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Potassium hydroxide is widely used in pharmaceutical for- mulations to adjust the pH of solutions. It can also be used to react with weak acids to form salts.

Therapeutically, potassium hydroxide is used in various dermatological applications.

Description

Potassium hydroxide occurs as a white or nearly white fused mass. It is available in small pellets, flakes, sticks and other shapes or forms. It is hard and brittle and shows a crystalline fracture. Potassium hydroxide is hygroscopic and deliquescent; on exposure to air, it rapidly absorbs carbon dioxide and water with the formation of potassium carbonate.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 13.5 (0.1 M aqueous solution) Melting point: 3608C; 3808C when anhydrous Solubility: see Table II.

Table I: Pharmacopeial specifications for potassium hydroxide.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Appearance of solution + + —

Aluminum — 40.2 ppm —

Characters — + —

Chloride 40.05% 450 ppm —

Heavy metals 430 ppm 410 ppm 40.003%

Insoluble substances — — +

Iron — 410 ppm —

Phosphates — 420 ppm —

Potassium carbonate 42.0% 42.0% —

Sodium + 41.0% —

Sulfates — 450 ppm —

Assay 585.0% 85.0–100.5% 585.0%

Table II: Solubility of potassium hydroxide.

Solvent Solubility at 208C unless otherwise stated

Ethanol (95%) 1 in 3

Ether Practically insoluble

Glycerin 1 in 2.5

Water 1 in 0.9

1 in 0.6 at 1008C

Stability and Storage Conditions

Potassium hydroxide should be stored in an airtight, non- metallic container in a cool, dry place.

Incompatibilities

Potassium hydroxide is a strong base and is incompatible with any compound that readily undergoes hydrolysis or oxidation. It should not be stored in glass or aluminum containers and will react with acids, esters, and ethers, especially in aqueous solution.

Method of Manufacture

Potassium hydroxide is made by the electrolysis of potassium chloride. Commercial grades may contain chlorides as well as other impurities.

Safety

Potassium hydroxide is widely used in the pharmaceutical and food industries and is generally regarded as a nontoxic material at low concentrations. At high concentrations it is a corrosive irritant to the skin, eyes, and mucous membranes.

LD50 (rat, oral): 0.273 g/kg(1)

606 Potassium Hydroxide

Handling Precautions

Potassium hydroxide is a corrosive irritant to the skin, eyes, and mucous membranes. The solid and solutions cause burns, often with deep ulceration. It is very toxic on ingestion and harmful on inhalation. Observe normal handling precautions appro- priate to the quantity and concentration of material handled. Gloves, eye protection, respirator, and other protective clothing should be worn.

Potassium hydroxide is strongly exothermic when dissolved in ethanol (95%) or water and considerable heat is generated. The reaction between potassium hydroxide solutions and acids is also strongly exothermic.

In the UK, the occupational exposure limit for potassium hydroxide has been set at 2 mg/m3 short-term.(2)

Regulatory Status

GRAS listed. Accepted for use in Europe in certain food applications. Included in the FDA Inactive Ingredients Guide (injections, infusions, and oral capsules and solutions). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Sodium hydroxide.

Comments

A specification for potassium hydroxide is contained in the Food Chemicals Codex (FCC). The EINECS number for potassium hydroxide is 215-181-3.

Specific References

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3033–3034.

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: HSE Books, 2002.

Potassium Metabisulfite

Nonproprietary Names

USPNF: Potassium metabisulfite

Synonyms

Disulfurous acid; dipotassium pyrosulfite; dipotassium salt; E224; kali disulfis; potassium pyrosulfite.

Chemical Name and CAS Registry Number

Dipotassium pyrosulfite [16731-55-8]

Empirical Formula and Molecular Weight

Antimicrobial preservative; antioxidant.

Applications in Pharmaceutical Formulation or Technology

Potassium metabisulfite is used in applications similar to those of sodium metabisulfite in pharmaceuticals and in the food, brewing, and wine making industries. It is used as an antioxidant, antimicrobial preservative and sterilizing agent.

Description

Potassium metabisulfite occurs as white or colorless free- flowing crystals, crystalline powder, or granules, usually with an odor of sulfur dioxide.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for potassium metabisulfite.

Organic volatile impurities +

Assay (as SO2) 51.8–57.6%

Typical Properties

Acidity/alkalinity: 3.5–4.5 (5% w/v aqueous solution)

Density (bulk): 1. 1–1.3 g/cm3

Density (tapped): 1. 2–1.5 g/cm3

Melting point: 1908C although potassium metabisulfite decom- poses at temperatures above 1508C.

Solubility: soluble 1 in 2.2 of water; practically insoluble in ethanol (95%).

