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Melting point / freezing point

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Endpoint:
melting point/freezing point
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Remarks on result:
not determinable
Remarks:
no melting point could be determined. the observed broad endotherm in the range 192-205 °C, probably representing a thermal transition
Conclusions:
The melting point of Liraglutide precursor was estimated based on read across to MI3 (S3) and X14DesB30 (S4). Based on the structural similarities very similar physical chemical properties would be expected.
The determination of the melting point for S2 (MI3) and S3 (X14desB30) was performed using DSC in accordance to OECD guideline 102 (1995) and EC Directive 92/69/EEC Methods A1. The melting point was not determined. The observed broad endotherm in the range 192-205 °C for MI3 and >185 °C for X14DesB30, probably representing a thermal transition rather than a melting point.
Therefore, the melting point for Liraglutide precursor is estimated to be >185 °C.
Executive summary:

The melting point of Liraglutide precursor was estimated based on read across to MI3 (S3) and X14DesB30 (S4). Based on the structural similarities very similar physical chemical properties would be expected.

The determination of the melting point for S3 (MI3) and S4 (X14desB30) was performed using DSC in accordance to OECD guideline 102 (1995) and EC Directive 92/69/EEC Methods A1. The melting point was not determined. The observed broad endotherm in the range 192-205 °C for MI3 and >185 °C for X14DesB30, probably representing a thermal transition rather than a melting point.

Therefore, the melting point for Liraglutide precursor is estimated to be >185 °C.

For further details, please refer to read across justification document in section 13.

Endpoint:
melting point/freezing 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:
OECD Guideline 102 (Melting point / Melting Range)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method A.1 (Melting / Freezing Temperature)
Deviations:
no
GLP compliance:
yes (incl. certificate)
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
Remarks on result:
not determinable
Remarks:
no melting point could be determined. the observed broad endotherm in the range 192-205 °C, probably representing a thermal transition

The table below lists the thermal data . A small broad endothermic peak between nominally 192 and 205°C , considered to be a thermal transition rather than a melting point.

Parameter

First Scan

Second Scan

Onset (°C)

191.8

194.4

Peak (°C)

199.3

200.8

Endset (°C)

205.3

205.1

Enthalpy (J/g)

-15.06

-7.15

 

Conclusions:
Determination of the melting temperature was performed in accordance to OECD 102. It was not possible to determine the melting temperaure, since a small broad endotherm, considered to be a thermal transistion rather than melting, was observed between approximately 192 and 205°C.
Executive summary:

Determination of the melting temperature was performed in accordance to OECD guideline 102 (1995) and EC Directive 92/69/EEC Methods A1 and A2. The thermal behavior of MI3 (dried) was assessed by Differential Scanning Calorimetry. It was not possible to determine the melting point. An endotherm onset nominally 193°C was generated, and because of its broad nature, was considered to be a thermal transition rather than a melting event.

Endpoint:
melting point/freezing 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:
OECD Guideline 102 (Melting point / Melting Range)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method A.1 (Melting / Freezing Temperature)
Deviations:
no
Principles of method if other than guideline:
NA
GLP compliance:
yes (incl. certificate)
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
- Storage condition of test material: Frozen below - 10°C


Key result
Remarks on result:
not determinable
Remarks:
The melting point could not be determined.

 The table below lists the thermal data. A small broad endothermic peak between nominally 186 and 198°C , considered to be a thermal transition rather than a melting point.

Parameter

First Scan

Second Scan

Onset (°C)

185.8

185.3

Peak (°C)

193.1

192.8

Endset (°C)

198.2

197.7

Enthalpy (J/g)

-8.45

-8.40

 

Conclusions:
The melting point of X14desB30 (dried) was assessed by Differential Scanning Calorimetry. The procedure conformed to the OECD Guideline 102 (1995). No melting point was determined.
Executive summary:

The melting point of X14desB30 (dried) was assessed by Differential Scanning Calorimetry. The procedure conformed to the EC Directive 92/69/EEC Method A1 and OECD Guideline 102 (1995). An endotherm with an onset at nominally 185oC was generated, and because of its broad nature, was considered a thermal transition rather than a melting event.

No melting point was determined.

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.

 

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 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.

For further details, please refer to read across justification document in section 13

Key value for chemical safety assessment

Melting / freezing point at 101 325 Pa:
185 °C

Additional information

The determination of the melting point for S3 (MI3) and S4 (X14desB30) was performed using DSC in accordance to OECD guideline 102 (1995) and EC Directive 92/69/EEC Methods A1. The melting point was not determinede. The observed broad endotherm in the range 192-205 °C for MI3 and > 185 °C for X14desB30, probably representing a thermal transition rather than a melting point.

Therefore, the melting point for the target substance (Liraglutide precursor) was estimated to be > 185 °C