for Physical Chemists by Physical Chemists


Proposed discussion points

The following points are proposed as starting points for discussion. Of course, other points may be raised from the floor. Points are presented here to allow time for more considered opinions to be formed before being debated during the session. Anyone wishing to raise further points for discussion should send them to

The importance of solubility in drug discovery
Mainly the consequence of poor solubility on other assays (bio-assays). I have been noticing that the Med chemists donít really care about poor solubility, because it is an issue that in early development is taken care of (with miraculous formulations). I am not concerned with solubility as such, but the consequences of a bad solubility in the tests done at very early stages of the research that often are decisive in the choice of proceeding or not with a compound.

The importance of solubility on permeability
What happened to a permeability measurement when the compounds assayed is not soluble in water? What really mean the bell-shaped profile of permeability vs Log D often published? The decrease of Permeability at logP/ D> ~5  (in these bell-shaped profile) means a real decrease of Pe or is a consequence of poor aqueous solubility? Why should a compound very lipophilic be less permeable (lower affinity towards lipophilic environment)? Membrane retention? But in this case, we have a problem of poor sink conditions (experimental set-up), and how well can we extrapolate these poor sink condition to the GUT environment, when the blood circulation creates a very big gradient in concentration?

The need of standardize PAMPA-Pe values, at international level
Pe values obtained with stirring conditions (which are used for more liphophilic compounds, due to the unstirred water layer limitation) are always much higher that Pe obtained in an assay without stirring (for the same compounds). So then the question is; what is high permeability? Is 50 x10-6 cm/s high permeability or low? If I use the stirring conditions I can measure Pe~ 4000x10-6 cm/s for verapamil, while without stirring conditions is Pe~ 50 x10-6 cm/s.

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Last modified: 28 April 2008