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

Gravimetricmoisture sorption and desorption curves of DB7z solid formsat 25 °C: (a) Form I, (b) Form II°,(c) Form III/Hy2, and (d) HyA. The gray circles represent data pointsthat fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses mark measurementvalues that did not reach equilibrium within the allowed time limit(48 h).
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Gravimetricmoisture sorption and desorption curves of DB7z solid formsat 25 °C: (a) Form I, (b) Form II°,(c) Form III/Hy2, and (d) HyA. The gray circles represent data pointsthat fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses mark measurementvalues that did not reach equilibrium within the allowed time limit(48 h).

Mentions: The hydration and dehydrationbehavior of the DB7z crystal forms was investigated between0% and 95% RH at 25 °C (Figure 7). Twoof the anhydrates, Forms I (Figure 7a) andII° (Figure 7b), show almost no wateruptake (Form I < 0.32% and Form II° < 0.04%) up to 95%RH. In contrast, anhydrate Form III undergoes a phase transformationwith a mass increase corresponding to 2 mol of water per mol of DB7at RH values >70% (Figure 7c). The producthydrate phase, confirmed to be Hy2 by XRPD, shows good RH stabilitywith a marginal weight loss between 95 and 25% RH. Below 25% RH, dehydrationis rapid. Hysteresis was observed in the Form III/Hy2 isotherm despitethe lengthy equilibration times (up to 48 h) at each RH. The profileof the moisture sorption/desorption isotherms for Form III ↔Hy2 with steps accompanied by phase changes, is typical of a stoichiometrichydrate.3 In contrast, highly crystallineHyA shows the typical (de)sorption isotherms of a nonstoichiometrichydrate3 (Figure 7d, see also Figure S3 of the Supporting Information) as the mass gradually changes depending on the humidity duringsorption and desorption. The lowest water content measured by TGA(Figure 7d) for HyA equilibrated at 0% RH correspondedto 1.29 mol of water per mol of DB7z. The maximum watervapor uptake into the HyA structure was estimated to be approximately1.85 mol of water per mol of DB7z at 95% RH.


Navigating the Waters of Unconventional Crystalline Hydrates.

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

Gravimetricmoisture sorption and desorption curves of DB7z solid formsat 25 °C: (a) Form I, (b) Form II°,(c) Form III/Hy2, and (d) HyA. The gray circles represent data pointsthat fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses mark measurementvalues that did not reach equilibrium within the allowed time limit(48 h).
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Gravimetricmoisture sorption and desorption curves of DB7z solid formsat 25 °C: (a) Form I, (b) Form II°,(c) Form III/Hy2, and (d) HyA. The gray circles represent data pointsthat fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses mark measurementvalues that did not reach equilibrium within the allowed time limit(48 h).
Mentions: The hydration and dehydrationbehavior of the DB7z crystal forms was investigated between0% and 95% RH at 25 °C (Figure 7). Twoof the anhydrates, Forms I (Figure 7a) andII° (Figure 7b), show almost no wateruptake (Form I < 0.32% and Form II° < 0.04%) up to 95%RH. In contrast, anhydrate Form III undergoes a phase transformationwith a mass increase corresponding to 2 mol of water per mol of DB7at RH values >70% (Figure 7c). The producthydrate phase, confirmed to be Hy2 by XRPD, shows good RH stabilitywith a marginal weight loss between 95 and 25% RH. Below 25% RH, dehydrationis rapid. Hysteresis was observed in the Form III/Hy2 isotherm despitethe lengthy equilibration times (up to 48 h) at each RH. The profileof the moisture sorption/desorption isotherms for Form III ↔Hy2 with steps accompanied by phase changes, is typical of a stoichiometrichydrate.3 In contrast, highly crystallineHyA shows the typical (de)sorption isotherms of a nonstoichiometrichydrate3 (Figure 7d, see also Figure S3 of the Supporting Information) as the mass gradually changes depending on the humidity duringsorption and desorption. The lowest water content measured by TGA(Figure 7d) for HyA equilibrated at 0% RH correspondedto 1.29 mol of water per mol of DB7z. The maximum watervapor uptake into the HyA structure was estimated to be approximately1.85 mol of water per mol of DB7z at 95% 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