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Sorbate 579

6 Nater JP. Allergic contact dermatitis caused by . 15 Chemicals Codex, 6th edn. Bethesda, MD: United States Dermatologica 1968; 136(6): 477–478. Pharmacopeia, 2008; 812. 7 Vena GA et al. Sulfite contact allergy. Contact Dermatitis 1994; 31(3): 172–175. 8 Twarog FJ. Metabisulfite sensitivity in asthma: a review. N Engl Reg 20 General References Allergy Proc 1983; 4(2): 100–103. 9 Mathison DA et al. Precipitating factors in asthma: aspirin, sulfites, and Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. Boca other drugs and chemicals. Chest 1985; 87(Suppl.): 50S–54S. Raton, FL: CRC Press, 1992; 393–406. 10 Anonymous. Sulfites in drugs and food. Med Lett Drugs Ther 1986; 28: Valade J-P, Le Bras G. Sulfur dioxide release from effervescent tablets. Rev Fr 74–75. Oenol 1998; 171: 22–25. 11 Belchi-Hernandez J et al. Sulfite-induced urticaria. Ann Allergy 1993; 71(3): 230–232. 12 Sweetman SC, ed. Martindale: The Complete Drug Reference, 36th 21 Author edn. London: Pharmaceutical Press, 2009; 1662–1663. PJ Sheskey. 13 Anonymous. Warning for prescription drugs containing sulfites. FDA Drug Bull 1987; 17: 2–3. 14 FAO/WHO. Evaluation of the toxicity of a number of antimicrobials 22 Date of Revision and antioxidants. Sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1962; No. 228. 10 March 2009.

Potassium Sorbate

1 Nonproprietary Names and stability in water. Like , potassium sorbate BP: Potassium Sorbate has minimal antibacterial properties in formulations above pH 6. PhEur: Potassium Sorbate USP-NF: Potassium Sorbate 8 Description Potassium sorbate occurs as a white crystalline powder with a faint, 2 Synonyms characteristic odor. E202; 2,4-hexadienoic acid (E,E)-potassium salt; kalii sorbas; potassium (E,E)-hexa-2,4-dienoate; potassium (E,E)-sorbate; sor- P bic acid potassium salt. 9 Pharmacopeial Specifications See Table I. 3 Chemical Name and CAS Registry Number 2,4-Hexadienoic acid potassium salt [24634-61-5] Table I: Pharmacopeial specifications for potassium sorbate. Test PhEur 6.0 USP32–NF27 4 Empirical Formula and Molecular Weight Identification þþ C6H7O2K 150.22 Characters þ — Appearance of solution þ — Acidity or alkalinity þþ 5 Structural Formula Loss on drying 41.0% 41.0% Heavy metals 410 ppm 40.001% 4 Aldehydes (as C2H4O) 0.15% — Assay (dried basis) 99.0–101.0% 98.0–101.0%

6 Functional Category Antimicrobial preservative. 10 Typical Properties Antimicrobial activity Potassium sorbate is predominantly used 7 Applications in Pharmaceutical Formulation or as an antifungal preservative, although it also has antibacterial Technology properties. Similarly to sorbic acid, the antimicrobial activity is Potassium sorbate is an antimicrobial preservative, with antibacter- dependent on the degree of dissociation; there is practically no ial and antifungal properties used in pharmaceuticals, , enteral antibacterial activity above pH 6. Preservative efficacy is preparations, and cosmetics. Generally, it is used at concentrations increased with increasing temperature,(2) and increasing con- of 0.1–0.2% in oral and topical formulations, especially those centration of potassium sorbate.(2) The efficacy of potassium containing nonionic surfactants. Potassium sorbate has been used to sorbate is also increased when used in combination with other enhance the ocular bioavailability of timolol.(1) antimicrobial preservatives or glycols since synergistic effects Potassium sorbate is used in approximately twice as many occur.(3) Reported minimum inhibitory concentrations (MICs) at pharmaceutical formulations as is sorbic acid owing to its greater the pH values indicated are shown in Table II.(3) 580 Potassium Sorbate

4.0 0.6 14 Safety 2348 Potassium sorbate is used as an antimicrobial preservative in oral 2388 and topical pharmaceutical formulations and is generally regarded 1766 2126 as a relatively nontoxic material. However, some adverse reactions to potassium sorbate have been reported, including irritant skin 0.0 reactions which may be of the allergic, hypersensitive type. There have been no reports of adverse systemic reactions following oral consumption of potassium sorbate. 1160 1199 1779 log(1/R) 1710 1750 The WHO has set an estimated total acceptable daily intake for 2371 2139 2462 sorbic acid, calcium sorbate, potassium sorbate, and sodium sorbate expressed as sorbic acid at up to 25 mg/kg body-weight.(4,5) (6) 2331 LD50 (mouse, IP): 1.3 g/kg 1000 × [2nd deriv. log(1/R)] −5.0 –0.2 1100 1300 1500 1700 1900 2100 2300 2500 LD50 (rat, oral): 4.92 g/kg See also Sorbic Acid. Wavelength/nm 15 Handling Precautions Figure 1: Near-infrared spectrum of potassium sorbate measured by reflectance. Observe normal precautions appropriate to the circumstances and quantity of material handled. Potassium sorbate is irritant to the skin, eyes, and mucous membranes; eye protection and gloves are Table II: Minimum inhibitory concentrations (MIC) of potassium recommended. In areas of limited ventilation, a respirator is also sorbate. recommended. MIC (mg/mL) at the stated pH 16 Regulatory Status 5.5 6.0 7.0 GRAS listed. Accepted for use as a food additive in Europe. Escherichia coli 1400 1500 3800 Included in the FDA Inactive Ingredients Database (nasal sprays; Pseudomonas aeruginosa 1600–2300 1900–2500 5600–9000 oral capsules, solutions, suspensions, syrups, tablets; topical creams Staphylococcus aureus 1200 1000 3800 and lotions). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Density 1.363 g/cm3 Ingredients. Melting point 2708C with decomposition. NIR spectra see Figure 1. 17 Related Substances Solubility see Table III. Sorbic acid.

