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.
Highlights
Hydrates are the most common solvates encountered in pharmaceutical compounds,[1−5] since water is ever present in the manufacturing environment of fine chemicals
Three structures containing the Orotic acid (OTA) molecule as a component can be found in the Cambridge Structural Database (CSD): a monohydrate cocrystal with melamine (LIDCAE79), a layer structure, and two dimethylammonium orotate−orotic acid complexes showing different stoichiometries (XARBID and XARBOJ44)
No structural information for anhydrous OTA has been found in literature
Summary
Hydrates are the most common solvates encountered in pharmaceutical compounds,[1−5] since water is ever present in the manufacturing environment of fine chemicals (atmospheric moisture or water in solvents, reactants, or excipients). Galwey classified the dehydration process according to water evolution type (WET) based on structural, observational, and kinetic criteria This model specifies six classes (i.e., crystal structure maintained, diffusion across an adherent barrier layer, interface advance/nucleation and growth or contracting envelope, homogeneous reactions in crystals, melting and formation of impervious outer layer, and comprehensive melting) and takes kinetic and rate controlling phenomena into consideration.[11] The latter two classifications and other frequently cited ones are based on either structural aspects of the hydrate,[12−15] sorption/ desorption behavior,[16] thermal dehydration behavior,[17,18] or relative stability estimations (thermodynamics) of two crystal forms (e.g., anhydrate and hydrate) at a given temperature and relative humidity.[19] none of the existing classifications can on its own reflect the complex interplay of structure, kinetics, and thermodynamics observed in (de)hydration processes, which are often difficult to control.[6,20−31]. By contrasting the thermodynamically feasible anhydrate and monohydrate crystal structures with structure and stability information derived for the experimental forms, we unravel factors that control crystallization of OTA
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