Ingenieurwissenschaften und zugeordnete Tätigkeiten
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- 2016 (3)
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- Englisch (3)
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- Cocrystal (3) (entfernen)
We present an in situ investigation of the mechanochemical formation of cocrystals using synchrotron XRD and Raman spectroscopy. This combination allows to study milling processes on the level of the molecular and crystalline structure thus obtaining reliable data for mechanistic studies. Thereby, mechanochemical syntheses can be optimized to isolate new crystal structures.
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.
In situ investigations using PXRD coupled with Raman spectroscopy permit the evaluation of the formation pathways of milling reactions. The liquid-assisted grinding cocrystallisation of theophylline with benzamide leading to polymorphic compounds was investigated. The dipole moment of the solvent used in the synthesis determines the structure of the polymorphic product. A detailed investigation allows determining 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. The evaluation of the mechanochemical formation pathways reveals the importance of in situ investigations for an in depth understanding of mechanochemical synthesis mechanisms. Our study demonstrates that the choice of the solvent in the LAG synthesis is decisive for the controlled formation of a desired polymorphic final product.