Liraglutide Formulation Can Be Compromised by Hidden Impurities in Common Pharmaceutical Ingredients

N-terminal histidine of liraglutide reacts with formaldehyde impurities in excipients and PLGA degradation products, forming imidazopyrimidine, glycolyl, and lactolyl interaction products.

Excipient compatibility study using LC-HRMS, MS/MS, and hydrogen-deuterium exchange mass spectrometry to identify and characterize peptide-excipient interaction products during liraglutide formulation development.

Peptide drug stability is critical for patient safety and drug efficacy. If excipient impurities silently modify the active peptide, it could reduce potency or create potentially immunogenic degradation products. This study highlights a previously underappreciated source of instability.

As peptide therapeutics become more common, understanding all sources of drug degradation becomes essential. This study shows that even "inactive" ingredients can actively degrade peptide drugs, and that the N-terminal histidine residue — present in many therapeutic peptides — is particularly vulnerable.

Focused solely on liraglutide and its specific excipient combinations. The clinical significance of the interaction products (e.g., whether they affect efficacy or safety) was not evaluated. Did not assess whether these interactions occur at levels that would affect commercial products.