Liraglutide precursor

Boiling point

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

boiling point

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

Reason / purpose for cross-reference:

read-across source

Key result

Remarks on result:

not determinable

Remarks:

A drop in baseline at approximately 250°C was assumed to be the start of decomposition, which would be a characteristic of a protein. It was not possible to determine the boiling point.

Conclusions:

Data on target substance not available. Thus, read-across has been applied using data from source substances (S3, S4).

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 precusor.

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 boiling point for S2 (MI3) and S3 (X14desB30) was performed using DSC in accordance to OECD guideline 103 (1995) and EC Directive 92/69/EEC Methods A2. Boiling point was not determinede due to decomposition. 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 substances (S3, S4).

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.

The determination of the boiling point for S3 (MI3) and S4 (X14desB30) was performed using DSC in accordance to OECD guideline 103 (1995) and EC Directive 92/69/EEC Methods A2. Boiling point was not determinede due to decomposition. Therefore, the same conclusion for the target substance, Liraglutide precursor, applies, justified by the read-across hypothesis.

Reference 2

Endpoint:

boiling point

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 103 (Boiling Point)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method A.2 (Boiling Temperature)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

differential scanning calorimetry

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

Key result

Decomposition:

yes

Decomp. temp.:

ca. 250 °C

Remarks on result:

not determinable

Remarks:

due to decomposition at 250°C , which is characteristic of a protein

A sudden decrease in the baseline and lower stability at approximately 250°C, which was assumed to be decomposition of the MI3 (dried), also characteristic of a protein.

 

Conclusions:

Determination of the melting temperature was performed in accordance to OECD guideline 103 (1995) and EC Directive 92/69/EEC Methods A2. The thermal behavior of MI3 (dried) was assessed by Differential Scanning Calorimetry. It was not possible to determine the boiling point.

Executive summary:

Determination of the melting temperature was performed in accordance to OECD guideline 103 (1995) and EC Directive 92/69/EEC Methods A2. The thermal behavior of MI3 (dried) was assessed by Differential Scanning Calorimetry. A drop in baseline at approximately 250°C was assumed to be the start of decomposition of MI3 (dried), which would be a characteristic of a protein.

It was not possible to determine the boiling point.

Reference 3

Endpoint:

boiling point

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003.05.12 -2003.10.24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 103 (Boiling Point)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method A.2 (Boiling Temperature)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

differential scanning calorimetry

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL (X14desB30, dried)
- Appearance: cream powder
- Source and lot/batch No.of test material: QX14203119
- Expiration date of the lot/batch: June 2004
- Purity test date: 2003-06-18
- Purity: 75% w/w

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL

Key result

Decomposition:

yes

Decomp. temp.:

ca. 250 °C

Remarks on result:

not determinable

Remarks:

decomposition at approximately 250 degrees celcius

In both scans a sharp decrease in the baseline at approximately 250°C, which was assumed decomposition of the X14desB30 (dried), which is also the characteristic of a protein.

Conclusions:

Determination of the boiling point of X14desB30 was performed using DSC in accordance to OECD guideline 103 (1995). No boiling point was observed.

Executive summary:

Determination of the boiling point of X14desB30 was performed using DSC in accordance to OECD guideline 103 (1995) and EC Directive 92/69/EEC Methods A2. A sharp decrease in the baseline at approximately 250°C, which was assumed decomposition of the X14desB30 (dried), which is also the characteristic of a protein. No boiling point was observed.

Description of key information

Data on target substance not available. Thus, read-across has been applied using data from source substances (S3, S4).

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 precusor.

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.

Additional information

The determination of the boiling point for S3 (MI3) and S4 (X14desB30) was performed using DSC in accordance to OECD guideline 103 (1995) and EC Directive 92/69/EEC Methods A2. Boiling point was not determined due to decomposition. Therefore, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis attached in section 13.