med 5

Commercially, L-(+)-tartaric acid is manufactured from potassium tartrate (cream of tartar), a by-product of wine making. Potassium tartrate is treated with hydrochloric acid, followed by the addition of a calcium salt to produce insoluble calcium tartrate. This precipitate is then removed by filtration and reacted with 70% sulfuric acid to yield tartaric acid and calcium sulfate.

Safety

Tartaric acid is widely used in food products and oral, topical, and parenteral pharmaceutical formulations. It is generally regarded as a nontoxic and nonirritant material, however, strong tartaric acid solutions are mildly irritant and if ingested undiluted may cause gastroenteritis.

An acceptable daily intake for L-(+)-tartaric acid has not been set by the WHO, although an acceptable daily intake of up to 30 mg/kg body-weight for monosodium L-(+)-tartrate has been established.(1)

LD50 (mouse, IV): 0.49 g/kg(2)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Tartaric acid may be irritant to the eyes; eye protection and rubber or plastic gloves are recommended. When heated to decomposition, tartaric acid emits acrid smoke and fumes.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM and IV

injections; oral solutions, syrups and tablets; sublingual tablets; topical films; rectal and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Citric acid monohydrate; fumaric acid; malic acid.

Comments

L-(+)-tartaric acid, the optical isomer usually encountered, is the naturally occurring form and is specified as tartaric acid in the PhEur 2005 and USPNF 23.

A specification for tartaric acid is contained in the Food Chemicals Codex (FCC). The EINECS number for tartaric acid is 205-105-7.

Specific References

FAO/WHO. Evaluation of certain food additives. Twenty-first report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1978; No. 617.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3349.

General References

Sendall FEJ, Staniforth JN. A study of powder adhesion to metal surfaces during compression of effervescent pharmaceutical tablets. J Pharm Pharmacol 1986; 38: 489–493.

Usui F, Carstensen JT. Interactions in the solid state I: interactions of sodium bicarbonate and tartaric acid under compressed conditions. J Pharm Sci 1985; 74: 1293–1297.

Tetrafluoroethane (HFC)

Nonproprietary Names

None adopted.

Synonyms

Dymel 134a/P; fluorocarbon 134a; Frigen 134a; Genetron 134a; HFA 134a; HFC 134a; Isceon 134a; Klea 134a; propellant 134a; refrigerant 134a; Solkane 134a; Suva 134a; Zephex 134a.

Chemical Name and CAS Registry Number

1,1,1,2-Tetrafluoroethane [811-97-2]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Tetrafluoroethane is a hydrofluorocarbon (HFC) or hydro- fluoroalkane (HFA) aerosol propellant (contains hydrogen, fluorine, and carbon) as contrasted to a CFC (chlorine, fluorine, and carbon). The lack of chlorine in the molecule and the presence of hydrogen reduces the ozone depletion activity to practically zero. Hence tetrafluoroethane can be considered as an alternative to CFCs in the formulation of metered-dose inhalers (MDIs).(1–9) It has replaced CFC-12 as a refrigerant since it has essentially the same vapor pressure. Its very low Kauri-butanol value and solubility parameter indicate that it is not a good solvent for the commonly used surfactants for MDIs. Sorbitan trioleate, sorbitan sesquioleate, oleic acid, and soya lecithin show limited solubility in tetrafluoroethane and the amount of surfactant that actually dissolves may not be sufficient to keep a drug readily dispersed.

When tetrafluoroethane (P-134a) is used for pharmaceutical aerosols and MDIs, the pharmaceutical grade must be specified. Industrial grades may not be satisfactory due to their impurity profiles.

Description

Tetrafluoroethane is a liquefied gas and exists as a liquid at room temperature when contained under its own vapor

pressure, or as a gas when exposed to room temperature and atmospheric pressure. The liquid is practically odorless and colorless. The gas in high concentrations has a slight etherlike odor. Tetrafluoroethane is noncorrosive, nonirritating, and nonflammable.

Pharmacopeial Specifications

—

Typical Properties

Boiling point: —26.28C

Critical pressure: 4.11 MPa (40.55 atm)

Critical temperature: 101.08C

Density:

1.226 g/cm3 for liquid at 208C;

1.207 g/cm3 for liquid at 258C. Flammability: nonflammable. Freezing point: —1088C

Kauri-butanol value: 8

Solubility: soluble in ethanol (95%), ether, and 1 in 1294 parts of water at 208C.