Table III: Solubility of potassium sorbate. 18 Comments Solvent Solubility at 208C unless otherwise stated Much of the information contained in the sorbic acid monograph P on safety, incompatibilities, and references also applies to potas- 1 in 1000 sium, calcium, and sodium sorbates. See Sorbic Acid for further Practically insoluble Very slightly soluble information. Corn oil Very slightly soluble Potassium sorbate has less antimicrobial activity than sorbic 1 in 50 acid, but is more water soluble. Most potassium sorbate Ethanol (95%) 1 in 35 compounds will contain sorbic acid. Ethanol (5%) 1 in 1.7 A specification for potassium sorbate is contained in the Food Ether Very slightly soluble Chemicals Codex (FCC).(7) 1 in 1.8 The EINECS number for potassium sorbate is 246-376-1. The 1 in 2.1 at 508C 8 PubChem Compound ID (CID) for potassium sorbate includes 1 in 5 at 100 C 23676745 and 24184641. Water 1 in 1.72 1 in 1.64 at 508C 1 in 1.56 at 1008C 19 Specific References 1 Mandorf TK et al. A 12 month, multicentre, randomized, double- masked, parallel group comparison of timolol-LA once daily and timolol maleate ophthalmic solution twice daily in the treatment of 11 Stability and Storage Conditions adults with glaucoma or ocular hypertension. Clin Ther 2004; 26(4): Potassium sorbate is more stable in aqueous solution than sorbic 541–551. acid; aqueous solutions may be sterilized by autoclaving. 2 Lusher P et al. A note on the effect of dilution and temperature on the bactericidal activity of potassium sorbate. J Appl Bacteriol 1984; 57: The bulk material should be stored in a well-closed container, 8 179–181. protected from light, at a temperature not exceeding 40 C. 3 Woodford R, Adams E. Sorbic acid. Am Perfum Cosmet 1970; 85(3): 25–30. 12 Incompatibilities 4 FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of Some loss of antimicrobial activity occurs in the presence of the joint FAO/WHO expert committee on food additives. World Health nonionic surfactants and some plastics. See also Sorbic Acid. Organ Tech Rep Ser 1974; No. 539. 5 FAO/WHO. Evaluation of certain food additives and contaminants. 13 Method of Manufacture Twenty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1986; No. 733. Potassium sorbate is prepared from sorbic acid and potassium 6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th hydroxide. edn. New York: Wiley, 2004; 3043. Povidone 581

7 Food Chemicals Codex, 6th edn. Bethesda, MD: United States 21 Authors Pharmacopeia, 2008; 818. ME Quinn, PJ Sheskey. 20 General References Smolinske SC, ed. Handbook of Food, Drug, and Cosmetic Excipients. Boca Raton, FL: CRC Press, 1992; 363–367. Sofos JN, Busta FF. Sorbates. Branen AL, Davidson PM, eds. Antimicrobials in Foods. New York: Marcel Dekker, 1983; 141–175. 22 Date of Revision Walker R. Toxicology of sorbic acid and sorbates. Food Add Contam 1990; 7(5): 671–676. 17 February 2009.

Povidone

1 Nonproprietary Names Table I: Approximate molecular weights for different grades of BP: Povidone povidone. JP: Povidone K-value Approximate molecular weight PhEur: Povidone 12 2 500 USP: Povidone 15 8 000 17 10 000 25 30 000 30 50 000 60 400 000 2 Synonyms 90 1 000 000 120 3 000 000 E1201; Kollidon; Plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone; polyvinylpyrrolidone; povidonum; Povipharm; PVP; 1- vinyl-2-pyrrolidinone polymer. See also Section 8. 5 Structural Formula P 3 Chemical Name and CAS Registry Number 1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]

4 Empirical Formula and Molecular Weight

(C6H9NO)n 2500–3 000 000 The USP 32 describes povidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing 6 Functional Category degree of polymerization of which results in polymers of various Disintegrant; dissolution enhancer; suspending agent; tablet binder. molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the 7 Applications in Pharmaceutical Formulation or range 10–120. The K-value is calculated using Fikentscher’s Technology (1) equation: Although povidone is used in a variety of pharmaceutical formulations, it is primarily used in solid-dosage forms. In tableting, povidone solutions are used as binders in wet-granulation processes.(2,3) Povidone is also added to powder blends in the dry where z is the relative viscosity of the solution of concentration c form and granulated in situ by the addition of water, alcohol, or (in % w/v), and k is the K-value 10–3. Alternatively, the K-value hydroalcoholic solutions. Povidone is used as a solubilizer in oral may be determined from the following equation: and parenteral formulations, and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms.(4–6) Povidone solutions may also be used as coating agents or as binders when coating active pharmaceutical ingredients on a support such as beads. where z is the relative viscosity of the solution of concentration c Povidone is additionally used as a suspending, stabilizing, or (in % w/v). Approximate molecular weights for different viscosity-increasing agent in a number of topical and oral povidone grades are shown in Table I. suspensions and solutions. The solubility of a number of poorly