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 and polyethylene oxide (PEO) share the same poly(ethylene oxide) backbone, but the terms are conventionally used for different molecular-weight ranges and pharmaceutical applications. PEG generally refers to lower- and intermediate-molecular-weight materials, whereas PEO is commonly used for much higher-molecular-weight polymers with pronounced swelling, thickening and matrix-forming properties.
Excipient Characterization Services
Excipia provides specialized polyethylene glycol (PEG) analysis and characterization to understand differences between grades, suppliers and batches that may not be apparent from routine Certificate of Analysis data.
We can investigate PEG content, molecular-weight distribution, physicochemical properties, oxidative degradation and reactive impurities, helping to identify material characteristics that may affect formulation performance or API stability.
Our experts can support supplier and grade selection, batch comparison, formulation troubleshooting, deformulation and the definition of additional PEG specifications or Functionality Related Characteristics (FRCs) where appropriate. substances, just like molecular weight distributions, reducing power and many other featured characteristics.
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 or suppository base, viscosity modifier, carrier or processing aid.
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 and purification conditions can therefore contribute to differences in molecular-weight distribution, hydroxyl value, end-group composition, residual water, low-molecular-weight components and impurity profile between PEG materials with the same nominal grade.
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 PEG materials with similar average molecular weights do not necessarily have identical molecular-weight distributions. They may differ in the proportion of shorter and longer polymer chains, the breadth of the distribution or the presence of distinct polymer populations. These differences may contribute to differences in viscosity, melting and solidification behaviour, crystallization, processing and other formulation-relevant properties.
This becomes particularly relevant when comparing nominally equivalent PEG grades from different suppliers. Average molecular weight or PEG grade alone may not establish whether two materials are structurally comparable. Size-exclusion chromatography (SEC) can provide a molecular-weight profile that allows batches, grades and suppliers to be compared beyond a single average value.
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.
Why Pharmaceutical PEG Can Vary
Although PEG is a synthetic polymer, commercial materials with the same nominal grade are not necessarily identical. Differences may occur in molecular-weight distribution, low-molecular-weight fractions, end-group composition, water content, thermal behaviour and process- or degradation-related components.
Such differences may arise from polymerization, purification, handling and storage and can distinguish materials from different manufacturers, suppliers or batches even when routine Certificate of Analysis results appear comparable.
For pharmaceutical development, the relevance of this variability depends on the intended function of PEG and the sensitivity of the formulation. Additional characterization can therefore be useful during supplier qualification, grade or batch changes, formulation troubleshooting and investigation of unexplained stability differences.
Physicochemical Properties of Polyethylene Glycol
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
Polyethylene glycol is susceptible to oxidative degradation. Oxidation can proceed through radical reactions involving the polyether chain, with hydroperoxides forming as intermediates and chain scission producing shorter polymer chains and low-molecular-weight degradation products. Heat, oxygen, light, transition metals and other oxidative stressors can influence these reactions. [3]
Important PEG degradation products reported in pharmaceutical studies include formaldehyde, formic acid, acetaldehyde and acetic acid. Their relative formation depends on factors such as PEG grade, water content, temperature, pH and the surrounding formulation environment. [1]
Importantly, peroxide concentration alone does not necessarily describe the complete oxidative history of a PEG material. Peroxides are intermediates in an evolving degradation process and may subsequently give rise to downstream aldehydes, organic acids and changes in polymer molecular weight. A stability investigation may therefore require characterization of several stages of PEG oxidation rather than peroxide testing alone. [1, 3]
PEG Reactive Impurities and API–Excipient Compatibility
Reactive degradation products present in or generated from PEG can interact with susceptible active pharmaceutical ingredients. This is particularly relevant for APIs containing amine or other nucleophilic functional groups and for drug substances that are sensitive to oxidation. [1,2]
Formaldehyde is one important example. Pharmaceutical literature has described PEG-derived formaldehyde contributing to hydroxymethylation and other API degradation reactions. Formaldehyde may also participate in reactions leading to N-methylated products, while formic acid can contribute to N-formylation pathways for susceptible amines. [2,3]
More recent stress studies with PEG 6000 have demonstrated how oxidative PEG degradation can generate formaldehyde and formic acid and promote N-methylation or N-formylation of amine-containing drug substances under suitable conditions. [3]
A separate famotidine–PEG study likewise demonstrated degradation associated with reactive species generated from PEG and showed the importance of excipient level when assessing compatibility risk. [4]
For formulation development or stability troubleshooting, it can therefore be useful to characterize the reactive impurity profile of the actual PEG grade and batch rather than assuming that all pharmacopeially compliant PEG materials present the same compatibility risk.
