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

Abstract

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 pK_a 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 ΔpK_a value (pK_a of base − pK_a of acid) and the crystalline environment determine the extent of proton transfer. A total of 20 complexes containing theophylline and guest molecules with ΔpK_a 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 ΔpK_a 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 ΔpK_a. Keywords: Salt; cocrystal; pK_a, proton transfer; molecular complex; pharmaceutical