[1,1'-Biphenyl]-2-carboxylic acid, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-, hydrochloride (1:1)

Hydrolysis

Administrative data

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6 August - 20 September 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in GLP compliance and in accordance with an internationally established guideline (see below).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

485-140-4

EC Name:

-

Cas Number:

515815-48-2

Molecular formula:

C33 H30 N4 O2 x HCl

IUPAC Name:

4’-(2-Propyl-4-methyl-6-(1-methylbenzimidazolyl-2-yl)-benzimidazol-1-ylmethyl)biphenyl-2-carbonsäure Hydrochlorid

Details on test material:

- Name of test material (as cited in study report): BIBR 277 CL
- Molecular formula (if other than submission substance): C33H30N4O2*HCl
- Molecular weight (if other than submission substance): 514.6 + 36.5 g/mol
- Structural formula attached as image file (if other than submission substance): see reference substance
- Physical state: solid; sligh brownish
- Analytical purity: 99.8 %
- Purity test date: 26. march 2007
- Lot/batch No.: 10
- Expiration date of the lot/batch: 8. march 2008
- Storage condition of test material: at room temperature, dark and dry

Study design

Details on sampling:

Samples were taken after 41, 72, 121 and 168 hours. The samples were filtered before the analysis.

Buffers:

20 mM Sodiumhexylsulfonate, 50 mM potassium dihydrogenphosphate
3.76 g sodium hexylsulfonate and 6.80 g potassium dihydrogenphosphate were dissolved in water and the pH was set to 3 with the addition of phosphoric acid solution. The final volume was 1000 ml.

Details on test conditions:

The hydrolysis was examined at 4 pH at 50 +- 0.5°C and at 25 +- 0.5°C in the dark.
Sterile buffer solution was prepared:
pH 4.0: 5 ml 0.2 M Sodium hydroxide and 625 ml 0.2 M Potassium hydrogen phthalate was diluted 2500 ml with ultra-pure water. The pH of the buffer solution was checked with calibrated pH meter. The hydrolysis reaction was carried out using a dark thermostat to avoid photolytic effects. Nitrogen was bubbled into the water for five minutes before the preparation of the solution in order to exclude oxygen.

Statistical methods:

The chromatograms were evaluated with the help of 'LaChrom Chromatogram Processor'.
Calculation of the rate constant:
k = 2.303/t * log (Co/Ct)
Calculation of the half-life:
t1/2 = 0.693 / k

with t = time; Co = concentration at time 0; Ct = concentration at time t

Results and discussion

Preliminary study:

A preliminary study was carried out indicating that more than 10% of the test substance hydrolyse at pH 4, 50°C after 5 days (see LAB International_06/134-336AN)

Dissipation DT50 of parent compound

Dissipation DT50 of parent compound 1

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

0

DT50:

101 d

Dissipation DT50 of parent compound 2

pH:

4

Temp.:

50 °C

Hydrolysis rate constant:

0

DT50:

85 d

Applicant's summary and conclusion

Conclusions:

A hydrolysis half life value of 101 d was determined at pH 4 at 25°C in a reliable study conducted according to an appropriate test protocol but not conducted according to GLP.