Process-Related Components, Degradation Products and Impurities in PEG
Depending on the PEG grade, production process and storage history, relevant components may include:
- ethylene glycol and diethylene glycol;
- short-chain glycols and low-molecular-weight PEG oligomers;
- residual water;
- catalyst- or process-related inorganic residues;
- peroxides and hydroperoxides;
- formaldehyde, acetaldehyde and other carbonyl compounds;
- formic acid, acetic acid and other organic acids;
- lower-molecular-weight polymer degradation products;
- trace metals or other components capable of influencing oxidation.
Ethylene glycol and diethylene glycol are specifically controlled because of their toxicity and are important quality attributes for relevant PEG grades. Other low-level components may become important when they influence API stability or formulation performance even though they are not the primary focus of routine compendial testing.
Functionality Related Characteristics (FRCs) of Polyethylene Glycol
Functionality Related Characteristics (FRCs) are physical, chemical or other material characteristics that can influence the functionality of an excipient in a particular pharmaceutical formulation. The relevant FRCs depend on the PEG grade, its intended function and the dosage form.
Potentially relevant PEG FRCs may include average molecular weight, molecular-weight distribution, viscosity, hydroxyl value, water content, melting or congealing behaviour, crystallinity and other thermal characteristics. Where chemical stability or API compatibility is important, peroxide level, reactive carbonyl compounds, organic acids and other indicators of oxidative degradation may also become relevant material characteristics.
Not every characteristic is critical for every PEG application. The objective of detailed characterization is therefore not simply to measure more parameters, but to identify which PEG characteristics are associated with the required formulation performance or observed stability behaviour.
Understanding relevant PEG FRCs can support supplier and grade selection, batch comparison, change control, formulation troubleshooting and the establishment of additional material specifications where routine CoA testing does not provide sufficient control.
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.
Polyethylene Glycol Characterization by Excipia
Excipia provides detailed analytical and physicochemical characterization of pharmaceutical PEG to investigate differences between grades, suppliers and batches and to understand PEG characteristics that may influence formulation performance or stability.
Depending on the pharmaceutical question, characterization can include:
- PEG identification and quantification;
- average molecular weight and molecular-weight distribution;
- comparison of PEG grades, batches and suppliers;
- low-molecular-weight components;
- peroxide and oxidative-degradation assessment;
- aldehydes and other reactive carbonyl compounds;
- formic acid and other relevant organic acids;
- water and relevant physicochemical properties;
- investigation of PEG-related API–excipient incompatibility;
- comparison of PEG in test and reference drug products;
- development of additional material specifications or FRC-based controls.
Molecular-weight distribution can be characterized by SEC to compare PEG materials beyond nominal grade or average molecular weight, while complementary chemical analyses can assess oxidative degradation and reactive components that are not described by the polymer molecular-weight profile alone.
PEG Identification and Quantification in Pharmaceutical Products
PEG may need to be identified and quantified during deformulation, reference-product comparison, generic or hybrid development, formulation troubleshooting or investigation of excipient-related stability problems.
The analytical approach depends on the PEG grade, dosage form and presence of other polyether-containing excipients. Because PEG has no strong UV chromophore, selective extraction and non-UV analytical techniques are often required.
Depending on the formulation, Excipia can investigate total PEG content, PEG grade or molecular-weight profile, PEG in coatings or formulation matrices, and differences between test and reference 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.
When Can More Detailed PEG Characterization Help?
Detailed PEG characterization can be useful when:
- changing PEG supplier, manufacturer, grade or batch;
- comparing PEG materials with the same nominal molecular weight;
- investigating unexpected API degradation or new stability impurities;
- evaluating potential peroxide-, aldehyde- or organic-acid-related incompatibilities;
- investigating N-formylation, N-methylation or other reactions involving susceptible APIs;
- routine CoA data do not explain a formulation-performance difference;
qualifying a PEG raw material for a sensitive formulation; - identifying or quantifying PEG during deformulation or reference-product comparison;
- defining additional material specifications or relevant FRCs.
