Propylparaben

Nonproprietary Names

BP: Propyl hydroxybenzoate

JP: Propyl parahydroxybenzoate PhEur: Propylis parahydroxybenzoas USPNF: Propylparaben

Synonyms

E216; 4-hydroxybenzoic acid propyl ester; Nipasol M; propagin; propyl p-hydroxybenzoate; Propyl parasept; Solbrol P; Uniphen P-23.

Chemical Name and CAS Registry Number

Propyl 4-hydroxybenzoate [94-13-3]

Empirical Formula and Molecular Weight

C10H12O3 180.20

Structural Formula

 

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Propylparaben is widely used as an antimicrobial preservative in cosmetics, food products, and pharmaceutical formulations; see Table I.

It may be used alone, in combination with other paraben esters, or with other antimicrobial agents. It is one of the most frequently used preservatives in cosmetics.(1)

The parabens are effective over a wide pH range and have a broad spectrum of antimicrobial activity, although they are most effective against yeasts and molds; see Section 10.

Owing to the poor solubility of the parabens, the paraben salts, particularly the sodium salt, are frequently used in formulations. This may cause the pH of poorly buffered formulations to become more alkaline.

Propylparaben (0.02% w/v) together with methylparaben (0.18% w/v) has been used for the preservation of various parenteral pharmaceutical formulations; see Section 14.

See Methylparaben for further information.

Table I: Uses of propylparaben in pharmaceutical preparations.

 

Use Concentration (%)    

IM, IV, SC injections 0.005–0.2    

Inhalation solutions 0.015    

Intradermal injections 0.02–0.26    

Nasal solutions 0.017    

Ophthalmic preparations 0.005–0.01    

Oral solutions and suspensions 0.01–0.02    

Rectal preparations 0.02–0.01    

Topical preparations 0.01–0.6    

Vaginal preparations 0.02–0.1  

Description

Propylparaben occurs as a white, crystalline, odorless, and tasteless powder.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for propylparaben.

 

Test JP 2001 PhEur 2005 USPNF 23    

Identification + + +    

Melting range 96.0–99.08C — 95.0–98.08C    

Acidity — + —    

Loss on drying 40.5% — 40.5%    

Residue on ignition 40.1% — 40.05%    

Sulfated ash — 40.1% —    

Appearance of — + —    

solution    

Chloride 40.035% — —    

Sulfate 40.024% — —    

Parahydroxy benzoic + — —    

acid and salicylic    

acid    

Heavy metals 420 ppm — —    

Related substances — + —    

Readily carbonizable + — —    

substances    

Organic volatile — — +    

impurities    

Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5%  

Typical Properties

Antimicrobial activity: propylparaben exhibits antimicrobial activity between pH 4–8. Preservative efficacy decreases with increasing pH owing to the formation of the phenolate anion. Parabens are more active against yeasts and molds than against bacteria. They are also more active against Gram-positive than against Gram-negative bacteria. The activity of the parabens increases with increasing chain length of the alkyl moiety; however, solubility decreases.

630 Propylparaben

Activity may be improved by using combinations of parabens, as additive effects occur. Propylparaben has been used with methylparaben in parenteral preparations, and is used in combination with other parabens in topical and oral formulations. Activity has also been reported to be improved by the addition of other excipients; see Methyl- paraben.

Reported minimum inhibitory concentrations (MICs) for propylparaben are provided in Table III.(2)

Table III: Minimum inhibitory concentrations (MICs) for propylparaben in aqueous solution.(2)

Microorganism MIC (mg/mL)

Aerobacter aerogenes ATCC 8308 1000

Aspergillus niger ATCC 9642 500

Aspergillus niger ATCC 10254 200

Bacillus cereus var. mycoides ATCC 6462 125

Bacillus subtilis ATCC 6633 500

Candida albicans ATCC 10231 250

Enterobacter cloacae ATCC 23355 1000

Escherichia coli ATCC 8739 500

Escherichia coli ATCC 9637 100

Klebsiella pneumoniae ATCC 8308 500

Penicillium chrysogenum ATCC 9480 125

Penicillium digitatum ATCC 10030 63

Proteus vulgaris ATCC 13315 250

Pseudomonas aeruginosa ATCC 9027 >1000

Pseudomonas aeruginosa ATCC 15442 >1000

Pseudomonas stutzeri 500

Rhizopus nigricans ATCC 6227A 125

Saccharomyces cerevisiae ATCC 9763 125

Table V: Solubility of propylparaben in various solvents.(2)

