(2S)-3-Methyl-2-[N-({2'-(1H-1,2,3,4-tetrazol-5-yl)-[1,1-biphenyl]-4-yl}methyl)pentanamido]alkanoic acid

Dissociation constant

Link to relevant study record(s)

Reference

Endpoint:

dissociation constant

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

Aug - Dec 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
PALLAS (pKalc)
2. MODEL (incl. version number)
Perrin calculation method (pKalc 5.0, module in Pallas 3.0, CompuDrug International, USA)
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Not specified
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
CompuDrug's pKalc calculates the accurate acidic and basic pKa values (negative logarithms of acidbase
ionization constants) for organic compounds, in most cases, within an error of 0.25 pKa units.
The calculation can be performed for any organic compound, including aromatics, mono and polyh
1
eteroaromatics, and small peptides. The applied logarithm, adapted after Hammett and Taft takes int
o account all necessary electronic, steric and other effects and relies on an extended database of
almost a thousand equations (Source: www.compudrug.com/pkalc; 15 April 2019)
5. APPLICABILITY DOMAIN
The substance is an organic compound
6. ADEQUACY OF THE RESULT
not specified

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)

Qualifier:

no guideline followed

Principles of method if other than guideline:

According to EC A.25 and OECD 112, there are two basic approaches to the determination of pKa.
One involves titrating a known amount of substance with standard acid or base, as appropriate; the
other involves determining the relative concentrations of the ionised and unionised forms and their pH
dependence. Methods based on those principles may be classified as titration, spectrophotometric
and conductometric procedures. In case it is not possible to perform a guideline study, pKa value(s)
might be calculated from substance's structural formula.
Since the titration method should be perfomed at a concentration that does not exceed 0.01 M or half
the saturation concentration, attemps were made to prepare a solution of approximately 90 mg/L:
-First attempt: 4.30 mg / 50 mL double distilled water: test item was not dissolved after ultrasonication
for 10 minutes.
-Second attempt: 4.32 mg of test item was weighed into a 50 mL volumetric flask. 0.5 mL acetonitril
e was added to dissolve the test item (maximum percentage of organic solvent allowed). After the te
st item was completely dissolved, the flask was filled up to the mark with double distilled water. While
adding double distilled water the test item precipitated from the solution.
As a rule of thumb, no realiable results can be obtained with the titration method when the pKa is
smaller than the negative logarithm of the concentration. The saturation concentration of the test item
concentration observed during these experiments was too low to determine the dissociation constant
experimentally by titration. Therefore, the calculation method was performed to determine the pKa of
the test item.

GLP compliance:

yes

Specific details on test material used for the study:

Water solubility: 0.18 g/L at 25°C

Dissociating properties:

yes

No.:

#1

pKa:

3.76

Temp.:

25 °C

Remarks on result:

other:

Remarks:

calculated for acidic group

No.:

#2

pKa:

4.38

Temp.:

25 °C

Remarks on result:

other:

Remarks:

calculated for acidic group

No pKa values for basic groups were found in the pH range 0-14.

Conclusions:

The following pKa values, in the environmentally relevant pH range 0-14, for acidic groups in the molecular structure of the test item were calculated using the Perrin calculation method:
RRCHCOOH 3.76
5-SUBST-TETRAZOL 4.38

Executive summary:

It is not possible to determine the pKa values of VALSARTAN/DS experimentally. As an alternative,

PALLAS pkalc software was used. Using the Perrin calculation method, two acidic functionalities

were found with pKa values of 3.8 and 4.4.

Description of key information

The following pKa values, in the environmentally relevant pH range 0-14, for acidic groups in the molecular structure of the test item were calculated using the Perrin calculation method:

RRCHCOOH                   3.76

5-SUBST-TETRAZOL     4.38

Key value for chemical safety assessment

pKa at 20°C:

3.76