1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}-1H-pyrazole-5-carboxamide

Solubility in organic solvents / fat solubility

Link to relevant study record(s)

Reference

Endpoint:

solubility in organic solvents / fat solubility

Type of information:

experimental study

Adequacy of study:

key study

Study period:

9 July to 11 October 2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study has been conducted using several organic solvents (non of which can be classified as fat) for which no guideline exists. Guideline for water solubility(OECD 105, flask method) has been adapted and used. The experimental temperature for fat solubility is 37 °C but the solubility at 20 °C has been reported. Since this endpoint is not mandatory for the substance's tonnage band (10-100 t/a, Annex VIII) results can be considered reliable with restrictions.

Qualifier:

according to guideline

Guideline:

other: EU Method A.6 (Water Solubility)

Version / remarks:

See remarks on "Rationale for reliability incl. deficiencies"

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 105 (Water Solubility)

Version / remarks:

See remarks on "Rationale for reliability incl. deficiencies"

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 830.7840 (Water Solubility)

Version / remarks:

See remarks on "Rationale for reliability incl. deficiencies"

GLP compliance:

yes (incl. QA statement)

Key result

Medium:

methanol

Solubility:

2.9 g/L

Temp.:

20 °C

Key result

Medium:

other: n-Heptane

Solubility:

< 0.001 g/L

Temp.:

20 °C

Key result

Medium:

toluene

Solubility:

0.17 g/L

Temp.:

20 °C

Key result

Medium:

other: Dichloromethane

Solubility:

5.3 g/L

Temp.:

20 °C

Key result

Medium:

acetone

Solubility:

21.8 g/L

Temp.:

20 °C

Key result

Medium:

ethyl acetate

Solubility:

6.4 g/L

Temp.:

20 °C

Key result

Medium:

other: Dimethyl sulfoxide

Solubility:

> 280 g/L

Temp.:

20 °C

Preliminary Range-Finding Tests

The first set of preliminary tests showed a solubility < 12.5 g/L in most of the solvents. Only in acetone and dimethyl sulfoxide the solubility was higher (12.5-25 g/L and ≥ 250 g/L, respectively). A subsequent test using a lower quantity of the test substance helped in better define solubility ranges.

 

Direct Addition Method

Due to the fact that the preliminary range-finding tests showed that the solubility of the test item in dimethyl sulfoxide was ≥ 250 g/L, additional experiments were performed. 2 mL of solvent were added to approx. 700 mg of the test item and left for 1 hour at 20 °C. After this time, the volumes of the solutions were determined. From the sample weight and the resulting volume the minimum solubility was calculated to be >280 g/L.

 

Results of the whole preliminary testing are summarized in the table below.

 

Solvent	Approx. solubility at 20 °C [g/L]
Methanol	2.5 – 6.25 g/L
n-Heptane	< 0.625 g/L
Toluene	< 0.625 g/L
Dichloromethane	2.5 – 6.25 g/L
Acetone	12.5 - 25 g/L
Ethyl acetate	2.5 – 6.25 g/L
Dimethyl sulfoxide	> 280 g/L

 

 

Main test

For dichloromethane several investigations were done: The treatment of the first sample set (flask 1 - 4) was equal to all other solvents. The result of flask 4 (4 h at 30 °C / 20 h at 20 °C) was significant higher than the results of flask 1 to 3. Therefore this test was repeated with flask 5 – but the result of the analysis of flask 5 was also significantly different to flask 1 to flask 3. It was decided to repeat the whole experiment with a second sample set (flask 6 - 9). The analysis confirms the results of the previous experiments: The flasks which were kept for 4 h at 30 °C were supersaturated and the subsequently storage for 20 °C was not useful to reach the saturation equilibrium. Finally a third sample set (flask 10 - 13) was kept only at 20 °C for two different time intervals (48 h at 20 °C and 72 h at 20 °C). In comparison with the flasks of the first and second sample set which were kept only at 20 °C (flask 1 - 2 and flask 6 - 7) it could be shown, that the saturation equilibrium was achieved.

 

Also for n-heptane several investigations were done: For the first sample set (flask 1 - 4) a sample volume of 10 mL n-heptane was used. After filtration, aliquots of 5 mL were removed, evaporated in a nitrogen steam and the residues were dissolved in 1 mL of acetonitrile / water 50/50 (v/v). Due to the poor solubility of the test item in n-heptane a precise analysis of the HPLC-chromatograms was not possible. Therefore it was decided to repeat the whole experiment with a second sample set (flask 5 - 8) with a sample volume of 45 mL. After filtration, aliquots of 40 mL were removed, evaporated in a nitrogen stream and the residues were dissolved in 1 mL of acetonitrile / water 50/50 (v/v). The results of the HPLC-analysis varied in the range between 2.7 μg/L and 7.9 μg/L.

 

The following table summarizes the final results obtained for the different solvents.

 

Solubility of the test substance in organic solvents

Solvent	Solubility at 20 °C
Methanol	2.9 g/L
n-Heptane	<<0.001 g/L
Toluene	0.17 g/L
Dichloromethane	5.3 g/L
Acetone	21.8 g/L
Ethyl acetate	6.4 g/L
Dimethyl sulfoxide	> 280 g/L

Description of key information

Solubility (at 20 °C) in different organic solvents has been tested:

Solvent	Solubility at 20°C
Methanol	2.9 g/L
n-Heptane	<<0.001 g/L
Toluene	0.17 g/L
Dichloromethane	5.3 g/L
Acetone	21.8 g/L
Ethyl acetate	6.4 g/L
Dimethyl sulfoxide	> 280 g/L

(OECD guideline 105, flask method)

Additional information

The study has been conducted using several organic solvents (none of which can be classified as fat) for which no guideline exists. Guideline for water solubility (OECD 105, flask method) has been adapted and used.