Polyethylene Glycol (PEG) as a Pharmaceutical Excipient
What is Polyethylene Glycol ?
Polyethylene glycol, commonly abbreviated as PEG, is a hydrophilic polyether used extensively as a pharmaceutical excipient. It consists of repeating oxyethylene units and is generally represented by the formula:
H–(O–CH₂–CH₂)ₙ–OH
The number of repeating ethylene oxide units determines the average molecular weight and strongly influences the physical form, viscosity, melting behaviour and pharmaceutical functionality of the material.
Low-molecular-weight PEG grades are generally clear, viscous liquids, whereas higher-molecular-weight grades are semi-solid, waxy or solid materials. Commercial PEG products are not single molecular compounds but distributions of polymer chains with different chain lengths centred around a specified average molecular weight.
In the European Pharmacopoeia and in European pharmaceutical terminology, polyethylene glycols are commonly referred to as macrogols. PEG and macrogol therefore refer to the same type of polymer, although the grade names and compendial descriptions may differ between regions.
PEG should not be confused with polyethylene oxide (PEO). Both consist primarily of repeating oxyethylene units, but the name PEO is generally used for considerably higher-molecular-weight polymers.
Excipient Characterization Services
Excipia offers fast and flexible hands-on polyethylene glycol quantification and characterization services to reveal and compare hidden polyethylene glycol properties like :
the presence of potential reactive impurities or functional groups, degradation products and related substances, just like molecular weight distributions, reducing power and many other featured characteristics.
In addition, we can help users of excipients to pick the most appropriate polyethylene glycol manufacturer, select the most suitable polyethylene glycol grade for their finished dosage form, or define customized polyethylene glycol specifications to control product performance, quality and safety.
Pharmaceutical Applications of PEG
Polyethylene glycol is used in a wide variety of pharmaceutical dosage forms. Depending on its molecular weight and grade, PEG can function as a solvent, co-solvent, plasticizer, lubricant, binder, ointment base, suppository base, viscosity modifier or matrix-forming polymer.
Liquid PEG grades are frequently used to dissolve or disperse active pharmaceutical ingredients in oral liquids, soft capsules, topical preparations and parenteral products where the selected grade and quality are suitable for the intended route of administration.
Higher-molecular-weight PEG grades are used in tablet and capsule formulations, film coatings, hot-melt processing, semi-solid preparations and solid dispersions. Mixtures of different PEG grades may be used to obtain a desired consistency, melting range, dissolution behaviour or mechanical performance.
PEG is also used as a building block or hydrophilic segment in surfactants, conjugates and more complex excipient systems. These chemically modified materials should be distinguished from unmodified polyethylene glycol.
Production of Polyethylene Glycol
Polyethylene glycol is produced by controlled polymerization of ethylene oxide in the presence of water, ethylene glycol or another suitable initiator. The polymerization is generally catalysed under alkaline conditions.
During the reaction, ethylene oxide units are added sequentially to the growing polymer chains. The ratio between initiator and ethylene oxide, reaction temperature, catalyst concentration, water content and reaction time influence the average chain length and molecular-weight distribution of the resulting PEG.
After polymerization, the material is neutralized and purified to reduce residual catalyst, unreacted starting materials, volatile components and process-related impurities. Depending on the intended grade, the product may subsequently be filtered, dried, solidified, milled or formed into flakes, granules or powder.
Manufacturing conditions can influence properties that are not completely described by the nominal PEG number, including molecular-weight distribution, hydroxyl value, end-group composition, residual water and susceptibility to oxidation.
Figure 1 Structural formula of polyethylene glycol
PEG Grades and Average Molecular Weight
Commercial polyethylene glycol products are identified by a numerical grade that approximately corresponds to their average molecular weight, for example PEG 200, PEG 400, PEG 600, PEG 1500, PEG 3350, PEG 4000, PEG 6000 and PEG 8000.
