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

Molecular diagrams ofDB7 in the charge neutral anhydrous FormsI–III and amorphous form and in the zwitterionic hydrates.The abbreviated name DB7 refers to the dibenzoxazepinyl ring system.47 The atomic numbering given on the charge neutralform is also used for zwitterionic phases, which are indicated withsuperscript “z”.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Molecular diagrams ofDB7 in the charge neutral anhydrous FormsI–III and amorphous form and in the zwitterionic hydrates.The abbreviated name DB7 refers to the dibenzoxazepinyl ring system.47 The atomic numbering given on the charge neutralform is also used for zwitterionic phases, which are indicated withsuperscript “z”.

Mentions: Another compound that shows water-induced protontransfer to formzwitterionic hydrates is the 5-HT2a and H1 inverseagonist, 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoicacid (LY2624803 or DB7, Figure 1). We previouslyused DB7 as a model compound to test the value of combining computationalcrystal structure prediction (CSP) methods with an industrial solidform screening program.47 From the experimentalscreen for solid forms, which encompassed a broad range of crystallizationconditions and totaled over 300 experiments, DB7 was identified innine solid forms, including three neat polymorphs (Forms I–III),a stoichiometric dihydrate (Hy2), a nonstoichiometric hydrate (HyA),three unstable isostructural solvates (from methanol, ethanol, and2-propanol), and an amorphous form. For an amphoteric molecule withmeasured pKa values of 2.95 (oxepine-N),4.03 (carboxylic acid), and 7.81 (piperidine-N), application of thepKa rule of three would suggest that protontransfer from the carboxylic acid to the piperidine-N is essentiallycomplete rendering DB7 zwitterionic, at least in aqueous solutionsat moderate pH.48 However, solid state 15N NMR spectra provided an initial indication that only Hy2and HyA contain zwitterions (DB7z); the neat forms containthe neutral DB7 molecule.47


Navigating the Waters of Unconventional Crystalline Hydrates.

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

Molecular diagrams ofDB7 in the charge neutral anhydrous FormsI–III and amorphous form and in the zwitterionic hydrates.The abbreviated name DB7 refers to the dibenzoxazepinyl ring system.47 The atomic numbering given on the charge neutralform is also used for zwitterionic phases, which are indicated withsuperscript “z”.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Molecular diagrams ofDB7 in the charge neutral anhydrous FormsI–III and amorphous form and in the zwitterionic hydrates.The abbreviated name DB7 refers to the dibenzoxazepinyl ring system.47 The atomic numbering given on the charge neutralform is also used for zwitterionic phases, which are indicated withsuperscript “z”.
Mentions: Another compound that shows water-induced protontransfer to formzwitterionic hydrates is the 5-HT2a and H1 inverseagonist, 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoicacid (LY2624803 or DB7, Figure 1). We previouslyused DB7 as a model compound to test the value of combining computationalcrystal structure prediction (CSP) methods with an industrial solidform screening program.47 From the experimentalscreen for solid forms, which encompassed a broad range of crystallizationconditions and totaled over 300 experiments, DB7 was identified innine solid forms, including three neat polymorphs (Forms I–III),a stoichiometric dihydrate (Hy2), a nonstoichiometric hydrate (HyA),three unstable isostructural solvates (from methanol, ethanol, and2-propanol), and an amorphous form. For an amphoteric molecule withmeasured pKa values of 2.95 (oxepine-N),4.03 (carboxylic acid), and 7.81 (piperidine-N), application of thepKa rule of three would suggest that protontransfer from the carboxylic acid to the piperidine-N is essentiallycomplete rendering DB7 zwitterionic, at least in aqueous solutionsat moderate pH.48 However, solid state 15N NMR spectra provided an initial indication that only Hy2and HyA contain zwitterions (DB7z); the neat forms containthe neutral DB7 molecule.47

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