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Water solubility

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Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
October 26, 2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Aqueous solubility is one of the most important physico-chemical properties; it has impact on ADME-related properties like substance uptake, distribution and even oral bioavailability. Solubility can also be a relevant descriptor for property-based computational screening methods in some substance discovery process.
The prediction uses a fragment-based method that identifies different structural fragments in the molecule and calculates their solubility contribution.
However, in many applications, it is also important to know the solubility in acidic/basic solutions at a given pH. Therefore the model should also be able to calculate the pH--solubility profile of a compound. The original solubility predictor method has been extended so that it is able to calculate the pH--dependent solubility.
The accuracy of the intrinsic solubility prediction was tested using two test sets. Tests for pH--logS profile were also run for different acidic, basic and zwitter-ionic compounds.
Guideline:
other: ECHA Guidance on information requirements and chemical safety assessment - Chapter R.06: QSARs and grouping of chemicals
Principles of method if other than guideline:
The intrinsic solubility of a nonelectrolyte is governed by the relative strengths of the intermolecular forces in the solute (i.e., its solid-state properties) and the affinity of the solute for the solvent (i.e., the strength of solute-solvent interactions). This is also the case for a weak electrolyte but is complicated by differences in ionization of the solute with changes in pH that, in turn, alter polarity and the affinity of the solute for the solvent.
Thus, a weak electrolyte will initially dissolve to an extent governed by the intrinsic solubility of the un-ionized form. Depending on the pH, a proportion of the dissolved species subsequently ionizes in accordance with the Henderson-Hasselbalch equation.
Ionization leads to further dissolution of solid drug to maintain a constant concentration (i.e., the saturated solubility) of the un-ionized form. This will continue within an unbuffered solution until the saturated solubility of both un-ionized and ionized species is reached. As the ionized species is able to form favorable ion-dipole interactions with polar solvents, it is more soluble than the un-ionized species, and therefore, drugs are more soluble in polar solvents at pH values that favor the ionized form.
The total solubility (S) of a weak acid (HA) or weak base (B) at a given pH is the sum of the solubility of the ionized and un-ionized forms and therefore function of the solubility of the un-ionized form (S0) and the pKa of the weak acid or base.
Type of method:
other: calculation method (fragments)
Water solubility:
54 g/L
Temp.:
20 °C
pH:
2
Remarks on result:
other: stomach
Water solubility:
3 410 g/L
Temp.:
20 °C
pH:
5.5
Remarks on result:
other: skin
Water solubility:
5 404 g/L
Temp.:
20 °C
pH:
6.9
Remarks on result:
other: soil
Water solubility:
5 404 g/L
Temp.:
20 °C
pH:
7.4
Remarks on result:
other: plasma
Water solubility:
5 404 g/L
Temp.:
20 °C
pH:
8
Remarks on result:
other: river

