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Ethylparaben Excipient | Uses, Suppliers, and Specifications

Ethylparaben is ethyl-4-hydroxybenzoate, a member of a family of alky esters of para-hydroxybenzoic acid differing by their chemical substituents on the benzene ring. Ethylparaben occurs as a white or colourless powder or crystalline, odourless, and tasteless powder.

Synonyms and Trade Names: Ethylparaben, Ethyl p-hydroxybenzoate; 4-Hydroxybenzoic Acid Ethyl Ester; CoSept E; Tegosept E; Trisept E; Unisept E

Pharmacopoeial Compliance: USP-NF; Ph. Eur; J.P; I.P

Uses and Applications: Antimicrobial Preservative in Pharmaceutical and Cosmetic formulations

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Ethylparaben - Sharon Laboratories

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CoSept® E - HallStar Inc

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Description

Ethylparaben (IUPAC name: Ethyl 4-hydroxybenzoate, and also known as Ethyl 4-hydroxybenzoate, Ethyl p-hydroxybenzoate or 4-hydroxybenzoic acid ethyl ester) is a member of a family of alkyl esters of para-hydroxybenzoic acid commonly known commonly as parabens. Ethylparaben is obtained synthetically from the formal condensation of the carboxy group of 4-hydroxybenzoic acid with ethanol. It is one of the parabens approved for use as an antimicrobial preservative in pharmaceutical products.

Parabens are a family of alkylated esters of para-Hydroxybenzoic acid (PHBA), and indeed, the term ‘paraben’ is a contraction of para-Hydroxybenzoic acid, a naturally occurring substance found in several fruits and vegetables, such as berries, cucumbers and onions. Respective parabens are obtained from the formal condensation of the carboxy group of PHBA with a suitable alkanol. Parabens are possibly the most commonly used antimicrobial substances in personal care, pharmaceutical formulations and industrial products.

The antimicrobial properties of parabens and their potential as preservatives were first demonstrated in the early 1920s, and subsequently introduced into cosmetic formulations as well as pharmaceutical and food products in the 1930s. Currently, there are seven documented parabens which differ at the para position of the benzene ring by the different chemical substituents, namely:

  • Methylparaben
  • Ethylparaben
  • Propylparaben
  • Butylparaben,
  • Isopropylparaben,
  • Isobutylparaben, and
  • Benzylparaben

Chemical substitutions provide each paraben with different solubility characteristics and antimicrobial activity.

In addition, 12 paraben salts are also documented and include Calcium paraben, Potassium Methylparaben, Potassium Butylparaben, Potassium Ethylparaben, Potassium Paraben, Potassium Propylparaben, Sodium Butylparaben, Sodium Ethylparaben, Sodium Isobutylparaben, Sodium Paraben, Sodium Isopropylparaben and Sodium Propylparaben.

In reality, only four parabens (and their corresponding sodium salts) are widely marketed and or approved for pharmaceutical use and include Methyl-, Ethyl-, Propyl-, and Butylparaben. Their respective structures and chemical substituents are shown below:

 

 

 

 

OH(C6H5)COOR

 

 

 

Paraben     R
 Methylparaben     -CH3
 Ethylparaben     -CH2CH3
 Propylparaben     -CH2CH2CH3
 Butylparaben     -CH2CH2CH2CH3

Parabens have come under increased scrutiny in recent years after the emergency of evidence suggesting a link between parabens and breast cancer and testosterone levels. Health authorities and the Cosmetic Ingredient Review Expert Panel have reevaluated their safety in recent years, and for now, Methyl-, Ethyl-, Propyl-, and Butylparaben are approved for use in pharmaceutical products. Methyl, Ethyl and Propylparaben are approved for cosmetics while Methylparaben can be used in certain food products.

Ethylparaben occurs as a white, odourless or almost odourless, crystalline powder.

Chemical Structure & Identifiers


Chemical Name 4-Hydroxybenzoic acid ethyl ester
CAS Registry Number [120-47-8]
Empirical Formula C9H10O3
Molecular Weight 166.17
EC Number 204-399-4
UNII Code (FDA) 14255EXE39

Regulatory Status

Ethylparaben is an approved pharmaceutical excipient and is listed in the B.P; USP-NF, Ph.Eur, J.P, I.P and Ch.P. It is included in the FDA Inactive Ingredients Database (covering oral and topical formulations). Ethylparaben is also approved for use in cosmetics and other personal care products.

Physicochemical Properties

Physical state Solid
Appearance Colourless crystalline or a white crystalline powder
True density 1.168 g/ml
Melting point 115 – 118 oC
Boiling point 287 – 298 oC
Flash Point 121 oC
Log P (computed) 2.03
Dissociation constant pKa = 8.4 (22 oC)
Partition coefficients 0.13 (Mineral oil:water)
Solubility (in 100g) 25oC

Water

Ethanol (95%)

Propylene glycol

Mineral Oil

Propylene glycol

 

<0.01%

Soluble

Soluble

<0.1%

Fairly soluble

Refractive index 1.538o

Pharmacopeoeal Specifications

Test J.P B.P Ph,Eur USP-NF
Official name Ethyl Parahydroxybenzoate Ethyl Hydroxybenzoate Ethyl Parahydroxybenzoate Ethylparaben
Authorised use Excipient Excipient Excipient Excipient
Definition specified specified specified specified
Identification specified specified specified specified
Appearance of solution specified specified specified specified
Characters n/a specified specified n/a
Heavy metals ≤20ppm n/a n/a n/a
Acidity specified specified specified specified
Melting range 115-118 oC n/a n/a 115-118 oC
Related substances specified specified specified specified
Residue on ignition ≤0.1% ≤0.1% ≤0.1% ≤0.1%
Assay (dried basis) 98.0 – 102.0% 98.0 – 102.0% 98.0 – 102.0% 98.0 – 102.0%

Key: n/a Specification is not listed

*All claims with respect to conformity are subject to our Terms and Conditions. No express or implied warranty is made for specific properties or fitness for any particular application or purpose.

