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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

(a) 13C CP/MASNMR spectra of DB7 Form III producedby dehydrating Hy2 under a variety of conditions (defined in the Supporting Information, Table S3). Highlightedare the C18 and C21 peaks characterizing the structural disorder ofthe dimethyl propionic acid side chain. (b) DSC thermograms of DB7Form III lots N2/0/RT/24 and N2/0/5/48 measured ata heating rate of 1 °C min–1. Lot N2/0/RT/24 was prepared by drying Hy2 under N2 purgeat room temperature for 24 h and lot N2/0/5/48 under N2 purge at 5 °C for 48 h.
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fig14: (a) 13C CP/MASNMR spectra of DB7 Form III producedby dehydrating Hy2 under a variety of conditions (defined in the Supporting Information, Table S3). Highlightedare the C18 and C21 peaks characterizing the structural disorder ofthe dimethyl propionic acid side chain. (b) DSC thermograms of DB7Form III lots N2/0/RT/24 and N2/0/5/48 measured ata heating rate of 1 °C min–1. Lot N2/0/RT/24 was prepared by drying Hy2 under N2 purgeat room temperature for 24 h and lot N2/0/5/48 under N2 purge at 5 °C for 48 h.

Mentions: Following ourobservation of batch-to-batch variability in the disorder ratio ofthe dimethylpropionic acid side chain in Form III, we performed systematicdrying studies of Hy2 to estimate the effects of RH and temperatureon the level of disorder present in the Form III dehydration productand to seek conditions that would select for the ordered structures.The disorder ratio was quantified from the intensities of the dimethylpropionicacid methyl 13C SSNMR peaks (Figure 14a, Table S3 of the Supporting Information). Unfortunately, despite the wide range of drying conditions surveyed,we were not successful in preparing either an ordered Form III sampleor one having the minor conformation dominating.


Navigating the Waters of Unconventional Crystalline Hydrates.

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

(a) 13C CP/MASNMR spectra of DB7 Form III producedby dehydrating Hy2 under a variety of conditions (defined in the Supporting Information, Table S3). Highlightedare the C18 and C21 peaks characterizing the structural disorder ofthe dimethyl propionic acid side chain. (b) DSC thermograms of DB7Form III lots N2/0/RT/24 and N2/0/5/48 measured ata heating rate of 1 °C min–1. Lot N2/0/RT/24 was prepared by drying Hy2 under N2 purgeat room temperature for 24 h and lot N2/0/5/48 under N2 purge at 5 °C for 48 h.
© Copyright Policy
Related In: Results  -  Collection

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

fig14: (a) 13C CP/MASNMR spectra of DB7 Form III producedby dehydrating Hy2 under a variety of conditions (defined in the Supporting Information, Table S3). Highlightedare the C18 and C21 peaks characterizing the structural disorder ofthe dimethyl propionic acid side chain. (b) DSC thermograms of DB7Form III lots N2/0/RT/24 and N2/0/5/48 measured ata heating rate of 1 °C min–1. Lot N2/0/RT/24 was prepared by drying Hy2 under N2 purgeat room temperature for 24 h and lot N2/0/5/48 under N2 purge at 5 °C for 48 h.
Mentions: Following ourobservation of batch-to-batch variability in the disorder ratio ofthe dimethylpropionic acid side chain in Form III, we performed systematicdrying studies of Hy2 to estimate the effects of RH and temperatureon the level of disorder present in the Form III dehydration productand to seek conditions that would select for the ordered structures.The disorder ratio was quantified from the intensities of the dimethylpropionicacid methyl 13C SSNMR peaks (Figure 14a, Table S3 of the Supporting Information). Unfortunately, despite the wide range of drying conditions surveyed,we were not successful in preparing either an ordered Form III sampleor one having the minor conformation dominating.

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