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

(a) Overlay of DB7z Hy2 (red) and HyA1.95 (blue) conformations (rmsd1 = 0.38 Å). (b) R22(12) dimer motif in HyA. (c) Packing diagram of HyA1.95 viewed along c. Centrosymmetric dimer, water positionW2, and 1D building block are highlighted; W1 and W3 are obscuredby the carboxylate groups in this view.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: (a) Overlay of DB7z Hy2 (red) and HyA1.95 (blue) conformations (rmsd1 = 0.38 Å). (b) R22(12) dimer motif in HyA. (c) Packing diagram of HyA1.95 viewed along c. Centrosymmetric dimer, water positionW2, and 1D building block are highlighted; W1 and W3 are obscuredby the carboxylate groups in this view.

Mentions: The HyA structurewas determined twice using a fresh and an aged crystal. DB7z HyA crystallizes in the monoclinic C2/c space group with Z′ = 1. The main differencein the molecular conformation of DB7z in HyA and Hy2 isa ∼52° rotation of the C18–C19–C20–O2dihedral (Figure 5a) moving the carboxylategroup from an intra- to intermolecular hydrogen bonding conformation.The conformation of DB7z in HyA is closely related to thatin anhydrate Form II° (Figure S2 of the SupportingInformation). Owing to the shape complementarity of the DB7z conformers in both hydrates, inversion related dimers similarto those formed in Hy2 are also seen in HyA (Figures 3a and 5c). However, the HyA structurealso features intermolecularly hydrogen bonded R22(12) dimers82 involving strong N+–H···O– hydrogen bonds (Figure 5b).


Navigating the Waters of Unconventional Crystalline Hydrates.

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

(a) Overlay of DB7z Hy2 (red) and HyA1.95 (blue) conformations (rmsd1 = 0.38 Å). (b) R22(12) dimer motif in HyA. (c) Packing diagram of HyA1.95 viewed along c. Centrosymmetric dimer, water positionW2, and 1D building block are highlighted; W1 and W3 are obscuredby the carboxylate groups in this view.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: (a) Overlay of DB7z Hy2 (red) and HyA1.95 (blue) conformations (rmsd1 = 0.38 Å). (b) R22(12) dimer motif in HyA. (c) Packing diagram of HyA1.95 viewed along c. Centrosymmetric dimer, water positionW2, and 1D building block are highlighted; W1 and W3 are obscuredby the carboxylate groups in this view.
Mentions: The HyA structurewas determined twice using a fresh and an aged crystal. DB7z HyA crystallizes in the monoclinic C2/c space group with Z′ = 1. The main differencein the molecular conformation of DB7z in HyA and Hy2 isa ∼52° rotation of the C18–C19–C20–O2dihedral (Figure 5a) moving the carboxylategroup from an intra- to intermolecular hydrogen bonding conformation.The conformation of DB7z in HyA is closely related to thatin anhydrate Form II° (Figure S2 of the SupportingInformation). Owing to the shape complementarity of the DB7z conformers in both hydrates, inversion related dimers similarto those formed in Hy2 are also seen in HyA (Figures 3a and 5c). However, the HyA structurealso features intermolecularly hydrogen bonded R22(12) dimers82 involving strong N+–H···O– hydrogen bonds (Figure 5b).

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