Synonyms: E339; trisodium orthophosphate; trisodium phos- phate; TSP.

Acidity/alkalinity: pH = 12.1 for a 1% w/v aqueous solution of the anhydrous material at 258C. A 1% w/v aqueous solution of the dodecahydrate at 258C has a pH of 12.0–12.2.

Density:

1.3 g/cm3 for the anhydrous material;

0.9 g/cm3 for the dodecahydrate.

Solubility: the anhydrous material is soluble 1 in 8 parts of water, while the dodecahydrate is soluble 1 in 5 parts of water at 208C.

Comments

One gram of anhydrous dibasic sodium phosphate represents approximately 14.1 mmol of sodium and 7.0 mmol of phos- phate.

One gram of dibasic sodium phosphate dihydrate represents approximately 11.2 mmol of sodium and 5.6 mmol of phos- phate.

One gram of dibasic sodium phosphate heptahydrate represents approximately 7.5 mmol of sodium and 3.7 mmol of phosphate.

One gram of dibasic sodium phosphate dodecahydrate represents approximately 5.6 mmol of sodium and 2.8 mmol of phosphate.

A specification for sodium phosphate, dibasic is contained in the Food Chemicals Codex (FCC).



Specific References

Lloyd CW, Johnson CE. Management of hypophosphatemia. Clin Pharm 1988; 7: 123–128.

Holland PC, Wilkinson AR, Diez J, Lindsell DRM. Prenatal deficiency of phosphate, phosphate supplementation, and rickets in very-low-birthweight infants. Lancet 1990; 335: 697–701.

Albert A, Serjearnt EP. Ionization Constants of Acids and Bases, 2nd edn. Edinburgh: Chapman and Hall, 1971.

Benjamin BE. Ciprofloxacin and sodium phosphates not compa- tible during actual Y-site injection [letter]. Am J Health Syst Pharm 1996; 53: 1850–1851.

Haskell LP. Hypocalcaemic tetany induced by hypertonic-phos- phate enema [letter]. Lancet 1985; ii: 1433.

Martin RR, Lisehora GR, Braxton M, Barcia PJ. Fatal poisoning from sodium phosphate enema: case report and experimental study. J Am Med Assoc 1987; 257: 2190–2192.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3273.

General References

Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1231.

Authors

AS Kearney.

Date of Revision

20 August 2005.

Sodium Phosphate, Monobasic

Nonproprietary Names

BP: Anhydrous sodium dihydrogen phosphate Sodium dihydrogen phosphate monohydrate Sodium dihydrogen phosphate dihydrate

PhEur: Natrii dihydrogenophosphas dihydricus USP: Monobasic sodium phosphate

Note that the BP 2004 contains three separate monographs for the anhydrous, the monohydrate, and the dihydrate; the PhEur 2005 contains a single monograph for the dihydrate; and the USP 28 contains one monograph for the anhydrous, the monohydrate and the dihydrate. See also Section 8.

Synonyms

Acid sodium phosphate; E339; Kalipol 32; monosodium orthophosphate; monosodium phosphate; phosphoric acid, monosodium salt; primary sodium phosphate; sodium biphos- phate; sodium dihydrogen orthophosphate; sodium dihydrogen phosphate.

Chemical Name and CAS Registry Number

Anhydrous monobasic sodium phosphate [7558-80-7] Monobasic sodium phosphate monohydrate [10049-21-5] Monobasic sodium phosphate dihydrate [13472-35-0]

Empirical Formula and Molecular Weight

The hydrated forms of monobasic sodium phosphate occur as odorless, colorless or white, slightly deliquescent crystals. The anhydrous form occurs as a white crystalline powder or granules.

9 Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sodium phosphate, monobasic.

Test PhEur 2005 USP 28

Identification + +

Characters + —

Appearance of solution + —

Aluminum, calcium and related — +

elements

NaH PO 119.98

2 4

NaH2PO4·H2O 137.99

NaH2PO4·2H2O 156.01

Structural Formula

NaH2PO4·xH2O where x = 0, 1, or 2.

Functional Category

Buffering agent; emulsifying agent; sequestering agent.

