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 (A° – C) and their packing modes differ only in the location of oxygen and hydrogen atoms. AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Anhydrates AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Analysis of the crystal energy landscape for alternative AH C 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–1 in lattice energy. These structures provide models for stacking faults. The three anhydrates A° – C show strong similarity in their powder X-ray diffraction, thermoanalytical and spectroscopic (IR and Raman) characteristics. The already known anhydrate AH A° was identified as the thermodynamically most stable form at ambient conditions; AH B and AH C are metastable but show high kinetic stability. The hydrate of thymine is stable only at water activities (aw) > 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 AH C or AH D is obtained. The hydrate is the only known precursor to AH D. 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.