Resolving Salt-Cocrystal Conundrum in Multicomponent Crystals by Using X‑Ray Quantum Crystallography

The structural identity of multicomponent crystals as
a salt or
cocrystal is dictated by the proton transfer state between the molecular
components. In pharmaceutical drugs, solid-state forms such as salts
or cocrystals can have significantly distinct stability, dissolution,
and solubility profiles. The accurate location of proton positions
is a formidable task using conventional X-ray crystallography, as
the atomic scattering factors are based on spherical electron density
models. Herein, we demonstrate that the X-ray quantum crystallographic
(QCr) technique of Hirshfeld Atom Refinement (HAR), based on aspherical
atomic scattering factors, can be effectively employed to resolve
this riddle. Our HAR models accurately located the proton positions,
thus distinguishing salts, cocrystals, and continuum crystal structures,
which are substantiated by the N 1s binding energies
from X-ray photoelectron spectroscopy (XPS) corresponding to the base
components in a series of crystals. The QCr models reveal the subtle
features of electron localization and bonding around the double-well
potential in the intermolecular proton-transfer regions in these crystals.