Applications in Pharmaceutical Formulation or Technology

Monobasic sodium phosphate is used in a wide variety of pharmaceutical formulations as a buffering agent and as a sequestering agent. Therapeutically, monobasic sodium phos- phate is used as a mild saline laxative and in the treatment of hypophosphatemia.(1–3)

Monobasic sodium phosphate is also used in food products, for example, in baking powders, and as a dry acidulant and sequestrant.

Description

The USP 28 states that monobasic sodium phosphate contains one or two molecules of water of hydration or is anhydrous.



Typical Properties

Acidity/alkalinity: pH = 4.1–4.5 for a 5% w/v aqueous solution of the monohydrate at 258C.

Density: 1.915 g/cm3 for the dihydrate.

Dissociation constant: pKa = 2.15 at 258C

Solubility: soluble 1 in 1 of water; very slightly soluble in ethanol (95%).

Stability and Storage Conditions

Monobasic sodium phosphate is chemically stable, although it is slightly deliquescent. On heating at 1008C, the dihydrate loses all of its water of crystallization. On further heating, it melts with decomposition at 2058C, forming sodium hydrogen pyrophosphate, Na2H2P2O7. At 2508C it leaves a final residue of sodium metaphosphate, NaPO3.

Aqueous solutions are stable and may be sterilized by autoclaving.

Monobasic sodium phosphate should be stored in an airtight container in a cool, dry place.

Sodium Phosphate, Monobasic 697

Incompatibilities

Monobasic sodium phosphate is an acid salt and is therefore generally incompatible with alkaline materials and carbonates; aqueous solutions of monobasic sodium phosphate are acidic and will cause carbonates to effervesce.

Monobasic sodium phosphate should not be administered concomitantly with aluminum, calcium, or magnesium salts since they bind phosphate and could impair its absorption from the gastrointestinal tract. Interaction between calcium and phosphate, leading to the formation of insoluble calcium phosphate precipitates, is possible in parenteral admix- tures.(4–6)

Method of Manufacture

Monobasic sodium phosphate is prepared by adding phospho- ric acid to a hot, concentrated solution of disodium phosphate until the liquid ceases to form a precipitate with barium chloride. This solution is then concentrated and the monobasic sodium phosphate is crystallized.

Safety

Monobasic sodium phosphate is widely used as an excipient in parenteral, oral, and topical pharmaceutical formulations.

Phosphate occurs extensively in the body and is involved in many physiological processes since it is the principal anion of intracellular fluid. Most foods contain adequate amounts of phosphate, making hypophosphatemia(1) virtually unknown except for in certain disease states(2) or in patients receiving total parenteral nutrition. Treatment is usually by the oral administration of up to 100 mmol of phosphate daily.

Approximately two-thirds of ingested phosphate is absorbed from the gastrointestinal tract, virtually all of it being excreted in the urine, and the remainder is excreted in the feces. Excessive administration of phosphate, particularly intra- venously, rectally, or in patients with renal failure, can cause hyperphosphatemia that may lead to hypocalcemia or other severe electrolyte imbalances.(7–9) Adverse effects occur less frequently following oral consumption, although phosphates act as mild saline laxatives when administered orally or rectally (2–4 g of monobasic sodium phosphate in an aqueous solution is used as a laxative). Consequently, gastrointestinal distur- bances including diarrhea, nausea, and vomiting may occur following the use of monobasic sodium phosphate as an excipient in oral formulations. However, the level of monobasic sodium phosphate used as an excipient in a pharmaceutical

formulation is not usually associated with adverse effects.

LD50 (rat, IM): 0.25 g/kg(10)

LD50 (rat, oral): 8.29 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Monobasic sodium phos- phate may be irritant to the skin, eyes, and mucous membranes. 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; infusions; ophthalmic, oral, topical, and vaginal preparations). Included in nonparenteral and parenteral medicines licensed in



the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Dibasic sodium phosphate; monobasic potassium phosphate.

Monobasic potassium phosphate Empirical formula: KH2PO4 Molecular weight: 136.09

CAS number: [7778-77-0]

Synonyms: E340; monopotassium phosphate; potassium acid phosphate; potassium biphosphate; potassium dihydrogen orthophosphate.

