Name: Polyethylene Glycol
CAS No: a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl) [25322-68-3]
BP: Macrogols JP: Macrogol 400 Macrogol 1500 Macrogol 4000 Macrogol 6000 Macrogol 20000 PhEur: Macrogols USP-NF: Polyethylene Glycol
Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; macrogola; PEG; Pluriol E; polyoxyethylene glycol.
a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl) [25322-68-3]
HOCH2(CH2OCH2)mCH2OH where m represents the average number of oxyethylene groups. Alternatively, the general formula H(OCH2CH2)nOH may be used to represent polyethylene glycol, where n is a number m in the previous formula þ 1. See Table I for the average molecular weights of typical polyethylene glycols. Note that the number that follows PEG indicates the average molecular weight of the polymer.
Polyethylene glycols (PEGs) are widely used in a variety of pharmaceutical formulations, including parenteral, topical, ophthalmic, oral, and rectal preparations. Polyethylene glycol has been used experimentally in biodegradable polymeric matrices used in controlled-release systems.(1) Polyethylene glycols are stable, hydrophilic substances that are essentially nonirritant to the skin; see Section 14. They do not readily penetrate the skin, although the polyethylene glycols are water-soluble and are easily removed from the skin by washing, making them useful as ointment bases.(2) Solid grades are generally employed in topical ointments, with the consistency of the base being adjusted by the addition of liquid grades of polyethylene glycol. Mixtures of polyethylene glycols can be used as suppository bases,(3) for which they have many advantages over fats. For example, the melting point of the suppository can be made higher to withstand exposure to warmer climates; release of the drug is not dependent upon melting point; the physical stability on storage is better; and suppositories are readily miscible with rectal fluids. Polyethylene glycols have the following disadvantages: they are chemically more reactive than fats; greater care is needed in processing to avoid inelegant contraction holes in the suppositories; the rate of release of water-soluble medications decreases with the increasing molecular weight of the polyethylene glycol; and polyethylene glycols tend to be more irritating to mucous membranes than fats. Aqueous polyethylene glycol solutions can be used either as suspending agents or to adjust the viscosity and consistency of other suspending vehicles. When used in conjunction with other emulsifiers, polyethylene glycols can act as emulsion stabilizers. Liquid polyethylene glycols are used as water-miscible solvents for the contents of soft gelatin capsules. However, they may cause hardening of the capsule shell by preferential absorption of moisture from gelatin in the shell. In concentrations up to approximately 30% v/v, PEG 300 and PEG 400 have been used as the vehicle for parenteral dosage forms. In solid-dosage formulations, higher-molecular-weight polyethylene glycols can enhance the effectiveness of tablet binders and impart plasticity to granules.(4) However, they have only limited binding action when used alone, and can prolong disintegration if present in concentrations greater than 5% w/w. When used for thermoplastic granulations,(5–7) a mixture of the powdered constituents with 10–15% w/w PEG 6000 is heated to 70–758C. The mass becomes pastelike and forms granules if stirred while cooling. This technique is useful for the preparation of dosage forms such as lozenges when prolonged disintegration is required. Polyethylene glycols can also be used to enhance the aqueous solubility or dissolution characteristics of poorly soluble compounds by making solid dispersions with an appropriate polyethylene glycol.