Surface tension: 8.6 kN/m

Vapor density (absolute): 4.466 g/cm3 at standard temperature and pressure.

Vapor density (relative): 3.53 (air = 1)

Vapor pressure:

569 kPa at 208C; 662 kPa at 258C. Viscosity (dynamic):

0.222 mPa s (0.222 cP) for liquid at 208C;

0.210 mPa s (0.210 cP) for liquid at 258C.

Stability and Storage Conditions

Tetrafluoroethane is a nonreactive and stable material. The liquified gas is stable when used as a propellant and should be stored in a metal cylinder in a cool dry place.

Incompatibilities

The major incompatibility of tetrafluoroethane is its lack of miscibility with water. Since it has a very low Kauri-butanol value, tetrafluoroethane is considered to be a very poor solvent for most drugs used in MDI formulations. It also shows a low solubility for some of the commonly used MDI surfactants.

Method of Manufacture

Tetrafluoroethane can be prepared by several different routes; however, the following routes of preparation illustrate the methods used:

Isomerization/hydrofluorination of 1,1,2-trichloro-1,2,2- trifluoroethane (CFC-113) to 1,1-dichloro-1,2,2,2-tetrafluoro- ethane (CFC-114a), followed by hydrodechlorination of the latter.

Hydrofluorination of trichloroethylene, via 1-chloro-1,1,1- trifluoroethane (HCFC-133a).

Tetrafluoroethane (HFC) 773

Safety

Tetrafluoroethane is used as a refrigerant and as a non-CFC propellant in various aerosols including pharmaceuticals (MDIs). Tetrafluoroethane is regarded as nontoxic and non- irritating when used as directed. No acute or chronic hazard is present when exposures to the vapor are below the acceptable exposure limit (AEL) of 1000 ppm, 8-hour and 12-hour time weighed average (TWA).(10) In this regard it has the same value as the threshold limit value (TLV) for CFC-12. Inhaling a high concentration of tetrafluoroethane vapors can be harmful and is similar to inhaling vapors of CFC-12. Intentional inhalation of vapors of tetrafluoroethane can be dangerous and may cause death. The same labeling required on CFC aerosols would be required for those containing tetrafluoroethane as a propellant (except for the EPA requirement). See Chlorofluorocarbons, Section 14.

Handling Precautions

Tetrafluoroethane is usually encountered as a liquefied gas and appropriate precautions for handling should be taken. Eye protection, gloves, and protective clothing are recommended. Tetrafluoroethane should be handled in a well-ventilated environment. The vapors are heavier than air and do not support life; therefore, when cleaning large tanks that have contained the propellant, adequate provisions for oxygen supply in the tanks must be made in order to protect workers cleaning the tanks.

Although nonflammable, when heated to decomposition tetrafluoroethane emits toxic fumes.

In the UK, the long-term exposure limit (8-hour TWA) for tetrafluoroethane is 4240 mg/m3 (1000 ppm).(11)

Regulatory Status

Included in the FDA Inactive Ingredients Guide (aerosol formulations for inhalation and nasal applications). Included in nonparenteral medicines licensed in the UK.

Related Substances

Difluoroethane; heptafluoropropane.

Comments

The use of tetrafluoroethane as a propellant for MDIs has been the subject of numerous patents throughout the world. These patents cover the formulation of MDIs and use of specific surfactants, cosolvents, etc. A US patent claims a self-propelling aerosol formulation that may be free of CFCs and which comprises a medicament, 1,1,1,2-tetrafluoroethane, a surface- active agent, and at least one compound having a higher polarity than 1,1,1,2-tetrafluoroethane.(12) Another patent has been issued by the European Patent Office and has 14 claims, among them a claim that includes tetrafluoroethane, an alcohol (such as ethanol), surfactant, and medicament.(13) The for- mulator is referred to the patent literature prior to formulating a MDI with tetrafluoroethane as the propellant. The formula- tion of MDI with this non-CFC propellant is complicated since tetrafluoroethane serves as a replacement for dichlorodifluor- omethane or dichlorotetrafluoroethane. The use of an HFC as the propellant also requires a change in manufacturing procedure, which necessitates a redesign of the filling and packaging machinery for a MDI.(14)

Currently, there are no pharmacopeial specifications for tetrafluoroethane. However, typical specifications are shown in Table I.

Table I: Typical product specifications for tetrafluoroethane.

