Methanesulfonamide, N-[2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)carbonyl]-6-fluorophenyl]-1,1-difluoro-N-methyl-

Dissociation constant

Link to relevant study record(s)

Reference

Endpoint:

dissociation constant

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 Oct - 25 Nov 2010

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, Mainzer Straße 80, D-65189 Wiesbaden

Dissociating properties:

no

Remarks:

No dissociation constant (pKa) was found in aqueous solution of AE1887196 in the pH range of 1.1 < pH < 10.4. This finding corresponds to the result that the test item shows no acidic nor basic properties in the range of approximately 1 < pKa < 10.5.

HPLC/MS/MS Result

At pH values above pH 10.5 a chemical degradation of AE 1887196 took place. Under basic conditions AE 1887196 loses one methoxy group from the triazine ring system, being replaced with a hydroxyl group.

 

Dissociation Constant of the Degradation Product BCS-CR18217

The dissociation constant of the degradation product BCS-CR18217 was determined using the spectrophotometric method (three individual experiments A, B and C).

Details of a representative experiment (Experiment A) are given in Table 3:

 

Table 3 – Experiment A (pKa of the degradation product BCS-CR18217)

Exp.	Volume and concentation of added HCl	Volume and concentation of added NaOH	Resulted pH value	Absorption [263 nm]	pKa
A3 (dI)	-	10 mL – 1 mol/L	13.01	0.105	^1)
A4	-	5 mL – 1 mol/L	12.75	0.112	11.87
A5	-	2 mL – 1 mol/L	12.37	0.123	12.00
A6	-	1 mL – 1 mol/L	12.07	0.131	11.95
A7	-	0.5 mL – 1 mol/L	11.73	0.145	12.03
A8	-	0.3 mL – 1 mol/L	11.51	0.153	12.11
A9	-	0.2 mL – 1 mol/L	11.34	0.158	12.22
A10 (dM)	-	0.1 mL – 1 mol/L	11.05	0.165	^2)
				Mean of A4 – A9	12.03 +/- 0.12

¹⁾Dissociated form d_I= absorption of the ionized form
²⁾Undissociated form d_M= absorption of the unionized form

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 ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 12.03 ± 0.95 → pH 11.08 to pH 12.98

Applying this pH range (i.e. experiments A4 to A9) the mean pKa-value is resulting in pKa = 12.03.

The mean value of the results of the three experiments (pKa 12.03 / 11.92 and 11.88) for the determination of the dissociation constant of the degradation product BCS-CR18217 was found to be pKa = 11.9

 

Final Results

The dissociation constant of AE 1887196 was examined using the spectro-photometric method based on the OECD-Guideline 112 and the EPA Product Properties Test Guideline OPPTS 830.7370.

 

UV/VIS spectra of the test item were recorded at pH 1.09, pH 6.75 and pH 10.37 at room temperature (mean temperature 22 °C).

The UV/VIS spectra were almost congruent, taking the UV absorption of aqueous sodium hydroxide and hydrochloric acid into account. No relevant difference was found between the UV/VIS absorption at the examined pH values.

No dissociation constant (pKa) was found in aqueous solution of AE 1887196 in the pH range of 1.1 < pH < 10.4.

This finding corresponds to the result that AE 1887196 shows no acidic or basic properties in the range of approximately 1 < pKa < 10.5.

Note:

At pH values above pH 10.5 a chemical degradation of AE 1887196 takes place. Under basic conditions (addition of sodium hydroxide solution) AE 1887196 loses one methoxy group from the triazine ring system, being replaced with a hydroxyl group. The degradation reaction was verified by HPLC/MS and HPLC/MS/MS experiments using neutral and alkaline solutions of AE 1887196.

The dissociation constant of the resulting hydroxy compound (= BCS-CR18217) was determined using the spectrophotometric method (pKa = 11.9).

Description of key information

No dissociation constant (pKa) in aqueous solution of test item in the pH range of 1.1 < pH < 10.4. (spectrophotometric method, OECD 112).

Additional information

At pH values above 10.5 a chemical degradation of the test item takes place. Under basic conditions (addition of NaOH solution) the test item loses on methoxy group from the traizine ring system, being replaced by a hydroxy group. The dissociation constant of the resulting hydroxy compound was determined using the spectrophotometric method to be pKa = 11.9