Liraglutide precursor

Density

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

relative density

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Key result

Type:

relative density

Density:

ca. 1.342 kg/m³

Temp.:

20.1 °C

Remarks on result:

other:

Remarks:

Standard deviation of 0.0038

Conclusions:

Data on target substance not available. Thus, read-across has been applied using data from source substance (S3).
The target substance liraglutide precursor 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 precursor be the addition of a plamitoyl-ϒ-glutamate unit attached to the amino acid lysine in position 26 of the precursor.

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

The determination of the relative density for S3 (MI3) was performed using DSC in accordance to OECD guideline 109 (1995) and EC Directive 92/69/EEC Methods A3. The relative density of MI3 (dried) was determined to be 1.342.± 0.0038 kg/m3at 20.1oC. Therefore, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis.

Executive summary:

Data on target substance not available. Thus, read-across has been applied using data from source substance (S3).

The target substance liraglutide precursor 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 precursor be the addition of a plamitoyl-ϒ-glutamate unit attached to the amino acid lysine in position 26 of the precursor.

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

 

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 for melting point, boiling point, flammability, self-ignition, and explosionwere identical and can be considered as representative for the target substance as well. 

The determination of the relative density for S3 (MI3) was performed using DSC in accordance to OECD guideline 109 (1995) and EC Directive 92/69/EEC Methods A3. The relative density of MI3 (dried) was determined to be 1.342.± 0.0038 kg/m³at 20.1^oC. Therefore, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis.

Reference 2

Endpoint:

relative density

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003.06.30 - 2003.07.14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 109 (Density of Liquids and Solids)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method A.3 (Relative Density)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

air comparison pycnometer (for solids)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL (MI3)
- Appearance: cream powder
- Source and lot/batch No.of test material: QC202426
- Expiration date of the lot/batch: June 2004
- Purity test date: 2003-06-18
- Purity: 84% w/w (stated ny Sponsor)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Frozen below - 10°C

Dynamic viscosity of test material:

NA

Key result

Type:

relative density

Density:

ca. 1.342 kg/m³

Temp.:

20.1 °C

Remarks on result:

other:

Remarks:

a Standard deviation of 0.0038

The calibration showed that the cell volume was within acceptable limits. The test temperature was 20.1°C. The sample cell volume was 37.9654 cm³. The expansion cell volume was 74.4377 cm³. The weight of MI3 (dried) 9.5727 g. The mean density was 1.342 kg/m³, with a standard deviation of 0.0038.

Conclusions:

The density of MI3 (dried) was determined by a gas comparison pyknometer method. The procedure conformed with EC Directive 92/69/EEC Method A3, and OECD Guideline 109 (1995). The relative density [D420] (dimensionless) of MI3 (dried) was determined to be 1.342 (σ,n-1 0.004).

Executive summary:

The density of MI3 (dried) was determined by a gas comparison pyknometer method. The procedure conformed with EC Directive 92/69/EEC Method A3, and OECD Guideline 109 (1995). The relative density [D₄²⁰] (dimensionless) of MI3 (dried) was determined to be 1.342 (σ(n-1) 0.004). The Relative Density as a D₄²⁰value was calculated by dividing the density value (in g/mL) of MI3 (dried) by the value of the density of water at 4°C.

Description of key information

Data on target substance not available. Thus, read-across has been applied using data from source substance (S3).

The target substance liraglutide precursor 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 precursor.

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

 

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 for melting 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.

Key value for chemical safety assessment

Relative density at 20C:

1.342

Additional information

The determination of the relative density for S3 (MI3) was performed using DSC in accordance to OECD guideline 109 (1995) and EC Directive 92/69/EEC Methods A3. The relative density of MI3 (dried) was determined to be 1.342.± 0.0038 at 20.1^oC. Therefore, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis.