Table I: Synonyms of selected polyoxyethylene alkyl ethers.

Name Synonym

Cetomacrogol 1000 Polyethylene glycol 1000; macrocetyl ether; polyoxyethylene glycol 1000 monocetyl ether; Cresmer 1000. Polyoxyl 6 cetostearyl ether Ceteareth 6; Cremophor A6; Volpo CS6.

Polyoxyl 20 cetostearyl ether Atlas G-3713; Ceteareth 20; Cremophor A 20 polyether; Volpo CS20. Polyoxyl 25 cetostearyl ether Ceteareth 25; Cremophor A25; Volpo CS25.

Polyoxyl 2 cetyl ether Brij 52; ceteth-2; Lipocol C-2; Procol CA-2. Polyoxyl 10 cetyl ether Brij 56; ceteth-10; Lipocol C-10; Procol CA-10. Polyoxyl 20 cetyl ether Brij 58; ceteth-20; Lipocol C-20; Volpo C20.

Polyoxyl 4 lauryl ether Brij 30; laureth-4; Lipocol L-4; Procol LA-4; Tego Alkanol L4; Volpo L4. Polyoxyl 9 lauryl ether Laureth-9; lauromacrogol 400; polidocanol; Volpo L9.

Polyoxyl 23 lauryl ether Brij 35; laureth-23; Lipocol L-23; Procol LA-23; Ritox 35; Tego Alkanol L23 P. Polyoxyl 2 oleyl ether Brij 92; Brij 93; oleth-2; Lipocol O-2; Procol 0A-2; Ritoleth 2;Volpo N2.

Polyoxyl 10 oleyl ether Brij 96; Brij 97; oleth-10; polyethylene glycol monooleyl ether; Lipocol O-10; Procol OA-10; Ritoleth 10; Volpo N 10. Polyoxyl 20 oleyl ether Brij 98; Brij 99; Lipocol O-20; oleth-20; Procol OA-20; Ritoleth 20; Volpo N 20.

Polyoxyl 2 stearyl ether Brij 72; Lipocol S-2; Procol SA-2; steareth-2; Tego Alkanol S2; Volpo S-2. Polyoxyl 10 stearyl ether Brij 76; Lipocol S-10; Procol SA-10; steareth-10; Tego Alkanol S10; Volpo S-10. Polyoxyl 21 stearyl ether Brij 721; Ritox 721; steareth-21.

Polyoxyl 100 stearyl ether Brij 700; steareth-100.

Polyoxyethylene Alkyl Ethers 565

numbers quoted are average values. In cetomacrogol 1000, for example, x is 15 or 17, and y is 20–24.

Functional Category

Emulsifying agent; penetration enhancer; solubilizing agent; wetting agent.

Applications in Pharmaceutical Formulation or Technology

Polyoxyethylene alkyl ethers are nonionic surfactants widely used in topical pharmaceutical formulations and cosmetics, primarily as emulsifying agents for water-in-oil and oil-in-water emulsions; and the stabilization of microemulsions and multi- ple emulsions.

Polyoxyethylene alkyl ethers are used as solubilizing agents for essential oils, perfumery chemicals, vitamin oils, and drugs of low-water solubility such as cortisone acetate, griseofulvin, menadione,(1) chlordiazepoxide(2) and choles- terol.(3) They have applications as antidusting agents for powders; wetting and dispersing agents for coarse-particle liquid dispersions; and detergents, especially in shampoos, face washes and similar cosmetic cleaning preparations. They are used as gelling and foaming agents (e.g. Brij 72 gives a quick- breaking foam, while Brij 97 (15–20%), Volpo N series and Cremophor A25 (21–30%) give clear gels).

Polyoxyethylene alkyl ethers have been used in formulation of oleosomes, hydrosomes, phosphosomes, vesicles(4) and



niosomes.(5,6) An increased flux of estradiol niosomes through human stratum corneum in vitro has been demonstrated.(7)

Polyoxyethylene alkyl ethers have been found to have an enhancing effect on the skin permeation of drugs such as ibuprofen,(8) methyl nicotinate,(9) and clotrimazole.(10) Enhanced ocular absorption of insulin from eye drops,(11) and an ocular insert device,(12) have been observed using polyoxyethylene alkyl ethers in the formulation systems. Increased buccal absorption of verapamil through porcine esophageal mucosa has also been reported.(13)

Polyoxyethylene alkyl ethers have also been used in suppository formulations to increase the drug release from the suppository bases.(14–16)

Polyoxyethylene alkyl ethers (especially laureth-23) have been used as a solubilizer and coating agent to provide hydrophilicity to polymeric nanoparticles.(17–19)

Polyoxyethylene alkyl ethers such as polidocanol are suitable for use in injectable formulations as a solubilizer or dispersant.(20)

Description

Polyoxyethylene alkyl ethers vary considerably in their physical appearance from liquids, to pastes, to solid waxy substances. They are colorless, white, cream-colored or pale yellow materials with a slight odor.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for polyoxyethylene alkyl ethers.

 

Test JP 2001 PhEur 2005 PhEur 2005 PhEur 2005 PhEur 2005 USPNF 23 USPNF 23 USPNF 23 USPNF 23    

Lauro- Macrogol Macrogol Macrogol Macrogol Polyoxyl 20 Polyoxyl 10 Polyoxyl Polyoxyl    

macrogol cetostearyl stearyl lauryl ether oleyl ether cetostearyl oleyl ether lauryl ether stearyl    

ether ether ether ether    

Appearance of — + + + + — — + +    

solution    

Identification + + + + + + + + +    

Characters + + + + + — — — —    

Water — 43.0% 43.0% 43.0% 43.0% 41.0% 43.0% 43.0% 43.0%    

pH (10% solution) — — — — — 4.5–7.5 — — —    

Alkalinity — + + + + — — + +    

Acidity + — — — — — — — —    

Residue on 40.20% — — — — 40.4% 40.4% — —    

ignition    

Heavy metals — — — — — 40.002% 40.002% — —    

Acid value — 41.0 41.0 41.0 41.0 40.5 41.0 41.0 41.0    

Hydroxyl value — + + + + 42–60 75–95 + +    

Iodine value — 42.0 42.0 42.0 + — 23–40 42.0 42.0    

Saponification — 43.0 43.0 43.0 43.0 42.0 43.0 43.0 43.0    

value    

Free polyethylene — — — — — 47.5% 47.5% — —    

glycols    

Free ethylene — 41 ppm 41 ppm 41 ppm 41 ppm 40.01% 40.01% 41 mg/g 41 mg/g    

oxide    

Dioxan — 410 ppm 410 ppm 410 ppm 410 ppm — — 410 mg/g 410 mg/g    

Peroxide value — — — — 410.0 — — — —    

Average polymer — — — — — 17.2–25.0 8.6–10.4 ≈3.0–23.0 ≈2.0–20.0    

length    

Organic volatile — — — — — + + — —    

impurities    

Total ash — 40.2% — 40.2% 40.2% — — 40.2% —  

566 Polyoxyethylene Alkyl Ethers

Typical Properties

See Tables III and IV.

Stability and Storage Conditions

Polyoxyethylene alkyl ethers are chemically stable in strongly acidic or alkaline conditions. The presence of strong electro- lytes may, however, adversely affect the physical stability of emulsions containing polyoxyethylene alkyl ethers.

On storage, polyoxyethylene alkyl ethers can undergo autoxidation, resulting in the formation of peroxides with an increase in acidity. Many commercially available grades are thus supplied with added antioxidants. Typically, a mixture of 0.01% butylated hydroxyanisole and 0.005% citric acid is used for this purpose.

Polyoxyethylene alkyl ethers should be stored in an airtight container, in a cool, dry place.

Incompatibilities

Discoloration or precipitation may occur with iodides, mercury salts, phenolic substances, salicylates, sulfonamides, and tannins. Polyoxyethylene alkyl ethers are also incompatible with benzocaine, tretinoin(21) and oxidizable drugs.(22)

The antimicrobial efficacy of some phenolic preservatives, such as the parabens, is reduced owing to hydrogen bonding. Cloud points are similarly depressed by phenols owing to hydrogen bonding between ether oxygen atoms and phenolic hydroxyl groups. Salts, other than nitrates, iodides, and thiocyanates (which cause an increase) can also depress cloud points.(23)

Method of Manufacture

Polyoxyethylene alkyl ethers are prepared by the condensation of linear fatty alcohols with ethylene oxide. The reaction is controlled so that the required ether is formed with the polyethylene glycol of the desired molecular weight.

