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

Dissociation constant

Link to relevant study record(s)

Reference

Endpoint:

dissociation constant

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 to 11 November 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 112 (Dissociation Constants in Water)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 830.7370 (Dissociation constants in water)

GLP compliance:

yes (incl. QA statement)

Remarks:

Hess, Ministerium für Umwelt, Energie, Landwirtschaft und Verbraucherschutz, Wiesbaden, Germany

Dissociating properties:

yes

No.:

#1

pKa:

9.1

Temp.:

23 °C

The following tables report the results of the experiments using the three stock solutions. The pH value, absorption (at 312 nm) and calculated pKa are reported for each solution obtained after the addition of different aliquots of hydrochloric acid or sodium hydroxide, as well as for the stock solutions.

 

[1] undissociated form (dM)

[2] dissociated form (dI)

[3] pH out of the range between the pH values associated with dM and dI

[4] no evaluation possible (absorption greater than dI)

[5] no evaluation possible (absorption less than dM)

 

Results using stock solution A

Exp.	Volume and concentration of added HCl	Volume and concentration of added NaOH	Resulted pH value	Absorption [ 312 nm ]	pKa
A1 (dM)	-	-	5.73	0.018	[1]
A2	10 mL – 1.0 mol/L	-	1.05	0.019	(3.04) [3]
A3	-	1 mL – 1.0 mol/L	12.10	0.144	[4]
A4	-	2 mL – 0.01 mol/L	10.42	0.132	[4]
A5 (dI)	-	1 mL – 0.01 mol/L	9.97	0.117	[2]
A6	-	9 mL – 0.001 mol/L	9.79	0.112	8.52
A7	-	7.5 mL – 0.001 mol/L	9.65	0.099	9.00
A8	-	6 mL – 0.001 mol/L	9.44	0.082	9.18
A9	-	5.5 mL – 0.001 mol/L	9.31	0.072	9.23
A10	-	5 mL – 0.001 mol/L	9.15	0.066	9.18
A11	-	4.5 mL – 0.001 mol/L	9.04	0.061	9.15
A12	-	4 mL – 0.001 mol/L	8.82	0.043	9.29
A13	-	3.5 mL – 0.001 mol/L	8.47	0.026	9.53
A14	-	3 mL – 0.001 mol/L	7.98	0.022	9.36
				Mean of A6 - A14	9.16 ± 0.28

 

Results using stock solution B

Exp.	Volume and concentration of added HCl	Volume and concentration of added NaOH	Resulted pH value	Absorption [ 312 nm ]	pKa
B1 (dM)	-	-	5.80	0.018	[1]
B2	10 mL – 1.0 mol/L	-	1.05	0.019	(3.05) [3]
B3	-	1 mL – 1.0 mol/L	12.12	0.142	[4]
B4	-	2 mL – 0.01 mol/L	10.41	0.134	[4]
B5 (dI)	-	1 mL – 0.01 mol/L	9.99	0.118	[2]
B6	-	9 mL – 0.001 mol/L	9.89	0.114	8.51
B7	-	7.5 mL – 0.001 mol/L	9.74	0.103	8.99
B8	-	6 mL – 0.001 mol/L	9.48	0.088	9.11
B9	-	5.5 mL – 0.001 mol/L	9.38	0.077	9.22
B10	-	5 mL – 0.001 mol/L	9.27	0.071	9.22
B11	-	4.5 mL – 0.001 mol/L	9.00	0.062	9.10
B12	-	4 mL – 0.001 mol/L	8.96	0.053	9.23
B13	-	3.5 mL – 0.001 mol/L	8.47	0.043	8.95
B14	-	3 mL – 0.001 mol/L	7.95	0.027	8.95
				Mean of B6 - B14	9.03 ± 0.23

 

Results using stock solution B

Exp.	Volume and concentration of added HCl	Volume and concentration of added NaOH	Resulted pH value	Absorption [ 312 nm ]	pKa
C1 (dM)	-	-	5.89	0.019	[1]
C2	10 mL – 1.0 mol/L	-	1.05	0.018	[5]
C3	-	1 mL – 1.0 mol/L	12.09	0.144	[4]
C4	-	2 mL – 0.01 mol/L	10.36	0.133	[4]
C5 (dI)	-	1 mL – 0.01 mol/L	9.88	0.110	[2]
C6	-	9 mL – 0.001 mol/L	9.70	0.101	8.74
C7	-	7.5 mL – 0.001 mol/L	9.35	0.084	8.95
C8	-	6 mL – 0.001 mol/L	9.17	0.070	9.06
C9	-	5.5 mL – 0.001 mol/L	9.02	0.054	9.22
C10	-	5 mL – 0.001 mol/L	8.78	0.048	9.11
C11	-	4.5 mL – 0.001 mol/L	8.45	0.028	9.41
C12	-	4 mL – 0.001 mol/L	7.76	0.026	8.84
C13	-	3.5 mL – 0.001 mol/L	7.24	0.020	9.19
C14	-	3 mL – 0.001 mol/L	7.10	0.020	9.05
				Mean of C6 - C14	9.07 ± 0.20

 

The pKa value for each determination was calculated as the average of individual values for which the dissociated portion laid between 10% and 90%. Data points for which the dissociated portion was outside this range were not used to calculate the final result.

To calculate the percentage of the dissociated test item and the usable pH range the following equations were used:

 

pH range = pKa(mean) ± log 9

 

The following table report the resulting pH range values, the solutions having a pH within this range (therefore considered for the mean pKa calculation), and the mean pKa.

 

Experiment	pH range	Solutions considered	pKa (mean)
A	8.21 to 10.11	A6 to A13	9.13 (SD = 0.29)
B	8.08 to 9.98	B6 to B13	9.04 (SD = 0.24)
C	8.12 to 10.02	C6 to C11	9.08 (SD = 0.23)

 

For all three cases, a re-calculation of the applicable pH range using this final pKa value resulted in the selection of the same solutions previously considered (A6-A13, B6-B13 and C6-C11, respectively).

 

Finale results

The dissociation constant in water of the test substance, calculated as the mean of the three experiments performed, resulted as pKa = 9.1 at 23 °C

Description of key information

The dissociation constant in water of the test substance resulted as pKa = 9.1 at 23 °C (OECD Guideline 112)