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 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 DeltapK(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 DeltapK(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 DeltapK(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 DeltapK(a).

Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids.

A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors. The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride. On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water.