Appearance: colorless crystals or a white, odorless, granular or crystalline powder.

Acidity/alkalinity: pH ≈ 4.5 for a 1% w/v aqueous solution at 258C.

Solubility: freely soluble in water; practically insoluble in ethanol (95%).

Comments: 1 g of monobasic potassium phosphate represents approximately 7.3 mmol of potassium and of phosphate.

The EINECS number for monobasic potassium phos- phate is 231-913-4.

Comments

One gram of anhydrous monobasic sodium phosphate represents approximately 8.3 mmol of sodium and of phos- phate.

One gram of monobasic sodium phosphate monohydrate represents approximately 7.2 mmol of sodium and of phos- phate.

One gram of monobasic sodium phosphate dihydrate represents approximately 6.4 mmol of sodium and of phos- phate.

A specification for sodium phosphate monobasic is con- tained in the Food Chemicals Codex (FCC). The EINECS number for monobasic sodium phosphate is 231-449-2.

Specific References

Lloyd CW, Johnson CE. Management of hypophosphatemia. Clin Pharm 1988; 7: 123–128.

Holland PC, Wilkinson AR, Diez J, Lindsell DRM. Prenatal deficiency of phosphate, phosphate supplementation, and rickets in very-low-birthweight infants. Lancet 1990; 335: 697–701.

Rosen GH, Boullata JI, O’Rangers EA, et al. Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia. Crit Care Med 1995; 23: 1204–

1210.

Eggert LD, Rusho WJ, Mackay MW, Chan GM. Calcium and phosphorus compatibility in parenteral nutrition solutions for neonates. Am J Hosp Pharm 1982; 39: 49–53.

Niemiec PW, Vanderveen TW. Compatibility considerations in parenteral nutrient solutions. Am J Hosp Pharm 1984; 41: 893– 911.

Pereira-da-Silva L, Nurmamodo A, Amaral JM, et al. Compat- ibility of calcium and phosphate in four parenteral nutrition solutions for preterm neonates. Am J Health Syst Pharm 2003; 60:

1041–1044.

Haskell LP. Hypocalcaemic tetany induced by hypertonic- phosphate enema [letter]. Lancet 1985; ii: 1433.

Larson JE, Swigart SA, Angle CR. Laxative phosphate poisoning: pharmacokinetics of serum phosphorus. Hum Toxicol 1986; 5: 45–49.

698 Sodium Phosphate, Monobasic

Martin RR, Lisehora GR, Braxton M, Barcia PJ. Fatal poisoning from sodium phosphate enema: case report and experimental study. J Am Med Assoc 1987; 257: 2190–2192.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3274.

General References

Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1230.

Authors

LY Galichet.

Date of Revision

17 August 2005.

Sodium Propionate

Nonproprietary Names

PhEur: Natrii propionas USPNF: Sodium propionate

Synonyms

E281; ethylformic acid, sodium salt, hydrate; methylacetic acid, sodium salt, hydrate; sodium propanoate hydrate; sodium propionate hydrate.

Chemical Name and CAS Registry Number

Propionic acid, sodium salt, hydrate [6700-17-0] Propionic acid, sodium salt, anhydrous [137-40-6]

Empirical Formula and Molecular Weight

C3H5NaO2·xH2O 114.06 (for monohydrate) C3H5NaO2 96.06 (for anhydrous)

Structural Formula

 

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

As an excipient, sodium propionate is used in oral pharma- ceutical formulations as an antimicrobial preservative. Like propionic acid, sodium propionate and other propionic acid salts are fungistatic and bacteriostatic against a number of Gram-positive cocci. Propionates are more active against molds than is sodium benzoate, but have essentially no activity against yeasts; see Section 10.

Therapeutically, sodium propionate has been used topically in concentrations up to 10% w/w alone or in combination with other propionates, caprylates, or other antifungal agents, in the form of ointments or solutions for the treatment of dermato- phyte infections. Eye drops containing 5% w/v sodium propionate have also been used. See Section 18.

