Polyethylene glycol

Polyethylene glycol
IUPAC name poly(oxyethylene) {structure-based}, poly(ethylene oxide) {source-based}[1]
Other names Carbowax, GoLYTELY, GlycoLax, Fortrans, TriLyte, Colyte, Halflytely, Macrogol, MiraLAX, MoviPrep
Identifiers
CAS number	25322-68-3 Y
ChEMBL	CHEMBL1201478 N
Properties
Molecular formula	C2nH4n+2On+1
Molar mass	variable
Hazards
Flash point	182 - 287 °C
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Polyethylene glycol (PEG) is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular weight, and under the tradename Carbowax.

Available forms

PEG, PEO, or POE refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but historically PEG has tended to refer to oligomers and polymers with a molecular mass below 20,000 g/mol, PEO to polymers with a molecular mass above 20,000 g/mol, and POE to a polymer of any molecular mass.^[2] PEG and PEO are liquids or low-melting solids, depending on their molecular weights. PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g/mol to 10,000,000 g/mol. While PEG and PEO with different molecular weights find use in different applications and have different physical properties (e.g., viscosity) due to chain length effects, their chemical properties are nearly identical. Different forms of PEG are also available dependent on the initiator used for the polymerization process, the most common of which is a monofunctional methyl ether PEG (methoxypoly(ethylene glycol)), abbreviated mPEG. Lower-molecular-weight PEGs are also available as purer oligomers, referred to as monodisperse, uniform or discrete. Very high purity PEG has recently been shown to be crystalline, allowing determination of a xray crystal structure.^[3] Since purification and separation of pure oligomers is difficult, the price for this type of quality is often 10-1000 fold that of polydisperse PEG. PEGs are also available with different geometries. Branched PEGs have three to ten PEG chains emanating from a central core group. Star PEGs have 10–100 PEG chains emanating from a central core group. Comb PEGs have multiple PEG chains normally grafted to a polymer backbone.

Their melting points vary depending on the Formula Weight of the polymer. PEG or PEO has the following structure:

HO-CH₂-(CH₂-O-CH₂-)_n-CH₂-OH

The numbers that are often included in the names of PEGs indicate their average molecular weights, e.g., a PEG with n=9 would have an average molecular weight of approximately 400 daltons and would be labeled PEG 400. Most PEGs include molecules with a distribution of molecular weights; i.e., they are polydisperse. The size distribution can be characterized statistically by its weight average molecular weight (Mw) and its number average molecular weight (Mn), the ratio of which is called the polydispersity index (Mw/Mn). Mw and Mn can be measured by mass spectrometry.

PEGylation is the act of covalently coupling a PEG structure to another larger molecule, for example, a therapeutic protein (which is then referred to as PEGylated). PEGylated interferon alfa-2a or -2b is a commonly used injectable treatment for Hepatitis C infection.

PEG is soluble in water, methanol, benzene, dichloromethane and is insoluble in diethyl ether and hexane. It is coupled to hydrophobic molecules to produce non-ionic surfactants.

PEGs contain potential toxic impurities such as ethylene oxide and 1,4-dioxane. PEGs are nephrotoxic if applied to damaged skin.^[4]

Polyethylene oxide (PEO, Mw 4kD) nanometric crystallites (4nm)

PEGs and methoxypolyethylene glycols are manufactured by Dow Chemical under the tradename Carbowax for industrial use and Carbowax Sentry for food and pharmaceutical use. They vary in consistency from liquid to solid, depending on the molecular weight, indicated by a number following the name. They are used in industry as surfactants, including foods, cosmetics, and pharmaceutics; in biomedicine, as dispersing agents, solvents, ointment, and suppository bases; as tablet excipients; and as laxatives. Some specific groups are lauromacrogols, nonoxynols, octoxynols and poloxamers.^[5]

Production

Polyethylene glycol is produced by the interaction of ethylene oxide with water, ethylene glycol, or ethylene glycol oligomers.^[6] The reaction is catalyzed by acidic or basic catalysts. Ethylene glycol and its oligomers are preferable as a starting material instead of water, because they allow the creation of polymers with a low polydispersity (narrow molecular weight distribution). Polymer chain length depends on the ratio of reactants.

HOCH₂CH₂OH + n(CH₂CH₂O) → HO(CH₂CH₂O)_n+1H

Depending on the catalyst type, the mechanism of polymerization can be cationic or anionic. The anionic mechanism is preferable because it allows one to obtain PEG with a low polydispersity. Polymerization of ethylene oxide is an exothermic process. Overheating or contaminating ethylene oxide with catalysts such as alkalis or metal oxides can lead to runaway polymerization, which can end with an explosion after a few hours.

