Specific References

Goldstein SW. Antibacterial agents in compounded ophthalmic solutions. J Am Pharm Assoc (Pract Pharm) 1953; 14: 498–524.

Heller WM, Foss NE, Shay DE, Ichniowski CT. Preservatives in solutions. J Am Pharm Assoc (Pract Pharm) 1955; 16: 29–36.

Hodges NA, Denyer SP, Hanlon GW, Reynolds JP. Preservative efficacy tests on formulated nasal products: reproducibility and factors affecting preservative activity. J Pharm Pharmacol 1996; 48: 1237–1242.

Staal SP, Rowe WP. Differential effect of phenylethyl alcohol on mycoplasmas and enveloped viruses. J Virol 1974; 14: 1620–1622.

Kohn SR, Gershenfeld L, Barr M. Effectiveness of antibacterial agents presently employed in ophthalmic preparations as pre- servatives against Pseudomonas aeruginosa. J Pharm Sci 1963; 52:

967–974.

Richards RME, McBride RJ. Cross-resistance in Pseudomonas aeruginosa resistant to phenylethanol. J Pharm Sci 1972; 61: 1075–1077.

Richards RME, McBride RJ. The preservation of ophthalmic solutions with antibacterial combinations. J Pharm Pharmacol 1972; 24: 145–148.

Richards RME, McBride RJ. Effect of 3-phenylpropan-1-ol, 2- phenylethanol, and benzyl alcohol on Pseudomonas aeruginosa. J Pharm Sci 1973; 62: 585–587.

Richards RME, McBride RJ. Enhancement of benzalkonium chloride and chlorhexidine acetate activity against Pseudomonas aeruginosa by aromatic alcohols. J Pharm Sci 1973; 62: 2035– 2037.

Richards RME, McBride RJ. Antipseudomonal effect of poly- myxin and phenylethanol. J Pharm Sci 1974; 63: 54–56.

Richards RME, Richards JM. Pseudomonas cepacia resistance to antibacterials. J Pharm Sci 1979; 68: 1436–1438.

Lilley BD, Brewer JH. The selective antibacterial action of phenylethyl alcohol. J Am Pharm Assoc (Sci) 1953; 42: 6–8.

Bahal CK, Kostenbauder HB. Interaction of preservatives with macromolecules V: binding of chlorobutanol, benzyl alcohol, and phenylethyl alcohol by nonionic agents. J Pharm Sci 1964; 53: 1027–1029.

Boer Y. Irritation by eyedrops containing 2-phenylethanol. Pharm Weekbl (Sci) 1981; 3: 826–827.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2879.

General References

Silver S, Wendt L. Mechanism of action of phenylethyl alcohol: breakdown of the cellular permeability barrier. J Bacteriol 1967; 93: 560–566.

Sklubalova Z. Antimicrobial substances in ophthalmic drugs. Ceska Slov Farm 2004; 53(3): 107–116.

Authors

SC Owen.

Date of Revision

17 August 2005.

Phenylmercuric Acetate

Nonproprietary Names

BP: Phenylmercuric acetate PhEur: Phenyldriargyri acetas USPNF: Phenylmercuric acetate

Synonyms

(Acetato-O)phenylmercury; acetoxyphenylmercury; Gallotox; Liquiphene; phenylmercury acetate; PMA; PMAC; PMAS.

Chemical Name and CAS Registry Number

(Acetato)phenylmercury [62-38-4]

Empirical Formula and Molecular Weight

C8H8HgO2 336.74

Structural Formula

 

Functional Category

Antimicrobial preservative; antiseptic.

Applications in Pharmaceutical Formulation or Technology

Phenylmercuric acetate is used as an alternative antimicrobial preservative to phenylmercuric borate or phenylmercuric nitrate in cosmetics (in concentrations not exceeeding 0.0065% of mercury calculated as the metal) and pharmaceu- ticals. It may be used in preference to phenylmercuric nitrate owing to its greater solubility.

Phenylmercuric acetate is also used as a spermicide, see

Table I.

See also Phenylmercuric Nitrate.

Table I: Uses of phenylmercuric acetate.

Use Concentration (%)

Bactericide in parenterals and eye-drops 0.001–0.002

SEM: 1

Excipient: Phenylmercuric acetate Manufacturer: Eastman Fine Chemicals Magnification: 600×

 

SEM: 2

 Excipient: Phenylmercuric acetate Manufacturer: Eastman Fine Chemicals Magnification: 1800×

Spermicide in vaginal suppositories and jellies (active ingredient)

0.02

Description

Phenylmercuric acetate occurs as a white to creamy white, odorless or almost odorless, crystalline powder, or as small white prisms or leaflets.



