title: Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms.
abstract: Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide 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 nonlayer 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.
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: School of Pharmacy, University of East Anglia , Norwich, Norfolk NR4 7TJ, United Kingdom.
authors.forename: Karol P
authors.initials: KP
authors.lastname: Nartowski
authors.affiliation: School of Pharmacy, University of East Anglia , Norwich, Norfolk NR4 7TJ, United Kingdom.
authors.forename: Yaroslav Z
authors.initials: YZ
authors.lastname: Khimyak
authors.affiliation: Lachman Institute for Pharmaceutical Analysis, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University-Brooklyn Campus , 75 DeKalb Avenue, Brooklyn, New York 11201, United States.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Morris
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47906, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
authors.affiliation: Institute of Pharmacy, University of Innsbruck , Innrain 52c, 6020 Innsbruck, Austria.
authors.forename: Ulrich J
authors.initials: UJ
authors.lastname: Griesser
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D009963:Orotic Acid / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D014867:Water; D009963:Orotic Acid
keywords: crystal structure prediction; dehydration; gravimetric moisture sorption/desorption; powder X-ray diffraction; solid-state NMR; thermal analysis; vibrational spectroscopy; water activity