Test Value

Appearance Clear and colorless

High boiling impurities 40.01%

Acidity as HCl 40.1 ppm

Non-volatile residue 45 ppm

Non-absorbable gases 41.5 %

Water 410 ppm

Total unidentified impurities 410 ppm

Assay 599.99 %

Specific References

Strobach DR. Alternative to CFCs. Aerosol Age 1988; 33(7): 32–

33, 42–43.

Daly J. Properties and toxicology of CFC alternatives. Aerosol Age 1990; 35(2): 26–27, 40.

Dalby RN, Byron PR, Shepherd HR, Papadopoulos E. CFC propellant substitution: P-134a as a potential replacement for P-12 in MDIs. Pharm Technol 1990; 14(3): 26–33.

Kontny MJ, Destefano G, Jagen PD, et al. Issues surrounding MDI formulation development with non-CFC propellants. J Aerosol Med 1991; 4(3): 181–187.

Anonymous. 3M first with a CFC-free asthma inhaler. Pharm J

1995; 254: 388.

Taggart SCO, Custovic A, Richards DH, Woodcock A. GR106642X: a new, non-ozone depleting propellant for inhalers. Br Med J 1995; 310: 1639–1640.

Elvecrog J. Metered dose inhalers in a CFC-free future. Pharm Technol Eur 1997; 9(1): 52–55.

Tansey IP. Changing to CFC-free inhalers: the technical and clinical challenges. Pharm J 1997; 259: 896–898.

McDonald KJ, Martin GP. Transition to CFC-free metered dose inhalers: into the new millenium. Int J Pharm 2000; 201: 89–107.

DuPont. Technical literature: Dymel 134a/P pharmaceutical grade HFC-134a propellant, 1996.

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

Purewal TS, Greenleaf DJ. Medicinal aerosol formulations. United States Patent No. 5,605,674; 1997.

Purewal TS, Greenleaf DJ. Medicinal aerosol formulations. European Patent 372777B1; 1993.

Tzou T, Pachuta RR, Coy RB, Schultz RK. Drug form selection in albuterol-containing metered-dose inhaler formulations and its impact on chemical and physical stability. J Pharm Sci 1997; 86: 1352–1357.

General References

Harrison LI, Donnell D, Simmons JL, et al. Twenty-eight day double- blind safety study of an HFA 134a inhalation aerosol system in healthy subjects. J Pharm Pharmacol 1996; 48: 596–600.

Hoet P, Graf MLM, Bourdi M, et al. Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet 1997; 350: 556–559.

Sawyer E, Green B, Colton HM. Microorganism survival in non-CFC propellant P134a and a combination of CFC propellants P11 and P12. Pharm Technol 2001; 25(3): 90–96.

774 Tetrafluoroethane (HFC)

Steed KP, Hooper G, Brickwell J, Newman SP. The oropharyngeal and lung deposition patterns of a fusafungine MDI spray delivered by HFA 134a propellant or by CFC 12 propellant. Int J Pharm 1995; 123: 291–293.

Tiwari D, Goldman D, Dixit S, et al. Compatibility evaluation of metered-dose inhaler valve elastomers with tetrafluoroethane (P134a), a non-CFC propellant. Drug Dev Ind Pharm 1998; 24: 345–352.

Authors

CJ Sciarra, JJ Sciarra.

E957; Talin; taumatin; thalin; thaumatine; thaumatins; thau- matins protein.

Chemical Name and CAS Registry Number

Thaumatin [53850-34-3]

Empirical Formula and Molecular Weight

See Section 5.

Structural Formula

Thaumatin is a mixture of five thaumatin proteins; thaumatins I, II, III, and a and b; where thaumatins I and II predominate. Thaumatins I and II consist of almost identical sequences of amino acids. There are no unusual side-chains or peptide linkages, and there are no end-group substitutions.

Functional Category

Flavor enhancer; sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Thaumatin is a naturally occurring intense sweetening agent approximately 2000–3000 times as sweet as sucrose. It has a delayed-onset taste profile and long (up to one hour) licorice- like aftertaste. It is used extensively in food applications as a sweetening agent and flavor enhancer and has potential for use in pharmaceutical applications such as oral suspensions.(1) The typical level used in foods is 0.5–3 ppm, although higher levels are used in certain applications such as chewing gum. Synergistic effects with other intense sweeteners such as acesulfame K and saccharin occur. The extensive disulfide crosslinking within thaumatin maintains the tertiary structure of the polypeptide: cleavage of just one disulfide bridge has been shown to result in the loss of the sweet taste of thaumatin.(2)

Description

Thaumatin occurs as a pale-brown colored, odorless, hygro- scopic powder with an intensely sweet taste.

