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Activity is also increased in the presence of phenylethyl alcohol, and in the presence of sodium metabisulfite at acid pH. Activity is decreased in the presence of sodium metabisulfite at alkaline pH.(1–3) When used as preservatives in topical creams, phenylmercuric salts are active at pH 5–8.(4)

Bacteria (Gram-positive): good inhibition, more moderate cidal activity. Minimum inhibitory concentration (MIC) against Staphylococcus aureus is 0.5 mg/mL.

Bacteria (Gram-negative): inhibitory activity for most Gram-negative bacteria is similar to that for Gram-positive bacteria (MIC is approximately 0.3–0.5 mg/mL). Phenyl- mercuric salts are less active against some Pseudomonas species, and particularly Pseudomonas aeruginosa (MIC is approximately 12 mg/mL).

Fungi: most fungi are inhibited by 0.3–1 mg/mL; phenyl- mercuric salts exhibit both inhibitory and fungicidal activity; e.g., for phenylmercuric acetate against Candida albicans, MIC is 0.8 mg/mL; for phenylmercuric acetate against Aspergillus niger, MIC is approximately 10 mg/mL. Spores: phenylmercuric salts may be active in conjunction with heat. The BP 1980 included heating at 1008C for 30 minutes in the presence of 0.002% w/v phenylmercuric acetate or phenylmercuric nitrate as a sterilization method. However, in practice this may not be sufficient to kill spores and heating with a bactericide no longer appears as a sterilization method in the BP 2004.

Dissociation constant: pKa = 3.3

Melting point: 187–1908C with decomposition.

Partition coefficients: Mineral oil : water = 0.58; Peanut oil : water = 0.4.

Solubility: more soluble in the presence of either nitric acid or alkali hydroxides. See Table III.

Table III: Solubility of phenylmercuric nitrate.

Solvent Solubility at 208C(a) unless otherwise stated

Ethanol (95%) 1 in 1000

Fixed oils Soluble

Glycerin Slightly soluble

Water 1 in 600–1500

1 in 160 at 1008C

(a) Compendial values for solubility vary considerably.

Stability and Storage Conditions

All phenylmercuric compound solutions form a black residue of metallic mercury when exposed to light or after prolonged storage. Solutions may be sterilized by autoclaving, although significant amounts of phenylmercuric salts may be lost, hence reducing preservative efficacy, owing to incompatibilities with packaging components or other excipients, e.g., sodium metabisulfite.(5–7) See Section 12.

Phenylmercuric nitrate should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

The antimicrobial activity of phenylmercuric salts may be reduced in the presence of anionic emulsifying agents and suspending agents, tragacanth, starch, talc, sodium metabisul- fite,(8) sodium thiosulfate,(2) disodium edetate,(2) and silicates

528 Phenylmercuric Nitrate

(bentonite, aluminum magnesium silicate, magnesium trisili- cate, and kaolin).(9,10)

Phenylmercuric salts are incompatible with halides, parti- cularly bromides and iodides, as they form less-soluble halogen compounds. At concentrations of 0.002% w/v precipitation may not occur in the presence of chlorides. Phenylmercuric salts are also incompatible with aluminum and other metals, ammonia and ammonium salts, amino acids, and with some sulfur compounds, e.g., in rubber.

Phenylmercuric salts are absorbed by rubber stoppers and some types of plastic packaging components; uptake is usually greatest to natural rubbers and polyethylene and least to polypropylene.(11–16)

Incompatibilities with some types of filter membranes may also result in loss of phenylmercuric salts following sterilization by filtration.(17)

Method of Manufacture

Phenylmercuric nitrate is readily formed by heating benzene with mercuric acetate, and treating the resulting acetate with an alkali nitrate.(18)

Safety

Phenylmercuric nitrate and other phenylmercuric salts are widely used as antimicrobial preservatives in parenteral and topical pharmaceutical formulations. However, concern over the use of phenylmercuric salts in pharmaceuticals has increased as a result of greater awareness of the toxicity of mercury and other mercury compounds. This concern must, however, be balanced by the effectiveness of these materials as antimicrobial preservatives and the low concentrations in which they are employed.

