Smooth operators
Polyethylene glycols (PEGs) have a wide range of applications in the pharma industry. Dr Torsten Henning, of German company Clariant, outlines the uses, manufacture, nomenclature, physical-chemical properties and toxicology of PEGs
Polyethylene glycols (PEGs) have a wide range of applications in the pharma industry. Dr Torsten Henning, of German company Clariant, outlines the uses, manufacture, nomenclature, physical-chemical properties and toxicology of PEGs
Using polyethylene glycols (PEGs) as an excipient in suppositories is an excellent way to smooth the passage of the drug into the body.
A versatile class of compound – they are also used in ointment bases and ophthalmic demulcents – PEGs are manufactured by the polymerisation of ethylene oxide (EO) with either monoethylene glycol or diethylene glycol under alkaline catalysis.1,2
After the desired molecular weight is reached, usually checked by viscosity measurements as an in-process control, the reaction is terminated by neutralising the catalyst with acid. The result is a very simple chemical structure: HO-[CH2-CH2-O]n-H, where (n) is the number of ethylene oxide units.
Although technically these products should be called polyethylene oxides, for products with mean molecular weights of 200 to 35,000 the term polyethylene glycols is normally used to indicate the significant influence of the hydroxyl end groups on the chemical and physical properties of these molecules.
Only products made by polymerisation of ethylene oxide in solvents with molecular weights up to several millions are called polyethylene oxides.
Nomenclature
The term PEG is used, in combination with a numerical value, which within the pharmaceutical industry indicates the mean molecular weight3. Since the molecular weight of ethylene oxide is 44, the average molecular weight values of the PEGs are given as round values of n x 44.
Unfortunately, the various pharmacopeias use different nomenclature for some PEG molecular weights. Table 1 lists in addition to the European, US and Japanese monographs, also the nomenclature of the British Pharmacopeia II from 1993. Even though this monograph is no longer valid, the nomenclature is still often used today. It is hoped that through the international harmonisation of the pharmacopeias4 a unique and less confusing nomenclature will be developed.
Properties
Polyethylene glycols with a mean molecular weight up to 400 are non-volatile liquids at room temperature. PEG 600 shows a melting range of about 17-22°C, so it may be liquid at room temperature but pasty at lower environmental temperatures, while PEGs with 800 to 2,000 mean molecular weight are pasty materials with a low melting range.
Above a molecular weight of 3,000, the polyethylene glycols are solids and are available not only in flaked form but also as powder. PEGs up to a molecular weight of 35,000 are commercially available. The hardness increases with increasing molecular weight; however the melting range goes up to a maximum of about 60°C.5
The most important property of all PEGs is their solubility in water, which makes them suitable for countless different applications. Liquid PEGs up to PEG 600 are miscible with water in any ratio. But even solid PEG grades have excellent solubility in water. Although it falls slightly with increasing molar mass, even 50% (w/w) of a PEG 35,000 can be dissolved at room temperature in water. The solubility and the viscosity of the solutions are not affected by the presence of electrolytes, since PEGs are nonionic substances. They are quite soluble in hard water or in other aqueous solutions of various salts.
Some substances react with PEGs by forming precipitates, for instance phenol, cresol, resorcinol, salicylic acid, tannin or potassium iodide. Some of those reactions can be used for qualitative detection or quantitative analysis of polyethylene glycols. In addition, liquid PEGs can be used as antidotes to remove toxic substances from burned skin.
Another very important property is the solvent power for numerous substances that are sparingly soluble in water. This action can be ascribed to the formation of a sort of complex between the polyethylene glycol and the active substance. Most of those complexes are loose and reversible, but there are some examples where the complexes tend to inactivate the active substance – well known are penicillin G and W and Bacitracine6 or acetylsalicylic acid.7
The polyethylene glycols show outstanding toxicological safety regarding acute and chronic oral toxicity, embryo toxicity or skin compatibility,8,9,10 supported by parenteral/absorption/excretion investigations.11-15 Therefore, they have been used for many years in the pharmaceutical industry and are registered in all relevant pharmacopeias.
Applications
PEGs as excipients
Solid PEGs are also frequently used in tablet coatings. The flexibility of sugar-coated tablets is increased by PEGs and since polyethylene glycol acts as a anticaking agent, the cores are prevented from sticking together. Used with film formers in sugar-free coatings, PEG acts as softener.
drug delivery
With the two hydroxyl groups at the ends of the polyethylene glycol molecules, reactions typical of alcohols are possible. To avoid chain-building reactions, methylether-capped PEGs, so called Methylpolyethylene glycols (MPEGs), are available. MPEGs are able to react at only one end of the molecule.
The wide field of PEG conjugation to proteins and other organic molecules, e.g. anticancer drugs, is also known. Concerning anticancer drugs, polyethylene glycol may work also without being linked to other molecules in some cases. In one animal test, polyglycol was found to prevent colon cancer,20 which should also prove true in humans.21,22 Most of the work is outside the range of this article, but articles by Harris23 and Greenwald24 are carefully written overviews of so-called 'PEGnology'. A first easy-to-read and shorter introduction might be the summaries of Bonora25 or Veronese.26
But even the brief overview of the properties and uses of polyethylene glycols given in this article shows their relevance for the pharmaceutical industry.