Pharmacopeial Specifications

—

Typical Properties

Solubility: see Table I.

Table I: Solubility of thaumatin

Solvent Solubility at 258C unless otherwise stated

Acetone Practically insoluble

Ethanol (95%) Soluble

Glycerin Soluble Propylene glycol Soluble

Water 1 in 5 at pH 3

Stability and Storage Conditions

Thaumatin is stable in aqueous solutions at pH 2–8. It is also heat-stable at less than pH 5.5 (e.g., during baking, canning, pasteurizing, or UHT processes).

Incompatibilities

—

Method of Manufacture

Thaumatin is a naturally occurring intense sweetener isolated from the fruit of the African plant Thaumatococcus daniellii (Benth).(3) Commercially, thaumatin is produced by aqueous extraction under reduced pH conditions followed by other physical processes such as reverse osmosis.

Safety

Thaumatin is accepted for use in food products either as a sweetener or as a flavor modifier in a number of areas including Europe and Australia. It is also used in oral hygiene products such as mouthwashes and toothpastes and has been proposed for use in oral pharmaceutical formulations. Thaumatin is generally regarded as a relatively nontoxic and nonirritant material when used as an excipient. In Europe, because of its lack of toxicity, an ADI has been set of ‘not specified’.(4,5)

LD50 (mouse, oral): >20 g/kg(5) LD50 (rat, oral): >20 g/kg

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 nonparenteral medicines licensed in the UK.

As thaumatin is a protein it has some calorific value; however, in food products and pharmaceutical formulations the quan- tities used are so small that the calorific value is insignificant.

The EINECS number for thaumatin is 258-822-2.

Specific References

Odusote MO, Nasipuri RN. Effect of pH and storage conditions on the stability of a novel chloroquine phosphate syrup formula- tion. Pharm Ind 1988; 50(3): 367–369.

Iyengar RB, Smits P, van der Oureraa F, et al. The complete amino- acid sequence of the sweet protein thaumatin. Eur J Biochem 1979; 96: 193–204.

Daniell WF. Katemfe, or the miraculous fruit of the Soudan. Pharm J 1855; 14: 158–160.

Higginbotham JD, Snodin DJ, Eaton KK, Daniel JW. Safety evaluation of thaumatin (Talin Protein). Food Chem Toxicol 1983; 21(6): 815–823.

FAO/WHO. Toxicological evaluation of certain food additives and contaminants. Twenty-ninth report of the joint FAO/WHO expert committee on food additives. WHO Food Add Ser 1985; No. 20.

General References

Dodson AG, Wright SJC. New sweeteners: confectioner’s viewpoint.

Food Flavour Ingred Packag Process 1982; 4(Sep): 29, 31, 32, 59.

Green C. Thaumatin: a natural flavour ingredient. World Rev Nutr Diet 1999; 85: 129–132.

Hart H. Thaumatin. In: Birch G, ed. Ingredients Handbook: Sweet- eners, 2nd edn. Leatherhead: Leatherhead Publishing, 2000: 255– 263.

Higginbotham JD. Talin protein (thaumatin). In: O’Brien Nabors L, Gelardi RC, eds. Alternative Sweeteners. New York: Marcel Dekker, 1986: 103–134.

Kinghorn AD, Compadre CM. Naturally occurring intense sweeteners.

Pharm Int 1985; 6(Aug): 201–204.

Kinghorn AD, Compadre CM. Less common high-potency sweeteners. In: O’Brien Nabors L, ed. Alternative Sweeteners, 3rd edn. New York: Marcel Dekker, 2001: 214–215.

Sanyude S. Alternative sweeteners. Can Pharm J 1990; 123(Oct): 455– 456, 459–460.

Witty M, Higginbotham JD, eds. Thaumatin. Boca Raton, FL: CRC Press, 1994.

BP: Thiomersal PhEur: Thiomersalum USP: Thimerosal

Synonyms

[(o-Carboxyphenyl)thio]ethylmercury sodium salt; ethyl (2-mercaptobenzoato-S)-mercury, sodium salt; ethyl (sodium o-mercaptobenzoato)mercury; mercurothiolate; sodium ethyl- mercurithiosalicylate; Thimerosal Sigmaultra; thiomersalate.

Chemical Name and CAS Registry Number

Ethyl[2-mercaptobenzoato(2–)-O,S]-mercurate(1–) sodium [54-64-8]

Empirical Formula and Molecular Weight

C9H9HgNaO2S 404.81

Structural Formula

Functional Category

Antimicrobial preservative; antiseptic.