LogS vs pH – 5 METHAc and 4-METHAc

5-METHAc

4-METHAc

5-METHAc

4-METHAc

5-METHAc

4-METHAc

5-METHAc

4-METHAc

pH

logS

pH

logS

pH

logS

pH

logS

0.00

-0.56

-0.80

3.50

-0.40

-0.76

7.00

1.44

1.20

10.50

1.44

1.20

0.10

-0.56

-0.80

3.60

-0.37

-0.75

7.10

1.44

1.20

10.60

1.44

1.20

0.20

-0.56

-0.80

3.70

-0.33

-0.74

7.20

1.44

1.20

10.70

1.44

1.20

0.30

-0.56

-0.80

3.80

-0.28

-0.72

7.30

1.44

1.20

10.80

1.44

1.20

0.40

-0.56

-0.80

3.90

-0.23

-0.71

7.40

1.44

1.20

10.90

1.44

1.20

0.50

-0.56

-0.80

4.00

-0.18

-0.68

7.50

1.44

1.20

11.00

1.44

1.20

0.60

-0.56

-0.80

4.10

-0.11

-0.66

7.60

1.44

1.20

11.10

1.44

1.20

0.70

-0.56

-0.80

4.20

-0.05

-0.63

7.70

1.44

1.20

11.20

1.44

1.20

0.80

-0.56

-0.80

4.30

0.03

-0.59

7.80

1.44

1.20

11.30

1.44

1.20

0.90

-0.56

-0.80

4.40

0.11

-0.55

7.90

1.44

1.20

11.40

1.44

1.20

1.00

-0.56

-0.80

4.50

0.19

-0.50

8.00

1.44

1.20

11.50

1.44

1.20

1.10

-0.56

-0.80

4.60

0.28

-0.44

8.10

1.44

1.20

11.60

1.44

1.20

1.20

-0.56

-0.80

4.70

0.37

-0.38

8.20

1.44

1.20

11.70

1.44

1.20

1.30

-0.56

-0.80

4.80

0.46

-0.31

8.30

1.44

1.20

11.80

1.44

1.20

1.40

-0.56

-0.80

4.90

0.56

-0.23

8.40

1.44

1.20

11.90

1.44

1.20

1.50

-0.56

-0.80

5.00

0.67

-0.14

8.50

1.44

1.20

12.00

1.44

1.20

1.60

-0.56

-0.80

5.10

0.77

-0.04

8.60

1.44

1.20

12.10

1.44

1.20

1.70

-0.56

-0.80

5.20

0.88

0.06

8.70

1.44

1.20

12.20

1.44

1.20

1.80

-0.56

-0.80

5.30

1.00

0.17

8.80

1.44

1.20

12.30

1.44

1.20

1.90

-0.56

-0.80

5.40

1.12

0.29

8.90

1.44

1.20

12.40

1.44

1.20

2.00

-0.56

-0.80

5.50

1.24

0.42

9.00

1.44

1.20

12.50

1.44

1.20

2.10

-0.55

-0.80

5.60

1.37

0.56

9.10

1.44

1.20

12.60

1.44

1.20

2.20

-0.55

-0.79

5.70

1.44

0.70

9.20

1.44

1.20

12.70

1.44

1.20

2.30

-0.55

-0.79

5.80

1.44

0.86

9.30

1.44

1.20

12.80

1.44

1.20

2.40

-0.55

-0.79

5.90

1.44

1.01

9.40

1.44

1.20

12.90

1.44

1.20

2.50

-0.54

-0.79

6.00

1.44

1.18

9.50

1.44

1.20

13.00

1.44

1.20

2.60

-0.54

-0.79

6.10

1.44

1.20

9.60

1.44

1.20

13.10

1.44

1.20

2.70

-0.53

-0.79

6.20

1.44

1.20

9.70

1.44

1.20

13.20

1.44

1.20

2.80

-0.52

-0.79

6.30

1.44

1.20

9.80

1.44

1.20

13.30

1.44

1.20

2.90

-0.52

-0.79

6.40

1.44

1.20

9.90

1.44

1.20

13.40

1.44

1.20

3.00

-0.50

-0.78

6.50

1.44

1.20

10.00

1.44

1.20

13.50

1.44

1.20

3.10

-0.49

-0.78

6.60

1.44

1.20

10.10

1.44

1.20

13.60

1.44

1.20

3.20

-0.47

-0.78

6.70

1.44

1.20

10.20

1.44

1.20

13.70

1.44

1.20

3.30

-0.45

-0.77

6.80

1.44

1.20

10.30

1.44

1.20

13.80

1.44

1.20

3.40

-0.43

-0.77

6.90

1.44

1.20

10.40

1.44

1.20

13.90

1.44

1.20

14.00

1.44

1.20

Conclusions:
Considering all the charge-state forms of methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (METHAc) dissolved in water, a LogS (log Solubility measured in mol/L) of 5-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (5-METHAc) was estimated taking account for the pH dependence of the substance in aqueous solution.
Executive summary:

Considering all the charge-state forms of methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (METHAc) dissolved in water, a LogS (log Solubility measured in mol/L) of 5-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (5-METHAc) was estimated taking account for the pH dependence of the substance in aqueous solution.

Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
October 26, 2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Aqueous solubility is one of the most important physico-chemical properties; it has impact on ADME-related properties like substance uptake, distribution and even oral bioavailability. Solubility can also be a relevant descriptor for property-based computational screening methods in some substance discovery process.
The prediction uses a fragment-based method that identifies different structural fragments in the molecule and calculates their solubility contribution.
However, in many applications, it is also important to know the solubility in acidic/basic solutions at a given pH. Therefore the model should also be able to calculate the pH--solubility profile of a compound. The original solubility predictor method has been extended so that it is able to calculate the pH--dependent solubility.
The accuracy of the intrinsic solubility prediction was tested using two test sets. Tests for pH--logS profile were also run for different acidic, basic and zwitter-ionic compounds.
Guideline:
other: ECHA Guidance on information requirements and chemical safety assessment - Chapter R.06: QSARs and grouping of chemicals
Principles of method if other than guideline:
The intrinsic solubility of a nonelectrolyte is governed by the relative strengths of the intermolecular forces in the solute (i.e., its solid-state properties) and the affinity of the solute for the solvent (i.e., the strength of solute-solvent interactions). This is also the case for a weak electrolyte but is complicated by differences in ionization of the solute with changes in pH that, in turn, alter polarity and the affinity of the solute for the solvent.
Thus, a weak electrolyte will initially dissolve to an extent governed by the intrinsic solubility of the un-ionized form. Depending on the pH, a proportion of the dissolved species subsequently ionizes in accordance with the Henderson-Hasselbalch equation.
Ionization leads to further dissolution of solid drug to maintain a constant concentration (i.e., the saturated solubility) of the un-ionized form. This will continue within an unbuffered solution until the saturated solubility of both un-ionized and ionized species is reached. As the ionized species is able to form favorable ion-dipole interactions with polar solvents, it is more soluble than the un-ionized species, and therefore, drugs are more soluble in polar solvents at pH values that favor the ionized form.
The total solubility (S) of a weak acid (HA) or weak base (B) at a given pH is the sum of the solubility of the ionized and un-ionized forms and therefore function of the solubility of the un-ionized form (S0) and the pKa of the weak acid or base.
Type of method:
other: calculation method (fragments)
Water solubility:
31.1 g/L
Temp.:
20 °C
pH:
2
Remarks on result:
other: stomach
Water solubility:
516 g/L
Temp.:
20 °C
pH:
5.5
Remarks on result:
other: skin
Water solubility:
3 110 g/L
Temp.:
20 °C
pH:
6.9
Remarks on result:
other: soil
Water solubility:
3 110 g/L
Temp.:
20 °C
pH:
7.4
Remarks on result:
other: plasma
Water solubility:
3 110 g/L
Temp.:
20 °C
pH:
8
Remarks on result:
other: river