Polyethylene oxide or high-molecular polyethylene glycol is synthesized by suspension polymerization. It is necessary to hold the growing polymer chain in solution in the course of the polycondensation process. The reaction is catalyzed by magnesium-, aluminium-, or calcium-organoelement compounds. To prevent coagulation of polymer chains from solution, chelating additives such as dimethylglyoxime are used.

Alkali catalysts such as sodium hydroxide NaOH, potassium hydroxide KOH, or sodium carbonate Na₂CO₃ are used to prepare low-molecular-weight polyethylene glycol.

Medical uses

It is the basis of a number of laxatives (e.g., macrogol-containing products such as Movicol and polyethylene glycol 3350, or SoftLax, MiraLAX or GlycoLax). Whole bowel irrigation (polyethylene glycol with added electrolytes) is used for bowel preparation before surgery or colonoscopy. It is sold under the brand names GoLYTELY, GaviLyte-C, NuLytely, GlycoLax, Fortrans, TriLyte, Colyte, Halflytely, Softlax, ClearLax and MoviPrep. In the United States, MiraLAX and Dulcolax Balance are sold without prescription for short term relief of chronic constipation, although there is now growing consensus in the medical community that these medications can be taken indefinitely to treat chronic constipation. A 2007 comparison showed that patients suffering from constipation had a better response to these two medications than to tegaserod.^[7]

When attached to various protein medications, polyethylene glycol allows a slowed clearance of the carried protein from the blood. This makes for a longer-acting medicinal effect and reduces toxicity, and it allows longer dosing intervals. Examples include PEG-interferon alpha, which is used to treat hepatitis C, and PEGfilgrastim (Neulasta), which is used to treat neutropenia. It has been shown that polyethylene glycol can improve healing of spinal injuries in dogs.^[8] One of the earlier findings that polyethylene glycol can aid in nerve repair came from the University of Texas (Krause and Bittner).^[9] Polyethylene glycol is commonly used to fuse B-cells with myeloma cells in monoclonal antibody production.

PEG is used as an excipient in pharmaceutical products. Lower-molecular-weight variants are used as solvents in oral liquids and soft capsules, whereas solid variants are used as ointment bases, tablet binders, film coatings, and lubricants.^[10]

PEG is also used in lubricant eye drops.

Research for new clinical uses

• PEG when labeled with a near-infrared fluorophore has been used in preclinical work as a vascular agent, lymphatic agent, and general tumor-imaging agent by exploiting the Enhanced permeability and retention effect (EPR) of tumors.^[11]
• High-molecular-weight PEG, e.g., PEG 8000, has been shown to be a dietary preventive agent against colorectal cancer in animal models.^[12]

The Chemoprevention Database shows it is the most effective agent to suppress chemical carcinogenesis in rats. Cancer prevention in humans has not yet been tested in clinical trials.^[13]

• The injection of PEG 2000 into the bloodstream of guinea pigs after spinal cord injury leads to rapid recovery through molecular repair of nerve membranes.^[14] The effectiveness of this treatment to prevent paraplegia in humans after an accident is not known yet.
• Research is being done in the use of PEG to mask antigens on red blood cells. Various research institutes have reported that using PEG can mask antigens without damaging the functions and shape of the cell.
• Research is also being done on the use of PEG in the field of gene therapy.

PEG is being used in the repair of motor neurons damaged in crush or laceration incidents in vivo and in vitro. When coupled with melatonin, 75% of damaged sciatic nerves were rendered viable.^[15]

Other uses

Polyethylene glycol has a low toxicity and is used in a variety of products.^[16] The polymer is used as a lubricating coating for various surfaces in aqueous and non-aqueous environments^[17].

It is the basis of many skin creams, as cetomacrogol, and sexual lubricants, frequently combined with glycerin.

PEG is used in a number of toothpastes as a dispersant; it binds water and helps keep Xanthan gum uniformly distributed throughout the toothpaste. It is also under investigation for use in body armor and tattoos to monitor diabetes.^[18][19]

Low-molecular-weight (PEG 400) is used in Hewlett-Packard designjet printers as an ink solvent and lubricant for the print heads.

PEG is a commonly used as precipitant for plasmid DNA isolation and protein crystallization. X-ray diffraction of protein crystals can reveal the atomic structure of proteins.

Polymer segments derived from PEG polyols impart flexibility to polyurethanes for applications such as elastomeric fibers (spandex) and foam cushions.