Applications in Pharmaceutical Formulation or Technology

Thimerosal has been used as an antimicrobial preservative in biological and pharmaceutical preparations since the 1930s;(1) see Table I.

It is used as an alternative to benzalkonium chloride and other phenylmercuric preservatives and has both bacteriostatic and fungistatic activity. Increasing concerns over its safety have, however, led to questions regarding its continued use in formulations; see Section 14.

Thimerosal is also used in cosmetics (see Section 16) and to preserve soft contact lens solutions.

Therapeutically, thimerosal is occasionally used as a bacteriostatic and fungistatic mercurial antiseptic, which is usually applied topically at a concentration of 0.1% w/w.(2) However, its use is declining owing to its toxicity and effects on the environment.

Description

Thimerosal is a light cream-colored crystalline powder with a slight, characteristic odor.

Table I: Uses of thimerosal.

Use Concentration (%)

IM, IV, SC injections 0.01

Ophthalmic solutions 0.001–0.15

Ophthalmic suspensions 0.001–0.004

Otic preparations 0.001–0.01

Topical preparations 0.01

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for thimerosal.

Appearance of solution + —

Melting point 103–1058C —

pH 6.0–8.0 —

Inorganic mercury compounds 40.70% —

Loss of drying 40.5% 40.5%

Ether-soluble substances — 40.8%

Mercury ions — 40.70%

Readily carbonizable substances — +

Assay 97.0–101.0% 97.0–101.0%

Typical Properties

Acidity/alkalinity: pH = 6.7 for a 1% w/v aqueous solution at 208C.

Antimicrobial activity: thimerosal is bactericidal at acidic pH, bacteriostatic and fungistatic at alkaline or neutral pH. Thimerosal is not effective against spore-forming organisms. See also Section 12. For reported minimum inhibitory concentrations (MICs), see Table III.(3)

Table III: Reported minimum inhibitory concentrations (MICs) for thimerosal.(3)

Microorganism MIC (mg/mL)

Aspergillus niger 128.0

Candida albicans 32.0

Escherichia coli 4.0

Klebsiella pneumoniae 4.0

Penicillium notatum 128.0

Pseudomonas aeruginosa 8.0

Pseudomonas cepacia 8.0

Pseudomonas fluorescens 4.0

Staphylococcus aureus 0.2

778 Thimerosal

Density (bulk): <0.33 g/cm3

Dissociation constant: pKa = 3.05 at 258C.

Melting point: 232–2338C with decomposition.

Solubility: soluble 1 in 8 of ethanol (95%), 1 in 1 of water; practically insoluble in benzene and ether.

Stability and Storage Conditions

Thimerosal is stable at normal temperatures and pressures; exposure to light may cause discoloration.

Aqueous solutions may be sterilized by autoclaving but are sensitive to light. The rate of oxidation in solutions is increased by the presence of trace amounts of copper and other metals. Edetic acid or edetates may be used to stabilize solutions but have been reported to reduce the antimicrobial efficacy of thimerosal solutions; see Section 12.

The solid material should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

Incompatible with aluminum and other metals, strong oxidiz- ing agents, strong acids and bases, sodium chloride solutions,(4) lecithin, phenylmercuric compounds, quaternary ammonium compounds, thioglycolate, and proteins. The presence of sodium metabisulfite, edetic acid, and edetates in solutions can reduce the preservative efficacy of thimerosal.(5)

In solution, thimerosal may be adsorbed by plastic packag- ing materials, particularly polyethylene. It is strongly adsorbed by treated or untreated rubber caps that are in contact with solutions.(6,7)

When it was used with cyclodextrin, the effectiveness of thimerosal was reduced; however, this was related to the lipid nature of the other ingredients in the preparation.(8)

Method of Manufacture

Thimerosal is prepared by the interaction of ethylmercuric chloride, or hydroxide, with thiosalicylic acid and sodium hydroxide, in ethanol (95%).

