Sodium Acetate

Nonproprietary Names

BP: Sodium acetate JP: Sodium acetate

PhEur: Natrii acetas trihydricus USP: Sodium acetate

Synonyms

Acetic acid, sodium salt; E262; sodium ethanoate.

Chemical Name and CAS Registry Number

Sodium acetate anhydrous [127-09-3] Sodium acetate trihydrate [6131-90-4]

Empirical Formula and Molecular Weight

C2H3NaO2 82.0 (for anhydrous) C2H3NaO2·3H2O   136.1 (for trihydrate)

Note that the trihydrate is the material described in the JP2001, PhEur 2005 and USP 28, although the PhEur 2005 is the only pharmacopeia that makes this explicit with the title of the monograph.

Structural Formula

 

Functional Category

Antimicrobial preservative; buffering agent; flavoring agent, stabilizing agent.

Applications in Pharmaceutical Formulation or Technology

Sodium acetate is used as a buffering agent in various intramuscular, intravenous, topical, ophthalmic, nasal, oral, otic, and subcutaneous formulations. It may be used to reduce the bitterness of oral pharmaceuticals.(1) It can be used to enhance the antimicrobial properties of formulations; it has been shown to inhibit the growth of S. aureus and E. coli, but not C. albicans in protein hydrolysate solutions.(2) It is widely used in the food industry as a preservative.(3) Sodium acetate has also been used therapeutically for the treatment of metabolic acidosis in premature infants,(4,5) and in hemo- dialysis solutions.(6,7)

Description

Sodium acetate occurs as colorless, transparent crystals or a granular crystalline powder with a slight acetic acid odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sodium acetate.

 

Test JP 2001 PhEur 2005 USP 28    

Identification + + +    

Description + — —    

Characters — + —    

Appearance of + + —    

solution    

Acid or alkali + — —    

pH — 7.5–9.0 7.5–9.2    

Insoluble matter — — 40.05%    

Chloride 40.011% 4200 ppm 40.035%    

Sulfate 40.017% 4200 ppm 40.005%    

Heavy metals 410 ppm 410 ppm 40.001%    

Calcium and

magnesium + 450 ppm +    

Potassium — — +    

Arsenic 42 ppm 42 ppm —    

Iron — 410 ppm —    

Reducing substances + + —    

Aluminum

Loss on drying — 40.2 ppm 40.2 mg/g    

anhydrous — — 41.0%    

trihydrate 39.0–40.5% 39.0–40.5% 38.0–41.0%    

Organic volatile — — +    

impurities    

Assay (dried basis) 599.5% 99.0–101.0% 99.0–101.0%  

Typical Properties

Acidity/alkalinity: pH = 7.5–9.0 (5% w/v aqueous solution)

Hygroscopicity: the anhydrous and trihydrate sodium acetate are hygroscopic.

Solubility: soluble 1 in 0.8 in water, 1 in 20 in ethanol (95%). Melting point: 588C for trihydrate; 3248C for anhydrous.(8) Specific gravity: 1.53

Stability and Storage Conditions

Sodium acetate should be stored in airtight containers.

Incompatibilities

Sodium acetate reacts with acidic and basic components. It will react violently with fluorine, potassium nitrate, and diketene.

Method of Manufacture

Sodium acetate is prepared by neutralization of acetic acid with sodium carbonate.

Sodium Acetate 655

Safety

Sodium acetate is widely used in cosmetics, foods, and pharmaceutical formulations (see Section 18), and is generally regarded as a nontoxic and nonirritant material.

A short-term feeding study in chickens with a diet supplemented with 5.44% sodium acetate showed reduced growth rates that were attributed to the sodium content.(9) Sodium acetate is poisonous if injected intravenously, is moderately toxic by ingestion, and is an irritant to the skin and eyes.(10)

LD50 (rat, oral): 3.53 g/kg(10) LD50 (mouse, IV): 0.38 g/kg(11) LD50 (mouse, SC): 8.0 g/kg(10)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium acetate is a mild skin and eye irritant; gloves and eye protection are recommended. On exposure, wash eyes and skin with large amounts of water. Inhalation of dust may cause pulmonary tract problems. When

heated to decomposition, sodium acetate emits toxic fumes of NaO2.(10)

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (injections, nasal, otic, ophthalmic, and oral preparations).

