Is It Salt, Cocrystal, or Continuum? Successes and Limitations of Computationally Efficient Periodic System Calculations
Yuriy A. Abramov, Jian Wang
Abstract
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.