Stability and Storage Conditions

Potassium metabisulfite should be stored in a cool, dark place. When stored at a maximum temperature of 258C and maximum relative humidity of 45%, the shelf-life is 6 months. Potassium metabisulfite decomposes at temperatures above 1508C. In the air, it oxidizes to the sulfate, more readily in the presence of moisture.

In aqueous solution, potassium metabisulfite forms potas- sium bisulfite (KHSO3) which exerts a strong reducing effect.

Incompatibilities

Potassium metabisulfite is incompatible with strong acids, water, and most common metals. It reacts with nitrites and sodium nitrate at room temperature, which occasionally results in the formation of flame. The reaction may be explosive if water is present. Potassium metabisulfite liberates SO2 with acids.

Sulfites, including potassium metabisulfite, can react with various pharmaceutical compounds including sympathomi- metics such as epinephrine (adrenaline),(1) chloramphenicol,(1) cisplatin,(2) and amino acids(3), which can result in their pharmacological inactivation. Sulfites are also reported to react with phenylmercuric nitrate,(4,5) and may adsorb onto rubber closures.

See also Section 18.

Method of Manufacture

—

Safety

Potassium metabisulfite is used in a variety of foods and pharmaceutical preparations, including oral, otic, rectal, and parenteral preparations. Potassium metabisulfite is considered a very irritating material, and may cause dermatitis on exposed skin.(6,7)

Hypersensitivity reactions to potassium metabisulfite and other sulfites, mainly used as preservatives in food products, have been reported. Reactions include bronchospasm and anaphylaxis; some deaths have also been reported, especially in those with a history of asthma or atopic allergy.(8–11) These reactions have led to restrictions by the FDA on the use of sulfites in food applications.(12) However, this restriction has not been extended to their use in pharmaceutical applications. Indeed, epinephrine (adrenaline) injections used to treat severe allergic reactions may contain sulfites.(11,12)

The WHO has set an acceptable daily intake of sulfites, as SO2, at up to 0.35 mg/kg body-weight.(13)

608 Potassium Metabisulfite

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Protective gloves and safety goggles are recommended, and precautions should be taken to minimize exposure to the mucous membranes and respiratory tract. When heated to decomposition, it emits toxic fumes of SO2. See also Section 12.

Regulatory Status

GRAS listed. Accepted in Europe for use as a food additive in certain applications. Included in the FDA Inactive Ingredients Guide (IM and IV injections, otic and rectal solutions and suspensions). Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Potassium bisulfite; sodium metabisulfite.

Potassium bisulfite Empirical formula: KHSO3 Molecular weight: 120.2

CAS number: [7773-03-7]

Synonyms: E228; potassium acid sulfite; potassium bisulphite; potassium hydrogen sulfite.

Comments: accepted in Europe as a food additive in certain applications. Included in food and pharmaceutical applica- tions similarly to potassium metabisulfite.

Comments

Like all sulfites, potassium metabisulfite is not recommended for use in foods that are a source of thiamin, owing to the instability of the vitamin in their presence. Such foods include meat, raw fruits and vegetables, fresh potatoes, and foods that are a source of vitamin B12. A specification for potassium metabisulfite is contained in the Food Chemicals Codex (FCC). The EINECS number for potassium metabisulfite is 240-

795-3.

Specific References

Higuchi T, Schroeter LC. Reactivity of bisulfite with a number of pharmaceuticals. J Am Pharm Assoc (Sci) 1959; 48: 535–540.

Garren KW, Repta AJ. Incompatibility of cisplatin and Reglan Injectable. Int J Pharm 1985; 24: 91–99.

Brawley V, Bhatia J, Karp WB. Effect of sodium metabisulphite on hydrogen peroxide production in light-exposed pediatric parent- eral amino acid solutions. Am J Health Syst Pharm 1998; 55: 1288–1292.

Richards RME, Reary JME. Changes in antibacterial activity of thiomersal and PMN on autoclaving with certain adjuvants. J Pharm Pharmacol 1972; 24 (Suppl.): 84P–89P.

Collins AJ, Lingham P, Burbridge TA, Bain R. Incompatibility of phenylmercuric acetate with sodium metabisulfite in eye drop formulations. J Pharm Pharmacol 1985; 37 (Suppl.): 123P.

Nater JP. Allergic contact dermatitis caused by potassium metabisulfite. Dermatologica 1968; 136(6): 477–478.

Vena GA, Foti C, Angelini G. Sulfite contact allergy. Contact Dermatitis 1994; 31(3): 172–175.

Mathison DA, Stevenson DD, Simon RA. Precipitating factors in asthma: aspirin, sulfites, and other drugs and chemicals. Chest 1985; 87 (Suppl.): 50S–54S.

Anonymous. Sulfites in drugs and food. Med Lett Drugs Ther

1986; 28: 74–75.

Belchi-Hernandez J, Florido-Lopez JF, Estrada-Rodriguez JL, et al. Sulfite-induced urticaria. Ann Allergy 1993; 71(3): 230–232.

Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1193.

Anonymous. Warning for prescription drugs containing sulfites.

FDA Drug Bull 1987; 17: 2–3.

FAO/WHO. Evaluation of the toxicity of a number of antimicro- bials and antioxidants. Sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1962; No. 228.

General References

Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients.

Boca Raton, FL: CRC Press, 1992: 393–406.

Valade J-P, Le Bras G. Sulfur dioxide release from effervescent tablets.

Rev Fr Oenol 1998; 171: 22–25.

BP: Potassium sorbate PhEur: Kalii sorbas USPNF: Potassium sorbate

Synonyms

E202; 2,4-hexadienoic acid (E,E)-potassium salt; potassium (E,E)-hexa-2,4-dienoate; potassium (E,E)-sorbate; sorbic acid potassium salt.

Chemical Name and CAS Registry Number

2,4-Hexadienoic acid potassium salt [24634-61-5]

Empirical Formula and Molecular Weight

C6H7O2K 150.22

Structural Formula

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Potassium sorbate is an antimicrobial preservative, with

Table I: Pharmacopeial specifications for potassium sorbate.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance of solution + —

Acidity or alkalinity + +

Loss on drying 41.0% 41.0%

Heavy metals 410 ppm 40.001%

Organic volatile impurities — +

Aldehydes (as C2H4O) 40.15% —

Assay (dried basis) 99.0–101.0% 98.0–101.0%

Typical Properties

Antimicrobial activity: potassium sorbate is predominantly used as an antifungal preservative although it also has antibacterial properties. Similarly to sorbic acid, the antimicrobial activity is dependent on the degree of dissociation; there is practically no antibacterial activity above pH 6. Preservative efficacy is increased with increas- ing temperature,(2) and increasing concentration of potas- sium sorbate.(2) The efficacy of potassium sorbate is also increased when used in combination with other antimicro- bial preservatives or glycols since synergistic effects occur.(3) Reported minimum inhibitory concentrations (MICs) at the pH values indicated are shown in Table II.(3)

Table II: Minimum inhibitory concentrations (MIC) of potassium sorbate.

Microorganism MIC (mg/mL) at the stated pH

5.5 6.0 7.0

Escherichia coli 1400 1500 3800

antibacterial and antifungal properties used in pharmaceuti- cals, foods, enteral preparations, and cosmetics. Generally, it is

Pseudomonas aeruginosa

1600–2300 1900–2500 5600–9000

used at concentrations of 0.1–0.2% in oral and topical formulations, especially those containing nonionic surfactants. Potassium sorbate has been used to enhance the ocular bioavailability of timolol.(1)

Potassium sorbate is used in approximately twice as many pharmaceutical formulations as is sorbic acid owing to its greater solubility and stability in water. Like sorbic acid, potassium sorbate has minimal antibacterial properties in formulations above pH 6.

Description

Potassium sorbate occurs as a white crystalline powder with a faint, characteristic odor.

Pharmacopeial Specifications

See Table I.

Staphylococcus aureus 1200 1000 3800

Density: 1.363 g/cm3

Melting point: 2708C with decomposition.

Solubility: see Table III.

Stability and Storage Conditions

Potassium sorbate is more stable in aqueous solution than sorbic acid; aqueous solutions may be sterilized by autoclaving. The bulk material should be stored in a well-closed container, protected from light, at a temperature not exceeding

408C.

Incompatibilities

Some loss of antimicrobial activity occurs in the presence of nonionic surfactants and some plastics. See also Sorbic Acid.

610 Potassium Sorbate

Table III: Solubility of potassium sorbate.

Solvent Solubility at 208C unless otherwise stated

Acetone 1 in 1000

Benzene Practically insoluble

Chloroform Very slightly soluble

Corn oil Very slightly soluble

Ethanol 1 in 50

Ethanol (95%) 1 in 35

Ethanol (5%) 1 in 1.7

Ether Very slightly soluble

Propylene glycol 1 in 1.8

Method of Manufacture

Potassium sorbate is prepared from sorbic acid and potassium hydroxide.

Safety

Potassium sorbate is used as an antimicrobial preservative in oral and topical pharmaceutical formulations and is generally regarded as a relatively nontoxic material. However, some adverse reactions to potassium sorbate have been reported, including irritant skin reactions which may be of the allergic, hypersensitive type. There have been no reports of adverse systemic reactions following oral consumption of potassium sorbate.

The WHO has set an estimated total acceptable daily intake for sorbic acid, calcium sorbate, potassium sorbate, and sodium sorbate expressed as sorbic acid at up to 25 mg/kg body- weight.(4,5)

LD50 (mouse, IP): 1.3 g/kg(6) LD50 (rat, oral): 4.92 g/kg

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