Formulation challenges in GLP-1 therapeutics: Why excipient purity matters

GLP-1-based peptide therapeutics are transforming the treatment of obesity and type 2 diabetes. As developers race to advance the next generation of these medicines, formulation scientists face a less visible challenge: protecting sensitive peptide molecules from degradation throughout manufacture, storage and use. 

Obesity is one of the most significant global health challenges of our time. According to the World Health Organization, more than 1 billion people worldwide were living with obesity in 2022 - approximately one in eight people globally¹. Against this backdrop, glucagon-like peptide-1 (GLP-1)-based medicines have reshaped weight management, generating unprecedented interest in peptide therapeutics for obesity and metabolic disease. 

But the clinical success of a peptide begins long before it reaches the patient. Behind every injectable peptide lies an extensive formulation-development programme designed to maintain the API's stability, potency and quality throughout its intended shelf life. 

And for sensitive peptide molecules, the excipients used to solubilise and stabilise the API matter just as much as the active ingredient itself. 

GLP-1 receptor agonists such as semaglutide and liraglutide - and dual agonists such as tirzepatide - have become some of the most recognisable peptide therapeutics in the pharmaceutical industry. But behind their clinical success lies a fundamental formulation challenge. 

Peptides are sensitive molecules whose stability can be affected by oxidation, aggregation, hydrolysis and reactions with other components of the formulation². For formulation scientists, this means that selecting an excipient based solely on its intended functional role may not be enough. 

Increasing evidence suggests that what is present at trace level within an excipient can matter too.

The hidden formulation challenge: reactive impurities

Low levels of reactive impurities - including aldehydes, peroxides, and trace metals - can be introduced through raw materials, manufacturing processes, storage or degradation of the excipient itself. Even at relatively low concentrations, these species may interact with susceptible amino acid residues within therapeutic peptides. 

Croda's GLP-1 formulation studies focus specifically on this challenge: semaglutide, tirzepatide and liraglutide can be sensitive to reactive impurities, while Super Refined™ excipients are manufactured using proprietary purification processes designed to minimise these species and provide tightly controlled impurity profiles⁷.  

Trace metals: a potential catalyst for peptide oxidation 

Trace metals can contribute to the oxidative degradation of therapeutic peptides. Redox-active transition metals such as iron and copper can catalyse the formation of reactive oxygen species (ROS), which can subsequently oxidise susceptible amino acid residues including histidine, cysteine and methionine².  

This susceptibility has also been demonstrated experimentally in therapeutic peptides. In studies with human parathyroid hormone, hPTH(1–34), metal-catalysed oxidation resulted in site-specific oxidation of methionine and histidine residues, illustrating how metal exposure can contribute to peptide degradation under oxidative conditions³.  

For formulation scientists, this highlights the importance of looking beyond the nominal function of an excipient. When developing oxidation-sensitive peptide formulations, controlling trace-metal content may help minimise an additional potential source of degradation. 

Aldehydes and peptide-excipient interactions

Aldehydes represent another important class of reactive impurity. 

A 2024 study by researchers at the National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, published in the Journal of Pharmaceutical Sciences, specifically investigated the interaction of liraglutide with excipients and excipient-derived impurities⁴. 

The researchers identified the N-terminal histidine of liraglutide as a reactive site and characterised interaction products formed during formulation development. In particular, the study found that formaldehyde present as an excipient impurity could contribute to degradation⁴. 

Their conclusion was particularly relevant for formulation development: “The quality of excipients with respect to presence of impurities must be considered as critical material attributes”⁴.  

This principle has direct relevance to commonly used pharmaceutical excipients. 

For example, benzyl alcohol can contain or generate low levels of benzaldehyde, a reactive aldehyde capable of contributing to peptide degradation ⁶. Controlling the impurity profile of the benzyl alcohol therefore provides another potential lever for protecting a sensitive peptide formulation. 

Peroxides: another hidden source of oxidative stress 

Peroxide-mediated oxidation is also well recognised during pharmaceutical development. 

A 2024 study from Eli Lilly examining peroxide quantitation in peptide drug products noted that, during early development, formulation excipients can represent a major source of peroxide, whether already present or generated over time through degradation ⁵.  

This is an important concept. 

A formulation scientist may carefully optimise pH, buffer composition, preservative level and peptide concentration while overlooking low-level reactive species introduced by an otherwise familiar excipient. 

For an oxidation-sensitive API, controlling those trace impurities may help remove an additional source of instability before it becomes a shelf-life problem. 

Compendial compliance and formulation performance are not always the same question 

Pharmacopoeial specifications provide essential standards for pharmaceutical excipient quality. 