The grade number does not indicate that every polymer molecule has the same molecular weight. Instead, each commercial PEG grade consists of a distribution of polymer chains of different lengths centred around a specified average molecular weight.
As the average molecular weight increases, polyethylene glycol gradually changes from a clear mobile liquid to a viscous liquid, semi-solid, waxy solid or free-flowing powder. This increase in chain length influences many functional properties, including viscosity, melting or congealing range, hygroscopicity, mechanical behaviour, solubilizing capacity and dissolution characteristics.
Consequently, selection of a PEG grade should be based on the intended pharmaceutical function rather than on the nominal grade number alone. In many formulations, the molecular-weight distribution and thermal behaviour of the polymer are equally important as its average molecular weight.
Molecular-Weight Distribution of Polyethylene Glycol
Average molecular weight is an important quality parameter, but it does not fully describe the polymer population present in a PEG material.
Two batches or grades with a comparable average molecular weight may have different proportions of shorter and longer polymer chains. Differences in molecular-weight distribution can influence viscosity, melting behaviour, solidification, crystallization, mechanical properties and drug-release performance.
Low-molecular-weight fractions may also affect hygroscopicity, solvent properties and migration within a formulation. Higher-molecular-weight fractions can influence hardness, matrix behaviour and processing characteristics.
Size-exclusion chromatography or gel-permeation chromatography can provide information about PEG molecular-weight distribution that cannot be obtained from a single average molecular-weight or viscosity result.
Physicochemical Properties of PEG
Polyethylene glycol is a non-ionic, hydrophilic polymer that is generally soluble or readily dispersible in water. Its physicochemical properties depend primarily on molecular weight and molecular-weight distribution, but can also be influenced by the manufacturing process, storage conditions and the presence of low-level impurities.
Important characteristics include average molecular weight, hydroxyl value, viscosity, water content, melting or congealing range, crystallinity, thermal behaviour and hygroscopicity. In addition, the levels of peroxides, aldehydes and low-molecular-weight oligomers may be relevant when PEG is used in formulations containing oxidation-sensitive active pharmaceutical ingredients.
PEG readily forms hydrogen bonds with water and with many pharmaceutical compounds. This behaviour contributes to its widespread use as a solvent, plasticizer, carrier and processing aid, but it can also influence drug solubility, crystallization, dissolution behaviour and long-term chemical stability. Consequently, understanding the complete physicochemical profile of a PEG grade is often important during formulation development and supplier qualification.
Stability and Oxidative Degradation of PEG
PEG is generally stable when suitably manufactured, packaged and stored, but it is susceptible to oxidative degradation.
Oxidation may be initiated or accelerated by heat, light, oxygen, trace metals, radical-forming substances or pre-existing peroxides. The process can produce hydroperoxides and subsequently form aldehydes, organic acids and shorter PEG chains.
Potential degradation products include formaldehyde, acetaldehyde, formic acid and other low-molecular-weight oxidation products. The exact profile depends on the PEG grade, manufacturing history, storage conditions and formulation environment.
Oxidative degradation can be important in pharmaceutical development because PEG-derived reactive impurities may:
- oxidize sensitive active substances
- react with amines or other nucleophilic functional groups
- contribute to colour or odour changes
- alter pH or impurity profiles
- increase during storage
- affect the stability of proteins, peptides or other sensitive molecules
Peroxide testing alone may not always provide a complete assessment. A PEG sample can contain downstream oxidation products even when its current peroxide level is relatively low. Investigation of a stability problem may therefore require a combination of peroxide, aldehyde, organic-acid and molecular-weight analyses.
Impurities and Related Substances
Potential impurities in pharmaceutical-grade PEG may originate from raw materials, polymerization, purification, packaging or degradation.