Pharmacopeial Specifications

See Table II.

522 Phenylmercuric Acetate

Table II: Pharmacopeial specifications for phenylmercuric acetate.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Appearance of solution + —    

Ionized mercury 40.2% +    

Loss on drying 40.5% —    

Polymercurated benzene 41.5% 41.5%    

compounds

Melting range

—

149–1538C    

Residue on ignition — 40.2%    

Organic volatile impurities + +    

Assay 98.0–100.5% 98.0–100.5%  

Typical Properties

Acidity/alkalinity: pH ≈4 for a saturated aqueous solution at 208C.

Antimicrobial activity: phenylmercuric acetate is a broad- spectrum antimicrobial preservative with slow bactericidal and fungicidal activity similar to phenylmercuric nitrate; see Phenylmercuric Nitrate.

Dissociation constant: pKa = 3.3

Melting point: 1508C

Partition coefficients:

Mineral oil : water = 0.1

Solubility: see Table III.

Table III: Solubility of phenylmercuric acetate.

Solvent Solubility at 208C(a)

Acetone 1 in 19

Chloroform 1 in 6.8

Ethanol (95%) 1 in 225

Ether 1 in 200

Water 1 in 180

(a) Compendial values for solubility vary considerably and in most instances do not show close agreement with laboratory-determined values, which also vary.

Stability and Storage Conditions

As for other phenylmercuric salts; see Phenylmercuric Nitrate.

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

Incompatibilities

As for other phenylmercuric salts; see Phenylmercuric Nitrate. Incompatible with: halides; anionic emulsifying agents and suspending agents; tragacanth; starch; talc; sodium metabisul- fite; sodium thiosulfate; disodium edetate; silicates; aluminum and other metals; amino acids; ammonia and ammonium salts;

sulfur compounds; rubber; and some plastics.

Phenylmercuric acetate is reported to be incompatible with cefuroxime and ceftazidime.(1)

Method of Manufacture

Phenylmercuric acetate is readily formed by heating benzene with mercuric acetate.

Safety

Phenylmercuric acetate is mainly used as an antimicrobial preservative in topical pharmaceutical formulations. A number of adverse reactions to mercury- containing preservatives have been reported; see Phenylmercuric Nitrate.

LD50 (chicken, oral): 60 mg/kg(2) LD50 (mouse, IP): 13 mg/kg

LD50 (mouse, IV): 18 mg/kg LD50 (mouse, oral): 13 mg/kg LD50 (mouse, SC): 12 mg/kg LD50 (rat, oral): 41 mg/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Phenylmercuric acetate may be irritant to the skin, eyes, and mucous membranes. Eye protection, gloves, and a respirator are recommended. Chronic exposure via any route can lead to central nervous system damage. 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.(3)

Regulatory Status

Phenylmercuric acetate is no longer permitted to be used as a pesticide in the USA. It is, however, included in the FDA Inactive Ingredients Guide (ophthalmic preparations), and is also included in nonparenteral medicines licensed in the UK. In France, a maximum concentration of 0.01% is permitted for use in pharmaceuticals. The use of phenylmercuric acetate in cosmetics is restricted in the UK; see Phenylmercuric Nitrate. Included in the Canadian List of Acceptable Non-medicinal Ingredients (however, there must be no other suitable pre- servatives available).

Related Substances

Phenylmercuric borate; phenylmercuric nitrate; thimerosal.

Comments

The EINECS number for phenylmercuric acetate is 200-532-5.

Specific References

Hill DB, Barnes AR. Compatibility of phenylmercuric acetate with cefuroxime and ceftazidime eye drops. Int J Pharm 1997; 147: 127–129.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 33–34.

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

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.

Phenylmercuric Acetate 523

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.

Authors

SE Hepburn.

Date of Revision

17 August 2005.

Phenylmercuric Borate

Nonproprietary Names

BP: Phenylmercuric borate PhEur: Phenylhydrargyri boras

Synonyms

(Dihydrogen borato)phenylmercury; phenylmercuriborate; phenylmercury borate; PMB.

Chemical Name and CAS Registry Number

[Orthoborato(3-)-O]-phenylmercurate(2-)dihydrogen [102-

98-7]

The CAS Registry Number, chemical name and synonyms all refer to phenylmercuric borate alone, rather than the compound. The name phenylmercuric borate and the syno- nyms may, however, be applied to the PhEur 2005 material, which is a compound or a mixture of compounds, see Section 4. Unique CAS Registry Numbers for phenylmercuric borate and the compounds are as follows:

C6H7BHgO3 [102-98-7]

C12H13BHg2O4 [8017-88-7]

C12H11BHg2O3 [6273-99-0]

Empirical Formula and Molecular Weight

The PhEur 2005 material is a compound consisting of equimolecular proportions of phenylmercuric hydroxide and phenylmercuric orthoborate (C12H13BHg2O4) or of the de- hydrated form (metaborate, C12H11BHg2O3), or a mixture of the two compounds.

