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Vapour pressure

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Reference
Endpoint:
vapour pressure
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000.03.16 – 2000.09.18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 104 (Vapour Pressure Curve)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method A.4 (Vapour Pressure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
effusion method: Knudsen cell
Remarks:
The MI3(solution) was highly hydroscopic and had unknown thermal (melting) characteristics, why an initial thermal analysis was performed by differential scanning calorimetry.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL (MI3 solution)
- Appearance: brown paste
- 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


Temp.:
< 54 °C
Remarks on result:
not determinable because of methodological limitations
Remarks:
At 54oC the vapour pressure of MI3 was 10-fold lower than the lowest detection limit of the apparatus.
Key result
Temp.:
ca. 20 °C
Vapour pressure:
<= 0 Pa
Remarks on result:
other: calculated
Remarks:
In cases where the test substance stability places constrains on the maximum temperature a, a highest estimate of the vapour pressure is made.
Transition / decomposition:
no
Remarks:
Reversible chemical change
Transition temp.:
> 58 - ca. 61 °C

DSC analysis revealed no endotherm due to water melting (around 0oC), nor any chemical change around 58oC. However, the thermograms were broadly similar above that temperature, and therefore no significant changes had occurred to the samples during the vapour pressure testing.

The measured weight losses were to small for reliable vapour pressure calculations to be made and to be measured by the system. At 54oC the vapour pressure of MI3 was 10-fold lower than the lowest detection limit of the apparatus (1x10-5Pa).

At temperatures at above 58oC there is a chemical change in MI3. Hence, extrapolation back to 20 or 25oC using the Ln(vapour pressure) versus 1/K relationship cannot be made above this temperature since it only holds true over one chemical phase.

In cases where the test substance stability places constrains on the maximum temperature a, a highest estimate of the vapour pressure is made. This is performed by assuming a vapour pressure of 1x10-5Pa at the highest temperature measured , and applying a slope of -2000 to the Ln (vapour pressure) versus 1/temperature (K) relationship. This figure is based on experimental evidence from many years of testing in different laboratories. A slope less negative than this has never been reported, typically the slopes are between – 18,000 and -8,000.

The calculated vapour pressure at 25oC will be 2.2 x 10-6Pa, and at 20oC will be 4.9 x 10-6Pa. from the measuremets it is evident that the vapour pressure will not exceed 4.9 x 10-6Pa at 20oC or 25oC.

Conclusions:
The vapour pressure of MI3 (solution) was determined by DSC and Knudsen cell effusion method. The procedure conformed with EC Directive 92/69/EEC Method A4, and OECD Guideline 104 (1995). The vapour pressure was below sensitivity of the apparatus, but calculated not to exceed 4.9 x 10-6 Pa at 20 oC or 25 oC.
Executive summary:

The vapour pressure of MI3 (solution) was determined by DSC and Knudsen cell effusion method. The procedure conformed with EC Directive 92/69/EEC Method A4, and OECD Guideline 104 (1995). The vapour pressure was below sensitivity of the apparatus and could not be determined experimentally. At temperatures at 58oC there is a chemical change in the MI3. Hence, extrapolation back to 20 or 25oC using the Ln(vapour pressure) versus 1/K relationship cannot be made above this temperature since it only holds true over one chemical phase. However, from calculations, it was estimated that MI3 will not exceed 4.9 x 10-6Pa at 20oC or 25oC.

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 and not a relevant parameter for further testing.

Key value for chemical safety assessment

Additional information

The determination of the vapour pressure for S3 (MI3) was performed using DSC in accordance to OECD guideline 104 (1995) and EC Directive 92/69/EEC Methods A4. The vapour pressure was below sensitivity of the apparatus, but calculated not to exceed 4.9 x 10-6 Pa at 20 oC or 25 oC. Therefore, the same conclusion for the target substance (Liraglutide precursor) applies justified by the read-across hypothesis.