SEM: 2

Excipient: Sodium stearyl fumarate

Manufacturer: JRS Pharma LP

Lot No.: 255-01

Magnification: 500×

 

SEM: 3

Excipient: Sodium stearyl fumarate

Manufacturer: JRS Pharma LP

Lot No.: 255-01

Magnification: 1000×

 

Safety

Sodium stearyl fumarate is used in oral pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material.

Metabolic studies of sodium stearyl fumarate in the rat and dog indicated that approximately 80% was absorbed and 35% was rapidly metabolized. The fraction absorbed was hydro- lyzed to stearyl alcohol and fumaric acid, with the stearyl alcohol further oxidized to stearic acid. In the dog, sodium stearyl fumarate that was not absorbed was excreted unchanged in the feces within 24 hours.(11)

Stearyl alcohol and stearic acid are naturally occurring constituents in various food products, while fumaric acid is a normal constituent of body tissue. Stearates and stearyl citrate have been reviewed by the WHO and an acceptable daily intake for stearyl citrate has been set at up to 50 mg/kg body- weight.(12) The establishment of an acceptable daily intake for stearates(12) and fumaric acid(13) was thought unnecessary.

Disodium fumarate has been reported to have a toxicity not greatly exceeding that of sodium chloride.(14,15)

See Fumaric Acid, Stearic Acid, and Stearyl Alcohol for further information.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium stearyl fumarate should be handled in a well-ventilated environment; eye protection is recommended.

Sodium Stearyl Fumarate 707

Regulatory Status

GRAS listed. Permitted by the FDA for direct addition to food for human consumption as a conditioning or stabilizing agent in various bakery products, flour-thickened foods, dehydrated potatoes, and processed cereals up to 0.2–1.0% by weight of the food. Included in nonparenteral medicines licensed in the UK. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

Comments

Sodium stearyl fumarate is supplied in a pure form and is often of value when the less pure stearate-type lubricants are unsuitable owing to chemical incompatibility. Sodium stearyl fumarate is less hydrophobic than magnesium stearate or stearic acid and has a less retardant effect on tablet dissolution than magnesium stearate. A specification for sodium stearyl fumarate is contained in the Food Chemicals Codex (FCC).

The EINECS number for sodium stearyl fumarate is 203- 743-0.

Specific References

Sure´n G. Evaluation of lubricants in the development of tablet formula. Dansk Tidsskr Farm 1971; 45: 331–338.

Ho¨ lzer AW, Sjo¨ gren J. Evaluation of sodium stearyl fumarate as a tablet lubricant. Int J Pharm 1979; 2: 145–153.

Ho¨ lzer AW, Sjo¨ gren J. Evaluation of some lubricants by the comparison of friction coefficients and tablet properties. Acta Pharm Suec 1981; 18: 139–148.

Saleh SI, Aboutaleb A, Kassem AA, Stamm A. Evaluation of some water soluble lubricants for direct compression. Lab Pharm Prob Tech 1984; 32: 588–591.

Chowhan ZT, Chi L-H. Drug–excipient interactions resulting from powder mixing IV: role of lubricants and their effect on in vitro dissolution. J Pharm Sci 1986; 75: 542–545.

Shah NH, Stiel D, Weiss M, et al. Evaluation of two new tablet lubricants sodium stearyl fumarate and glyceryl behenate. Measurement of physical parameters (compaction, ejection and residual forces) in the tableting process and the effect on the dissolution rate. Drug Dev Ind Pharm 1986; 12: 1329–1346.



Davies PN, Storey DE, Worthington HEC. Some pitfalls in accelerated stability testing with tablet and capsule lubricants. J Pharm Pharmacol 1987; 39: 86P.

Mu X, Tobyn MJ, Stanforth JN. Investigations into the food effect on a polysaccharide dosage form. Eur J Pharm Sci 1996; 4 (Suppl. 1): S184.

Michoel A, Rombaut P, Verhoye A. Comparative evaluation of co- processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Pharm Dev Technol 2002; 7(1): 79–87.

