filtration. 628 Sodium Benzoate

SEM 1: Excipient: sodium benzoate; manufacturer: Bush Boake Allen 3.0 0.3 Corp.; magnification: 60 . 2436

2124 1645

0.0

1135 log(1/R) 2287

1660 2379

2138 2460 1000 × [2nd deriv. log(1/R) −3.0 −0.2 1100 1300 1500 1700 1900 2100 2300 2500 Wavelength/nm

Figure 1: Near-infrared spectrum of sodium benzoate measured by reflectance.

Table II: Solubility of sodium benzoate. Solvent Solubility at 208C unless otherwise stated (95%) 1 in 75 Ethanol (90%) 1 in 50 Water 1 in 1.8 SEM 2: Excipient: sodium benzoate; manufacturer: Bush Boake Allen 1 in 1.4 at 1008C Corp.; magnification: 2400.

systemic benzoate toxicity resemble those of salicylates.(3) Whereas oral administration of the free-acid form may cause severe gastric irritation, benzoate salts are well tolerated in large quantities: e.g. 6 g of sodium benzoate in 200 mL of water is administered orally as a liver function test. Clinical data have indicated that sodium benzoate can produce nonimmunological contact urtcaria and nonimmunological immediate contact reactions.(4) However, it is also recognized that these reactions are strictly cutaneous, and sodium benzoate can therefore be used safely at concentrations up to 5%. However, this nonimmunological phenomenon should be considered when designing formulations for infants and children. Other adverse effects include anaphylaxis(5–7) and urticarial reactions, although a controlled study has shown that the incidence S of urticaria in patients given benzoic acid is no greater than that with a lactose placebo.(8) It has been recommended that caffeine and sodium benzoate injection should not be used in neonates;(9) however, sodium benzoate has been used by others in the treatment of some neonatal metabolic disorders.(10) It has been suggested that there is a general adverse effect of benzoate on the behavior of 3-year- old children, which is detectable by parents, but not by a simple The bulk material should be stored in a well-closed container, in clinical assessment.(11) a cool, dry place. The WHO acceptable daily intake of total benzoates, calculated as benzoic acid, has been estimated at up to 5 mg/kg of body- 12 Incompatibilities weight.(12,13) Incompatible with quaternary compounds, gelatin, ferric salts, LD (mouse, IM): 2.3 g/kg(13,14) calcium salts, and salts of heavy metals, including silver, lead, and 50 mercury. Preservative activity may be reduced by interactions with LD50 (mouse, IV): 1.4 g/kg (2) kaolin or nonionic surfactants. LD50 (mouse, oral): 1.6 g/kg LD50 (rabbit, oral): 2.0 g/kg

13 Method of Manufacture LD50 (rat, IV): 1.7 mg/kg

Prepared by the treatment of benzoic acid with either sodium LD50 (rat, oral): 4.1 g/kg carbonate or sodium bicarbonate. See also Benzoic Acid.