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.
Frequently Asked Questions About Pharmaceutical PEG
What is the difference between PEG and polyethylene oxide (PEO)?
Polyethylene glycol (PEG) and polyethylene oxide (PEO) have the same poly(ethylene oxide) backbone, but the terms are conventionally associated with different molecular-weight ranges and pharmaceutical applications. PEG generally refers to lower- and intermediate-molecular-weight materials, whereas PEO is commonly used for much higher-molecular-weight polymers with pronounced swelling, gel-forming and matrix-forming properties. For more information, see our dedicated Polyethylene Oxide (PEO) page.
Can PEG materials with the same nominal molecular weight differ between suppliers?
Yes. A nominal PEG grade or average molecular weight does not completely define the polymer. PEG materials from different suppliers or batches may differ in molecular-weight distribution, low-molecular-weight fractions, end-group composition, water content, thermal properties and process- or degradation-related components. Additional characterization can therefore be useful when comparing alternative PEG sources or investigating a supplier or batch change.
Why does molecular-weight distribution matter for pharmaceutical PEG?
Average molecular weight describes only the average size of the PEG molecules present. Two PEG materials with similar average molecular weights can have different distributions of shorter and longer polymer chains. Size-exclusion chromatography (SEC) can be used to compare these molecular-weight distributions and identify differences between PEG batches, grades or suppliers that are not apparent from the nominal PEG grade alone.
Can polyethylene glycol cause API degradation?
PEG itself is widely used as a pharmaceutical excipient, but reactive impurities or degradation products present in or generated from PEG can interact with susceptible APIs. Oxidative degradation of PEG can produce peroxides, aldehydes and organic acids. These components may contribute to API degradation, particularly for oxidation-sensitive drug substances or APIs containing susceptible amine or other nucleophilic functional groups.
Can PEG generate formaldehyde and formic acid?
Yes. Pharmaceutical studies have demonstrated that oxidative degradation of PEG can generate formaldehyde, formic acid and other low-molecular-weight degradation products, including acetaldehyde and acetic acid under certain conditions. The resulting impurity profile depends on factors such as PEG grade, temperature, water content, pH, oxygen and the surrounding formulation environment.
Is peroxide testing alone sufficient to assess PEG oxidative degradation?
Not necessarily. Peroxides and hydroperoxides are intermediates in PEG oxidation and can subsequently decompose or participate in further reactions. A PEG material may therefore contain downstream oxidation products such as aldehydes and organic acids even when the peroxide value alone does not fully describe its degradation history. For stability or compatibility investigations, complementary analysis of relevant degradation products can provide a more complete picture.
When is additional PEG characterization beyond the Certificate of Analysis useful?
Additional characterization can be useful when changing PEG supplier, grade or batch; comparing materials with the same nominal molecular weight; investigating unexpected API degradation or stability impurities; evaluating potential reactive-impurity problems; troubleshooting formulation-performance differences; or characterizing PEG during deformulation and reference-product comparison. The appropriate measurements should be selected according to the intended function of PEG and the specific pharmaceutical question.
Be in control of your product!
Selected Literature
1. Hemenway JN, Carvalho TC, Rao VM, et al. Formation of reactive impurities in aqueous and neat polyethylene glycol 400 and effects of antioxidants and oxidation inducers. Journal of Pharmaceutical Sciences. 2012;101:3305–3318.
2. Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility. AAPS PharmSciTech. 2011;12:1248–1263.
3. Robnik B, Naumoska K, Časar Z. A Novel Testing Approach for Oxidative Degradation Dependent Incompatibility of Amine Moiety Containing Drugs with PEGs in Solid-State. Pharmaceutics. 2020;12(1):37. doi:10.3390/pharmaceutics12010037.
4. Saraf I, Modhave D, Kushwah V, et al. Feasibility of rapidly assessing reactive impurities mediated excipient incompatibility using a new method: A case study of famotidine-PEG system. Journal of Pharmaceutical and Biomedical Analysis. 2019; article 112893.
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