Safety

Thimerosal is widely used as an antimicrobial preservative in parenteral and topical pharmaceutical formulations. However, concern over the use of thimerosal in pharmaceuticals has increased as a result of a greater awareness of the toxicity of mercury and other associated mercury compounds.(9,10) The increasing number of reports of adverse reactions, particularly hypersensitivity,(11,12) to thimerosal and doubts as to its effectiveness as a preservative have led to suggestions that it should not be used as a preservative in eye drops(13) or vaccines.(14–16) In both Europe and the USA, regulatory bodies

have recommended that thimerosal in vaccines be phased out.(17–19)

More recent studies assessing the safety of thimerosal in vaccines have however suggested that while the risk of hypersensitivity reactions is present, the relative risk of neurological harm in infants is negligible given the quantities of thimerosal present in vaccines.(20–22) Regulatory bodies in Europe and the USA have therefore updated their advice on the use of thimerosal in vaccines by stating that while it would be desirable for thimerosal to not be included in vaccines and other formulations the benefits of vaccines far outweigh any risks of adverse effects associated with their use.(23,24)

The most frequently reported adverse reaction to thimer- osal, particularly in vaccines,(14–27) is hypersensitivity, usually

with erythema and papular or vesicular eruptions. Although not all thimerosal-sensitive patients develop adverse reactions to vaccines containing thimerosal, there is potential risk. Patch testing in humans and animal experiments have suggested that 0.1% w/v thimerosal can sensitize children.(28) The incidence of sensitivity to thimerosal appears to be increasing; a study of 256 healthy subjects showed approximately 6% with positive sensitivity.(29)

Adverse reactions to thimerosal used to preserve contact lens solutions have also been reported. Reactions include ocular redness, irritation, reduced lens tolerance, and conjunctivi- tis.(30–32) One estimate suggests that approximately 10% of contact lens wearers may be sensitive to thimerosal.(33)

Thimerosal has also been associated with false positive reactions to old tuberculin,(34) ototoxicity,(35) and an unusual reaction to aluminum(36) in which a patient suffered a burn 5 cm in diameter at the site of an aluminum foil diathermy electrode after preoperative preparation of the skin with a 0.1% w/v thimerosal solution in ethanol (50%). Investigation showed that considerable heat was generated when such a solution came into contact with aluminum.

An interaction between orally administered tetracyclines and thimerosal, which resulted in varying extents of ocular irritation, has been reported in patients using a contact lens solution preserved with thimerosal.(37)

Controversially, some have claimed a connection between the use of thimerosal in vaccines and the apparent rise in the incidence of autism. However, recent studies have shown no association between thimerosal exposure and autism.(38,39)

LD50 (mouse, oral): 91 mg/kg(40) LD50 (rat, oral): 75 mg/kg

LD50 (rat, SC): 98 mg/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Thimerosal is irritant to the skin and mucous membranes and may be systemically absorbed through the skin and upper respiratory tract. Thimerosal should be handled in a well-ventilated environment. Eye protection, gloves, and a respirator are recommended.

Chemical decomposition may cause the release of toxic fumes containing oxides of carbon, sulfur, and mercury in addition to mercury vapor. 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.(41)

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections; ophthalmic, otic, and topical preparations). Included in nonparenteral and parenteral medicines licensed in the UK. In the UK, the use of thimerosal in cosmetics is limited to 0.003% w/w (calculated as mercury) as a preservative in shampoos and hair-creams, which contain nonionic emulsifiers that would render other preservatives ineffective. The total permitted concentration (calculated as mercury) when mixed with other mercury compounds is 0.007% w/w.(42) Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Phenylmercuric acetate; phenylmercuric borate; phenylmercu- ric nitrate.

Thimerosal 779

Comments

Some variation between the results obtained when comparing different thimerosal assay methods has been reported.(43)

The EINECS number for thimerosal is 200-210-4.

Specific References

Amieson WA, Powell HM. Merthiolate as a preservative for biological products. Am J Hyg 1931; 14: 218–224.

Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th edn. London. Pharmaceutical Press. 2005: 1194.

Wallha¨ usser KH. Thimerosal. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 735–737.

Reader MJ. Influence of isotonic agents on the stability of thimerosal in ophthalmic formulations. J Pharm Sci 1984; 73(6): 840–841.

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.

Wiener S. The interference of rubber with the bacteriostatic action of thiomersalate. J Pharm Pharmacol 1955; 7: 118–125.

Birner J, Garnet JR. Thimerosal as a preservative in biological preparations III: factors affecting the concentration of thimerosal in aqueous solutions and in vaccines stored in rubber-capped bottles. J Pharm Sci 1964; 53: 1424–1426.

Lehner SJ, Muller BW, Seydel JK. Effect of hydroxypropyl-beta- cyclodextrin on the antimicrobial action of preservatives. J Pharm Pharmacol 1994; 46(3): 186–191.

