Physical, Crystallographic, and Spectroscopic Characterization of a Crystalline Pharmaceutical Hydrate: Understanding the Role of Water

The single-crystal X-ray diffraction structure of the sodium salt of N-(3-(aminosulfonyl)-4-chloro-2-hydroxyphenyl)-N‘-(2,3-dichlorophenyl) urea at 173 K is reported. The structure contains 3 mol of water situated in distinct channels in the vicinity
of the sodium cation. Powders of this phase undergo isomorphic dehydration, losing 0.5% w/w water between 90 and 15% relative
humidity (RH) at 25 °C without changing the powder X-ray pattern. Below 15% RH and above 50 °C, additional dehydration
occurs in conjunction with a reversible phase transition. A third semicrystalline dehydrated phase appears after vacuum-drying and
at high temperatures and also can be reversibly rehydrated to the original form. Single crystals of the dehydrated phases could not
be prepared, so a combination of methods were used to understand the structural changes occurring during the desolvation process,
including thermal analysis, vapor sorption measurements, variable-humidity and variable-temperature powder X-ray diffraction,
vibrational spectroscopy, and 1H, 13C, 15N, and 23Na magic-angle spinning (MAS) solid-state NMR. The uptake of water vapor into
the trihydrate form was investigated by NMR and vibrational spectroscopy using isotopically labeled water. Static 2H and 17O NMR
quadrupolar line shape analysis combined with changes in MAS spectra showed exchanged sites on the parent and water molecules.
The results indicate that two moles of ion-associated water in the larger tunnel are more labile than a hydrogen-bonded mole of
water. Entire water molecules can exchange into the lattice to a small extent, but more efficient hydrogen transfer exchange is
observed in the main channel and a smaller perpendicular side channel. The exchanged water deuterons execute rapid three-site
jump motions at 273 K.