Safety

Polyoxyethylene alkyl ethers are used as nonionic surfactants in a variety of topical pharmaceutical formulations and cosmetics. The polyoxyethylene alkyl ethers form a series of materials with varying physical properties and manufacturers’ literature should be consulted for information on the applications and safety of specific materials.

Although generally regarded as essentially nontoxic and nonirritant materials, some polyoxyethylene alkyl ethers, particularly when used in high concentration (>20%), appear to have a greater irritant potential than others.

Animal toxicity studies suggest that polyoxyethylene alkyl ethers have a similar oral toxicity to other surfactants and can be regarded as being moderately toxic.

Polyoxyethylene cetyl ether:(24)

LD50 (mouse, oral): 2.60 g/kg

LD50 (rabbit, skin): 40 g/kg/4 week intermittent LD50 (rat, oral): 2.50 g/kg

Polyoxyethylene lauryl ether:(24)

LD50 (mouse, IP): 0.16 g/kg LD50 (mouse, IV): 0.10 g/kg LD50 (mouse, oral): 4.94 g/kg

LD50 (mouse, SC): 0.79 g/kg LD50 (rat, IV): 0.027 g/kg LD50 (rat, oral): 8.60 g/kg LD50 (rat, SC): 0.95 g/kg

Polyoxyethylene oleyl ether:(24)

LD50 (rat, oral): 25.8 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended.

Regulatory Status

Included in nonparenteral medicines licensed in the USA and UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Nonionic emulsifying wax.

Comments

Many other polyoxyethylene ethers are commercially available and are also used as surfactants. In addition to their surfactant properties, the series of polyoxyethylene ethers with lauryl side chains, e.g. nonoxynol 10, are also widely used as spermicides.

Specific References

Elworthy PH, Patel MS. Demonstration of maximum solubiliza- tion in a polyoxyethylene alkyl ether series of non-ionic surfactants. J Pharm Pharmacol 1982; 34: 543–546.

Abdel Rahman AA, Aboutaleb AE, Samy EM. Factors affecting chlordiazepoxide solubilization by non-ionic surfactants. Bull Pharm Sci 1991; 14(1–2): 35–45.

Mueller-Goymann CC, Usselmann B. Solubilization of cholesterol in liquid crystals of aqueous systems of polyoxyethylene cetyl ethers. Acta Pharm Jugosl 1988; 38(4): 327–329.

Friberg SE, Yang H, Fei L, Sadasivan S, et al. Preparation of vesicles from hydrotope solutions. J Dispersion Sci Technol 1998; 19(1): 19–30.

Arunothayanun P, Uchegbu IF, Craig DQ, et al. In vitro/in vivo characterization of polyhedral niosomes. Int J Pharm. 1999; 183(1): 57–61.

Parthasarathi G, Udupa N, Pillai GK. Formulations and in vitro evaluation of vincristine encapsulated niosomes. Int J Pharm 1994; 56(3): 90–94.

Van Hal D, Van Rensen A, De Vringer T, et al. Diffusion of estradiol from non-ionic surfactant vesicles through human stratum corneum in vitro. STP Pharm Sci 1996; 6(1): 72–78.

Park ES, Chang SY, Hahn M, Chi SC. Enhancing effect of polyoxyethylene alkyl ethers on the skin permeation of ibuprofen. Int J Pharm 2001; 218(1–2): 167–168.

Ashton P, Walters KA, Brain KR, Hadgraft J. Surfactant effects in percutaneous absorption. Part 1. Effects on the transdermal flux of methyl nicotinate. Int J Pharm 1992; 87(10): 261–264.

Ibrahim SA, Hafez E, El-Shanawany SM, et al. Formulation and evaluation of some topical anti mycotics. Part 3. Effect of promoters on the in vitro and in vivo efficacy of clotrimazole ointment. Bull Pharm Sci 1991; 14(1–2): 82–94.

Zhang WY, Zhang LH. Study of absorption enhancers of insulin eye drops. J China Pharm Univ 1997; 28(5): 275–277.