Solvent Solubility at 208C

unless otherwise stated

Acetone Freely soluble

Ethanol (95%) 1 in 1.1

Ethanol (50%) 1 in 5.6

Ether Freely soluble

Glycerin 1 in 250

Mineral oil 1 in 3330

Peanut oil 1 in 70

Propylene glycol 1 in 3.9

Propylene glycol (50%) 1 in 110

Water 1 in 4350 at 158C

1 in 2500

1 in 225 at 808C

Stability and Storage Conditions

Aqueous propylparaben solutions at pH 3–6 can be sterilized by autoclaving, without decomposition.(4) At pH 3–6, aqueous solutions are stable (less than 10% decomposition) for up to about 4 years at room temperature, while solutions at pH 8 or above are subject to rapid hydrolysis (10% or more after about 60 days at room temperature).(5)

See Table VI, for the predicted rate constants and half-lives at 258C for propylparaben.(5)

Propylparaben should be stored in a well-closed container in a cool, dry place.

Table VI: Predicted rate constants and half-lives at 258C for propylparaben dissolved in hydrochloric acid solution.

Salmonella typhosa ATCC 6539 500

Serratia marcescens ATCC 8100 500

Staphylococcus aureus ATCC 6538P 500

Initial pH of solution

Rate constant

k  s(a) (h—1)

Half-life

t1/2  s(a) (day)

Boiling point: 2958C

Density (bulk): 0.426 g/cm3 Density (tapped): 0.706 g/cm3 Density(true): 1.288 g/cm3

Dissociation constant: pKa = 8.4 at 228C

Flash point: 1408C

Partition coefficients: values for different vegetable oils vary considerably and are affected by the purity of the oil; see



(a) s indicates the standard error.

The predicted amount of propylparaben remaining after autoclaving is given in Table VII.(5)

Table VII: Predicted amount of propylparaben dissolved in hydrochloric acid, after autoclaving.

Table IV.

Initial pH of solution Rate constant

k  s(a) (h—1)

Predicted residual

amount after sterilization (%)

Table IV: Partition coefficients for propylparaben in vegetable oil and water.(3)



1 (4.42  0.10) × 10—1 86.30  0.30

2 (4.67 0.19) × 10–2 98.46 0.06

Refractive index: n14 = 1.5049

Solubility: see Table V.

3 (2.96  0.24) × 10–3 99.90  0.01

4 (7.8  1.1) × 10–4 99.97  0.004

(a) s indicates the standard error.

Incompatibilities

The antimicrobial activity of propylparaben is reduced considerably in the presence of nonionic surfactants as a result of micellization.(6) Absorption of propylparaben by plastics has been reported, with the amount absorbed dependent upon the

Propylparaben 631

type of plastic and the vehicle.(7) Magnesium aluminum silicate, magnesium trisilicate, yellow iron oxide, and ultramarine blue have also been reported to absorb propylparaben, thereby reducing preservative efficacy.(8,9)

Propylparaben is discolored in the presence of iron and is subject to hydrolysis by weak alkalis and strong acids.

See also Methylparaben.

Method of Manufacture

Propylparaben is prepared by the esterification of p-hydroxy- benzoic acid with n-propanol.

Safety

Propylparaben and other parabens are widely used as antimicrobial preservatives in cosmetics, food products, and oral and topical pharmaceutical formulations.

Propylparaben and methylparaben have been used as preservatives in injections and ophthalmic preparations; how- ever they are now generally regarded as being unsuitable for these types of formulations owing to the irritant potential of the parabens.