Pesonen T, Kanerva H, Hirvonen J, et al. Incompatibilities between chlorhexidine diacetate and some tablet excipients. Drug Dev Ind Pharm 1995; 21: 747–752.

Figdor SK, Pinson R. The absorption and metabolism of orally administered tritium labelled sodium stearyl fumarate in the rat and dog. J Agric Food Chem 1970; 18(5): 872–877.

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. Thirty-fifth report of the FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1990; No. 789.

Bodansky O, Gold H, Zahm W. The toxicity and laxative action of sodium fumarate. J Am Pharm Assoc (Sci) 1942; 31: 1–8.

Locke A, Locke RB, Schlesinger H, Carr H. The comparative toxicity and cathartic efficiency of disodium tartrate and fumarate, and magnesium fumarate, for the mouse and rabbit. J Am Pharm Assoc (Sci) 1942; 31: 12–14.

General References

JRS Pharma LP 2003. Pruv sodium stearyl fumarate. http://www.jrspharma.com/lubricants_pdfs/pruv_rev_02.pdf (accessed 19 April 2005).

Nicklasson M, Brodin A. The coating of disk surfaces by tablet lubricants, determined by an intrinsic rate of dissolution method. Acta Pharm Suec 1982; 19: 99–108.

Zanowiak P. Lubrication in solid dosage form design and manufacture. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 9. New York: Marcel Dekker, 1994: 87–111.

Authors

PJ Weller.

Date of Revision

19 April 2005.

Sodium Sulfite

Nonproprietary Names

BP: Sodium sulphite anhydrous JP: Dried sodium sulfite

PhEur: Natrii sulfis anhydricus USPNF: Sodium sulfite anhydrous

Synonyms

Anhydrous sodium sulfite; disodium sulfite; exsiccated sodium sulfite; E221; sulfurous acid disodium salt.

Chemical Name and CAS Registry Number

Sodium sulfite [7757-83-7]

Empirical Formula and Molecular Weight

Na2SO3 126.04

Structural Formula

Na2SO3

Functional Category

Antimicrobial preservative; antioxidant.

Applications in Pharmaceutical Formulation or Technology

Sodium sulfite is used as an antioxidant in applications similar to those for sodium metabisulfite(1) It is also an effective antimicrobial preservative, particularly against fungi at low pH (0.1% w/v of sodium sulfite is used). Sodium sulfite is used in cosmetics, food products, and pharmaceutical applications such as parenteral formulations, inhalations, oral formulations, and topical preparations.

See also Sodium Metabisulfite.

Description

Sodium sulfite occurs as an odorless white powder or hexagonal prisms. Note that the commercially available sodium sulfite is often presented as a white to tan- or pink- colored powder that would not conform to the pharmacopeial specification.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sodium sulfite.

 

Test JP 2001 PhEur 2005 USPNF 23    

Characters + + —    

Identification + + +    

Appearance of solution — + +    

Heavy metals 420 ppm 410 ppm 410 ppm    

Iron — 410 ppm 410 ppm    

Selenium — 410 ppm 410 ppm    

Thiosulfates + 40.1% +    

Zinc — 425 ppm 425 ppm    

Assay 597% 95.0–100.5% 95.0–100.5%  

Typical Properties

Acidity/alkalinity: pH = 9 for an aqueous solution.

Density: 2.633 g/cm3

Hygroscopicity: hygroscopic.

Solubility: soluble 1 in 3.2 parts of water; soluble in glycerin; practically insoluble in ethanol (95%).

Stability and Storage Conditions

Sodium sulfite should be stored in a well-closed container in a cool, dry, place. In solution, sodium sulfite is slowly oxidized to sulfate by dissolved oxygen; strong acids lead to formation of sulfurous acid/sulfur dioxide. On heating, sodium sulfite decomposes liberating sulfur oxides.

Incompatibilities

Sodium sulfite is incompatible with acids, oxidizing agents, many proteins, and vitamin B1. See also Sodium Metabisulfite.

