Registration Dossier

Physical & Chemical properties

Endpoint summary

Administrative data

Description of key information

The physical state:       Liraglutide precurser is a solid at 20 C. However the substance is only manfacutend and handled in aqaeous suspension.

Melting point:       Melting point could not determined. Thermal transition/ decomposition at 185 -205 °C (read-across data)

Boiling point:       Could not be determined due to decomposition (read-across data)

Relative density:       About 1.342 at 20.1oC for dryed substance (read-across data)

Particle size distribution:       not relevant as only used in suspension

Vapour pressure:       4.9 x 10-6 Pa at 20oC or 25oC (read-across data)

Partition coefficient:      LogPow = approximately 0.4 (estimated at pH 7 .9 for aquaous solution; read-across data).

Water solubility:       very pH dependent. Insoluble at pH 4.5-6.5.In pure water solubility is high (> 60 g/L)

Surface tension:       surface tension of a 90% saturated solution: 58.0 mN/m (read-across data)

Flash point:       negligible vapour pressure and consequently will not emit flammable vapours (Read-across data)

Auto-flammability:       No self-ignition observed when heated to 400 ºC (Read-across data)

Flammability:       not flammable (read-across data)

Explosiveness:       not explosive (read-across data)

Oxidising properties:       no chemical groups with oxidising properties in the molecule

Additional information

The target substance (T): liraglutide precusor is a single-chain polypeptide consisting of 31 amino acids having an almost identical amino acid sequence as the human glucagon-like peptide 1 (GLP-1) that has 30 amino acids of which 29 amino acids in common with the target substance.

The target substance is a part of the active pharmaceutical ingredient: liraglutide (S1) as the liraglutide molecule has been obtained from the liraglutide precusor be the addition of a plamitoyl-ϒ-glutamate unit attached to the amino acid lysine in position 26 of the precusor.

Another active pharmaceutical ingredient: semiglutide (S2) is very similar to (S1) and has nearly identical amino acid sequence compared to liraglutide precusor as well.

S3 and S4 substances are somewhat larger polypeptides as consisting of 53 and 50 amino acids in the polypeptide chain.

 

Hypothesis and justification for read-across of physicochemical properties

Each of the amino acids in the above mentioned substances are and very polar molecules and when linked together in polypeptides the very polar nature of the polypeptides are considered as having very similar physicochemical properties irrespective whether they contain 31 (T) or 50 amino acids (S3,S4) for which physicochemical properties have been obtained. Thus, the results from physicochemical guideline testing for S3 and S4 formelting point, boiling point, flammability, self-ignition, and explosionwere identical and can be considered as representative for the target substance as well. With respect to vapour pressure the vapour pressure for single amino acids is extremely low (below 0.4 Pa) and thus, the vapour pressure for polypeptides would be expected to be even lower and not a relevant parameter for further testing.

See attached read-across justification in section 13.