Related Substances

—

Comments

Sodium acetate was shown to enhance aqueous humor to plasma concentration ratio of timolol by about 20-fold in an ophthalmic monoisopropyl PVM-MA matrix system, presum- ably by decreasing systemic absorption.(12)

Sodium acetate has also been used experimentally in matrix tablet formulations, where it increased the effect of carbomer as a sustained release matrix.(13)

A specification for sodium acetate is contained within the Food Chemicals Codex (FCC). The PhEur 2005 also contains a monograph on sodium acetate [1-11C] injection under Radio- pharmaceutical Preparations.

The EINECS number for sodium acetate is 204-823-8.



Specific References

Keast RS, Breslin PA. Modifying the bitterness of selected oral pharmaceuticals with cation and anion series of salts. Pharm Res 2002; 19(7): 1019–1026.

Frech G, Allen LV. Sodium acetate as a preservative in protein hydrolysate solutions. Am J Hosp Pharm 1979; 36: 1672–1675.

Bedie GK, Smaelis J, Sofos JN. Antimicrobials in the formulation to control Listeria monocytogenes postprocessing contamination on frankfurters stored at 48C in vacuum packages. J Food Prot 2001; 64(12): 1949–1955.

Ekblad H, Kero P, Takala J. Slow sodium acetate infusion in the correction of metabolic acidosis in premature infants. Am J Dis Child 1985; 139(7): 708–710.

Kasik JW, Vafai J, Goodrich P. Sodium acetate infusion to correct acidosis in premature infants. Am J Dis Child 1986; 140(1): 9–10.

Katiuchi T, Mabuchi H, et al. Hemodynamic change during hemodialysis, especially on cardiovascular effects of sodium acetate. Jpn J Artif Organs 1982; 11(2): 456–459.

Jackson JK, Derleth DP. Effects of various arterial infusion solutions on red blood cells in the newborn. Arch Dis Child Fetal Neonatal Ed 2000; 83(2): F130–F134.

Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. Endicott, NY: Synapse Information Resources, 2002: 706.

Waterhouse HN, Scott HM. Effect of sex, feathering, rate of growth and acetates on chicks need for glycine. Poultry Sci 1962; 41: 1957–1962.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3225.

Spector WS. Handbook of Toxicology. Philadelphia: WB Saun- ders, 1956: 268.

Finne U, Salivirta J, Urtti A. Sodium acetate improves the ocular/ systemic absorption ratio of timolol applied ocularly in mono- isopropyl PVM-MA matrices. Int J Pharm 1991; 75; R1–R4.

Meshali MM, El-Sayed GM, El-Helw A. Effect of added substances on theophylline release from carbopol 934P matrix. STP Pharma Sci 1997; 7(3): 195–198.

General References

—

Authors

WG Chambliss.

Date of Revision

8 August 2005.

Sodium Alginate

Nonproprietary Names

BP: Sodium alginate PhEur: Natrii alginas USPNF: Sodium alginate

Synonyms

Algin; alginic acid, sodium salt; E401; Kelcosol; Keltone; Protanal; sodium polymannuronate.

Chemical Name and CAS Registry Number

Sodium alginate [9005-38-3]

Empirical Formula and Molecular Weight

Sodium alginate consists chiefly of the sodium salt of alginic acid, which is a mixture of polyuronic acids composed of residues of D-mannuronic acid and L-guluronic acid.

The block structure and molecular weight of sodium alginate samples has been investigated.(1)

Structural Formula

See Section 4.

