A group at Merck published work in the Journal of Pharmaceutical Sciences on 2 September 2026 testing what three common surfactants do to peptide stability under agitation stress.
Surfactants are added to protein formulations precisely to prevent aggregation. In this work, two of the three made it worse.
That result is worth the attention of anyone responsible for peptide stability at a bench, because it is the opposite of the assumption most handling advice is built on.
A framing note. This is laboratory formulation chemistry, not a clinical study. Everything Peptra Labs supplies is on a research use only basis, and nothing below is guidance about human use.
Why peptide stability is a separate problem
The authors open with the reason the question needed asking at all.
Peptide therapeutics are prone to aggregation, denaturation and interfacial adsorption, which the authors say can compromise product quality, reduce potency, increase immunogenicity and shorten shelf life. Surfactants are widely used to stabilise protein biologics. Their use in commercial parenteral peptide formulations is more selective, and the authors state plainly that the literature does not provide a clear rationale for using them in this context.
So the starting position was not a settled practice being confirmed. It was a habit borrowed from a neighbouring field and never tested properly on peptides.
The closing sentence of the abstract explains why the borrowing was risky. Unlike monoclonal antibodies, which adopt monomeric structures held together by extensive intramolecular and interdomain interactions, peptides are more flexible and therefore more susceptible to perturbation by surfactants.
Flexibility is the whole difference. A large folded protein has a structure that resists being pulled apart. A short peptide does not have much structure to lose, and what holds it together is often an association with copies of itself.
What the peptide stability study tested
Three surfactants: polysorbate 80, polysorbate 20 and poloxamer 188, referred to as PS80, PS20 and PX188.
Liraglutide was the primary model peptide, with semaglutide and glucagon evaluated in an exploratory capacity. The stress applied was agitation, which is the ordinary mechanical insult of transport, handling and mixing rather than an exotic laboratory condition.
The readouts were size exclusion chromatography and circular dichroism for aggregation and structure, and nuclear magnetic resonance for direct interactions.
Where peptide stability held and where it failed
| Peptide | Behaviour reported |
|---|---|
| Liraglutide | dynamic oligomers, not intrinsically stable under agitation; extensive aggregation and structural rearrangement with PS80 and PX188 |
| Semaglutide | more stable oligomers; only limited changes in aggregation behaviour with surfactants |
| Glucagon | strong intrinsic tendency to fibrillate; surfactants modestly changed aggregation rates but did not prevent fibril formation |
Liraglutide is the clearest case. The authors report extensive aggregation with both PS80 and PX188, with PS80 driving more rapid aggregation. Nuclear magnetic resonance showed strong, specific interactions between liraglutide and PS80 but not with PX188.
That difference points at two separate mechanisms. PS80 appears to perturb the native oligomer through direct peptide-surfactant interaction. PX188 appears to promote aggregation through interfacial stress instead, without binding the peptide.
PS20, which has a shorter and less hydrophobic chain than PS80, caused less disruption. The authors read that as evidence that the strength of the peptide-surfactant interaction is what governs peptide stability here.
The peptide stability conclusion, as the authors state it
Their summary is that surfactant effects on peptide stability are highly molecule-dependent and reflect a balance among peptide-peptide interactions, peptide-surfactant interactions, surfactant-mediated interfacial stress, and the intrinsic stability of the peptide oligomers.
Four competing forces, and which one wins depends on the specific molecule.
That is a more useful conclusion than a recommendation would have been. It says there is no general answer to whether an additive helps, and that the answer for one peptide does not transfer to another, even within the same drug class. Liraglutide and semaglutide are both GLP-1 receptor agonists and they behaved differently, because their oligomers differ in stability.
What it means for peptide stability at a bench
Most of our catalogue is short synthetic peptides supplied lyophilised, which is a different starting condition from a commercial parenteral formulation. The transferable parts are still substantial.
The first is that agitation is a peptide stability risk in itself. The stress in this study was mechanical, and mechanical stress is what a vial experiences during shipping, during vortexing and during repeated handling. Gentle mixing after reconstitution is standard advice, and this paper gives a mechanism for why it is not fussiness.
The second is that additives are not automatically protective. Any diluent or excipient introduced during reconstitution is a variable, and the assumption that something helpful for proteins is helpful for a fifteen-residue peptide is exactly the assumption this paper tests and finds wanting.
The third is about what you can see. Aggregation often shows up as haze or visible particulates before it shows up in an assay, which is why visual inspection against a plain background is worth doing every time.
Short catalogue compounds such as BPC-157 and MOTS-c are much shorter than liraglutide and have their own aggregation behaviour, none of which is characterised anywhere near this thoroughly. That absence is the honest position: this study tells you the question matters, not what the answer is for any particular research peptide.
Our guides on lyophilisation and peptide stability, on peptide storage, and our laboratory protocol guide cover handling in more detail, and the analytical methods used to characterise peptides covers the techniques this paper used, including size exclusion chromatography.
What this paper does not settle
It is a formulation study on three peptides under one kind of stress.
Agitation is not the only threat to peptide stability. Temperature cycling, freeze-thaw, light exposure and pH shifts each produce their own failure modes, and none of them was tested here. Nor was long-term storage: this is a stress study, not a shelf-life study.
The peptides chosen are also all clinically established molecules with well-characterised oligomer behaviour. Whether the same balance of forces governs peptide stability in a short research peptide with no known oligomeric state is exactly the question this design cannot answer.
What it does establish is that the peptide stability question is real, that the answer is molecule-specific, and that a surfactant is not a safe default.
References
- Hamada N, Wuelfing WP, Su Y, Ling J. Impact of surfactants on the stability of therapeutic peptides under interfacial stress. Journal of Pharmaceutical Sciences, 2 September 2026, 104493. doi 10.1016/j.xphs.2026.104493
- Zhang H, Shao L, Feng Q, Guo Q, Wang H, Zhang H. Efficient Expression of Small Molecule Bioactive Peptides in Bacillus licheniformis. Applied Biochemistry and Biotechnology, 29 August 2026. doi 10.1007/s12010-026-05885-6
- Suliman ME, Rahman A, Qureshi AR, et al. AGEs-RAGE Axis and Mitochondrial-Derived Peptides in Advanced Chronic Kidney Disease. Antioxidants (Basel), 30 July 2026, 15(8):956
The products referenced on this site are supplied for laboratory research use only. They are not medicines and are not intended for human or veterinary use. This article summarises published research for informational purposes and is not medical advice. Statements about third-party studies belong to their authors.