Phenylmercuric salts are irritant to the skin at 0.1% w/w concentration in petrolatum.(19) In solution, they may give rise to erythema and blistering 6–12 hours after administration. In a modified repeated insult patch test, a 2% w/v solution was found to produce extreme sensitization of the skin.(20,21)

Eye drops containing phenylmercuric nitrate as a preserva- tive should not be used continuously for prolonged periods as mercurialentis, a brown pigmentation of the anterior capsule of the lens may occur. Incidence is 6% in patients using eye drops for greater than 6 years; however, the condition is not associated with visual impairment.(22,23) Cases of atypical band keratopathy have also been attributed to phenylmercuric nitrate preservative in eye drops.(24)

Concern that the absorption of mercury from the vagina may be harmful has led to the recommendation that phenylmercuric nitrate should not be used in intravaginal formulations.(25)

LD50 (mouse, IV): 27 mg/kg(26) LD50 (mouse, oral): 50 mg/kg LD50 (rat, SC): 63 mg/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Phenylmercuric nitrate may be irritant to the skin, eyes, and mucous membranes. Eye protection, gloves, and a respirator are recommended. In the UK, the occupational exposure limit for mercury-containing compounds, calculated as mercury, is 0.01 mg/m3 long-term (8- hour TWA) and 0.03 mg/m3 short-term.(27)

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM and ophthalmic preparations). Included in nonparenteral medicines licensed in the UK. In the UK, the use of phenylmercuric salts in cosmetics is limited to 0.003% (calculated as mercury, equivalent to approximately 0.0047% of phenylmercuric nitrate) as a preservative in shampoos and hair creams, which contain nonionic emulsifiers that would render other preserva- tives ineffective. Total permitted concentration, as mercury, when mixed with other mercury compounds is 0.007% (equivalent up to approximately 0.011% of phenylmercuric nitrate).(28) Included in the Canadian List of Acceptable Non- medicinal Ingredients (ophthalmic, nasal and otic preparations only; there must be no other suitable alternative preservative).

Related Substances

Phenylmercuric acetate; phenylmercuric borate; thimerosal.

Comments

Phenylmercuric salts should be used in preference to benzal- konium chloride as a preservative for salicylates and nitrates and in solutions of salts of physostigmine and epinephrine that contain 0.1% sodium sulfite.

Specific References

Buckles J, Brown MW, Porter GS. The inactivation of phenylmer- curic nitrate by sodium metabisulphite. J Pharm Pharmacol 1971; 23 (Suppl.): 237S–238S.

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.

Richards RME, Fell AF, Butchart JME. Interaction between sodium metabisulphite and PMN. J Pharm Pharmacol 1972; 24: 999–1000.

Parker MS. The preservation of pharmaceuticals and cosmetic products. In: Russell AD, Hugo WB, Ayliffe GAJ, eds. Principles and Practice of Disinfection, Preservation and Sterilization. Oxford: Blackwell Scientific, 1982: 287–305.

Hart A. Antibacterial activity of phenylmercuric nitrate in zinc sulphate and adrenaline eye drops BPC 1968. J Pharm Pharmacol 1973; 25: 507–508.

Miezitis EO, Polack AE, Roberts MS. Concentration changes during autoclaving of aqueous solutions in polyethylene contain- ers: an examination of some methods for reduction of solute loss. Aust J Pharm Sci 1979; 8(3): 72–76.

Parkin JE, Marshall CA. The instability of phenylmercuric nitrate in APF ophthalmic products containing sodium metabisulfite. Aust J Hosp Pharm 1991; 20: 434–436.

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

Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceu- tical materials on the bactericidal activities of preservatives. Can J Pharm Sci 1973; 8: 54–56.

Horn NR, McCarthy TJ, Ramsted E. Interactions between powder suspensions and selected quaternary ammonium and organomer- curial preservatives. Cosmet Toilet 1980; 95(2): 69–73.

Ingversen J, Andersen VS. Transfer of phenylmercuric compounds from dilute aqueous solutions to vials and rubber closures. Dansk Tidsskr Farm 1968; 42: 264–271.

Eriksson K. Loss of organomercurial preservatives from medica- ments in different kinds of containers. Acta Pharm Suec 1967; 4: 261–264.

Christensen K, Dauv E. Absorption of preservatives by drip attachments in eye drop packages. J Mond Pharm 1969; 12(1): 5– 11.