LogS vs pH – 5-METHAc and 4-METHAc

5-METHAc

4-METHAc

5-METHAc

4-METHAc

5-METHAc

4-METHAc

5-METHAc

4-METHAc

pH

logS

pH

logS

pH

logS

pH

logS

0.00

-0.56

-0.80

3.50

-0.40

-0.76

7.00

1.44

1.20

10.50

1.44

1.20

0.10

-0.56

-0.80

3.60

-0.37

-0.75

7.10

1.44

1.20

10.60

1.44

1.20

0.20

-0.56

-0.80

3.70

-0.33

-0.74

7.20

1.44

1.20

10.70

1.44

1.20

0.30

-0.56

-0.80

3.80

-0.28

-0.72

7.30

1.44

1.20

10.80

1.44

1.20

0.40

-0.56

-0.80

3.90

-0.23

-0.71

7.40

1.44

1.20

10.90

1.44

1.20

0.50

-0.56

-0.80

4.00

-0.18

-0.68

7.50

1.44

1.20

11.00

1.44

1.20

0.60

-0.56

-0.80

4.10

-0.11

-0.66

7.60

1.44

1.20

11.10

1.44

1.20

0.70

-0.56

-0.80

4.20

-0.05

-0.63

7.70

1.44

1.20

11.20

1.44

1.20

0.80

-0.56

-0.80

4.30

0.03

-0.59

7.80

1.44

1.20

11.30

1.44

1.20

0.90

-0.56

-0.80

4.40

0.11

-0.55

7.90

1.44

1.20

11.40

1.44

1.20

1.00

-0.56

-0.80

4.50

0.19

-0.50

8.00

1.44

1.20

11.50

1.44

1.20

1.10

-0.56

-0.80

4.60

0.28

-0.44

8.10

1.44

1.20

11.60

1.44

1.20

1.20

-0.56

-0.80

4.70

0.37

-0.38

8.20

1.44

1.20

11.70

1.44

1.20

1.30

-0.56

-0.80

4.80

0.46

-0.31

8.30

1.44

1.20

11.80

1.44

1.20

1.40

-0.56

-0.80

4.90

0.56

-0.23

8.40

1.44

1.20

11.90

1.44

1.20

1.50

-0.56

-0.80

5.00

0.67

-0.14

8.50

1.44

1.20

12.00

1.44

1.20

1.60

-0.56

-0.80

5.10

0.77

-0.04

8.60

1.44

1.20

12.10

1.44

1.20

1.70

-0.56

-0.80

5.20

0.88

0.06

8.70

1.44

1.20

12.20

1.44

1.20

1.80

-0.56

-0.80

5.30

1.00

0.17

8.80

1.44

1.20

12.30

1.44

1.20

1.90

-0.56

-0.80

5.40

1.12

0.29

8.90

1.44

1.20

12.40

1.44

1.20

2.00

-0.56

-0.80

5.50

1.24

0.42

9.00

1.44

1.20

12.50

1.44

1.20

2.10

-0.55

-0.80

5.60

1.37

0.56

9.10

1.44

1.20

12.60

1.44

1.20

2.20

-0.55

-0.79

5.70

1.44

0.70

9.20

1.44

1.20

12.70

1.44

1.20

2.30

-0.55

-0.79

5.80

1.44

0.86

9.30

1.44

1.20

12.80

1.44

1.20

2.40

-0.55

-0.79

5.90

1.44

1.01

9.40

1.44

1.20

12.90

1.44

1.20

2.50

-0.54

-0.79

6.00

1.44

1.18

9.50

1.44

1.20

13.00

1.44

1.20

2.60

-0.54

-0.79

6.10

1.44

1.20

9.60

1.44

1.20

13.10

1.44

1.20

2.70

-0.53

-0.79

6.20

1.44

1.20

9.70

1.44

1.20

13.20

1.44

1.20

2.80

-0.52

-0.79

6.30

1.44

1.20

9.80

1.44

1.20

13.30

1.44

1.20

2.90

-0.52

-0.79

6.40

1.44

1.20

9.90

1.44

1.20

13.40

1.44

1.20

3.00

-0.50

-0.78

6.50

1.44

1.20

10.00

1.44

1.20

13.50

1.44

1.20

3.10

-0.49

-0.78

6.60

1.44

1.20

10.10

1.44

1.20

13.60

1.44

1.20

3.20

-0.47

-0.78

6.70

1.44

1.20

10.20

1.44

1.20

13.70

1.44

1.20

3.30

-0.45

-0.77

6.80

1.44

1.20

10.30

1.44

1.20

13.80

1.44

1.20

3.40

-0.43

-0.77

6.90

1.44

1.20

10.40

1.44

1.20

13.90

1.44

1.20

14.00

1.44

1.20

Conclusions:
Considering all the charge-state forms of methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (METHAc) dissolved in water, a LogS (log Solubility measured in mol/L) of 1-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (4-METHAc) was estimated taking account for the pH dependence of the substance in aqueous solution.
Executive summary:

Considering all the charge-state forms of methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (METHAc) dissolved in water, a LogS (log Solubility measured in mol/L) of 1-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (4-METHAc) was estimated taking account for the pH dependence of the substance in aqueous solution.

Description of key information

Estimated water solubility: 4260 g/L

Key value for chemical safety assessment

Water solubility:
4 260 g/L
at the temperature of:
20 °C

Additional information

In accordance with REACH Regulation 1907/2006, Annex VII, Column 2, testing need not be conducted if the substance is hydrolytically unstable (with a half-life of <12 hours).

A water solubility of 4260 g/L at pH > 6 was estimated as mean value for methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (METHAc), obtained ad hydrolysis product of 1,2,3,6-tetrahydromethyl-3,6-methanophthalic anhydride (METH).