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

Abstract

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 1 H, 13 C, 15 N, and 23 Na 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 2 H and 17 O 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.

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution 1H Solid-State NMR Spectroscopy

“…1-3 While 13 C crosspolarisation (CP) MAS is an established workhouse technique, the power of high-resolution 1 H solidstate NMR experiments is starting to be recognised: 1 H chemical shifts have been determined from onedimensional fast-MAS spectra and two-dimensional 1 H- 13 C correlation spectra, [4][5][6][7][8][9][10][11][12][13] with H-H proximities being identified in two-dimensional 1 H-1 H DQ (double-quantum) MAS and DQ CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra. [10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures.…”

Physico-chemical solid-state characterization of omeprazole sodium: Thermal, spectroscopic and crystallinity studies

“…The removal of water from the crystal lattice leads to more or less distinct internal structural changes that can result in considerably altered physical and chemical properties [17]. Dehydrated forms fall into two categories: those that exhibit significant phase changes upon desolvation (such as a polymorphic transformation or conversion from a crystalline phase to an amorphous phase) and those that do not show such changes [18].…”

3D–2D–0D Stepwise Deconstruction of a Water Framework Templated by a Nanoporous Organic–Inorganic Hybrid Host

“…This attribution is in accord with the assignment proposed in a previous study on a pharmaceutical crystalline hydrate. [5] To further pursue this assignment, 2 H MAS NMR spectra ( Figure 8) were recorded (at room temperature), and they clearly show the presence of two main 2 H chemical environments: 1) a peak at 4.7 ppm, superimposed on a broader resonance centred at 5-6 ppm, attributed to water, and 2) a second peak at 9.8 ppm, assigned to the ND 2 species of the piperazine rings. This is in excellent agreement with the assignment proposed in reference [2].…”