(8) Animal studies have also been performed using polyethylene glycols as solvents for steroids in osmotic pumps. In film coatings, solid grades of polyethylene glycol can be used alone for the film-coating of tablets or can be useful as hydrophilic polishing materials. Solid grades are also widely used as plasticizers in conjunction with film-forming polymers.(9) The presence of polyethylene glycols in film coats, especially of liquid grades, tends to increase their water permeability and may reduce protection against low pH in enteric-coating films. Polyethylene glycols are useful as plasticizers in microencapsulated products to avoid rupture of the coating film when the microcapsules are compressed into tablets. Polyethylene glycol grades with molecular weights of 6000 and above can be used as lubricants, particularly for soluble tablets. The lubricant action is not as good as that of magnesium stearate, and stickiness may develop if the material becomes too warm during compression. An antiadherent effect is also exerted, again subject to the avoidance of overheating. Polyethylene glycols have been used in the preparation of urethane hydrogels, which are used as controlled-release agents. Polyethylene glycol has also been used in insulin-loaded microparticles for the oral delivery of insulin;(10,11) it has been used in inhalation preparations to improve aerosolization;(12) polyethylene glycol nanoparticles have been used to improve the oral bioavailability of cyclosporine;(13) it has been used in self-assembled polymeric nanoparticles as a drug carrier;(14) and copolymer networks of polyethylene glycol grafted with poly(methacrylic acid) have been used as bioadhesive controlled drug delivery formulations.(15)
The USP32–NF27 describes polyethylene glycol as being an addition polymer of ethylene oxide and water. Polyethylene glycol grades 200–600 are liquids; grades 1000 and above are solids at ambient temperatures. Liquid grades (PEG 200–600) occur as clear, colorless or slightly yellow-colored, viscous liquids. They have a slight but characteristic odor and a bitter, slightly burning taste. PEG 600 can occur as a solid at ambient temperatures. Solid grades (PEG>1000) are white or off-white in color, and range in consistency from pastes to waxy flakes. They have a faint, sweet odor. Grades of PEG 6000 and above are available as freeflowing milled powders.
See Table II.
Density 1.11–1.14 g/cm3 at 258C for liquid PEGs; 1.15–1.21 g/cm3 at 258C for solid PEGs. Flash point 1828C for PEG 200; 2138C for PEG 300; 2388C for PEG 400; 2508C for PEG 600. Freezing point <658C PEG 200 sets to a glass; 15 to 88C for PEG 300; 4–88C for PEG 400; 15–258C for PEG 600. Melting point 37–408C for PEG 1000; 44–488C for PEG 1500; 40–488C for PEG 1540; 45–508C for PEG 2000; 48–548C for PEG 3000; 50–588C for PEG 4000; 55–638C for PEG 6000; 60–638C for PEG 8000; 60–638C for PEG 20000. Moisture content Liquid polyethylene glycols are very hygroscopic, although hygroscopicity decreases with increasing molecular weight. Solid grades, e.g. PEG 4000 and above, are not hygroscopic. See Figures 1, 2, and 3. Particle size distribution see Figures 4 and 5. Refractive index nD 25 = 1.459 for PEG 200; nD 25 = 1.463 for PEG 300; nD 25 = 1.465 for PEG 400; nD 25 = 1.467 for PEG 600. Solubility All grades of polyethylene glycol are soluble in water and miscible in all proportions with other polyethylene glycols (after melting, if necessary). Aqueous solutions of highermolecular- weight grades may form gels. Liquid polyethylene glycols are soluble in acetone, alcohols, benzene, glycerin, and glycols. Solid polyethylene glycols are soluble in acetone, dichloromethane, ethanol (95%), and methanol; they are slightly soluble in aliphatic hydrocarbons and ether, but insoluble in fats, fixed oils, and mineral oil. Surface tension Approximately 44mN/m (44 dynes/cm) for liquid polyethylene glycols; approximately 55mN/m (55 dynes/cm) for 10% w/v aqueous solution of solid polyethylene glycol. Viscosity (kinematic) see Tables IV, V, and VI.
