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Navigating the Waters of Unconventional Crystalline Hydrates.

Braun DE, Koztecki LH, McMahon JA, Price SL, Reutzel-Edens SM - Mol. Pharm. (2015)

Bottom Line: HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z).Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°.Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions.

View Article: PubMed Central - PubMed

Affiliation: †Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.

ABSTRACT
Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

No MeSH data available.


Related in: MedlinePlus

Solvent accessible voidscontaining waters of crystallization in(a) HyA1.95, (b) HyA1.73, (c) HyA1.32, and (d) Hy2, calculated using a 1.2 Å probe radius.
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fig17: Solvent accessible voidscontaining waters of crystallization in(a) HyA1.95, (b) HyA1.73, (c) HyA1.32, and (d) Hy2, calculated using a 1.2 Å probe radius.

Mentions: Two distinctly different moisture sorption behaviors were establishedfor Hy2 and HyA through detailed characterization of highly crystalline,phase pure samples as a function of water vapor pressure. Curiously,our initial attempts to rationalize the different hygroscopicity ofthe DB7z hydrates in terms of structural features (solventpockets, channels) common to stoichiometric and nonstoichiometrichydrates yielded anything but expected results. Figure 17 shows the void space (default probe radius = 1.2 Å)created by removing the waters of crystallization from the HyA1.95, HyA1.73, HyA1.32, and Hy2 structures.Counterintuitively, the water accessible voids in nonstoichiometricHyA appear to be isolated from one another (Figure 17a–c), while water channels are clearly seen runningzigzag along the crystallographic b-axis in the stoichiometrichydrate, Hy2 (Figure 17d).


Navigating the Waters of Unconventional Crystalline Hydrates.

Braun DE, Koztecki LH, McMahon JA, Price SL, Reutzel-Edens SM - Mol. Pharm. (2015)

Solvent accessible voidscontaining waters of crystallization in(a) HyA1.95, (b) HyA1.73, (c) HyA1.32, and (d) Hy2, calculated using a 1.2 Å probe radius.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525282&req=5

fig17: Solvent accessible voidscontaining waters of crystallization in(a) HyA1.95, (b) HyA1.73, (c) HyA1.32, and (d) Hy2, calculated using a 1.2 Å probe radius.
Mentions: Two distinctly different moisture sorption behaviors were establishedfor Hy2 and HyA through detailed characterization of highly crystalline,phase pure samples as a function of water vapor pressure. Curiously,our initial attempts to rationalize the different hygroscopicity ofthe DB7z hydrates in terms of structural features (solventpockets, channels) common to stoichiometric and nonstoichiometrichydrates yielded anything but expected results. Figure 17 shows the void space (default probe radius = 1.2 Å)created by removing the waters of crystallization from the HyA1.95, HyA1.73, HyA1.32, and Hy2 structures.Counterintuitively, the water accessible voids in nonstoichiometricHyA appear to be isolated from one another (Figure 17a–c), while water channels are clearly seen runningzigzag along the crystallographic b-axis in the stoichiometrichydrate, Hy2 (Figure 17d).

Bottom Line: HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z).Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°.Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions.

View Article: PubMed Central - PubMed

Affiliation: †Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.

ABSTRACT
Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

No MeSH data available.


Related in: MedlinePlus