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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

(a,b) Representative experimental HyA spectra differingin watercontent and (c–h) six of 80 NMR-CASTEP computed 13C CP/MAS NMR spectra. (c,d) The two DB7z environmentsobserved in the ordered P1 cHyA2.0 model and (e–h) the four environments observed inthe ordered P1 cHyA1.25(13) model, which correspond to 0.75 W1, 0.25 W2, and 0.25 W3.
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fig10: (a,b) Representative experimental HyA spectra differingin watercontent and (c–h) six of 80 NMR-CASTEP computed 13C CP/MAS NMR spectra. (c,d) The two DB7z environmentsobserved in the ordered P1 cHyA2.0 model and (e–h) the four environments observed inthe ordered P1 cHyA1.25(13) model, which correspond to 0.75 W1, 0.25 W2, and 0.25 W3.

Mentions: The suggestion of water mobility/disorderfrom the diffraction experiments and static lattice energy modelingled to the use of 13C CP/MAS NMR spectroscopy90 to characterize HyA as a function of water content.Except for slight peak intensity variations, the SSNMR spectra ofHyA samples equilibrated between 22 and 90% RH were essentially identical(Figure 10a; Figure S5 of the Supporting Information). Since partial occupancy of the HyAwater sites over this RH range would necessarily result in a distributionof hydrogen bonding arrangements (Figure 6),the observation of a single 13C resonance for each carbonatom in DB7z shows that the different hydrogen bondingenvironments are effectively “averaged” as the watersof crystallization move in and out of the water sites in the HyA crystalstructure. Thus, SSNMR shows that the water of crystallization ishighly mobile over a wide range of moderate and high RH.


Navigating the Waters of Unconventional Crystalline Hydrates.

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

(a,b) Representative experimental HyA spectra differingin watercontent and (c–h) six of 80 NMR-CASTEP computed 13C CP/MAS NMR spectra. (c,d) The two DB7z environmentsobserved in the ordered P1 cHyA2.0 model and (e–h) the four environments observed inthe ordered P1 cHyA1.25(13) model, which correspond to 0.75 W1, 0.25 W2, and 0.25 W3.
© Copyright Policy
Related In: Results  -  Collection

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

fig10: (a,b) Representative experimental HyA spectra differingin watercontent and (c–h) six of 80 NMR-CASTEP computed 13C CP/MAS NMR spectra. (c,d) The two DB7z environmentsobserved in the ordered P1 cHyA2.0 model and (e–h) the four environments observed inthe ordered P1 cHyA1.25(13) model, which correspond to 0.75 W1, 0.25 W2, and 0.25 W3.
Mentions: The suggestion of water mobility/disorderfrom the diffraction experiments and static lattice energy modelingled to the use of 13C CP/MAS NMR spectroscopy90 to characterize HyA as a function of water content.Except for slight peak intensity variations, the SSNMR spectra ofHyA samples equilibrated between 22 and 90% RH were essentially identical(Figure 10a; Figure S5 of the Supporting Information). Since partial occupancy of the HyAwater sites over this RH range would necessarily result in a distributionof hydrogen bonding arrangements (Figure 6),the observation of a single 13C resonance for each carbonatom in DB7z shows that the different hydrogen bondingenvironments are effectively “averaged” as the watersof crystallization move in and out of the water sites in the HyA crystalstructure. Thus, SSNMR shows that the water of crystallization ishighly mobile over a wide range of moderate and high RH.

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