Since PEG is a flexible, water-soluble polymer, it can be used to create very high osmotic pressures (tens of atmospheres). It also is unlikely to have specific interactions with biological chemicals. These properties make PEG one of the most useful molecules for applying osmotic pressure in biochemistry experiments, in particular when using the osmotic stress technique.^{[citation needed]}

PEO (polyethylene oxide) can serve as the separator and electrolyte solvent in lithium polymer cells. Its low diffusivity often requires high temperatures of operation, but its high viscosity even near its melting point allows very thin electrolyte layers. While crystallization of the polymer can degrade performance, many of the salts used to carry charge can also serve as a kinetic barrier to the formation of crystals. Such batteries carry greater energy for their weight than other lithium ion battery technologies.

When working with phenol in a laboratory situation, PEG 300 can be used on phenol skin burns to deactivate any residual phenol.

Polyethylene glycol is also commonly used as a polar stationary phase for gas chromatography, as well as a heat transfer fluid in electronic testers.

PEG is also one of the main ingredients in Paintball fill because it is thick and flexible. However, as early as 2006, some Paintball manufacturers have been substituting cheaper alternatives for PEG.^{[citation needed]}

PEG has also been used to preserve objects that have been salvaged from underwater, as was the case with the warship Vasa in Stockholm,^[20] the Mary Rose in England and the Ma'agan Michael Ship in Israel.^[21] It replaces water in wooden objects, which makes the wood dimensionally stable and prevents warping or shrinking of the wood when it dries. In addition, PEG is used when working with green wood as a stabilizer and to prevent shrinkage.^[22]

PEG is often used (as an internal calibration compound) in mass spectrometry experiments, with a characteristic fragmentation pattern.

In the field of microbiology, PEG precipitation is used to concentrate viruses. PEG is also used to induce complete fusion (mixing of both inner and outer leaflets) in liposomes reconstituted in vitro.

PEG derivatives such as narrow range ethoxylates are used as surfactants.

Dimethyl ethers of PEG are the key ingredient of Selexol, a solvent used by coal-burning, integrated gasification combined cycle (IGCC) power plants to remove carbon dioxide and hydrogen sulfide from the gas waste stream.

PEG has been used as the hydrophilic block of amphiphilic block copolymers used to create some polymersomes.^[23]

Gene therapy vectors (such as viruses) can be PEG-coated to shield them from inactivation by the immune system and to de-target them from organs where they may build up and have a toxic effect.^[24] The size of the PEG polymer has been shown to be important, with large polymers achieving the best immune protection.

PEG is a component of stable nucleic acid lipid particles (SNALPs) used to package siRNA for use in vivo.^[25][26]

PEG is also used as a polymer host for solid polymer electrolytes. Although not yet in commercial production, many groups around the globe are engaged in research in solid polymer electrolytes involving PEG, with the aim of improving their properties, permitting their use in batteries, electro-chromic display systems and other products in the future.

PEG is also as a food additive used as an anti-foaming agent;^[27] its INS number is 1521^[28] or E1521 in the EU.^[29]