Relevant components can include:
- ethylene glycol
- diethylene glycol
- higher glycols and short PEG oligomers
- residual water
- residual catalyst or inorganic residues
- formaldehyde and other aldehydes
- formic acid and other organic acids
- hydroperoxides and peroxides
- lower-molecular-weight degradation products
- trace metals
- process- or packaging-related contaminants
Ethylene glycol and diethylene glycol require particular attention because contamination or adulteration of pharmaceutical raw materials with these toxic glycols has caused serious poisoning incidents. Current compendial and regulatory initiatives increasingly emphasize appropriate testing of excipients considered at risk.
The impurity profile should be assessed in relation to the PEG grade, route of administration, daily exposure, API sensitivity and intended shelf life.
PEG Analysis and Characterization
Because PEG lacks a strong, distinctive UV chromophore, conventional LC-UV analysis is often not the most suitable approach for its direct determination.
Depending on the analytical objective, PEG may be investigated using:
- size-exclusion or gel-permeation chromatography
- liquid chromatography with refractive-index detection
- liquid chromatography with charged-aerosol detection
- gas chromatography for volatile glycols and degradation products
- hydroxyl-value determination
- nuclear magnetic resonance spectroscopy
- infrared or Raman spectroscopy
- mass spectrometry
- viscosity and rheological measurements
- differential scanning calorimetry
- thermogravimetric analysis
- water determination
- peroxide, aldehyde and organic-acid testing
No single method provides all relevant information. Identification of the PEG grade, determination of its quantity and investigation of oxidative degradation generally require different analytical approaches.
Quantification of PEG in Pharmaceutical Products
Determination of PEG in a finished pharmaceutical product can be challenging, particularly when several PEG grades, surfactants, glycerides or other polyether-containing excipients are present. The analytical strategy may involve selective extraction, separation of the active substance, precipitation, chromatographic fractionation or detection using non-UV techniques.
Depending on the formulation, Excipia can investigate:
- total PEG content
- individual PEG grades or fractions
- average molecular weight
- molecular-weight distribution
- PEG present in coatings, tablet cores or semi-solid matrices
- PEG degradation during processing or storage
- PEG-related impurities
- differences between test and reference products
For reverse-engineering projects, analytical results should be interpreted together with the dosage form, declared excipients, manufacturing process and expected function of the PEG.
PEG Variability
Although polyethylene glycol is a synthetic polymer, commercial PEG grades are not chemically identical. Materials with the same nominal molecular weight may differ in molecular-weight distribution, end-group composition, residual water, low-molecular-weight fractions and process-related impurities. These differences originate from variations in initiator composition, polymerization conditions, purification, catalyst removal and storage history.
Such variability may influence viscosity, melting behaviour, crystallization, compatibility with active pharmaceutical ingredients, hot-melt processing and long-term product stability. Differences in oxidative degradation products, including peroxides and aldehydes, may also affect the stability of oxidation-sensitive drug substances.
Because many of these characteristics are not fully described by routine pharmacopoeial tests or certificates of analysis, additional physicochemical characterization may be valuable when comparing suppliers, qualifying new PEG grades or investigating unexpected formulation behaviour.
Difference Between PEG and PEO
Polyethylene glycol and polyethylene oxide consist of the same fundamental oxyethylene repeating unit. The distinction is primarily based on molecular weight and conventional usage.
The term PEG is generally applied to lower- and intermediate-molecular-weight materials ranging from liquids to waxy or solid polymers.
The term PEO is generally applied to substantially higher-molecular-weight polymers, which may have molecular weights from hundreds of thousands to several million daltons.
Because of this molecular-weight difference, PEO can provide strong thickening, swelling and matrix-forming behaviour and is widely used in controlled-release and swellable drug-delivery systems. PEG is more commonly used as a solvent, plasticizer, lubricant, low-melting carrier, ointment base or solid-dispersion polymer.
For more information, see our dedicated page on polyethylene oxide.
Difference Between PEG and Macrogol
Polyethylene glycol and macrogol are names for the same basic polymer.
