Computational and Experimental Characterization of Five Crystal Forms of Thymine: Packing Polymorphism, Polytypism/Disorder and Stoichiometric 0.8-Hydrate

New polymorphs of thymine emerged in an experimental search for solid forms, which was guided by the computationally generated crystal energy landscape. Three of the four anhydrates (AH) are homeoenergetic ( - ) and their packing modes differ only in the location of oxygen and hydrogen atoms. and are ordered phases, whereas shows disorder (X-ray diffuse scattering). Anhydrates and are ordered phases, whereas shows disorder (X-ray diffuse scattering). Analysis of the crystal energy landscape for alternative hydrogen bonded ribbon motifs identified a number of different packing modes, whose 3D structures were calculated to deviate by less than 0.24 kJ mol in lattice energy. These structures provide models for stacking faults. The three anhydrates ° - show strong similarity in their powder X-ray diffraction, thermoanalytical and spectroscopic (IR and Raman) characteristics. The already known anhydrate ° was identified as the thermodynamically most stable form at ambient conditions; and are metastable but show high kinetic stability. The hydrate of thymine is stable only at water activities () > 0.95 at temperatures ≤ 25 °C. It was found to be a stoichiometric hydrate despite being a channel hydrate with an unusual water:thymine ratio of 0.8:1. Depending on the dehydration conditions, either or is obtained. The hydrate is the only known precursor to . This study highlights the value and complementarity of simultaneous explorations of computationally and experimentally generated solid form landscapes of a small molecule anhydrate ↔ hydrate system.