Systemically, no adverse reactions to parabens have been reported, although they have been associated with hypersensi- tivity reactions. The WHO has set an estimated acceptable total daily intake for methyl, ethyl, and propyl parabens at up to 10 mg/kg body-weight.(10)

LD50 (mouse, IP): 0.2 g/kg(11) LD50 (mouse, oral): 6.33 g/kg LD50 (mouse, SC): 1.65 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Propylparaben may be irritant to the skin, eyes, and mucous membranes and should be handled in a well-ventilated environment. Eye protection, gloves, and a dust mask or respirator are recommended.

Regulatory Status

Propylparaben and methylparaben are affirmed GRAS direct food substances in the USA at levels up to 0.1%. All esters except the benzyl ester are allowed for injection in Japan.

In cosmetics, the EU and Brazil allow use of each paraben at 0.4%, but the total of all parabens may not exceed 0.8%. The upper limit in Japan is 1.0%.

Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections; inhala- tions; ophthalmic preparations; oral capsules, solutions, suspensions, and tablets; otic, rectal, topical, and vaginal preparations). Included in parenteral and nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Butylparaben; ethylparaben; methylparaben; propylparaben potassium; propylparaben sodium.

Propylparaben potassium Empirical formula: C10H11KO3 Molecular weight: 218.30

CAS number: [84930-16-5]



Synonyms: potassium propyl hydroxybenzoate; propyl 4-hydroxybenzoate potassium salt.

Propylparaben sodium

Empirical formula: C10H11NaO3

Molecular weight: 202.20

CAS number: [35285-69-9]

Synonyms: E217; propyl 4-hydroxybenzoate sodium salt; sodium propyl hydroxybenzoate; soluble propyl hydroxy- benzoate.

Appearance: white, odorless or almost odorless, hygroscopic crystalline powder.

Acidity/alkalinity: pH = 9.5–10.5 (0.1% w/v aqueous solu- tion).

Solubility: 1 in 50 of ethanol (95%); 1 in 2 ethanol (50%); 1 in 1 of water; practically insoluble in fixed oils.

Comments: propylparaben sodium may be used instead of propylparaben because of its greater aqueous solubility. However, it may cause the pH of a formulation to become more alkaline.

Comments

A specification for propylparaben is contained in the Food Chemicals Codex (FCC). The EINECS number for propyl- paraben is 202-307-7.

See Methylparaben for further information and references.

Specific References

Decker RL, Wenninger JA. Frequency of preservative use in cosmetic formulas as disclosed to FDA—1987. Cosmet Toilet 1987; 102(12): 21–24.

Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid. In: Kabara JJ, ed. Cosmetic and Drug Preservation. New York: Marcel Dekker, 1984: 63–77.

Wan LSC, Kurup TRR, Chan LW. Partition of preservatives in oil/ water systems. Pharm Acta Helv 1986; 61: 308–313.

Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters as preservatives I: uses, antibacterial and antifungal studies, properties and determination. J Am Pharm Assoc (Sci) 1953; 42: 449–457.

Kamada A, Yata N, Kubo K, Arakawa M. Stability of p- hydroxybenzoic acid esters in acidic medium. Chem Pharm Bull 1973; 21: 2073–2076.

Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of surface active agents to pharmaceutical preparations I: effect of Tween 20 upon the antifungal activities of p-hydroxybenzoic acid esters in solubilized preparations [in Japanese]. J Pharm Soc Jpn 1956; 76: 939–943.

Kakemi K, Sezaki H, Arakawa E, et al. Interactions of parabens and other pharmaceutical adjuvants with plastic containers. Chem Pharm Bull 1971; 19: 2523–2529.

Allwood MC. The adsorption of esters of p-hydroxybenzoic acid by magnesium trisilicate. Int J Pharm 1982; 11: 101–107.

Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of some cosmetic pigments on the bactericidal activities of preservatives. J Soc Cosmet Chem 1987; 38: 83–98.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2053.

632 Propylparaben

General References

Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical excipients: adverse effects associated with inactive ingredients in drug products (part I). Med Toxicol 1988; 3: 128–165.

Jian L, Li Wan Po A. Ciliotoxicity of methyl- and propyl-p- hydroxybenzoates: a dose-response and surface-response study. J Pharm Pharmacol 1993; 45: 925–927.

Authors

R Johnson, R Steer.

Date of Revision

23 August 2005.