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- Cocrystal (3) (entfernen)
The cocrystal formation of pyrazinamide (PZA) with malonic acid (MA) was studied in situ. The mechanochemical reaction proceeds via conversion of a crystalline intermediate (PZA:MA II) into the thermodynamically more stable form (PZA:MA I) upon further grinding. The information derived from in situ powder X-ray diffraction (PXRD) enabled the isolation of this new metastable polymorph. On the basis of the PXRD data, the crystal structure of the 1:1 cocrystal PZA:MA II was solved. The polymorphs were further characterized and compared by Raman spectroscopy, solid-state NMR spectroscopy, differential thermal analysis/thermogravimetric analysis, and scanning electron microscopy. Our study demonstrates how monitoring mechanochemical reactions by in situ PXRD can direct the discovery and isolation of even short-lived intermediates not yet accessed by conventional methods.
Mechanochemical reactions often result in 100% yields of single products, making purifying procedures obsolete. Mechanochemistry 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 apparent activation energy for a mechanochemical reaction. In a temperaturedependent 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.
The stability of different theophylline cocrystals under milling conditions was investigated by competitive cocrystal reactions. To determine the most stable cocrystal form under milling conditions, the active pharmaceutical ingredient theophylline was either ground with two similar coformers (benzoic acid, benzamide, or isonicotinamide), or the existing theophylline cocrystals were ground together with a competitive coformer. All competitive reactions were investigated by in situ powder X-ray diffraction disclosing the formation pathway of the milling processes. On the basis of these milling reactions, a stability order (least to most stable) was derived: tp/bs < tp/ba < tp/ina < bs/ina.