Functional Category

Stabilizing agent; suspending agent; tablet and capsule disin- tegrant; tablet binder; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Sodium alginate is used in a variety of oral and topical pharmaceutical formulations.(2) In tablet formulations, sodium alginate may be used as both a binder and disintegrant;(3) it has been used as a diluent in capsule formulations.(4) Sodium alginate has also been used in the preparation of sustained- release oral formulations since it can delay the dissolution of a drug from tablets,(5–7) capsules,(8) and aqueous suspensions.(9) In topical formulations, sodium alginate is widely used as a thickening and suspending agent in a variety of pastes, creams, and gels, and as a stabilizing agent for oil-in-water emulsions. Recently, sodium alginate has been used for the aqueous microencapsulation of drugs,(10) in contrast with the more conventional microencapsulation techniques which use organic-solvent systems. It has also been used in the formation

of nanoparticles.(11)

The adhesiveness of hydrogels prepared from sodium algin- ate has been investigated(12) and drug release from oral mucosal adhesive tablets,(13) and buccal gels,(14,15) based on sodium alginate have been reported. Other novel delivery systems containing sodium alginate include ophthalmic solutions that form a gel in situ when administered to the eye;(16,17) an in situ forming gel containing paracetamol for oral administration;(18) and a freeze-dried device intended for the delivery of bone- growth factors.(19)

Hydrogel systems containing alginates have also been investigated for delivery of proteins and peptides.(20)

Therapeutically, sodium alginate has been used in combina- tion with an H2-receptor antagonist in the management of gastroesophageal reflux,(21) and as a hemostatic agent in surgical dressings.(22,23) Alginate dressings, used to treat exuding wounds, often contain significant amounts of sodium alginate as this improves the gelling properties.(24) Sponges composed of sodium alginate and chitosan produce a sustained drug release and may be useful as wound dressings or as tissue engineering matrices.(25)

Sodium alginate is also used in cosmetics and food products;

see Table I.

 

Table I: Uses of sodium alginate.    

Use Concentration (%)    

Pastes and creams 5–10    

Stabilizer in emulsions 1–3    

Suspending agent 1–5    

Tablet binder 1–3    

Tablet disintegrant 2.5–10  

Description

Sodium alginate occurs as an odorless and tasteless, white to pale yellowish-brown colored powder.

Pharmacopeial Specifications

See Table II.

Table II:  Pharmacopeial specifications for sodium alginate.

 

Test PhEur 2005 USPNF 23    

Characters + +    

Identification + +    

Appearance of solution + —    

Microbial limits 41000/g 4200/g    

Loss on drying 415.0% 415.0%    

Ash — 18.0–27.0%    

Sulfated ash 30.0–36.0% —    

Arsenic — 41.5 ppm    

Calcium 41.5% —    

Chlorides 41.0% —    

Lead — 40.001%    

Heavy metals 420 ppm 40.004%    

Assay (dried basis) — 90.8–106.0%  

Typical Properties

Acidity/alkalinity: pH ≈7.2 for a 1% w/v aqueous solution.

Solubility: practically insoluble in ethanol (95%), ether, chloro- form, and ethanol/water mixtures in which the ethanol content is greater than 30%. Also, practically insoluble in other organic solvents and aqueous acidic solutions in which

Sodium Alginate 657

the pH is less than 3. Slowly soluble in water, forming a viscous colloidal solution.

Viscosity (dynamic): various grades of sodium alginate are commercially available that yield aqueous solutions of varying viscosity. Typically, a 1% w/v aqueous solution, at 208C, will have a viscosity of 20–400 mPa s (20–400 cP). Viscosity may vary depending upon concentration, pH, temperature, or the presence of metal ions.(26–28) Above pH 10, viscosity decreases, see also Alginic Acid and Section 11.

Stability and Storage Conditions

Sodium alginate is a hygroscopic material, although it is stable if stored at low relative humidities and a cool temperature.

Aqueous solutions of sodium alginate are most stable at pH 4–10. Below pH 3, alginic acid is precipitated. A 1% w/v aqueous solution of sodium alginate exposed to differing temperatures had a viscosity 60–80% of its original value after storage for 2 years.(29) Solutions should not be stored in metal containers.