Van’t Veen AJ. Vaccines without thiomersal: why so necessary, why so long in coming? Drugs 2001; 61(5): 565–572.

Clements CJ, Ball LK, Ball R, Pratt RD. Thimerosal in vaccines: is removal warranted? Drug Saf 2001; 24(8): 567–574.

Suneja T, Belsito DV. Thimerosal in the detection of clinically relevant allergic, contact reactions. J Am Acad Dermatol 2001; 45(1): 23–27.

Audicana MT, Munoz D, del Pozo MD, et al. Allergic contact dermatitis from mercury antiseptics and derivatives: study proto- col of tolerance to intramuscular injections of thimerosal. Am J Contact Dermat 2002; 13(1): 3–9.

Ford JL, Brown MW, Hunt PB. A note on the contamination of eye-drops following use by hospital out-patients. J Clin Hosp Pharm 1985; 10(2): 203–209.

Cox NH, Forsyth A. Thiomersal allergy and vaccination reactions.

Contact Dermatitis 1988; 18: 229–233.

Seal D, Ficker L, Wright P, Andrews V. The case against thiomersal [letter]. Lancet 1991; 338(8762): 315–316.

Noel I, Galloway A, Ive FA. Hypersensitivity to thiomersal in hepatitis B vaccine [letter]. Lancet 1991; 338: 705.

Anonymous. Thiomersal to be removed from vaccines in the US.

Pharm J 1999; 263: 112.

European Agency for the Evaluation of Medicinal Products (EMEA). EMEA public statement on thiomersal containing medicinal products, 8 July 1999. EMEA publication no. (20962/ 99). Full version: http://www.emea.eu.int/pdfs/human/press/pus/ 2096299EN.pdf (accessed 13 April 2005).

American Academy of Pediatrics, United States Public Health Service. Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service. MMWR 1999; 48: 563–565.

Clements CJ. The evidence for the safety of thimerosal in newborn and infant vaccines. Vaccine 2004; 22(15–16): 1854–1861.

Counter SA, Buchanan LH. Mercury exposure in children: a review. Toxicol Appl Pharmacol 2004; 198(2): 209–230.

Bigham M, Copes R. Thimerosal in vaccines: balancing the risks of adverse effects with the risk of vaccine-preventable disease. Drug Safety 2005; 28(2): 89–101.

European Medicines Evaluation Agency 2004. EMEA public statement on thiomersal in vaccines for human use—recent evidence supports safety of thiomersal-containing vaccines. http://www.emea.eu.int/pdfs/human/press/pus/119404eu.pdf (accessed 13 April 2005).

Committee on Safety of Medicines. Safety of thiomersal-contain- ing vaccines. Current Problems 2003; 29: 9.

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Lee-Wong M, Resnick D, Chong K. A generalized reaction to thimerosal from an influenza vaccine. Ann Allergy Asthma Immunol 2005; 94(1): 90–94.

Osawa J, Kitamura K, Ikezawa Z, Nakajima H. A probable role for vaccines containing thimerosal in thimerosal hypersensitivity. Contact Dermatitis 1991; 24(3): 178–182.

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36(3): 209–211.

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General References

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BP: Thymol PhEur: Thymolum USPNF: Thymol

Synonyms

Acido trimico; 3-p-cymenol; p-cymen-3-ol; Flavinol; 3- hydroxy-p-cymene; 3-hydroxy-1-methyl-4-isopropylbenzene; Intrasol; isopropyl cresol; isopropyl-m-cresol; 6-isopropyl-m- cresol; isopropyl metacresol; 2-isopropyl-5-methylphenol; 1- methyl-3-hydroxy-4-isopropylbenzene; 5-methyl-2-isopropyl- phenol; 5-methyl-2-(1-methylethyl) phenol; Medophyll; thyme camphor; thymic acid; m-thymol; timol.

Chemical Name and CAS Registry Number

Thymol [89-83-8]

Empirical Formula and Molecular Weight

C10H14O 150.24

Structural Formula

Functional Category

Antioxidant; antiseptic; cooling agent; disinfectant; flavoring agent; skin penetrant; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Thymol is a phenolic antiseptic, which has antibacterial and antifungal activity. However, it is not suitable for use as a preservative in pharmaceutical formulations because of its low aqueous solubility. The antimicrobial activity of thymol against eight oral bacteria has been studied in vitro. Inhibitory activity was noted against almost all organisms, and a synergistic effect was observed for combinations of thymol and eugenol and of thymol and carvacrol.(1) The activity of thymol against bacteria commonly involved in upper respiratory tract infections has also been shown.(2)

Thymol is a more powerful disinfectant than phenol, but its low water solubility, its irritancy to tissues, and its inactivation by organic material, such as proteins, limit its use as a disinfectant. Thymol is chiefly used as a deodorant in antiseptic

mouthwashes, gargles, and toothpastes, such as in Compound Thymol Glycerin BP, in which it has no antiseptic action.