Phenylmercuric hydroxide and phenylmercuric orthoborate: C12H13BHg2O4 633.2

Phenylmercuric hydroxide and phenylmercuric metaborate: C12H11BHg2O3 615.2

Structural Formula

 

Functional Category

Antimicrobial preservative; antiseptic.

Applications in Pharmaceutical Formulation or Technology

Phenylmercuric borate is used as an alternative antimicrobial preservative to phenylmercuric acetate or phenylmercuric nitrate. It is more soluble than phenylmercuric nitrate and has also been reported to be less irritant than either phenylmercuric acetate or phenylmercuric nitrate.(1) See Table I.

See also Phenylmercuric Nitrate.

Table I: Uses of phenylmercuric borate.

Use Concentration (%)

Antimicrobial agent in ophthalmics 0.002–0.004

Antimicrobial agent in parenterals 0.002

Description

Phenylmercuric borate occurs as colorless, shiny flakes or as a white or slightly yellow, odorless, crystalline powder.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for phenylmercuric borate.

Test PhEur 2005

Identification +

Appearance of solution +

Ionized mercury (as heavy metals) +

Loss on drying (at 458C) 43.5%

Assay (dried basis) of

Mercury 64.5–66.0%

Borates (as H3BO3) 9.8–10.3%

Typical Properties

Acidity/alkalinity: pH = 5.0–7.0 for 0.6% w/v aqueous solution at 208C.

Antimicrobial activity: phenylmercuric borate is a broad- spectrum antimicrobial preservative with slow bactericidal and fungicidal activity similar to that of phenylmercuric nitrate; see Phenylmercuric Nitrate.

Dissociation constant: pKa = 3.3 Melting point: 112–1138C Solubility: see Table III.

Stability and Storage Conditions

As for other phenylmercuric salts; see Phenylmercuric Nitrate. Solutions may be sterilized by autoclaving.

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

Phenylmercuric Borate 525

Table III: Solubility of phenylmercuric borate.

Solvent Solubility at 208C(a) unless otherwise stated

Ethanol (95%) 1 in 150 Glycerin Soluble Propylene glycol Soluble Water 1 in 125

1 in 100 at 1008C

(a) Compendial values for solubility vary considerably.

Incompatibilities

As for other phenylmercuric salts; see Phenylmercuric Nitrate. Incompatible with: halides; anionic emulsifying agents and suspending agents; tragacanth; starch; talc; sodium metabisul- fite; sodium thiosulfate; disodium edetate; silicates; aluminum and other metals; amino acids; ammonia and ammonium salts;

sulfur compounds; rubber; and some plastics.

Method of Manufacture

Phenylmercuric borate may be prepared by heating mercuric borate with benzene or by evaporating to dryness, under vacuum, an alcoholic solution containing equimolar propor- tions of phenylmercuric hydroxide and boric acid.

Safety

Phenylmercuric borate is mainly used as an antimicrobial preservative in topical pharmaceutical formulations. A number of adverse reactions to mercury-containing preservatives have been reported; see Phenylmercuric Nitrate.

Although phenylmercuric borate is an irritant, it has been reported to be less so than either phenylmercuric acetate or phenylmercuric nitrate.(1) There is, however, some cross- sensitization potential with other mercurial preservatives.

Systemic absorption has been reported following regular use of a hand disinfectant soap containing 0.04% phenylmercuric borate, resulting in an increase in the estimated total daily body load of mercury from 30–100 mg per 24 hours.(2)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Phenylmercuric borate 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.(3)

Regulatory Status

Included in nonparenteral medicines licensed in Europe. In France, a maximum concentration of up to 0.01% is permitted for use in pharmaceutical formulations. In the UK, the use of



phenylmercuric borate in cosmetics is restricted;(4) see Phenyl- mercuric Nitrate. Included in the Canadian List of Acceptable Non-medicinal Ingredients (ophthalmic, nasal and otic pre- parations; there must be no other suitable alternative pre- servative).

Related Substances

Phenylmercuric acetate; phenylmercuric nitrate; thimerosal.

Comments

The EINECS number for phenylmercuric borate is 203-068-1.

Specific References

Marzulli FN, Maibach HI. Antimicrobials: experimental contact sensitization in man. J Soc Cosmet Chem 1973; 24: 399–421.