Method of Manufacture

Sodium bisulfite is prepared by reacting sulfur dioxide gas with sodium hydroxide solution. The solid material is obtained by evaporation of water. Further neutralization with sodium hydroxide while keeping the temperature above 33.68C leads to crystallization of the anhydrous sodium sulfite (below this temperature the heptahydrate form is obtained).

Safety

Sodium sulfite is widely used in food and pharmaceutical applications as an antioxidant. It is generally regarded as relatively nontoxic and nonirritant when used as an excip- ient.(2,3) However, contact dermatitis and hypersensitivity reactions have been reported.(4,5) The acceptable daily intake for sodium sulfite has been set at up to 350 mg/kg bodyweight daily.(6)

LD50 (mouse, IP): 0.950 g/kg(7) LD50 (mouse, IV): 0.130 g/kg LD50 (mouse, oral): 0.820 g/kg LD50 (rabbit, IV): 0.065 g/kg LD50 (rabbit, oral): 1.181 g/kg LD50 (rat, IV): 0.115 g/kg

Sodium Sulfite 709

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in FDA Inactive Ingredients Guide (epidural, IM, IV, and SC injections; inhalation solution; ophthalmic solutions; oral syrups and suspensions; otic solutions; topical creams and emulsions). Included in nonparenteral medicines licensed in the UK.

Related Substances

Sodium sulfite heptahydrate; sodium metabisulfite.

Sodium sulfite heptahydrate Synonyms: natrii sulfis heptahydricus. CAS number: [7785-83-7]

Molecular weight: 252.15 Description: colorless crystals. Density: 1.56 g/cm3

Solubility: 1 in 1.6 of water; 1 in 30 of glycerin; sparingly soluble in ethanol (95%).

Comments: sodium sulfite heptahydrate is included in the PhEur 2005. The heptahydrate is unstable, oxidizing in the air to the sulfate.

Comments

The EINECS number for sodium sulfite is 231-821-4.



Specific References

Islam MS, Asker AF. Photoprotection of daunorubicin hydro- chloride with sodium sulfite. PDA J Pharm Sci Technol 1995; 49: 122–126.

Nair B, Elmore AR. Final report on the safety assessment of sodium sulfite, potassium sulfite, ammonium sulfite, sodium bisulfite, ammonium bisulfite, sodium metabisulfite and potassium metabisulfite. Int J Toxicol 2003; 22(2): 63–88.

Gunnisson AF. Sulphite toxicity: a critical review of in vitro and in vivo data. Food Cosmet Toxicol 1981; 19: 667–682.

Vissers-Croughs KJ, van der Kley AM, Vulto AG, Hulsman RF. Allergic contact dermatitis from sodium sulfite. Contact Derma- titis 1988; 18(4): 252–253.

Gunnisson AF, Jacobsen DW. Sulphite hypersensitivity: a critical review. CRC Crit Review Toxicol 1987; 17(3): 185–214.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirtieth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1987: No. 751.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3281–3282.

General References

—

Authors

HJ de Jong.

Date of Revision

17 August 2005.

Sorbic Acid

Nonproprietary Names

BP: Sorbic acid

PhEur: Acidum sorbicum USPNF: Sorbic acid

Synonyms

E200; (2-butenylidene) acetic acid; crotylidene acetic acid; hexadienic acid; hexadienoic acid; 2,4-hexadienoic acid; 1,3- pentadiene-1-carboxylic acid; 2-propenylacrylic acid; (E,E)- sorbic acid; Sorbistat K.

Chemical Name and CAS Registry Number

(E,E)-Hexa-2,4-dienoic acid [22500-92-1]

Empirical Formula and Molecular Weight

C6H8O2 112.13

Structural Formula

 

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Sorbic acid is an antimicrobial preservative(1) with antibacterial and antifungal properties used in pharmaceuticals, foods, enteral preparations, and cosmetics. Generally, it is used at concentrations of 0.05–0.2% in oral and topical pharmaceu- tical formulations, especially those containing nonionic surfac- tants. Sorbic acid is also used with proteins, enzymes, gelatin, and vegetable gums.(2) It has been shown to be an effective preservative for promethazine hydrochloride solutions in a concentration of 1 g/L.(3)

Sorbic acid has limited stability and activity against bacteria and is thus frequently used in combination with other antimicrobial preservatives or glycols, when synergistic effects appear to occur; see Section 10.

