11  The polar headgroups of lipid membranes produce a large dipole potential (membrane core positive) which favours permeation of anions over cations (see e.g. [529, 614–619]. None of the descriptors that are suitable for describing neutral molecules can be expected to allow the LFER approach to be able to cope with this difference. It is thus not at all surprising that when Abraham came to consider charged molecules explicitly, he found it necessary to introduce descriptors that allow for the charge on the molecule [168].
One difficulty encountered when attempting to correlate permeability and lipophilicity for ions is that it is only possible to measure Kn-octanol/water for neutral combinations of ions. This is an example of the consequences of the Principle of electroneutrality (see Section 6.1.2 in [4] for another example and further discussion). This difficulty could be avoided by measuring partition into unilamellar liposomes, lipid bilayers or biological membranes rather than into a hydrophobic solvent, because with these systems the counterions can remain in the aqueous phases. However, while partition into membranes has been measured, there has not been any attempt to correlate these measurements with blood–brain barrier permeability (see e.g. [161]).