Solubility

Poor solubility can have an impact on various stages of the drug discovery process, whist perhaps the most important is the impact poor solubility can have on gastrointestinal absorption it may also preclude other routes of administration (intravenous), in some cases this can be addressed by Formulation. However complex formulations can have a significant effect on the development cost and timelines.
Solubility may also have an impact on preclinical assays, limited solubility in preclinical ADMET assays may give a false impression of the compounds profile in in vitro assays.

Other concern with poorly soluble compounds is that solubility might be further compromised if a new crystalline form is discovered during development.

Assays

Solubility can be measured in either Kinetic or Equilibrium Methods.

Kinetic assays usually involve diluting a DMSO solution with aqueous buffer, turbidity is measured using UV-vis spectrophotometry at 620 nM. These assays can be carried out in multi-well format and can thus be part of a screening cascade, and the conditions are easily modified to explore the influence of temperature or pH of the aqueous buffer. A citrate buffer pH2 is usually used to mimic the conditions found in the stomach. The data is useful for relative ranking but should not be regarded as an absolute figure. Coloured compounds can cause interference.

Equilibrium assays require large amounts of compound and can be very time-consuming, they usually involve preparation of a saturated solution (stirred 24 hours) followed by filtration and HPLC analysis. The results are more accurate but are usually only determined as part of the development program for a candidate compound.

Tip: Ask for the samples back, you can recover grams of material.

Updated 6 December 2009
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