Phenylmercuric Nitrate 529

Aspinall JA, Duffy TD, Saunders MB, Taylor CG. The effect of low density polyethylene containers on some hospital-manufactured eye drop formulations I: sorption of phenylmercuric acetate. J Clin Hosp Pharm 1980; 5: 21–29.

McCarthy TJ. Interaction between aqueous preservative solutions and their plastic containers, III. Pharm Weekbl 1972; 107: 1–7.

Aspinall JA, Duffy TD, Taylor CG. The effect of low density polyethylene containers on some hospital-manufactured eye drop formulations II: inhibition of the sorption of phenylmercuric acetate. J Clin Hosp Pharm 1983; 8: 223–240.

Naido NT, Price CH, McCarthy TJ. Preservative loss from ophthalmic solutions during filtration sterilization. Aust J Pharm Sci 1972; 1(1): 16–18.

Pyman FL, Stevenson HA. Phenylmercuric nitrate. Pharm J 1934;

133: 269.

Koby GA, Fisher AA. Phenylmercuric acetate as primary irritant.

Arch Dermatol 1972; 106: 129.

Kligman AM. The identification of contact allergens by human assay, III. The maximization test: a procedure for screening and rating contact sensitizers. J Invest Dermatol 1966; 47: 393–409.

Galindo PA, Feo F, Garcia R, et al. Mercurochrome allergy: immediate and delayed hypersensitivity. Allergy 1997; 52(11): 1138–1141.

Garron LK, Wood IS, Spencer WH, et al. A clinical and pathologic study of mercurialentis medicamentosus. Trans Am Ophthalmol Soc 1977; 74: 295.

Winder AF, Astbury NJ, Sheraidah GAK, Ruben M. Penetration of mercury from ophthalmic preservatives into the human eye. Lancet 1980; ii: 237–239.

Brazier DJ, Hitchings RA. Atypical band keratopathy following long-term pilocarpine treatment. Br J Ophthalmol 1989; 73: 294–

296.

Lohr L. Mercury controversy heats up. Am Pharm 1978; 18(9): 23.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. Cincinnati: US Department of Health, 1987: 3060–3093.

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

Statutory Instrument (SI) 1989: No. 2233. Consumer Protection: The Consumer Products (Safety) Regulations 1989. London: HMSO, 1989.

General References

Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local anaesthetics and their binary combinations with preservatives. J Clin Pharm Ther 1988; 13: 249–256.

Barkman R, Germanis M, Karpe G, Malmborg AS. Preservatives in eye drops. Acta Ophthalmol 1969; 47: 461–475.

Grier N. Mercurials inorganic and organic. In: Block SS, ed. Disinfection, Sterilization and Preservation, 3rd edn. Philadelphia: Lea and Febiger, 1983: 346–374.

Hecht G. Ophthalmic preparations. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 2000: 821–835.

Parkin JE. The decomposition of phenylmercuric nitrate in sulph- acetamide drops during heat sterilization. J Pharm Pharmacol 1993; 45: 1024–1027.

Parkin JE, Button KL, Maroudas PA. The decomposition of phenyl- mercuric nitrate caused by disodium edetate in neomycin eye drops during the process of heat sterilization. J Clin Pharm Ther 1992; 17: 191–196.

Parkin JE, Duffy MB, Loo CN. The chemical degradation of phenylmercuric nitrate by disodium edetate during heat sterilization at pH values commonly encountered in ophthalmic products. J Clin Pharm Ther 1992; 17: 307–314.

PhEur: Acidum phosphoricum concentratum USPNF: Phosphoric acid

See also Section 17.

Synonyms

Acid fosforico; acide phosphorique; E338; hydrogen phos- phate; syrupy phosphoric acid.

Chemical Name and CAS Registry Number

Orthophosphoric acid [7664-38-2]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Phosphoric acid is widely used as an acidifying and buffering agent in a variety of pharmaceutical formulations. It is also widely used in food preparations as an acidulant, flavor, and synergistic antioxidant (0.001–0.005%) and sequestrant.

Therapeutically, dilute phosphoric acid has been used well- diluted in preparations used in the treatment of nausea and vomiting. Phosphoric acid 35% gel has also been used in dentistry to etch tooth enamel.

