title: Navigating the Waters of Unconventional Crystalline Hydrates.
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.
authors.affiliation: †Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
authors.forename: Doris E
authors.initials: DE
authors.lastname: Braun
authors.affiliation: §Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Lien H
authors.initials: LH
authors.lastname: Koztecki
authors.affiliation: §Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: McMahon
authors.affiliation: ‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Price
authors.affiliation: §Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Reutzel-Edens
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization / Q000379:methods*; D018360:Crystallography, X-Ray; D003989:Dibenzoxazepines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011422:Propionates / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D003989:Dibenzoxazepines; D004364:Pharmaceutical Preparations; D010879:Piperazines; D011422:Propionates; D014867:Water
keywords: NMR prediction; Raman spectroscopy; crystal polymorphism; crystal structure; electronic structure calculations; gravimetric moisture sorption/desorption; hydrate; hydrogen/deuterium exchange; proton transfer; solid state NMR spectroscopy; thermal analysis