Theophylline (originally extracted from tea in the 19th century) is a natural product that is widely used in medicine of humans and related fields. Theophylline is a solid, which forms several so-called polymorphs. All these polymorphs consist of theophylline molecules only, but the arrangements of the molecules to each other in these solids are different. Because of these differences their physical properties may significantly differ. Especially the solubility in water is an important feature for its use in medicine and is normally different for polymorphs.
A joined research team from Kharkiv Institute for Single Crystals National Academy of Science of Ukraine, the Max Planck Institut für Kohleforschung, Mülheim und der Heinrich-Heine Universität reinvestigated the question of polymorphism of theophylline and published their results in RSC Advances (Konovalova et al., RSC Adv., 2024, 14, 29774-29788. DOI: https://doi.org/10.1039/D4RA04368E).
In this joint study – as part of the longstanding interest of the Düsseldorf-located part of the aforementioned team – the literature known crystal structures of theophylline has been re-evaluated to verify that there are five different polymorphs and one water-containing phase. For two of these solids a revision of the structural data was undertaken.
Finally, the calculations of pairwise interaction energies between the molecules have shown that the studied crystals can be divided into two groups according to their basic structural motifs: columnar-layered or columnar ones. The energetic approach also allows the role of different interactions in the crystal structure formation to be estimated. It was found, that strong N–H⋯N, N–H⋯O hydrogen bonds and stacking interactions play the most important roles in polymorphic modifications of THP and the THP monohydrate. The lattice energies calculations in periodic conditions for polymorphic structures have shown that polymorph with the most anisotropic energetic structure may be considered as stable and all others forms to be metastable.