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 degrees C without changing the powder X-ray pattern. Below 15% RH and above 50 degrees 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 H-1, C-13, N-15, and Na-23 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 H-2 and O-17 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.