Abstract:
There has been significant recent interest in differentiating multicomponent
solid forms, such as salts and cocrystals, and, where appropriate, in determining
the position of the proton in the X—HA—Y XH—A+
—Y continuum in
these systems, owing to the direct relationship of this property to the clinical,
regulatory and legal requirements for an active pharmaceutical ingredient
(API). In the present study, solid forms of simple cocrystals/salts were
investigated by high-field (700 MHz) solid-state NMR (ssNMR) using samples
with naturally abundant 15N nuclei. Four model compounds in a series of
prototypical salt/cocrystal/continuum systems exhibiting {PyNH—O—}/
{PyN+
—HO} hydrogen bonds (Py is pyridine) were selected and prepared.
The crystal structures were determined at both low and room temperature using
X-ray diffraction. The H-atom positions were determined by measuring the
15N—1
H distances through 15N-1
H dipolar interactions using two-dimensional
inversely proton-detected cross polarization with variable contact-time (invCPVC) 1
H!15N!1
H experiments at ultrafast (R 60–70 kHz) magic angle
spinning (MAS) frequency. It is observed that this method is sensitive enough to
determine the proton position even in a continuum where an ambiguity of
terminology for the solid form often arises. This work, while carried out on
simple systems, has implications in the pharmaceutical industry where the salt/
cocrystal/continuum condition of APIs is considered seriously