Description

Sorbic acid is a tasteless, white to yellow-white crystalline powder with a faint characteristic odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sorbic acid.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Appearance of solution + —    

Melting range 132–1368C 132–1358C    

Water 41.0% 40.5%    

Residue on ignition — 40.2%    

Sulfated ash 40.2% —    

Heavy metals 410 ppm 40.001%    

Aldehyde (as C2H4O) 40.15% —    

Organic volatile impurities — +    

Assay (anhydrous basis) 99.0–101.0% 99.0–101.0%  

Typical Properties

Antimicrobial activity: sorbic acid is primarily used as an antifungal agent, although it also possesses antibacterial properties. The optimum antibacterial activity is obtained at pH 4.5; and practically no activity is observed above pH 6.(4,5) The efficacy of sorbic acid is enhanced when it is used in combination with other antimicrobial preservatives or glycols since synergistic effects occur.(6) Reported minimum inhibitory concentrations (MICs) at pH 6 are shown in Table II.(7)

Table II: Minimum inhibitory concentrations (MICs) of sorbic acid at pH 6.

Microorganism MIC (mg/mL)

Aspergillus niger 200–500

Candida albicans 25–50

Clostridium sporogenes 100–500

Escherichia coli 50–100

Klebsiella pneumoniae 50–100

Penicillium notatum 200–300

Pseudomonas aeruginosa 100–300

Pseudomonas cepacia 50–100

Pseudomonas fluorescens 100–300

Saccharomyces cerevisiae 200–500

Staphylococcus aureus 50–100

Boiling point: 2288C with decomposition.

Density: 1.20 g/cm3

Dissociation constant: pKa = 4.76

Flash point: 1278C

Melting point: 134.58C

Solubility: see Table III. In syrup, the solubility of sorbic acid decreases with increasing sugar content.

Vapor pressure: <1.3 Pa (<0.01 mmHg) at 208C

Sorbic Acid 711

Table III: Solubility of sorbic acid.

Solvent Solubility at 208C unless otherwise stated

Acetone 1 in 11

Chloroform 1 in 15

Ethanol 1 in 8

Ethanol (95%) 1 in 10

Ether 1 in 30

Glycerin 1 in 320

Methanol 1 in 8

Propylene glycol 1 in 19

Water 1 in 400 at 308C

1 in 26 at 1008C

SEM: 1

Excipient: Sorbic acid Manufacturer: Pfizer Ltd. Magnification: 60×

 

Stability and Storage Conditions

Sorbic acid is sensitive to oxidation, particularly in the presence of light; oxidation occurs more readily in aqueous solution than in the solid form. Sorbic acid may be stabilized by phenolic antioxidants such as 0.02% propyl gallate.(6)

Sorbic acid is combustible when exposed to heat or flame. When heated to decomposition, it emits acrid smoke and irritating fumes. The bulk material should be stored in a well- closed container, protected from light, at a temperature not exceeding 408C.

Incompatibilities

Sorbic acid is incompatible with bases, oxidizing agents, and reducing agents. Some loss of antimicrobial activity occurs in the presence of nonionic surfactants and plastics. Oxidation is catalyzed by heavy-metal salts. Sorbic acid will also react with sulfur-containing amino acids, although this can be prevented



by the addition of ascorbic acid, propyl gallate, or butyl- hydroxytoluene.

When stored in glass containers, the solution becomes very pH sensitive; therefore, preparations using sorbic acid as a preservative should be tested for their microbial purity after prolonged periods of storage.

Aqueous solutions of sorbic acid without the addition of antioxidants are rapidly decomposed when stored in poly- propylene, polyvinylchloride, and polyethylene containers.