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A new cocrystal of pyrazinamide with oxalic acid was prepared mechanochemically and characterized by PXRD, Raman spectroscopy, solid-state NMR spectroscopy, DTA-TG, and SEM. Based on powder X-ray diffraction data the structure was solved. The formation pathway of the reaction was studied in situ using combined synchrotron PXRD and Raman spectroscopy. Using oxalic acid dihydrate the initially neat grinding turned into a rapid self-accelerated liquid-assisted grinding process by the release of crystallization water. Under these conditions, the cocrystal was formed directly within two minutes.
The synthesis of the polymorphic cocrystal caffeine:anthranilic acid was investigated to obtain a better understanding of the processes leading to the formation of different polymorphic forms. In the case of these cocrystal polymorphs synthesized by liquid-assisted grinding a distinct influence of the dipole moment of the solvent was found. A pre-coordination between the solvent molecules and the caffeine:anthranilic acid cocrystal could be identified in the formation of form II. In the case of form II the solvent can be regarded as a catalyst. The formation pathway of each polymorph was evaluated using synchrotron X-ray diffraction.
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.
Mechanochemistry is increasingly used for synthesizing various materials including cocrystals and metal organic compounds. Although this synthesis approach offers a fast and pure synthesis in high yields there is a lack in understanding the mechanisms of milling reactions. The driving forces triggering the formation of cocrystals under milling conditions were investigated using a set of multi-component competitive milling reactions. In these reactions, different active pharmaceutical ingredients were ground together with a further compound acting as coformer. The study was based on new cocrystals including the coformer anthranilic acid. The results of the competitive milling reactions indicate that the formation of cocrystals driven by intermolecular recognition are influenced and inhibited by kinetic aspects including the formation of intermediates and the stability of the reactants.
Milling reactions often result in 100% yields of single products, making purifying procedures obsolete. Mech-anochemistry is also a sustainable and eco-friendly method. The ever increasing interest in this method is contrasted by a lack in mechanistic understanding of the mechanochemical reactivity and selectivity. Recent in situ investigations provided direct insight into formation pathways. However, the currently available theories do not predict temperature T as an influential factor. Here, we report the first determination of an activation energy for a mechanochemical reaction. In a temperature-dependent in situ study the cocrystallisation of ibuprofen and nicotinamide was investigated as a model system. These experiments provide a pivotal step towards a comprehensive understanding of milling reaction mechanisms.