polar surface area

Polar surface area adds up the patches of a molecule's outer surface that are 'sticky' to water, namely the parts contributed by its oxygen and nitrogen atoms (and the hydrogens attached to them). If you imagined coloring every water-attracting region of the molecule, PSA is the total colored area, usually given in square angstroms.

These polar patches form hydrogen bonds with surrounding water, and that clinging water must be stripped away for the molecule to enter a fatty membrane. A larger polar surface therefore means slower passive permeability and weaker absorption. In practice chemists most often use the topological version, TPSA, which is computed quickly from the molecular structure rather than a 3D surface.

Useful rules of thumb emerged from this: oral drugs tend to have a TPSA under about 140 square angstroms for good gut absorption, and under roughly 90 for crossing into the brain. These are guidelines, not laws, and clever molecules sometimes break them by masking their polarity through internal hydrogen bonds.