Limits...
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

Photomicrographsof Hy2 (left) and HyA (right) crystals.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4525282&req=5

fig2: Photomicrographsof Hy2 (left) and HyA (right) crystals.

Mentions: Ourability to meaningfully study the structures, stability relationships,and interconversion pathways of the DB7z hydrates at amolecular level relied on securing highly crystalline, phase puresamples of each form through exquisite control over crystallization,filtration, and drying. Since both Hy2 and HyA are metastable withrespect to some or all of the neat polymorphs depending on the RH,they needed to be crystallized under carefully controlled conditions,then isolated and characterized before subsequent conversion to themore stable neat forms. Selecting for the metastable hydrates in crystallizationrequired that amorphous DB7 be used as the starting material to ensurethat the solutions were supersaturated with respect to the hydratesand free of crystalline seeds of the neat polymorphs. Even then, thefiltration and drying of these materials was surprisingly tricky,with under or over drying leading to form conversions, amorphization,particle agglomeration, and mostly brittle, chunky solids. Eventually,conditions were identified to selectively crystallize and recoverthe hydrates in highly crystalline form, each with reasonably goodmaterial handling properties. The Hy2 and HyA materials used to fundour experimental effort were generally composed of well-formed crystalsof similar size and shape commensurate with their high degree of crystallinity,phase purity, and homogeneity (Figure 2).


Navigating the Waters of Unconventional Crystalline Hydrates.

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

Photomicrographsof Hy2 (left) and HyA (right) crystals.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Photomicrographsof Hy2 (left) and HyA (right) crystals.
Mentions: Ourability to meaningfully study the structures, stability relationships,and interconversion pathways of the DB7z hydrates at amolecular level relied on securing highly crystalline, phase puresamples of each form through exquisite control over crystallization,filtration, and drying. Since both Hy2 and HyA are metastable withrespect to some or all of the neat polymorphs depending on the RH,they needed to be crystallized under carefully controlled conditions,then isolated and characterized before subsequent conversion to themore stable neat forms. Selecting for the metastable hydrates in crystallizationrequired that amorphous DB7 be used as the starting material to ensurethat the solutions were supersaturated with respect to the hydratesand free of crystalline seeds of the neat polymorphs. Even then, thefiltration and drying of these materials was surprisingly tricky,with under or over drying leading to form conversions, amorphization,particle agglomeration, and mostly brittle, chunky solids. Eventually,conditions were identified to selectively crystallize and recoverthe hydrates in highly crystalline form, each with reasonably goodmaterial handling properties. The Hy2 and HyA materials used to fundour experimental effort were generally composed of well-formed crystalsof similar size and shape commensurate with their high degree of crystallinity,phase purity, and homogeneity (Figure 2).

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