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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

Packing diagram of Hy2 viewed along the crystallographic b axis (a) and c axis (b). Hydrogen bondsare denoted as green dotted lines and the centrosymmetric DB7z dimer and zigzag sheet are highlighted.
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fig3: Packing diagram of Hy2 viewed along the crystallographic b axis (a) and c axis (b). Hydrogen bondsare denoted as green dotted lines and the centrosymmetric DB7z dimer and zigzag sheet are highlighted.

Mentions: DB7z Hy2 crystallizes in the monoclinic P21/c space group with Z′=1.The molecular conformationin this zwitterionic form is closely related to one of the Form IIIconformers (Figure S2 of the Supporting Information), but with the carboxylic acid proton moved to the piperazine N3.Thus, the protonated piperazine is intramolecularly hydrogen bondedto the carboxylate ion (N+–H···O–). The DB7z molecules form centrosymmetricdimers (Figure 3a), which are arranged in layersparallel to the bc plane. Each of the two water molecules(W1 and W2) forms an O–H···O hydrogen bond toone of the DB7z carboxylate oxygens (Figure 4); the other water protons are disordered over two positionseach with a site occupancy of 0.5. W1 and W2 form infinite corrugatedchains, which are interlinked by the carboxylate group of DB7z (Figure 4), leading to zigzag sheets(Figure 3b). The zigzag sheets, containingall of the strong hydrogen bonds, are interleaved in a zip motif along a.


Navigating the Waters of Unconventional Crystalline Hydrates.

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

Packing diagram of Hy2 viewed along the crystallographic b axis (a) and c axis (b). Hydrogen bondsare denoted as green dotted lines and the centrosymmetric DB7z dimer and zigzag sheet are highlighted.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Packing diagram of Hy2 viewed along the crystallographic b axis (a) and c axis (b). Hydrogen bondsare denoted as green dotted lines and the centrosymmetric DB7z dimer and zigzag sheet are highlighted.
Mentions: DB7z Hy2 crystallizes in the monoclinic P21/c space group with Z′=1.The molecular conformationin this zwitterionic form is closely related to one of the Form IIIconformers (Figure S2 of the Supporting Information), but with the carboxylic acid proton moved to the piperazine N3.Thus, the protonated piperazine is intramolecularly hydrogen bondedto the carboxylate ion (N+–H···O–). The DB7z molecules form centrosymmetricdimers (Figure 3a), which are arranged in layersparallel to the bc plane. Each of the two water molecules(W1 and W2) forms an O–H···O hydrogen bond toone of the DB7z carboxylate oxygens (Figure 4); the other water protons are disordered over two positionseach with a site occupancy of 0.5. W1 and W2 form infinite corrugatedchains, which are interlinked by the carboxylate group of DB7z (Figure 4), leading to zigzag sheets(Figure 3b). The zigzag sheets, containingall of the strong hydrogen bonds, are interleaved in a zip motif along a.

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