Safety

Ingested sodium benzoate is conjugated with glycine in the liver to yield hippuric acid, which is excreted in the urine. Symptoms of 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 uricartia and nonimmuno- logical immediate contact reactions.(4) However, it is also recognized that these reactions are strictly cutaneous, and 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 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 preservatives on the behavior of 3-year-old children, which is detectable by parents, but not by a simple clinical assessment.(11)

The WHO acceptable daily intake of total benzoates, calculated as benzoic acid, has been estimated at up to 5 mg/kg of body-weight.(12,13)

LD50 (mouse, IM): 2.3 g/kg(13,14) LD50 (mouse, IV): 1.4 g/kg

LD50 (mouse, oral): 1.6 g/kg LD50 (rabbit, oral): 2.0 g/kg LD50 (rat, IV): 1.7 mg/kg LD50 (rat, oral): 4.1 g/kg

See also Benzoic Acid.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium benzoate may be irritant to the eyes and skin. Eye protection and rubber or plastic gloves are recommended.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (dental preparations; IM and IV injections; oral capsules, solutions and tablets; rectal; and topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Benzoic acid; potassium benzoate.

Comments

Sodium benzoate has been used as an antimicrobial agent used in polymeric films in food packaging.(15) A specification for sodium benzoate is contained in the Food Chemicals Codex (FCC). The EINECS number for sodium benzoate is 208-534-8.

664 Sodium Benzoate

Specific References

Saleh SI, Wehrle´ P, Stamm A. Improvement of lubrication capacity of sodium benzoate: effects of milling and spray drying. Int J Pharm 1988; 48: 149–157.

Clarke CD, Armstrong NA. Influence of pH on the adsorption of benzoic acid by kaolin. Pharm J 1972; 209: 44–45.

Michils A, Vandermoten G, Duchateau J, Yernault J-C. Anaphy- laxis with sodium benzoate [letter]. Lancet 1991; 337: 1424–1425.

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.

Rosenhall L. Evaluation of intolerance to analgesics, preservatives and food colorants with challenge tests. Eur J Respir Dis 1982; 63: 410–419.

Michae¨lsson G, Juhlin L. Urticaria induced by preservatives and dye additives in food and drugs. Br J Dermatol 1973; 88: 525–532.

Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br J Dermatol 1976; 94: 401–406.

Lahti A, Hannuksela M. Is benzoic acid really harmful in cases of atopy and urticaria? Lancet 1981; ii: 1055.

Edwards RC, Voegeli CJ. Inadvisability of using caffeine and sodium benzoate in neonates. Am J Hosp Pharm 1984; 41: 658.

Brusilow SW, Danney M, Waber LJ, et al. Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Engl J Med 1984; 310: 1630–1634.

Anonymous. The effects of a double blind, placebo controlled, artificial food colorings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Child Care Health Dev 2004; 30(5): 561.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1983; No. 696.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3232.

Buonocore GG, Del-Nobile MA, Panizza A, et al. A general approach to describe the antimicrobial agent release from highly swellable films intended for food packaging applications. J Controlled Release 2003; 90(1): 97–107.

General References

Nishijo J, Yonetani I. Interaction of theobromine with sodium benzoate. J Pharm Sci 1982; 71: 354–356.

Authors

SC Owen.

Date of Revision

16 August 2005.

Sodium Bicarbonate

Nonproprietary Names

BP: Sodium bicarbonate JP: Sodium bicarbonate

PhEur: Natrii hydrogenocarbonas USP: Sodium bicarbonate

Synonyms

Baking soda; E500; Effer-Soda; monosodium carbonate; Sal de Vichy; sodium acid carbonate; sodium hydrogen carbonate.

Chemical Name and CAS Registry Number

Carbonic acid monosodium salt [144-55-8]

Empirical Formula and Molecular Weight

NaHCO3 84.01

Structural Formula

NaHCO3

Functional Category

Alkalizing agent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Sodium bicarbonate is generally used in pharmaceutical formulations as a source of carbon dioxide in effervescent tablets and granules. It is also widely used to produce or maintain an alkaline pH in a preparation.