See also

• PEGylation

References

1. ^ J. Kahovec, R. B. Fox and K. Hatada (2002). "Nomenclature of regular single-strand organic polymers". Pure and Applied Chemistry 74 (10): 1921–1956. doi:10.1351/pac200274101921. 
2. ^ For example, in the online catalog of Scientific Polymer Products, Inc., poly(ethylene glycol) molecular weights run up to about 20,000, while those of poly(ethylene oxide) have six or seven digits.
3. ^ High Purity Discrete PEG Oligomer Crystals Allow Structural Insight A.C. French, A.L. Thompson, B.G. Davis Angew. Chem. Intl Ed. 2009, 48, 1248-1252
4. ^ "Final Report on the Safety Assessment of PEG-2, -3, -5, -10, -15, and -20 Cocamine". International Journal of Toxicology 18 (3): 43–50. 1999. doi:10.1080/109158199225620.  edit
5. ^ Carbowax web page from Dow
6. ^ Polyethylene glycol, Chemindustry.ru
7. ^ Di Palma, Jack A.; Cleveland, Mark vB.; McGowan, John; Herrera, Jorge L. (2007). "A Randomized, Multicenter Comparison of Polyethylene Glycol Laxative and Tegaserod in Treatment of Patients With Chronic Constipation". The American Journal of Gastroenterology 102 (9): 1964–71. doi:10.1111/j.1572-0241.2007.01365.x. PMID 17573794. 
8. ^ Lee Bowman (4 December 2004). "Study on dogs yields hope in human paralysis treatment". seattlepi.com. http://www.seattlepi.com/health/202292_spinal04.html. 
9. ^ T. L. Krause and G. D. Bittner (1990). "Rapid morphological fusion of severed myelinated axons by polyethylene glycol". PNAS 87 (4): 1471–1475. doi:10.1073/pnas.87.4.1471. PMC 53497. PMID 2304913. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=53497. 
10. ^ Smolinske, Susan C. (1992). Handbook of Food, Drug, and Cosmetic Excipients. Boca Raton: CRC Press. p. 287. ISBN 084933585X. 
11. ^ Kovar, J., Wang, Y., Simpson, M.A., and Olive, D.M., "Imaging Lymphatics With A Variety of Near-Infrared-Labeled Optical Agents", World Molecular Imaging, (2009)
12. ^ D. E. Corpet, G. Parnaud, M. Delverdier, G. Peiffer and S. Tache (2000). "Consistent and Fast Inhibition of Colon Carcinogenesis by Polyethylene Glycol in Mice and Rats Given Various Carcinogens". Cancer Research 60 (12): 3160–3164. PMID 10866305. 
13. ^ Chemoprevention Database
14. ^ R. B. Borgens and D. Bohnert (2001). "Rapid recovery from spinal cord injury after subcutaneously administered polyethylene glycol". Journal of Neuroscience Research 66 (6): 1179–1186. doi:10.1002/jnr.1254. PMID 11746451. 
15. ^ G. Bittner el. al. (2005). "Melatonin enhances the in vitro and in vivo repair of severed rat sciatic axons". Neouroscience Letters 376 (2): 98–101.. doi:10.1016/j.neulet.2004.11.033. PMID 15698928. 
16. ^ Victor O. Sheftel (2000). Indirect Food Additives and Polymers: Migration and Toxicology. CRC. pp. 1114–1116. http://www.mindfully.org/Plastic/Polymers/Polyethylene-Glycols-PEGs.htm. 
17. ^ [Nalam PC, Clasoahm JN, Mashaghi A et al. Macrotribological Studies of Poly(L-lysine)-graft-Poly(ethylene glycol) in Aqueous Glycerol Mixtures (2010) http://www.springerlink.com/content/7l283620353453pk/]
18. ^ Tonya Johnson (21 April 2004). "Army Scientists, Engineers develop Liquid Body Armor". http://www.militaryinfo.com/news_story.cfm?textnewsid=961. 
19. ^ "Tattoo to monitor diabetes". BBC News. 1 September 2002. http://news.bbc.co.uk/2/hi/health/2225404.stm. 
20. ^ Lars-Åke Kvarning, Bengt Ohrelius (1998), The Vasa - The Royal Ship, ISBN 91-7486-581-1, pp. 133-141
21. ^ Linder, Elisha (1992). "Excavating an Ancient Merchantman". Biblical Archaeology Review (Biblical Archaeology Society) 18 (6): 24–35. 
22. ^ http://www.rockler.com/blog/index.cfm?mode=entry&entry=7F49011C-1372-6771-F623DAC0E0A1171A
23. ^ Rameez, Shahid; Alosta, Houssam; Palmer, Andre F. (2008). "Biocompatible and Biodegradable Polymersome Encapsulated Hemoglobin: A Potential Oxygen Carrier". Bioconjugate Chemistry 19 (5): 1025–32. doi:10.1021/bc700465v. PMID 18442283. 
24. ^ Kreppel, Florian; Kochanek, Stefan (2007). "Modification of Adenovirus Gene Transfer Vectors With Synthetic Polymers: A Scientific Review and Technical Guide". Molecular Therapy 16 (1): 16–29. doi:10.1038/sj.mt.6300321. PMID 17912234. 
25. ^ J.J. Rossi (2006). "RNAi therapeutics: SNALPing siRNAs in vivo". Gene Therapy 13 (7): 583–584. doi:10.1038/sj.gt.3302661. PMID 17526070. http://www.nature.com/gt/journal/v13/n7/full/3302661a.html. 
26. ^ Thomas W. Geisbert et al. (2010-05-29). "Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study". The Lancet 375 (9729): 1896–905. doi:10.1016/S0140-6736(10)60357-1. PMID 20511019. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960357-1/fulltext.  (free with registration)
27. ^ US GOvernment - Food and Drug Agency "Listing of Food Additive Status Part II". http://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm. Retrieved 2011-10-21. 
28. ^ "Codex Alimentarius". http://www.codexalimentarius.net/web/index_en.jsp. 
29. ^ UK Government - Food Standards Agency "Current EU approved additives and their E Numbers". http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist. Retrieved 2010-10-21. 

External links

• Oregon State University informational paper on using PEG as a wood stabilizer