Supramolecular architecture of theophylline polymorphs, monohydrate and co-crystals with iodine: study from the energetic viewpoint.

The regularities of crystal structure organization were thoroughly studied in all to date known polymorphic modifications of theophylline (THP) using an energetic approach. The monohydrate and a co-crystal of theophylline with one half equivalent of an iodine molecule were similarly investigated. The calculations of pairwise interaction energies have showed that the crystals studied can be divided into two groups according to their basic structural motifs: or . 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. In the case of the co-crystal with iodine, N-H⋯O hydrogen bond participates in the dimeric building unit formation. However, instead of a stacking interaction the π⋯π interaction between carbonyl groups of neighboring molecules plays the highest role in the supramolecular architecture of this crystal. 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 metastable. In the polymorphic modification 1 of THP a zwitter-ionic resonance form is predominant, which affects significantly the solubility and the intermolecular interactions of this modification.