In effervescent tablets and granules, sodium bicarbonate is usually formulated with citric and/or tartaric acid;(1) combina- tions of citric and tartaric acid are often preferred in formulations as citric acid alone produces a sticky mixture that is difficult to granulate, while if tartaric acid is used alone, granules lose firmness. When the tablets or granules come into contact with water, a chemical reaction occurs, carbon dioxide is evolved, and the product disintegrates.(2,3) Melt granulation in a fluidized bed dryer has been suggested as a one-step method for the manufacture of effervescent granules composed of anhydrous citric acid and sodium bicarbonate, for subsequent compression into tablets.(4)

Tablets may also be prepared with sodium bicarbonate alone since the acid of gastric fluid is sufficient to cause effervescence and disintegration. Sodium bicarbonate is also used in tablet formulations to buffer drug molecules that are weak acids, thereby increasing the rate of tablet dissolution and reducing gastric irritation.(5–7)

The effects of tablet binders, such as polyethylene glycols, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, and povidone, on the physical and mechanical properties of sodium bicarbonate tablets have also been investigated.(8,9)

Additionally, sodium bicarbonate is used in solutions as a buffering agent for erythromycin,(10) lidocaine,(11) local anes- thetic solutions,(12) and total parenteral nutrition (TPN) solutions.(13) In some parenteral formulations, e.g., niacin, sodium bicarbonate is used to produce a sodium salt of the active ingredient that has enhanced solubility. Sodium bicarbo- nate has also been used as a freeze-drying stabilizer(14) and in toothpastes.

Recently, sodium bicarbonate has been used as a gas- forming agent in alginate raft systems(15–17) and in floating, controlled-release oral dosage forms of furosemide(18) and cisapride.(19) Tablet formulations containing sodium bicarbo- nate have been shown to increase the absorption of para- cetamol,(20,21) and improve the stability of levothyroxine.(22)

Therapeutically, sodium bicarbonate may be used as an antacid, and as a source of the bicarbonate anion in the treatment of metabolic acidosis. Sodium bicarbonate may also be used as a component of oral rehydration salts and as a source of bicarbonate in dialysis fluids.

Sodium bicarbonate is used in food products as an alkali or as a leavening agent, e.g. baking soda. See Table I.

Table I: Uses of sodium bicarbonate.

Use Concentration (%)

Buffer in tablets 10–40

Effervescent tablets 25–50

Isotonic injection/infusion 1.39

Description

Sodium bicarbonate occurs as an odorless, white, crystalline powder with a saline, slightly alkaline taste. The crystal structure is monoclinic prisms. Grades with different particle sizes, from a fine powder to free-flowing uniform granules, are commercially available.

Pharmacopeial Specifications

See Table II.

Typical Properties

Acidity/alkalinity: pH = 8.3 for a freshly prepared 0.1 M aqueous solution at 258C; alkalinity increases on standing, agitation, or heating.

Density (bulk): 0.869 g/cm3 Density (tapped): 1.369 g/cm3 Density(true): 2.173 g/cm3

Freezing point depression: 0.3818C (1% w/v solution)

Melting point: 2708C (with decomposition)

Moisture content: below 80% relative humidity, the moisture content is less than 1% w/w. Above 85% relative humidity, sodium bicarbonate rapidly absorbs excessive amounts of water and may start to decompose with loss of carbon dioxide.

666 Sodium Bicarbonate

SEM: 1

Excipient: Sodium bicarbonate

Manufacturer: Merck Ltd.

Magnification: 120×

 

Osmolarity: a 1.39% w/v aqueous solution is isoosmotic with serum.

Refractive index: n20 = 1.3344 (1% w/v aqueous solution)

Solubility: see Table III.

