The Salt−Cocrystal Continuum: The Influence of Crystal Structure on Ionization State

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
not predictable and a continuum exists between the two extremes. For these systems, both the
ΔpKa value (pKa of base − pKa of acid) and the crystalline environment determine the extent of
proton transfer. A total of 20 complexes containing theophylline and guest molecules with ΔpKa
values less than 3 have been prepared, resulting in 13 cocrystals, five salts, and two complexes
with mixed ionization states based on IR spectroscopy and single-crystal diffraction data. We
propose modifications to the ΔpKa rule for selecting salt screen counterions that focus on the
discovery of solid forms with useful physical properties rather than an arbitrary cutoff value
for ΔpKa.
Keywords: Salt; cocrystal; pKa, proton transfer; molecular complex; pharmaceutical