Is It Salt, Cocrystal, or Continuum? Successes and Limitations of Computationally Efficient Periodic System Calculations

Definitive characterization of pharmaceutical salt and cocrystal solid forms is crucial from regulatory and intellectual property perspectives. Consequently, predicting acid–base solid-state configurations along the salt–cocrystal spectrum has become a quest for modern computational methods. The successes and limitations of two computationally efficient GGA and m-GGA periodic system density functional (DFT) methods were benchmarked against a data set of 19 organic crystals displaying 24 N···H···O intermolecular hydrogen bonds, with proton positions assigned by solid-state NMR or single-crystal neutron diffraction experiments. The m-GGA revTPSS method demonstrated accurate and reliable performance in predicting cocrystal and salt N···H···O configurations, while GGA PBE-MBD* calculations yielded somewhat less accurate results. However, the periodic system calculations at both levels failed to describe salt–cocrystal continuum configurations characterized by short (below ∼2.57 Å at 100–120 K) N···O intermolecular bonds. A practical computational workflow to support the characterization of pharmaceutical acid–base crystals in conjunction with routine single crystal X-ray diffraction measurements was proposed.