The term polyethylene glycol is widely used in scientific literature, manufacturing and USP–NF terminology. Macrogol is commonly used in European pharmaceutical nomenclature and in the European Pharmacopoeia.
A number is generally added to indicate the approximate average molecular weight, for example PEG 400 or macrogol 400.
Although the names describe the same polymer family, users should verify the applicable compendial requirements, grade specifications and nomenclature for the intended market.
Difference Between PEG and Propylene Glycol
Polyethylene glycol and propylene glycol are different substances.
Propylene glycol is a small diol with a defined molecular structure and molecular weight. PEG is a polymeric distribution containing repeating ethylene oxide units.
Both may be used as solvents or formulation aids, but they differ in viscosity, volatility, analytical behaviour, impurity risks and pharmaceutical functionality. They should not be treated as interchangeable excipients.
Pharmacopoeial Monographs for PEG
Polyethylene glycol grades are covered by compendial standards in the major pharmacopoeias.
Relevant texts may include:
- USP–NF: Polyethylene Glycol
- specific USP–NF texts for certain PEG grades or PEG-containing substances;
- European Pharmacopoeia: Macrogols
- relevant Japanese Pharmacopoeia or Japanese pharmaceutical-excipient standards for specified macrogol grades.
The applicable tests depend partly on the molecular-weight range and may include identification, appearance, acidity or alkalinity, viscosity, average molecular weight, hydroxyl value, water, residue on ignition, ethylene glycol, diethylene glycol and other quality attributes.
Compendial requirements and test procedures may be revised. Users should therefore consult the current legally applicable edition rather than relying on historical specifications or secondary summaries.
Compendial Compliance Versus Functional Equivalence
Compliance with a pharmacopoeial monograph demonstrates that a polyethylene glycol grade satisfies established requirements for identity, purity and specified quality attributes. However, pharmacopoeial compliance alone does not guarantee that different PEG grades, batches or manufacturers will perform identically in a pharmaceutical formulation.
Commercial PEG products may differ in molecular-weight distribution, low-molecular-weight oligomer content, hydroxyl value, end-group composition, crystallization behaviour, oxidative degradation profile and susceptibility to peroxide formation. These differences can influence processing characteristics, compatibility with active pharmaceutical ingredients, dissolution behaviour and long-term product stability.
When polyethylene glycol performs a critical function within a formulation, additional characterization beyond routine compendial testing may therefore be appropriate. Comparative evaluation of molecular-weight distribution, degradation products and other functionality-related properties can provide valuable information during supplier qualification, formulation development, reverse engineering and investigation of product-performance differences.
Be in control of your product!
Polyethylene Glycol Characterization by Excipia
Excipia provides independent analytical and physicochemical characterization of polyethylene glycol as a raw material and after incorporation into pharmaceutical products.
Our work can include determination of PEG content, molecular-weight distribution, low-molecular-weight components, oxidative degradation products, peroxides, aldehydes, organic acids, water content and thermal properties.
Excipia can support:
- PEG grade and supplier selection
- batch-to-batch comparison
- raw-material qualification
- investigation of API–excipient compatibility
- stability troubleshooting
- reverse engineering
- PEG identification and quantification
- comparison of test and reference products
- development of customized material specifications
More than 25 years of pharmaceutical formulation and analytical-development experience has shown that routine certificate-of-analysis information does not always explain differences in product behaviour.
Detailed knowledge of PEG composition, molecular-weight distribution and degradation profile can be essential when addressing unexpected impurities, instability, processing differences or drug-release behaviour.
Welcome to Excipia, a service platform of Avivia, dedicated to the composition, quality and quantity of excipients in medicinal products.
Discover our unique services such as quantitative excipient analysis, identification, selection or specific formulation development support. Don’t forget to check out our case studies.
Feel free to contact us using the “Contact” button or by sending a message to Excipia@avivia.nl.
Menno Wiltink
Founder of Excipia.