Table II: Pharmacopeial specifications for sodium bicarbonate.

SEM: 2

Excipient: Sodium bicarbonate

Manufacturer: Merck Ltd.

Magnification: 600×

 

Table III: Solubility of sodium bicarbonate.

Solvent Solubility at 208C unless otherwise stated

Ethanol (95%) Practically insoluble

Ether Practically insoluble

Water 1 in 11

1 in 4 at 1008C(a) 1 in 10 at 258C 1 in 12 at 188C

(a) Note that in hot water, sodium bicarbonate is converted to the carbonate.

Stability and Storage Conditions

When heated to about 508C, sodium bicarbonate begins to dissociate into carbon dioxide, sodium carbonate, and water; on heating to 250–3008C, for a short time, sodium bicarbonate is completely converted into anhydrous sodium carbonate. However, the process is both time- and temperature-dependent, with conversion 90% complete within 75 minutes at 938C. The reaction proceeds via surface-controlled kinetics; when sodium bicarbonate crystals are heated for a short period of time, very fine needle-shaped crystals of anhydrous sodium carbonate are formed on the sodium bicarbonate surface.(23)

The effects of relative humidity and temperature on the moisture sorption and stability of sodium bicarbonate powder have been investigated. Sodium bicarbonate powder is stable below 76% relative humidity at 258C and below 48% relative

(24)

humidity at 408C. At 54% relative humidity, the degree of

(a) Where it is labeled as intended for use in hemodialysis.

pyrolytic decarboxylation of sodium bicarbonate should not exceed 4.5% in order to avoid detrimental effects on stability.(25)

At ambient temperatures, aqueous solutions slowly decom- pose with partial conversion into the carbonate; the decom- position is accelerated by agitation or heat.

Aqueous solutions of sodium bicarbonate may be sterilized by filtration or autoclaving. To minimize decomposition of

Sodium Bicarbonate 667

sodium bicarbonate by decarboxylation on autoclaving, carbon dioxide is passed through the solution in its final container, which is then hermetically sealed and autoclaved. The sealed container should not be opened for at least 2 hours after it has returned to ambient temperature, to allow time for the complete reformation of the bicarbonate from the carbonate produced during the heating process.

Aqueous solutions of sodium bicarbonate stored in glass containers may develop deposits of small glass particles. Sediments of calcium carbonate with traces of magnesium or other metal carbonates have been found in injections sterilized by autoclaving; these are due to impurities in the bicarbonate or to extraction of calcium and magnesium ions from the glass container. Sedimentation may be retarded by the inclusion of 0.01–0.02% disodium edetate.(26–28)

Sodium bicarbonate is stable in dry air but slowly decomposes in moist air and should therefore be stored in a well-closed container in a cool, dry place.

Incompatibilities

Sodium bicarbonate reacts with acids, acidic salts, and many alkaloidal salts, with the evolution of carbon dioxide. Sodium bicarbonate can also intensify the darkening of salicylates.

In powder mixtures, atmospheric moisture or water of crystallization from another ingredient is sufficient for sodium bicarbonate to react with compounds such as boric acid or alum. In liquid mixtures containing bismuth subnitrate, sodium bicarbonate reacts with the acid formed by hydrolysis of the bismuth salt.

In solution, sodium bicarbonate has been reported to be incompatible with many drug substances such as ciproflox- acin,(29,30) amiodarone,(31) nicardipine,(32) and levofloxacin.(33)

Method of Manufacture

Sodium bicarbonate is manufactured either by passing carbon dioxide into a cold saturated solution of sodium carbonate, or by the ammonia–soda (Solvay) process, in which first ammonia and then carbon dioxide is passed into a sodium chloride solution to precipitate sodium bicarbonate while the more- soluble ammonium chloride remains in solution.

Safety

Sodium bicarbonate is used in a number of pharmaceutical formulations including injections and ophthalmic, otic, topical, and oral preparations.

