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Aqueous solubility – turbidimetric / kinetic – thermodynamic

Low solubility can be a major obstacle during drug discovery and development, as low solubility can impact the generation of quality in vitro DMPK or biology data, can cause issues in the generation of an appropriate formulation for in vivo pharmacokinetic studies or can cause issues with drug absorption following oral dosing in vivo. If the solubility is known, then solutions can easily be made to the correct concentrations.

Solubility is defined as the maximum amount of a chemical (the solute) that dissolves in a given volume of a solvent. Although solubility is determined by a compound’s physicochemical properties such as lipophilicity (logD7.4), acid dissociation constant (pKa), the number of hydrogen bond donors and acceptors and its polar surface area (PSA), in silico predictions are often not very accurate.

For drugs, aqueous solubility is a fundamentally important property that affects not only the potential for drug absorption after oral administration and the ability to administer the drug parenterally, but also the ease of manipulation and testing in the laboratory and during manufacture. (Williams et al.,2013)

Potential issues with poorly soluble compounds include:

  • Limited and variable intestinal absorption causing low and variable oral bioavailability
  • Development of low solubility drug candidates is often time-consuming and costly
  • Difficult to test in vitro, as they might precipitate at higher concentrations

The degree of solubility that is required for an individual drug candidate depends on its pharmacological potency and dose level.

Solubility results can be used to rank order compounds, to validate other in vitro results or to flag potential formulation issues early during pre-clinical and clinical development.

The solubility of ionisable compounds (acids or bases) is strictly dependent on pH value. Therefore, it is essential to measure solubility in a buffered system at the appropriate pH value.

Experimentally, aqueous solubility can be measured in two ways:

Kinetic solubility

The turbidimetric solubility assay is a discovery screening assay and calculates the kinetic solubility of a test compound by measuring its turbidimetry at seven concentrations and determining when a validated threshold is surpassed. This measurement provides Log S which is then converted into a solubility value using the following equation: S = 10Log S.

For most test compounds, a solubility of >100 µM is sufficient to determine high solubility, however, if required the assay may return results up to 200 µM if 20mM stock solution is provided. Nicardipine is used as a positive control compound.

Thermodynamic solubility

The thermodynamic solubility assay is usually a late discovery screening assay that calculates the equilibrium solubility of a test compound by measuring its concentration in a solution containing excess compound which has been allowed to reach thermodynamic equilibrium.

For most test compounds, a solubility of >100 µM is sufficient to determine high solubility. This assay returns results up to 200 µM. Haloperidol is used as a positive control compound.

 

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