14 Safety 15 Handling Precautions Ingested sodium benzoate is conjugated with glycine in the liver to Observe normal precautions appropriate to the circumstances and yield hippuric acid, which is excreted in the urine. Symptoms of quantity of material handled. Sodium benzoate may be irritant to Sodium Bicarbonate 629 the eyes and skin. Eye protection and rubber or plastic gloves are 7 Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br J recommended. Dermatol 1976; 94: 401–406. 8 Lahti A, Hannuksela M. Is benzoic acid really harmful in cases of atopy and urticaria? Lancet 1981; ii: 1055. 16 Regulatory Status 9 Edwards RC, Voegeli CJ. Inadvisability of using caffeine and sodium GRAS listed. Accepted as a food additive in Europe. Included in the benzoate in neonates. Am J Hosp Pharm 1984; 41: 658. FDA Inactive Ingredients Database (dental preparations; IM and IV 10 Brusilow SW et al. Treatment of episodic hyperammonemia in children injections; oral capsules, solutions and tablets; rectal; and topical with inborn errors of urea synthesis. N Engl J Med 1984; 310: 1630– preparations). Included in nonparenteral medicines licensed in the 1634. UK. Included in the Canadian List of Acceptable Non-medicinal 11 Bateman B et al. The effects of a double blind, placebo controlled, Ingredients. artificial food colorings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child 2005; 90(8): 875. 17 Related Substances 12 FAO/WHO. Toxicological evaluation of certain food additives with a Benzoic acid; benzoate. review of general principles and of specifications. Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health 18 Comments Organ Tech Rep Ser 1974; No. 539. 13 FAO/WHO. Evaluation of certain food additives and contaminants. Sodium benzoate has been used as an antimicrobial agent used in Twenty-seventh report of the joint FAO/WHO expert committee on (15) polymeric films in food packaging. food additives. World Health Organ Tech Rep Ser 1983; No. 696. A specification for sodium benzoate is contained in the Food 14 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th Chemicals Codex (FCC).(16) edn. New York: Wiley, 2004; 3232. The EINECS number for sodium benzoate is 208-534-8. The 15 Buonocore GG et al. A general approach to describe the antimicrobial PubChem Compound ID (CID) for sodium benzoate is 517055. agent release from highly swellable films intended for food packaging applications. J Control Release 2003; 90(1): 97–107. 19 Specific References 16 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 876. 1 Saleh SI et al. Improvement of lubrication capacity of sodium benzoate: effects of milling and spray drying. Int J Pharm 1988; 48: 149–157. 2 Clarke CD, Armstrong NA. Influence of pH on the adsorption of 20 General References benzoic acid by kaolin. Pharm J 1972; 209: 44–45. Nishijo J, Yonetani I. Interaction of theobromine with sodium benzoate. J 3 Michils A et al. Anaphylaxis with sodium benzoate [letter]. Lancet Pharm Sci 1982; 71: 354–356. 1991; 337: 1424–1425. 4 Nair B. Final report on the safety assessment of benzyl alcohol, benzoic acid, and sodium benzoate. Int J Toxicol 2001; 20(Suppl. 3): 23–50. 21 Author 5 Rosenhall L. Evaluation of intolerance to analgesics, preservatives and T Sakurai. food colorants with challenge tests. Eur J Respir Dis 1982; 63: 410– 419. 22 Date of Revision 6 Michae¨lsson G, Juhlin L. Urticaria induced by preservatives and dye additives in food and drugs. Br J Dermatol 1973; 88: 525–532. 20 January 2009.

Sodium Bicarbonate S

1 Nonproprietary Names 5 Structural Formula BP: Sodium Bicarbonate See Section 4. JP: Sodium Bicarbonate PhEur: Sodium Hydrogen Carbonate 6 Functional Category USP: Sodium Bicarbonate Alkalizing agent; therapeutic agent.

7 Applications in Pharmaceutical Formulation or 2 Synonyms Technology Baking soda; E500; Effer-Soda; monosodium carbonate; natrii Sodium bicarbonate is generally used in pharmaceutical formula- hydrogenocarbonas; Sal de Vichy; sodium acid carbonate; sodium tions as a source of carbon dioxide in effervescent tablets and hydrogen carbonate. granules. It is also widely used to produce or maintain an alkaline pH in a preparation. In effervescent tablets and granules, sodium bicarbonate is 3 Chemical Name and CAS Registry Number usually formulated with citric and/or tartaric acid;(1) combinations monosodium salt [144-55-8] of citric and tartaric acid are often preferred in formulations as alone produces a sticky mixture that is difficult to granulate, while if tartaric acid is used alone, granules lose firmness. When the 4 Empirical Formula and Molecular Weight tablets or granules come into contact with water, a chemical NaHCO3 84.01 reaction occurs, carbon dioxide is evolved, and the product