Sodium alginate solutions are susceptible on storage to microbial spoilage, which may affect solution viscosity. Solutions are ideally sterilized using ethylene oxide, although filtration using a 0.45 mm filter also has only a slight adverse effect on solution viscosity.(30) Heating sodium alginate solutions to temperatures above 708C causes depolymerization with a subsequent loss of viscosity. Autoclaving of solutions can cause a decrease in viscosity, which may vary depending upon the nature of any other substances present.(30,31) Gamma irradiation should not be used to sterilize sodium alginate

solutions since this process severely reduces solution viscos- ity.(30,32)

Preparations for external use may be preserved by the addition of 0.1% chlorocresol, 0.1% chloroxylenol, or parabens. If the medium is acidic, benzoic acid may also be used.

The bulk material should be stored in an airtight container in a cool, dry place.

Incompatibilities

Sodium alginate is incompatible with acridine derivatives, crystal violet, phenylmercuric acetate and nitrate, calcium salts, heavy metals, and ethanol in concentrations greater than 5%. Low concentrations of electrolytes cause an increase in viscosity but high electrolyte concentrations cause salting-out of sodium alginate; salting-out occurs if more than 4% of sodium chloride is present.

Method of Manufacture

Alginic acid is extracted from brown seaweed and is neutralized with sodium bicarbonate to form sodium alginate.

Safety

Sodium alginate is widely used in cosmetics, food products, and pharmaceutical formulations, such as tablets and topical products, including wound dressings. It is generally regarded as a nontoxic and nonirritant material, although excessive oral consumption may be harmful. A study in five healthy male volunteers fed a daily intake of 175 mg/kg body-weight of sodium alginate for 7 days, followed by a daily intake of 200 mg/kg body-weight of sodium alginate for a further 16 days, showed no significant adverse effects.(33)



The WHO has not specified an acceptable daily intake for alginic acid and alginate salts as the levels used in food do not represent a hazard to health.(34)

Inhalation of alginate dust may be irritant and has been associated with industrial-related asthma in workers involved in alginate production. However, it appears that the cases of asthma were linked to exposure to seaweed dust rather than pure alginate dust.(35)

LD50 (cat, IP): 0.25 g/kg(36)

LD50 (mouse, IV): 0.2 g/kg LD50 (rabbit, IV): 0.1 g/kg LD50 (rat, IV): 1 g/kg

LD50 (rat, oral): >5 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium alginate may be irritant to the eyes or respiratory system if inhaled as dust; see Section 14. Eye protection, gloves, and a dust respirator are recommended. Sodium alginate should be handled in a well- ventilated environment.

Regulatory Status

GRAS listed. Accepted in Europe for use as a food additive. Included in the FDA Inactive Ingredients Guide (oral suspen- sions and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Alginic acid; calcium alginate; potassium alginate; propylene glycol alginate.

Comments

A number of different grades of sodium alginate, which have different solution viscosities, are commercially available. Many different alginate salts and derivatives are also commercially available including ammonium alginate; calcium alginate; magnesium alginate, and potassium alginate.

To assist in the preparation of dispersions of sodium alginate, the material may be mixed with a dispersing agent such as sucrose, ethanol, glycerol, or propylene glycol. A specification for sodium alginate is contained in the Food Chemicals Codex (FCC).

See also Alginic Acid for further information.

Specific References

Johnson FA, Craig DQM, Mercer AD. Characterization of the block structure and molecular weight of sodium alginates. J Pharm Pharmacol 1997; 49: 639–643.

Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug Dev Ind Pharm 2002; 28(6): 621–630.

Sakr AM, Elsabbagh HM, Shalaby AH. Effect of the technique of incorporating sodium alginate on its binding and/or disintegrating effectiveness in sulfathiazole tablets. Pharm Ind 1978; 40(10): 1080–1086.

Veski P, Marvola M. Sodium alginates as diluents in hard gelatin capsules containing ibuprofen as a model drug. Pharmazie 1993; 48(10): 757–760.

Klaudianos S. Alginate sustained-action tablets [in German]. Dtsch Apoth Ztg 1978; 118: 683–684.

658 Sodium Alginate