期刊
MOLECULAR PHARMACEUTICS
卷 12, 期 8, 页码 3069-3088出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00357
关键词
hydrate; crystal polymorphism; proton transfer; crystal structure; electronic structure calculations; NMR prediction; thermal analysis; gravimetric moisture sorption/desorption; Raman spectroscopy; solid state NMR spectroscopy; hydrogen/deuterium exchange
资金
- Hertha Firnberg Programme of the Austrian Science Fund (FWF) [T593-N19]
- Eli Lilly and Company
- Austrian Science Fund (FWF) [T593] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [T 593] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039229/1, EP/F03573X/1] Funding Source: researchfish
- EPSRC [EP/F03573X/1, EP/K039229/1] Funding Source: UKRI
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 degrees, 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 degrees. 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.
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