2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzoic acid

Hydrolysis

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

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

Test material information

Constituent 1

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 test

Duration of test 1

Duration:

2.4 h

pH:

9

Temp.:

50 °C

Initial conc. measured:

ca. 155.48 other: ug/ml

Duration of test 2

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:

No preliminary study was performed

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.

Transformation products:

no

Total recovery of test substance (in %)

Total recovery of test substance (in %) 1

% Recovery:

100

pH:

4

Temp.:

50 °C

Total recovery of test substance (in %) 2

% Recovery:

98.4

pH:

7

Temp.:

50 °C

Total recovery of test substance (in %) 3

% Recovery:

100

pH:

9

Temp.:

50

Dissipation DT50 of parent compound

Dissipation DT50 of parent compound 1

Key result

pH:

9

Temp.:

25 °C

DT50:

> 1 yr

Type:

(pseudo-)first order (= half-life)

Dissipation DT50 of parent compound 2

Key result

pH:

7

Temp.:

25

DT50:

> 1 yr

Type:

(pseudo-)first order (= half-life)

Dissipation DT50 of parent compound 3

Key result

pH:

4

Temp.:

25 °C

DT50:

> 1 yr

Type:

(pseudo-)first order (= half-life)

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.