Ingenieurwissenschaften und zugeordnete Tätigkeiten
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- theophylline (2) (entfernen)
Theophylline has been used as an active pharmaceutical ingredient (API) in the treatment of pulmonary diseases, but due to its low water solubility reveals very poor bioavailability. Based on its different hydrogen-bond donor and acceptor groups, theophylline is an ideal candidate for the formation of cocrystals. The crystal structure of the 1:1 benzamide cocrystal of theophylline, C7H8N4O2·-C7H7NO, was determined from synchrotron X-ray powder diffraction data. The compound crystallizes in the tetragonal space group P41 with four Independent molecules in the asymmetric unit. The molecules form a hunter’s fence packing.
The crystal structure was confirmed by dispersion-corrected DFT calculations.
The possibility of salt formation was excluded by the results of Raman and 1H solid-state NMR spectroscopic analyses.
The liquid-assisted grinding cocrystallisation of theophylline with benzamide leading to polymorphic compounds was investigated. A solvent screening with seventeen different solvents was performed. The dipole moment of the solvent used in the synthesis determines the structure of the polymorphic product. A detailed investigation leads to the determination of the kinetically and thermodynamically favored product. In situ observations of the formation pathway during the grinding process of both polymorphs show that the thermodynamically favored cocrystal is formed in a two-step mechanism with the kinetic cocrystal as intermediate.