Peters-Haefeli L, Michod JJ, Aelhg A, et al. Urinary excretion of mercury after the use of an antiseptic soap containing 0.04% of phenylmercuric borate [in French]. Schweiz Med Wochenschr 1976; 106(6): 171–178.

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.

Authors

SE Hepburn.

Date of Revision

17 August 2005.

Phenylmercuric Nitrate

Nonproprietary Names

BP: Phenylmercuric nitrate PhEur: Phenylhydrargyri nitras USPNF: Phenylmercuric nitrate

Synonyms

Basic phenylmercury nitrate; mercuriphenyl nitrate; merphenyl nitrate; nitratophenylmercury; phenylmercury nitrate; Phe- Mer-Nite; PMN.

Note that the synonyms above are usually used to refer to phenylmercuric nitrate alone. However, confusion with nomen- clature and CAS Registry Number has led to these synonyms also being applied to the PhEur 2005 and USPNF 23 material, which is a compound of phenylmercuric nitrate and phenyl- mercuric hydroxide.

Chemical Name and CAS Registry Number

There are two CAS Registry Numbers associated with phenylmercuric nitrate. One refers to the mixture of phenyl- mercuric nitrate and phenylmercuric hydroxide (C12H11Hg2NO4) while the other refers to phenylmercuric nitrate alone (C6H5HgNO3). The PhEur 2005, and USPNF 23 use the name phenylmercuric nitrate to describe the mixture and use the CAS Registry Number [55-68-5].

Hydroxyphenylmercury mixture with (nitrato-O)phenyl- mercury:

C12H11Hg2NO4 [8003-05-2]

(Nitrato-O)phenylmercury: C6H5HgNO3 [55-68-5]

Empirical Formula and Molecular Weight

C12H11Hg2NO4 634.45

Structural Formula

 

Functional Category

Antimicrobial preservative; antiseptic.

Applications in Pharmaceutical Formulation or Technology

Phenylmercuric salts are used as antimicrobial preservatives mainly in ophthalmic preparations, but are also used in cosmetics (see Section 16), parenteral, and topical pharmaceu- tical formulations; see Table I.

Phenylmercuric salts are active over a wide pH range against bacteria and fungi and are usually used in neutral to alkaline solutions, although they have also been used effectively at slightly acid pH; see Section 10. In acidic formulations, phenylmercuric nitrate may be preferred to phenylmercuric acetate or phenylmercuric borate as it does not precipitate.

Phenylmercuric nitrate is also an effective spermicide, although its use in vaginal contraceptives is no longer recommended; see Section 14.

A number of adverse reactions to phenylmercuric salts have been reported and concern at the toxicity of mercury compounds may preclude the use of phenylmercuric salts under certain circumstances; see Section 14.

Table I: Uses of phenylmercuric nitrate.

Use Concentration (%)

Bactericide in parenterals 0.001

Bactericide in vaginal suppositories and jellies 0.02

Preservative in eye drops 0.002

Description

Phenylmercuric nitrate PhEur 2005, and USPNF 23, is an equimolecular compound of phenylmercuric hydroxide and phenylmercuric nitrate; it occurs as a white, crystalline powder with a slight aromatic odor.

Pharmacopeial Specifications

See Table II.

Table II: Pharmcopeial specifications for phenylmercuric nitrate.

Test PhEur 2005 USPNF 23

Identification + +

Appearance of solution + —

Loss on drying 41.0% —

Residue on ignition — 40.1%

Mercury ions — +

Inorganic mercuric compounds + +

Organic volatile impurities — +

Assay (dried basis) of:

Mercury 62.5–64.0%  62.75–63.50%

Phenylmercuric ion — 87.0–87.9%

Phenylmercuric Nitrate 527

SEM: 1

Excipient: Phenylmercuric nitrate Manufacturer: Eastman Fine Chemicals Magnification: 180×

 

SEM: 2

Excipient: Phenylmercuric nitrate Manufacturer: Eastman Fine Chemicals Magnification: 1800×

 

Typical Properties

Acidity/alkalinity: a saturated aqueous solution is acidic to litmus.

Antimicrobial activity: phenylmercuric salts are broad-spec- trum, growth-inhibiting agents at the concentrations nor- mally used for the preservation of pharmaceuticals. They possess slow bactericidal and fungicidal activity. Antimicro- bial activity tends to increase with increasing pH, although in solutions of pH 6 and below, activity against Pseudomo- nas aeruginosa has been demonstrated. Phenylmercuric salts are included in several compendial eye drop formulations of acid pH.