But meeting a monograph does not necessarily mean that every impurity potentially relevant to a particularly sensitive peptide is controlled to the lowest achievable level. 

That distinction becomes increasingly important as modern peptide therapeutics grow more structurally sophisticated. 

For developers of GLP-1-based medicines, several questions are therefore worth considering early in formulation development: 

1. Which degradation pathways are most relevant to the peptide? Oxidation, aggregation and direct chemical reactions can each affect peptide stability differently.  
2. Could the excipients introduce reactive impurities? Aldehydes, peroxides and trace metals may warrant consideration alongside the excipient's primary functional role.  
3. Could excipient variability contribute to formulation variability? Tighter and more consistent impurity profiles may help reduce another variable during development and scale-up. 
4. Has the excipient actually been evaluated with a relevant peptide? Head-to-head stability studies can reveal performance differences that would not necessarily be apparent from a specification sheet alone.  

That last question is particularly important. 

Putting excipient purity to the test 

Croda Pharma has evaluated Super Refined™ excipients in formulations containing three commercially relevant incretin-based peptide therapeutics: semaglutide, tirzepatide and liraglutide⁷. 

The results demonstrate how excipient selection and purity can translate into measurable differences in peptide stability. 

Semaglutide: maintaining API recovery over 90 days

Semaglutide is a GLP-1 receptor agonist used in the treatment of obesity and type 2 diabetes. 

In stability studies conducted in collaboration with global peptide API manufacturer TAPI, semaglutide formulations containing Super Refined™ Propylene Glycol were assessed under both refrigerated and accelerated storage conditions. 

At 2-8 °C, Super Refined™ Propylene Glycol maintained ≥98% semaglutide API recovery over 90 days, with negligible impurity formation⁷. Performance was comparable to the reference listed drug product, while the formulation containing standard-grade propylene glycol showed rapid degradation. 

Under accelerated conditions at 30 °C, Super Refined™ Propylene Glycol similarly maintained high API recovery and minimal impurity formation over the study period⁷.  

Tirzepatide: more than three-fold higher API recovery

Tirzepatide is a dual GIP/GLP-1 receptor agonist used in diabetes and chronic weight management. 

When aqueous tirzepatide formulations containing benzyl alcohol were evaluated under refrigerated conditions, Super Refined™ Benzyl Alcohol delivered more than three-fold higher API recovery compared with standard benzyl alcohol⁷. 

The observed stability advantage is consistent with the reduced levels of reactive impurities such as benzaldehyde present in Super Refined™ Benzyl Alcohol⁷.  

Improved API recovery compared with standard grade was also maintained under room-temperature conditions⁷.  

Liraglutide: supporting aggregation control

Liraglutide, another GLP-1 receptor agonist used in obesity and type 2 diabetes, presents an additional formulation challenge: aggregation-related degradation. 

In Croda studies, liraglutide formulations containing Super Refined™ Propylene Glycol demonstrated higher API recovery than a no-excipient control during 12 weeks of refrigerated storage⁷. 

Aggregation-related species were monitored using size-exclusion chromatography, with the results indicating a clear stabilising effect from Super Refined™ Propylene Glycol⁷. 

Formulating the next generation of GLP-1 therapeutics

The rapid emergence of GLP-1-based medicines has transformed the possibilities for treating obesity and metabolic disease. 

As competition grows and the therapeutic class continues to evolve, attention is increasingly turning toward the next challenges: developing differentiated products, expanding into oral dosage forms, supporting longer shelf life, maintaining consistent product quality and designing robust formulations capable of moving confidently from development to commercial manufacture. 

Excipient selection provides formulation scientists with another tool for addressing those challenges. 

For sensitive peptide therapeutics, choosing an excipient should therefore involve more than asking ‘What function does this ingredient perform?’ 

It may also require asking: 

What else is present - and could those trace impurities affect my peptide?

By reducing reactive impurities such as aldehydes, peroxides and trace metals, highly purified excipients can help minimise potential contributors to degradation and provide greater confidence during peptide formulation development. 

Croda Pharma's Super Refined™ excipients combine highly purified pharmaceutical excipients with analytical characterisation, stability data and expert formulation support to help developers address the increasingly complex requirements of next-generation peptide therapeutics.  

As GLP-1s continue to reshape obesity care, seemingly small formulation choices may have an increasingly important role to play in enabling their long-term stability and performance. 

Explore Croda Pharma's latest stability data for semaglutide, tirzepatide and liraglutide in our new Super Refined™ excipients for GLP-1 peptide therapeutics brochure.