Polyethylene glycols are chemically stable in air and in solution, although grades with a molecular weight less than 2000 are hygroscopic. Polyethylene glycols do not support microbial growth, and they do not become rancid. Polyethylene glycols and aqueous polyethylene glycol solutions can be sterilized by autoclaving, filtration, or gamma irradiation.(16) Sterilization of solid grades by dry heat at 1508C for 1 hour may induce oxidation, darkening, and the formation of acidic degradation products. Ideally, sterilization should be carried out in an inert atmosphere. Oxidation of polyethylene glycols may also be inhibited by the inclusion of a suitable antioxidant. If heated tanks are used to maintain normally solid polyethylene glycols in a molten state, care must be taken to avoid contamination with iron, which can lead to discoloration. The temperature must be kept to the minimum necessary to ensure fluidity; oxidation may occur if polyethylene glycols are exposed for long periods to temperatures exceeding 508C. However, storage under nitrogen reduces the possibility of oxidation. Polyethylene glycols should be stored in well-closed containers in a cool, dry place. Stainless steel, aluminum, glass, or lined steel containers are preferred for the storage of liquid grades.
The chemical reactivity of polyethylene glycols is mainly confined to the two terminal hydroxyl groups, which can be either esterified or etherified. However, all grades can exhibit some oxidizing activity owing to the presence of peroxide impurities and secondary products formed by autoxidation. Liquid and solid polyethylene glycol grades may be incompatible with some coloring agents. The antibacterial activity of certain antibiotics is reduced in polyethylene glycol bases, particularly that of penicillin and bacitracin. The preservative efficacy of the parabens may also be impaired owing to binding with polyethylene glycols. Physical effects caused by polyethylene glycol bases include softening and liquefaction in mixtures with phenol, tannic acid, and salicylic acid. Discoloration of sulfonamides and dithranol can also occur, and sorbitol may be precipitated from mixtures. Plastics, such as polyethylene, phenolformaldehyde, polyvinyl chloride, and cellulose-ester membranes (in filters) may be softened or dissolved by polyethylene glycols. Migration of polyethylene glycol can occur from tablet film coatings, leading to interaction with core components.
Polyethylene glycol polymers are formed by the reaction of ethylene oxide and water under pressure in the presence of a catalyst.
Polyethylene glycols are widely used in a variety of pharmaceutical formulations. Generally, they are regarded as nontoxic and nonirritant materials.(17–19) Adverse reactions to polyethylene glycols have been reported, the greatest toxicity being with glycols of low molecular weight. However, the toxicity of glycols is relatively low. Polyethylene glycols administered topically may cause stinging, especially when applied to mucous membranes. Hypersensitivity reactions to polyethylene glycols applied topically have also been reported, including urticaria and delayed allergic reactions.(20) The most serious adverse effects associated with polyethylene glycols are hyperosmolarity, metabolic acidosis, and renal failure following the topical use of polyethylene glycols in burn patients.(21) Topical preparations containing polyethylene glycols should therefore be used cautiously in patients with renal failure, extensive burns, or open wounds. Oral administration of large quantities of polyethylene glycols can have a laxative effect. Therapeutically, up to 4 L of an aqueous mixture of electrolytes and high-molecular-weight polyethylene glycol is consumed by patients undergoing bowel cleansing.(22) Liquid polyethylene glycols may be absorbed when taken orally, but the higher-molecular-weight polyethylene glycols are not significantly absorbed from the gastrointestinal tract. Absorbed polyethylene glycol is excreted largely unchanged in the urine, although polyethylene glycols of low molecular weight may be partially metabolized. The WHO has set an estimated acceptable daily intake of polyethylene glycols at up to 10 mg/kg body-weight.(23) In parenteral products, the maximum recommended concentration of PEG 300 is approximately 30% v/v as hemolytic effects have been observed at concentrations greater than about 40% v/v. For animal toxicity data, see Table VII.(24)
Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection is recommended.
Included in the FDA Inactive Ingredients Database (dental preparations; IM and IV injections; ophthalmic preparations; oral capsules, solutions, syrups, and tablets; rectal, topical, and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
Polyoxyethylene alkyl ethers; polyethylene oxide; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates; suppository bases.
Polyethylene glycol is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the ‘State of Work’ document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. A specification for polyethylene glycol is contained in the Food Chemicals Codex (FCC).(25)