Structural Properties, Order-Disorder Phenomena and Phase Stability of Orotic Acid Crystal Forms

Braun, Doris, Nartowski, Karol, Khimyak, Yaroslav, Morris, Kenneth, Byrn, Stephen and Griesser, Ulrich (2016) Structural Properties, Order-Disorder Phenomena and Phase Stability of Orotic Acid Crystal Forms. Molecular Pharmaceutics, 13 (3). pp. 1012-1029. ISSN 1543-8384

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Abstract

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1) and dimethylsulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135°C and loses only a small part of the water when stored over desiccants (25°C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen-bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a non-layer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.

Item Type: Article
Additional Information: This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Uncontrolled Keywords: crystal structure prediction,,thermal analysis,desorption,water activity,powder x-ray diffraction,vibrational spectroscopy,solid state nmr,dehydration
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Pure Connector
Date Deposited: 17 Mar 2016 10:00
Last Modified: 31 Oct 2019 14:46
URI: https://ueaeprints.uea.ac.uk/id/eprint/57495
DOI: 10.1021/acs.molpharmaceut.5b00856

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