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Is there any published stability data for orforglipron at 4 °C?

Asked 31 Mar 2025Modified 14 months agoViewed 21k times
21

Setup, so nobody has to ask: orforglipron · 4 °C.

This is asserted often enough that I assumed it was established, and then I went looking for the source.

I have searched the primary literature and found one paper that is adjacent but not on point.

Can anyone point me at a primary source, or confirm that there is not one?

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askedleah_ferrers12k1631 Mar 2025
What temperature, and for how long? Both are needed before anyone can say anything useful. – Dr_Elias_Weiss 10 months ago
Do you know the residual moisture? It predicts this better than any date does. – Dr_Bram_Verhoeven 43 days ago
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4 Answers

Accepted answer first, then by votes
81

Accepted answer

Probably not at 4 °C specifically, because that is not where stability programmes take their readings. Accelerated work is conventionally run at 25 °C and 40 °C, with the refrigerated condition as the control, so 4 °C sits between or beyond the published points and what you will find is bracketing rather than a measurement. 4 °C is the condition the rule of thumb is anchored to, so it is the baseline rather than a multiplier: everything else in this thread is quoted relative to it. Whatever you find, check what was measured before you use it: a paper reporting purity at 4 °C has not measured content, and the two fail at different rates for different reasons.

In practice, this is answerable from the chemistry rather than from anecdote, which is unusual and welcome.

A mass spectrum resolves most of this: minus eighteen is dehydration or succinimide, plus one is deamidation, plus sixteen is oxidation, and an unchanged mass with a shifted retention time is an isomer.

Reported and extrapolated stability by condition

StateConditionUsable windowBasis
Lyophilised solid−20 °C, sealed, dry24–36 monthsSupplier guidance
Lyophilised solid2–8 °C, sealed12–24 monthsSupplier guidance
Lyophilised solid25 °C, sealed4–8 weeksExtrapolated (Arrhenius)
Lyophilised solid40 °C, sealed1–2 weeksExtrapolated
Solution, preserved2–8 °C28 daysUSP microbiological convention
Solution, preserved25 °C3–7 daysExtrapolated
Solution, unpreserved2–8 °C24 hoursUSP microbiological convention

Windows for the solid state are chemical; windows for solution are microbiological and usually shorter than the chemical limit.

Concretely, adsorption onto glass and plastic is significant at low concentrations — micrograms per millilitre — and negligible at milligrams per millilitre. It is the usual explanation for an apparent loss in a dilute preparation.

Metal-catalysed oxidation of methionine is documented across peptide and protein formulations and is why chelators appear in some formulations.

Nothing here is medical advice, and research-use compounds are not approved for human use.

Swirl, never shake. Aggregation is a handling problem more than a time problem.

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DL
answered · acceptedDr_Otto_Lindqvist72k5828 Apr 2025
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31

Put another way, asparagine and glutamine are the deamidation risk, and methionine is the oxidation risk.

Oxidation targets methionine, cysteine and tryptophan, adding sixteen daltons per oxygen. It is catalysed by trace metals and promoted by dissolved oxygen and by light.

Stated carefully, freeze-thaw cycling drives aggregation through concentration at the ice interface and pH shifts as buffer components crystallise out at different rates. Each cycle costs something.

Adsorption losses at low concentrations are quantified in formulation studies and are the reason carrier proteins are used in dilute preparations.

Apparent loss in a dilute preparation is usually adsorption rather than degradation and is worth ruling out first.

Sequence decides which pathways are even available. Check the residues.

edited 24 May 2025 by marta_okonkwo — tightened the wording; no substantive change

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MO
answeredmarta_okonkwo190k2589 May 2025
20

Start with the sequence, because which pathways are available depends on which residues are present.

Deamidation converts asparagine or glutamine to the corresponding acid via a succinimide intermediate, adding one dalton. It is base-catalysed, accelerates above neutral pH and is the dominant aqueous pathway for many peptides.

Put another way, hydrolysis cleaves the backbone, most readily at aspartate-proline and aspartate-glycine sequences, and is acid-catalysed. In a dry solid it barely proceeds at all.

Aggregation at air-liquid interfaces is established from surface-tension and particle-count studies and is the basis for anti-agitation handling guidance.

A mass spectrum names the pathway. Plus one, plus sixteen, minus eighteen.

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DV
answeredDr_Bram_Verhoeven84k24831 May 2025
Thank you — this is the answer I was looking for. – lucia_marchetti 27 days ago
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-3

The honest answer is that most reported "degradation" is adsorption and dilution error rather than chemistry.

Aggregation is physical: peptides unfold at air-liquid interfaces and associate. Shaking maximises that interface, which is why swirling and shaking produce visibly different outcomes on the same vial.

Deamidation via the succinimide intermediate is well characterised, with sequence-dependent rates highest for asparagine-glycine motifs.

The caveat is that none of these pathways can be seen by looking at a vial, and a clear solution can be substantially degraded.

Cold, dry, dark, still. Those four words cover most of the mitigation.

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MO
answeredmarta_okonkwo190k25820 May 2025
3Aliquoting before the first freeze is the advice I wish I had read two years ago. – bea_forsberg 40 days ago
2Two lots stored differently, reassayed at a year — the difference was smaller than I expected. – Dr_Nadia_Farsi 10 months ago
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Your answer

Ask PeptideStack is a static archive. Posting is closed, but the norms are worth stating: answer the question that was asked, show your working, cite the trial or the certificate, and say plainly where the evidence runs out.

Not medical advice. Research-use-only compounds are not approved for human use.