Solubility prediction

Aqueous solubility is one of the key factors that determines the oral bioavailability of a drug. Being related to the absorption and distribution in the ADME-Tox, it is one of the main physico-chemical properties to be optimized in drug discovery.

There are many types of solubility defined in the drug discovery literature. Most methods developed for in-silico prediction calculates intrinsic solubility for the given compound. Intrinsic solubility of a compound is the concentration in equilibrium with the solid phase that dissolved into the solution. Instead of the concentration its natural logarithm, logS, is used for convenience in the literature.

ChemAxon's solubility predictor is able to calculate the aqueous solubility of a compound at a given pH, its intrinsic solubility and its pH dependence, too. It can provide quantitative result, giving the solubility in logS, mg/mL or mol/L. In case only a rough estimation is needed, the plugin can give a solubility category as a qualitative measure.

Like ChemAxon's other calculators for physico-chemical properties (e.g. pKa, logP), the prediction is made using only structural information of the molecule.

The solubility prediction functionality is built in different ChemAxon products.

Solubility Plugin

The solubility predictor is integrated into MarvinSketch as a plugin, enabling prediction in a fast and easy way. The Solubility Plugin can be reached via the Calculations > Solubility menu.

It offers the following options for calculation:

Options menu

• Measurement Unit:
  • logS: sets the measurement unit to logS (default).
  • mol/l: sets the measurement unit to mol/l.
  • mg/ml: sets the measurement unit to mg/ml.

File menu

• Export to PDF: generates a PDF report of the solubility prediction.

The result window displays the pH-logS plot and a table that with prediction results given in one of the following ways :

• Solubility information: displays intrinsic solubility value, solubility at pH 7.4 and a qualitative category for the predicted solubility. These categories are:
  • low: if solubility is < 0.01 mg/ml
  • moderate: if solubility is between 0.01 and 0.06 mg/ml
  • high: if solubility is > 0.06 mg/ml
• pH-Solubility table: displays a table containing the predicted pH-solubility values.

Solubility prediction with cxcalc

cxcalc [general options] [input files/strings] logs [logs options] [input files/strings]

logs options: 
    -h  --help           this help message
    -U  --unit           measurement unit  [mg/ml | mol/l | logS] (default:
                         logS)
    -i  --intrinsic      intrinsic solubility (default: false)
    -c  --category       solubility category (default: false)
    -H  --pH              solubility at this pH (default: not set)
    -l  --lower           (default: 0)
    -u  --upper           (default: 14)
    -s  --step            (default: 1)

• Calculating intrinsic solubility and solubility at pH 7.4 for compounds:

  cxcalc logs -i true -H 7.4 molecules.smiles

• Calculating solubility values between pH 7.0 and 13.0 in mol/l unit:

  cxcalc logs -U mol/l -l 7.0 -u 13.0 molecules.smiles

• Predicting qualitative solubility category:

  cxcalc logs -c true test.mol

Solubility predicition with ChemAxon's Chemical Terms

• logS(param pH): calculates logS at the pH given as a parameter.
• logS0(): calculates intrinsic logS value.
• logSCategory(): determines qualitative solubility category.

• Calculating intrinsic solubility for acetic acid:

  evaluate -e "logS0()" "CC(O)=O"

• Calculating solubility at pH 7.0:

  evaluate -e "logS('7.0')" molecule.mol

• Determines qualitative solubility category:

  evaluate -e "logSCategory()" molecule.mol