Description

Concentrated phosphoric acid occurs as a colorless, odorless, syrupy liquid.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for phosphoric acid.

PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance of solution + —

Relative density ≈1.7 —

Sulfate 4100 ppm +

Chloride 450 ppm —

Heavy metals 410 ppm 40.001%

Substances precipitated with ammonia + —

Arsenic 42 ppm —

Iron 450 ppm —

Alkali phosphates — +

Limit of nitrate — +

Phosphorous or hypophosphorous acid + +

Assay (of H3PO4) 84.0–90.0% 85.0–88.0%

Typical Properties

Acidity/alkalinity: pH = 1.6 (1% w/w aqueous solution)

Boiling point: 117.878C

Dissociation constant:

pKa1 = 2.15;

pKa2 = 7.09;

pKa3 = 12.32.

Melting point: 42.358C

Refractive index:

n17.5 = 1.35846 (30% w/w aqueous solution); n17.5 = 1.35032 (20% w/w aqueous solution); n17.5 = 1.3423 (10% w/w aqueous solution).

Solubility: miscible with ethanol (95%) and water with the evolution of heat.

Specific gravity:

1.874 (100% w/w) at 258C;

1.6850 (85% w/w aqueous solution) at 258C; 1.3334 (50% w/w aqueous solution) at 258C; 1.0523 (10% w/w aqueous solution) at 258C.

Stability and Storage Conditions

When stored at a low temperature, phosphoric acid may solidify, forming a mass of colorless crystals, comprised of the hemihydrate, which melt at 288C. Phosphoric acid should be stored in an airtight container in a cool, dry place. Stainless steel containers may be used.

Incompatibilities

Phosphoric acid is a strong acid and reacts with alkaline substances. Mixtures with nitromethane are explosive.

Method of Manufacture

The majority of phosphoric acid is made by digesting phosphate rock (essentially tricalcium phosphate) with sulfuric acid; the phosphoric acid is then separated by slurry filtration.

Phosphoric Acid 531

Purification is achieved via chemical precipitation, solvent extraction, crystallization, or ion exchange.

Safety

In the concentrated form, phosphoric acid is an extremely corrosive and harmful acid. However, when used in pharma- ceutical formulations it is usually very diluted and is generally regarded as an essentially nontoxic and nonirritant material.

The lowest lethal oral dose of concentrated phosphoric acid in humans is reported to be 1286 mL/kg.(1)

LD50 (rabbit, skin): 2.74 g/kg(1) LD50 (rat, oral): 1.53 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Phosphoric acid is corrosive and can cause burns on contact with the skin, eyes and mucous membranes; contact should be avoided. Splashes should be washed with copious quantities of water. Protective clothing, gloves and eye protection are recommended.

Phosphoric acid is also irritant on inhalation. In the UK, the occupational exposure limit for phosphoric acid is 8 mg/m3 long-term (8-hour TWA) and 2 mg/m3 short-term (15-min- utes).(2)

Phosphoric acid emits toxic fumes on heating.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (infusions, injections, oral solutions, topical creams, lotions, ointments and solutions, and vaginal preparations). Included in nonparenteral and parent- eral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Dilute phosphoric acid.

Dilute phosphoric acid

Synonyms: acidum phosphoricum dilutum; diluted phosphoric acid.

Comments: the PhEur 2005 states that dilute phosphoric acid contains 9.5–10.5% w/w H3PO4 and may be prepared by mixing phosphoric acid 115 g with 885 g of water. The USPNF 23 contains a monograph for diluted phosphoric acid and states that it contains 9.5–10.5% w/v H3PO4 and may be prepared by mixing phosphoric acid 69 mL with water to 1000 mL.

Comments

In the UK, a 1 in 330 aqueous solution of phosphoric acid is approved as a disinfectant for foot-and-mouth disease. A specification for phosphoric acid is contained in the Food Chemicals Codex (FCC).

The EINECS number for phosphoric acid is 231-633-2.

Specific References

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 2948–2949.

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

USPNF: Polacrilin potassium

Synonyms

Amberlite IRP-88; methacrylic acid polymer with divinylben- zene, potassium salt; polacrilinum kalii.

Chemical Name and CAS Registry Number

Methyl-2-propenoic acid polymer with divinylbenzene, potassium salt [39394-76-5]

Empirical Formula and Molecular Weight

See Sections 5,13 and 18.

