Salts and cocrystals are multicomponent crystals that can be distinguished by the
location of the proton between an acid and a base. At the salt end of the spectrum proton transfer
is complete, and on the opposite end proton transfer is absent in cocrystals. However, for
acid-base complexes with similar pKa values, the extent of proton transfer in the solid state is
The propensity of an acid to give up a proton is represented
by its pKa, the negative logarithm of the dissociation constant.
Traditionally, a ¢pKa value of 2 or 3 is used for selecting
counterions for salt preparations.7 It must be remembered
that pKa relates to equilibrium behavior in aqueous
solution and that measured pKa values will vary depending
on measurement technique, solvent, temperature, and
other factors. The extent to which proton transfer occurs
depends on the relation of the pKa values of the reacting
acid and base, as well as the magnitude of their difference.
The effect of the magnitude of pKa separation on proton
transfer can be determined by subtracting the pKa value
of the acid from the pKa value of the base to give an
equilibrium constant. An illustration of these principals is
shown below for acetic acid and the bases methylamine and
pyridine.