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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

HyA hydrogen bonded motifs involving the water molecules and COO– groups. The distinct water sites are coded in differentcolors: W1A, rose; W1B, red; W2, blue; W3, green.Note that only one of the two differently colored W3 orientationscan be occupied as the two positions are related by a 2-fold axisat a proton position. (a) Showing the time-averaged water occupancyand (b) one of many possible instantaneous snapshots of the waterpositions in HyA in the range of occupancies seen in the two crystals.
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fig6: HyA hydrogen bonded motifs involving the water molecules and COO– groups. The distinct water sites are coded in differentcolors: W1A, rose; W1B, red; W2, blue; W3, green.Note that only one of the two differently colored W3 orientationscan be occupied as the two positions are related by a 2-fold axisat a proton position. (a) Showing the time-averaged water occupancyand (b) one of many possible instantaneous snapshots of the waterpositions in HyA in the range of occupancies seen in the two crystals.

Mentions: The HyA structures of the fresh and aged crystals differ in containing1.95 (HyA1.95) and 1.73 (HyA1.73) mol of waterper mol of DB7z, respectively. The loss of 0.22 mol ofwater on aging resulted in a volume change of −3.5%, with the c-axis change of −2.5% being the most significant.Three water sites (W1–3) were identified in HyA. Water siteW1 is disordered over two positions, which are so close in proximitythat only one of the two positions can be occupied at any time (Figure 6a). The W1 sites refined to an occupancy of 46%(W1A) and 52% (W1B) for HyA1.95,and 68% (W1A) and 30% (W1B) for HyA1.73. The site occupancy from the refinement of W2 was similar to thatof W1B, i.e., 52% for HyA1.95 and 30% for HyA1.73. Thus, if W2 is present, W1B is occupied, andif not, W1A is likely to be occupied (Figure 6b). Water site W3 is also disordered over two positions, whichare too close to be occupied at any one time. In HyA, one of the W3water protons is located on a special position, a 2-fold axis, soa maximum of 0.5 mol water per mol DB7 would be present at full occupancy.Refinement of the W3 waters revealed nearly full occupancy, 45% forboth HyA1.95 and HyA1.73, across the symmetryrelated sites.


Navigating the Waters of Unconventional Crystalline Hydrates.

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

HyA hydrogen bonded motifs involving the water molecules and COO– groups. The distinct water sites are coded in differentcolors: W1A, rose; W1B, red; W2, blue; W3, green.Note that only one of the two differently colored W3 orientationscan be occupied as the two positions are related by a 2-fold axisat a proton position. (a) Showing the time-averaged water occupancyand (b) one of many possible instantaneous snapshots of the waterpositions in HyA in the range of occupancies seen in the two crystals.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: HyA hydrogen bonded motifs involving the water molecules and COO– groups. The distinct water sites are coded in differentcolors: W1A, rose; W1B, red; W2, blue; W3, green.Note that only one of the two differently colored W3 orientationscan be occupied as the two positions are related by a 2-fold axisat a proton position. (a) Showing the time-averaged water occupancyand (b) one of many possible instantaneous snapshots of the waterpositions in HyA in the range of occupancies seen in the two crystals.
Mentions: The HyA structures of the fresh and aged crystals differ in containing1.95 (HyA1.95) and 1.73 (HyA1.73) mol of waterper mol of DB7z, respectively. The loss of 0.22 mol ofwater on aging resulted in a volume change of −3.5%, with the c-axis change of −2.5% being the most significant.Three water sites (W1–3) were identified in HyA. Water siteW1 is disordered over two positions, which are so close in proximitythat only one of the two positions can be occupied at any time (Figure 6a). The W1 sites refined to an occupancy of 46%(W1A) and 52% (W1B) for HyA1.95,and 68% (W1A) and 30% (W1B) for HyA1.73. The site occupancy from the refinement of W2 was similar to thatof W1B, i.e., 52% for HyA1.95 and 30% for HyA1.73. Thus, if W2 is present, W1B is occupied, andif not, W1A is likely to be occupied (Figure 6b). Water site W3 is also disordered over two positions, whichare too close to be occupied at any one time. In HyA, one of the W3water protons is located on a special position, a 2-fold axis, soa maximum of 0.5 mol water per mol DB7 would be present at full occupancy.Refinement of the W3 waters revealed nearly full occupancy, 45% forboth HyA1.95 and HyA1.73, across the symmetryrelated sites.

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