Structural Formula

Functional Category

Tablet and capsule disintegrant.

Applications in Pharmaceutical Formulation or Technology

Polacrilin potassium is a cation-exchange resin used in oral pharmaceutical formulations as a tablet disintegrant.(1–3) Concentrations of 2–10% w/w have been used for this purpose although 2% w/w of polacrilin potassium is usually sufficient. Other polacrilin ion-exchange resins have been used as excipients to stabilize drugs, to mask or modify the taste of drugs, and in the preparation of sustained-release dosage forms(4) and drug carriers.

Polacrilin resins are also used in the analysis and manu- facture of pharmaceuticals and food products.

Description

Polacrilin potassium occurs as a cream-colored, odorless and tasteless, free-flowing powder. Aqueous dispersions have a bitter taste.

Pharmacopeial Specifications

See Table I.

Figure 1: Particle size distribution of polacrilin potassium (Amberlite IRP-88).

Table I: Pharmacopeial specifications for polacrilin potassium.

Test USPNF 23

Identification +

Loss on drying 410.0%

Powder fineness 41.0% on a #100 mesh

430.0% on a #200 mesh

Iron 40.01%

Sodium 40.20%

Heavy metals 40.002%

Organic volatile impurities +

Assay of potassium (dried basis) 20.6%–25.1%

Typical Properties

Density (bulk): 0.48 g/cm3 for Amberlite IRP-88.(3) Density (tapped): 0.62 g/cm3 for Amberlite IRP-88.(3) Particle size distribution: see Figure 1.(3)

Solubility: practically insoluble in water and most other liquids, although polacrilin resins swell rapidly when wetted.

Stability and Storage Conditions

Polacrilin potassium and other polacrilin resins are stable to light, air, and heat up to their maximum operation temperature; see Table II. Excessive heating can cause thermal decomposition of the resins and may yield one or more oxides of carbon, nitrogen, sulfur, and/or amines.

Polacrilin Potassium 533

Table II: Summary of physicochemical properties of pharmaceutical grade Amberlite resins.

Amberlite

Copolymer Type Functional

Cation-exchange resins

IRP-69 Styrene and DVB(a)

IRP-64 Methacrylic acid and DVB

IRP-88 Methacrylic acid and DVB

Anion-exchange resins

3 3

Note that all of the above grades, with the exception of Amberlite IRP-88, are available in particle-size grades <325 mesh.

(a) DVB: divinylbenzene.

Polacrilin resins should be stored in well-closed containers in a cool, dry place.

Incompatibilities

Incompatible with strong oxidizing agents, amines, particularly tertiary amines, and some other substances that interact with polacrilin resins.(5)

Method of Manufacture

Polacrilin resin (Amberlite IRP-64) is prepared by the copolymerization of methacrylic acid with divinylbenzene (DVB). Polacrilin potassium (Amberlite IRP-88) is then produced by neutralizing this resin with potassium hydroxide. Other resins are similarly produced by copolymerization between styrene and divinylbenzene (Amberlite IRP-69, Amberlite IRP-67, Amberlite IR-120, and Amberlite IRA-

400). Phenolic-based polyamine condensates (Amberlite IRP- 58) may also be produced.

The homogeneity of the resin structure depends on the purity, nature, and properties of the copolymers used as well as the controls and conditions employed during the polymeriza- tion reaction. The nature and degree of crosslinking have significant influence on the physicochemical properties of the resin matrix. The functional groups introduced on the matrix confer the property of ion exchange. Depending upon the acidity or basicity of the functional groups, strongly acidic to strongly basic types of ion-exchange resins may be produced.

Safety

Polacrilin potassium and other polacrilin resins are used in oral pharmaceutical formulations and are generally regarded as nontoxic and nonirritant materials. However, excessive inges- tion of polacrilin resins may disturb the electrolyte balance of the body.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Polacrilin potassium may be irritating to the eyes; eye protection and gloves are recom- mended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in non-parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Polacrilin.

Polacrilin

CAS number: [54182-62-6]

Synonyms: Amberlite IRP-64; methacrylic acid polymer with divinylbenzene; 2-methyl-2-propenoic acid polymer with divinylbenzene.

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