Speciality Chemicals Magazine MAR / APR 2026 | Page 36

Lixisenatide Semaglutide

Liraglutide

" dimer

•• ���----.-----.----,----,----.-

3 4 S,:,dll muilation COilrClOrl rs

• In solution mainly as tetramer( 88.5 %) and dimer( 11.2 %)

• No concentration-dependent equilibrium detected

•• TO 15 2. $vd mf,fllatiotlC011lrclOn1tS

• Concentration-dependant equilibrium

' ' 5 5;;dl mvilatiotlcoelr <: 001fS

• In solution as heptamer( 96.7 %) + aggregates

• No concentration-dependent equilibrium detected

Figure 4- Example of SV-AUC distributions for GLP-1 analogues

association shifts from irreversible aggregation and particulate formation.

For oral delivery, semaglutide has been co-formulated with the absorption enhancer SNAC to enable uptake in the stomach, underlining that formulation can be an active part of the product concept and can directly influence which stability risks and which orthogonal readouts are most relevant from early selection through to commercial supply.

These examples reinforce the principle that study design should be decision-led, not protocol-driven. The choice of stress conditions, analytical endpoints and timelines should reflect both the peptide ' s intrinsic liabilities and its intended clinical use.

AUC

TEM

SEC

DLS / MALS

AF4

nm Monomers

SEM

I

(:

Visual inspection

:)

( FTIR microscopy for ID)

C

Light Microscopy)

---------

SEM-EDX for ID

)

FlowCam Nano

C

I(

�

)

I

Light obscuration

MFI

)

)

100 nm Soluble aggregates µ m Insoluble aggregates

10 µ m Particulates

Figure 5- Aggregation & particle control methods across the nm – mm continuum

100 µ m Visible particulates

I

mm

Study design

Stability studies should be decisionled and stage-appropriate( Figure 2). In early work, the aim is to rank sequences and formulations quickly, using small volumes and accelerated timelines. Later, programmes shift toward defining shelf-life, supporting comparability and building the narrative needed for regulatory submissions. A pragmatic workflow would be: 1. Forced degradation and targeted stress studies to map likely pathways and generate characterised material for method development

2. Short accelerated screens to identify dominant formulation drivers( pH and buffer species, ionic strength, excipients and concentration)

3. DP studies that explicitly include container – closure / device stresses alongside container closure integrity testing( CCIT) and extractables and leachables( E & L) where relevant

4. Intermediate and long-term studies under ICH-aligned conditions, including in-use testing when applicable

‘ Formulation-relevant’ means that the stresses applied should mirror the

dominant real-world exposures for the intended presentation. For highconcentration peptide injectables, that typically includes interfacerich handling( air, device surfaces and, where relevant, silicone oil), agitation, temperature excursions and in-use holds.

Orthogonal toolbox

Soluble aggregation and oligomerisation often sit in a regime where techniques overlap but can disagree, especially when equilibria are reversible. Orthogonality helps distinguish true irreversible aggregation from equilibrium shifts

36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981