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Environmental fate & pathways

Hydrolysis

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Administrative data

Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Between 25 November and 9 December 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study carried out in accordance with method C7 of commission directive 92/69/EEC and in accordance with GLP. The test material was well characterised

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)
Principles of method if other than guideline:
Hydrolysis of test substance at either pH 4, pH 7 or pH 9 over 5 days.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Intended use: Pharmaceutical intermediate



Appearance: White powder



Storage conditions: Room temperature



Sample reference: CPI/96/070



Expiry date: Not supplied



Purity: 99.4%



Date received: 2 October 1996
Specific details on test material used for the study:
Details on properties of test surrogate or analogue material (migrated information):
acetylsalicylic acid
Radiolabelling:
no

Study design

Analytical monitoring:
yes
Details on sampling:
HPLC method validated in the water solubility study performed on this compound.
Buffers:
pH 4 buffer

Potassium dihydrogen citrate (23.03 g) was d issolved in distilled water (900 ml) and the pH of the solution adjusted to 4.0 with I M aq ueous sodium hydroxide at elevated temperature (50°C ± 5°C). The solution was then diluted to 1000 ml with distilled water.

pH 7 buffer

Potassium dihydrogen orthophosphate (13.66 g) was dissolved in distilled water (900 ml) and the pH of the solution adjusted to 7.0 with l M aqueous sodium hydroxide at elevated temperature (50°C ± 5°C). The solution was then diluted to 1000 ml with distilled water.

pH 9 buffer

Potassium chloride (7.82 g) and boric acid (6.22 g) were dissolved in distilled water (900 m l) and the pH of the solution adjusted to 9.0 with J M aqueous sodium hydroxide at elevated temperature (50°C ± 5°C). The solution was then diluted to 1000 ml with distilled water.

pH 2 buffer

Potassium dihydrogen orthophosphate (2.72 g, 1.36 g and 1.45 g) was dissolved in distilled water (2 litres, 1 litre and 1 litre respectively). The solutions were adjusted to pH 2.0 with l M hydrochloric acid. These pH 2 buffer solutions were used to prepare mobile phase.
Details on test conditions:
Ni ne I00 ml volumetric flasks were calibrated at 50°C by heating I00 ml of distilled water at 20°C to 50°C in a water bath. The flasks were then marked at their new level.

Prior to the test, the recalibrated vol umetric flasks were rinsed with ethanol and allowed to drip dry. The buffer solutions were autoclaved at 122°C for 15 minutes and then purged with nitrogen for 5 min utes prior to use. The pH value of each buffer solution was then rechecked at 50°C and was seen to be 4.00, 7.03 and 9.04 respectively.

PER 21/970568

Test substance (approximately 0.1 g) was weighed accurately into each of 6 volumetric flasks. The test substance was dissolved in buffer at 50°C to produce 2 solutions at each pH. The remaining 3 flasks were filled with buffer to act as blanks at each pH.

An al iquot from each solution was then poured into a polystop bottle and allowed to cool in a water bath at 20°C.

The flasks containing the remainder of each sol ution were stoppered, covered in aluminium foil and placed in a water bath at 50°C.

After 2.4 hours and 5 days a further aliquot of each solution was taken and cooled as before prior to analysis.
Duration of testopen allclose all
Duration:
2.4 h
pH:
9
Temp.:
50 °C
Initial conc. measured:
ca. 155.48 other: ug/ml
Duration:
5 d
pH:
9
Temp.:
50 °C
Initial conc. measured:
ca. 164.48 other: ug/ml
Number of replicates:
2
Positive controls:
yes
Negative controls:
no
Statistical methods:
used but not described

Results and discussion

Preliminary study:
NA
Test performance:
Under the test cond itions UK-143,108 was found to undergo no significant hydrolysis after 5 days at pH 4, 7 or 9.
Details on hydrolysis and appearance of transformation product(s):
According to the test method it can be estimated that:

50% hydrolysis occurring in 2.4 hours at 50°C is equivalent to a half-life time of 1 day at 25°C. 10% hydrolysis occurring in 5 days at 50°C is equivalent to a half-life time of l year at 25°C.
Applying these criteria to the results obtained for UK-143,108 the half-life at 25°C can be estimated as greater than one year at pH 4, 7 and 9.
Total recovery of test substance (in %)open allclose all
% Recovery:
100
pH:
4
Temp.:
50 °C
% Recovery:
98.4
pH:
7
Temp.:
50 °C
% Recovery:
100
pH:
9
Temp.:
50
Details on results:
No significant peaks were seen in any of the blank chromatograms

Applicant's summary and conclusion

Validity criteria fulfilled:
yes
Conclusions:
UK-143,108 has been found to undergo no significant hydrolysis at pH 4, 7 or 9 over 5 days at 50°C.

The results indicate that at 25°C, the test substance will possess a half-life of greater than one year at pH 4, 7 and 9.