Thymol is also a true antioxidant and has been used at concentrations of 0.01% as an antioxidant for halothane, trichloroethylene, and tetrachloroethylene.

More recently, thymol has been shown to enhance the in vitro percutaneous absorption of a number of drugs, including 5-fluorouracil,(3) piroxicam,(4) propranolol,(5) naproxen,(6) and tamoxifen.(7) Studies have also demonstrated that the melting point of lidocaine is significantly lowered when it is mixed with thymol.(8,9)

The inhalation of thymol, in combination with other volatile substances, is used to alleviate the symptoms of colds, coughs, and associated respiratory disorders. Externally, thymol has been used in dusting powders for the treatment of fungal skin infections. Thymol was formerly used in the treatment of hookworm infections but has now been superseded by less toxic substances.

In dentistry, thymol has been mixed with phenol and camphor to prepare cavities before filling, and mixed with zinc oxide to form a protective cap for dentine.

Thymol has been included in food, perfume, and cosmetic products, and has also been used as a pesticide and fungicide.

Description

Thymol occurs as colorless or often large translucent crystals, or as a white crystalline powder with a herbal odor (aromatic and thyme-like) and a pungent caustic taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for thymol.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Melting range 48–528C 48–518C

Appearance of solution + —

Acidity + —

Related substances + —

Residue on evaporation 40.05% 40.05%

Organic volatile impurities — +

Assay — 99.0–101.0%

Typical Properties

Acidity/alkalinity: a 4% solution in ethanol (50%) is neutral to litmus.

Boiling point: about 2338C

Density: 0.97 g/cm3 at 258C; has a greater density than water, but when liquefied by fusion is less dense than water.

Dissociation constant: pKa = 10.6 at 208C

Melting point: 48–518C, but, once melted, remains liquid at a considerably lower temperature.

Thymol 781

Partition coefficient: log (octanol–water) = 3.3

Phenol coefficient: about 50

Refractive index:

n25 = 0.15204;

n20 = 0.15227.

Solubility: soluble 1 in 0.7–1.0 of chloroform, 1 in 1 of ethanol

(95%), 1 in 1.5 of ether, glacial acetic acid, 1 in 1.7–2.0 of olive oil, 1 in 1000 of water. Freely soluble in essential oils, fixed oils, and fats. Sparingly soluble in glycerin. Dissolves in dilute solutions of alkali hydroxides, forming salts that have increased solubility but whose solutions darken on standing.

Vapor pressure: 0.04 mmHg at 208C

Volatility appreciable volatility at 1008C; volatile in water vapor at 258C.

Stability and Storage Conditions

Thymol should be stored in well-closed, light-resistant contain- ers, in a cool, dry, place. Thymol is affected by light.

Incompatibilities

Thymol is incompatible with iodine, alkalis, and oxidizing agents. It liquefies, or forms soft masses, on trituration with acetanilide, antipyrine, camphor, monobromated camphor, chloral hydrate, menthol, phenol, or quinine sulfate.

Method of Manufacture

Thymol is obtained from the volatile oil of thyme (Thymus vulgaris Linne (Fam Labiatae)) by fractional distillation followed by extraction and recrystallization. Thyme oil yields about 20–30% thymol. Thymol may also be produced synthetically from p-cymene, menthone, or piperitone, or by the interaction of m-cresol with isopropyl chloride.

Safety

Thymol is used in cosmetics, foods, and pharmaceutical applications as an excipient. However, thymol may be irritating when inhaled or following contact with the skin or eyes. It may also cause abdominal pain and vomiting, and sometimes stimulation followed by depression of the central nervous system following oral consumption.

Respiratory arrest, attributed to acute nasal congestion and edema, has been reported in a 3-week-old patient due to the erroneous intranasal application of Karvol, a combination product that includes thymol. The patient recovered, but it was recommended that inhalation decongestants should not be used in children under the age of 5 years.(10)

heated to decomposition, carbon dioxide and carbon monoxide are formed.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (inhalation, liquid; oral, powder for solution). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

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