Sodium bicarbonate is metabolized to the sodium cation, which is eliminated from the body by renal excretion, and the bicarbonate anion, which becomes part of the body’s bicarbo- nate store. Any carbon dioxide formed is eliminated via the lungs. Administration of excessive amounts of sodium bicar- bonate may thus disturb the body’s electrolyte balance, leading to metabolic alkalosis or possibly sodium overload with potentially serious consequences. The amount of sodium present in antacids and effervescent formulations has been sufficient to exacerbate chronic heart failure, especially in elderly patients.(34)

Orally ingested sodium bicarbonate neutralizes gastric acid with the evolution of carbon dioxide and may cause stomach cramps and flatulence.

When used as an excipient, sodium bicarbonate is generally regarded as an essentially nontoxic and nonirritant material.

LD50 (mouse, oral): 3.36 g/kg(35) LD50 (rat, oral): 4.22 g/kg



Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (injections; ophthalmic preparations; oral capsules, solutions, and tablets). Included in parenteral (intravenous infusions and injections) and nonparenteral medicines (ear drops; eye lotions; oral capsules, chewable tablets, effervescent powders, effervescent tablets, granules, and tablets; suppositories and suspensions) licensed in the UK.

Related Substances

Potassium bicarbonate.

Comments

Each gram of sodium bicarbonate represents approximately

11.9 mmol of sodium and of bicarbonate. Each gram of sodium bicarbonate will neutralize 12 mEq of gastric acid in 60 minutes.

The yield of carbon dioxide from sodium bicarbonate is approximately 52% by weight.

Three molecules of sodium bicarbonate are required to neutralize one molecule of citric acid, and two molecules of sodium bicarbonate to neutralize one molecule of tartaric acid. A specification for sodium bicarbonate is contained in the Food Chemicals Codex (FCC).

The EINECS number for sodium bicarbonate is 205-633-8.

Specific References

Usui F, Carstensen JT. Interactions in the solid state I: interactions of sodium bicarbonate and tartaric acid under compressed conditions. J Pharm Sci 1985; 74(12): 1293–1297.

Anderson NR, Banker GS, Peck GE. Quantitative evaluation of pharmaceutical effervescent systems I: design of testing apparatus. J Pharm Sci 1982; 71(1): 3–6.

Anderson NR, Banker GS, Peck GE. Quantitative evaluation of pharmaceutical effervescent systems II: stability monitoring by reactivity and porosity measurements. J Pharm Sci 1982; 71(1): 7–

13.

Yanze FM, Duru C, Jacob M. A process to produce effervescent tablets: fluidised bed dryer melt granulation. Drug Dev Ind Pharm 2000; 26(11): 1167–1176.

Javaid KA, Cadwallader DE. Dissolution of aspirin from tablets containing various buffering agents. J Pharm Sci 1972; 61(9): 1370–1373.

Rainsford KD. Gastric mucosal ulceration induced in pigs by tablets but not suspensions or solutions of aspirin. J Pharm Pharmacol 1978; 30: 129–131.

Mason WD, Winer N. Kinetics of aspirin, salicylic acid and salicyluric acid following oral administration of aspirin as a tablet and two buffered solutions. J Pharm Sci 1981; 70(3): 262–265.

Olsson H, Mattsson S, Nystro¨ m C. Evaluation of the effects of polyethylene glycols of differing molecular weights on the mechanical strength of sodium chloride and sodium bicarbonate tablets. Int J Pharm 1998; 171(1): 31–44.

Mattsson S, Nystro¨ m C. Evaluation of critical binder properties affecting the compactibility of binary mixtures. Drug Dev Ind Pharm 2001; 27(3): 181–194.

Allwood MC. The influence of buffering on the stability of erythromycin injection in small-volume infusions. Int J Pharm 1992; 80 (Suppl.): R7–R9.

668 Sodium Bicarbonate