Applications in Pharmaceutical Formulations or Technology

The main use of Ethylparaben in pharmaceutical products is as an antimicrobial preservative. It is also similarly used in cosmetic, food and industrial products, and may be used either alone or in combination with other paraben esters or with other antimicrobial agents. In cosmetics, it is one of the most frequently used preservatives.

Parabens are generally popular because they are inexpensive, colourless, odourless, and nontoxic. They are also effective over a wide pH range and have a wide spectrum of antimicrobial activity.

Generally, longer chained parabens possess greater antimicrobial properties but they are limited by their lower aqueous solubility, thus making the shorter-chained parabens, i.e Methyl and Propylparaben best suited for use in oral products. Long-chained parabens are best suited for topical products, especially if they are rich in lipophilic content.

Parabens are effective against the growth of yeasts and molds at much lower concentrations compared with benzoic acid, although they are less active against bacteria, especially Gram-negative organisms. However, unlike benzoic acid, parabens retain their efficacy at higher pH levels (of up to 8.0), making them a suitable choice for products of pH close to neutral pH.

Where solubility of a particular paraben limits usage, paraben salts (especially the sodium salt) can be used in the formulations. However, they may raise the pH of the formulation unless buffered.

Safety and Precautions

The antimicrobial properties of parabens have been known for almost a century and utilised for over nine decades. They are currently added to cosmetic, food and pharmaceutical products. Ethylparaben is approved for direct addition to food. In the past parabens were used as preservatives in injections and ophthalmic preparations. They are now generally considered inappropriate for these types of dosage forms due to the irritant potential of parabens.

In spite of their effectiveness and many years of use, parabens have attracted scrutiny across the world and within the scientific community. Their potential to cause several health problems, including breast cancer, reproductive health problems and allergies has been widely discussed.

These concerns have led to a number of acute, subchronic, and chronic toxicity tests to be performed on the parabens using a wide variety of routes of administration. From these data, it has been established that parabens exhibit a very low potential of toxicity and should be considered safe in this respect for cosmetic and pharmaceutical uses in the quantities typically used as preservatives.

When tested on human skin, each of the parabens only produced evidence of irritation in concentrations that exceeded 5 to 12 per cent, which is several orders of magnitude typically used in formulations. Therefore, it has been concluded that the parabens are relatively nonirritating at the concentrations used in cosmetic products.

Parabens are considered nonteratogenic and noncarcinogenic. Sensitization is rarely observed, and they do not exhibit significant levels of photocontact sensitization or phototoxicity. However, hypersensitivity reactions, mostly of the delayed type, occurring as contact dermatitis, have been described. However, given the widespread use of parabens as preservatives, such reactions are comparatively rare. Therefore, the categorisation of parabens in certain quarters as high-rate sensitizers may be exaggerated.

Immediate hypersensitivity reactions upon injection of products formulated with parabens have also been documented. Surprisingly, products containing parabens may be used by patients who have reacted previously with contact dermatitis provided they are applied to another, unaffected, site. This phenomenon is known as the paraben paradox.

The JEFCA/WHO has set an estimated total acceptable daily intake for Methyl-, Ethyl-, and Propylparaben at up to 10mg/kg body- weight.

Toxicology: LD40 (mouse, IP): 0.96 kg

Stability and Storage Conditions

Parabens are chemically stable and effective over a wide pH range, with wide antimicrobial activity, particularly against Gram-positive bacteria and fungi (including molds). Aqueous solutions at pH 3 – 6 are stable (less than 10% decomposition) for up to about 48 months under ambient conditions. However, the same solutions maintained at ≥pH 8 undergo rapid degradation (≥10% after 2 months of storage under ambient conditions).

Ethylparaben is assigned a shelf-life of 24-36 months. The bulk material should be stored in a well-dosed container in a cool, dry place.

When processing Ethylparaben, observe applicable SHEQ protocols appropriate to the circumstances and quantity of material being handled. As Methylparaben may be an irritant to the skin, eyes, and mucous membranes, it should be handled in a well-ventilated environment. Suitable PPE (eye protection, gloves, and a dust mask or respirator) is recommended.

Sustainability and Environmental Impact

A sustainability assessment for Ethylparaben has not been undertaken. Although a number of parabens occur naturally, commercial products are products of industrial synthetic chemistry. The long-term impact of parabens on human and animal health, and on ecosystems is currently a matter of great debate. There is evidence that they may be endocrine disruptors, this effect being pertinent to wastewater discharges.

Manufacturers & Suppliers

Clariant International

  • NIPAGIN® A

Indukern AG

  • Uniphen® P-23 NIB

Sharon Laboratories

  • Ethylparaben

HallStar Inc

  • CoSept® E

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References and Literature Used

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