In food processes, particularly baking, sodium propionate is used as an antifungal agent; it may also be used as a flavoring agent in food products. In veterinary medicine, sodium propionate is used therapeutically as a glucogenic substance in ruminants.(1)

Description

Sodium propionate occurs as colorless transparent crystals or as a granular, free-flowing, crystalline powder. It is odorless, or with a slight characteristic odor, and is deliquescent in moist air. Sodium propionate has a characteristic, slightly cheeselike taste, although by itself it is unpalatable.

Pharmacopeial Specifications

See Table I.

Table I:  Pharmacopeial specifications for sodium propionate.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Characters + —    

Appearance of solution + —    

Alkalinity — +    

pH 7.8–9.2 —    

Water — 41.0%    

Heavy metals 410 ppm 40.001%    

Related substances + —    

Readily oxidizable substances + —    

Iron 410 ppm —    

Organic volatile impurities — +    

Loss on drying 0.50% —    

Assay (dried basis) 99.0–101.0% 99.0–100.5%  

Typical Properties

Antimicrobial activity: sodium propionate, propionic acid, and other propionates possess mainly antifungal activity and are used as preservatives primarily against molds; they exhibit essentially no activity against yeasts. Although, in general, propionates exhibit little activity against bacteria, sodium propionate is effective against Bacillus mesenterium, the organism that causes ‘rope’ in bread. Antimicrobial activity is largely dependent upon the presence of the free acid and hence propionates exhibit optimum activity at acid pH, notably at less than pH 5. Synergistic effects occur between propionates and carbon dioxide or sorbic acid. See also Propionic acid.

Solubility: soluble 1 in 24 of ethanol (95%), 1 in 1 of water, and 1 in 0.65 of boiling water; practically insoluble in chloro- form and ether.

Stability and Storage Conditions

Sodium propionate is deliquescent and should therefore be stored in an airtight container in a cool, dry place.

Incompatibilities

Incompatibilities for sodium propionate are similar to those of other weak organic acids.

700 Sodium Propionate

Method of Manufacture

Sodium propionate is prepared by the reaction of propionic acid with sodium carbonate or sodium hydroxide.

Safety

Sodium propionate and other propionates are used in oral pharmaceutical formulations, food products, and cosmetics. The free acid, propionic acid, occurs naturally at levels up to 1% w/w in certain cheeses.

Following oral consumption, propionate is metabolized in mammals in a manner similar to that of fatty acids. Toxicity studies in animals have shown sodium propionate and other propionates to be relatively nontoxic materials.(2,3) In veter- inary medicine, sodium propionate is used as a therapeutic agent for cattle and sheep.(1)

In humans, 6 g of sodium propionate has been administered daily without harm.(2) However, allergic reactions to propio-

Appearance: white crystalline powder.

Solubility: soluble in water; slightly soluble in ethanol (95%) and methanol; practically insoluble in acetone and benzene.

Method of manufacture: prepared by the reaction of propionic acid and calcium hydroxide.

Comments: occurs as the monohydrate or trihydrate.

Potassium propionate Empirical formula: C3H5O2K Molecular weight: 112.17

CAS number: [327-62-8]

Synonyms: E283; propanoic acid, potassium salt; propionic acid, potassium salt.

Appearance: white crystalline powder.

Comments: occurs as the anhydrous form and the monohy- drate. Decomposes in moist air to give off propionic acid.

Zinc propionate

Empirical formula: C H O Zn

nates can occur.

Molecular weight:

6  10  4

LD50 (mouse, oral): 6.33 g/kg(4) LD50 (mouse, SC): 2.1 g/kg LD50 (rabbit, skin): 1.64 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium propionate may be irritant to the eyes and skin. Gloves, eye protection, and a dust- mask are recommended. When heated to decomposition, sodium propionate emits toxic fumes of sodium monoxide, Na2O.

In the UK, the occupational exposure limits for propionic acid are 31 mg/m3 (10 ppm) long-term (8-hour TWA) and 46 mg/m3 (15 ppm) short-term.(5)

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. In cheese products, propionates are limited to 0.3% w/w concentration; a limit of 0.32% w/w is applied in flour and white bread rolls, while a limit of 0.38% w/w is applied in whole wheat products.

Included in the FDA Inactive Ingredients Guide (oral capsules, powder, suspensions, and syrups). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.