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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

Gravimetric moisturesorption and desorption curve of DB7z Hy2 spiked with FormsI and II° at 25 °C. The gray circlesare data points that fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses markmeasurement values that did not reach the equilibrium within the allowedtime limit (48 h). The encircled numbers indicate the order of subsequent(de)sorption cycles. The forms noted in parentheses were identifiedas minor components by XRPD.
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fig16: Gravimetric moisturesorption and desorption curve of DB7z Hy2 spiked with FormsI and II° at 25 °C. The gray circlesare data points that fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses markmeasurement values that did not reach the equilibrium within the allowedtime limit (48 h). The encircled numbers indicate the order of subsequent(de)sorption cycles. The forms noted in parentheses were identifiedas minor components by XRPD.

Mentions: The Hy2 to HyA transformation in water did not allow us to estimatethe Hy2 aw dependency. Therefore, we usedgravimetric sorption/desorption experiments to estimate the influenceof moisture. The Hy2 sample used in Figure 16 was spiked with 1–2% of both Forms I and II° beforesubjection to moisture sorption/desorption cycles. The desorptioncurve is similar to that of phase pure Hy2 (Figure 7c). The water is released at RH < 25%, and the productcontains Forms I and II° from the spiking and Form III as thedehydration product. Upon subsequently increasing the RH of the mixedanhydrate sample, hydration of Form III to Hy2 is observed as wellas a transformation to Form II° (Figure 16, 2). The latter, which is indicated by the decrease in mass despiteincreasing the humidity at RH values >85%, is consistent with thegreater stability (lower solubility) of Form II° than Hy2 observedin 1:1 acetonitrile/water (aw ≈0.9), Figure 15.


Navigating the Waters of Unconventional Crystalline Hydrates.

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

Gravimetric moisturesorption and desorption curve of DB7z Hy2 spiked with FormsI and II° at 25 °C. The gray circlesare data points that fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses markmeasurement values that did not reach the equilibrium within the allowedtime limit (48 h). The encircled numbers indicate the order of subsequent(de)sorption cycles. The forms noted in parentheses were identifiedas minor components by XRPD.
© Copyright Policy
Related In: Results  -  Collection

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

fig16: Gravimetric moisturesorption and desorption curve of DB7z Hy2 spiked with FormsI and II° at 25 °C. The gray circlesare data points that fulfill the preset equilibrium conditions (see Experimental Section), whereas the crosses markmeasurement values that did not reach the equilibrium within the allowedtime limit (48 h). The encircled numbers indicate the order of subsequent(de)sorption cycles. The forms noted in parentheses were identifiedas minor components by XRPD.
Mentions: The Hy2 to HyA transformation in water did not allow us to estimatethe Hy2 aw dependency. Therefore, we usedgravimetric sorption/desorption experiments to estimate the influenceof moisture. The Hy2 sample used in Figure 16 was spiked with 1–2% of both Forms I and II° beforesubjection to moisture sorption/desorption cycles. The desorptioncurve is similar to that of phase pure Hy2 (Figure 7c). The water is released at RH < 25%, and the productcontains Forms I and II° from the spiking and Form III as thedehydration product. Upon subsequently increasing the RH of the mixedanhydrate sample, hydration of Form III to Hy2 is observed as wellas a transformation to Form II° (Figure 16, 2). The latter, which is indicated by the decrease in mass despiteincreasing the humidity at RH values >85%, is consistent with thegreater stability (lower solubility) of Form II° than Hy2 observedin 1:1 acetonitrile/water (aw ≈0.9), Figure 15.

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