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Eingeladener Vortrag
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We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ballmilling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/DL-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail
N-H⋯O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong chargeassisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization.
Proline has been widely used for various cocrystallization applications, including pharmaceutical cocrystals. Combining enantiopure and racemic flurbiprofen and proline, we discovered 18 new crystal structures. Liquid-assisted grinding proved highly efficient to explore all the variety of crystal forms. A unique combination of stateof-the-art characterization techniques, comprising variable temperature in situ X-ray diffraction and in situ ball-milling, along with other physicochemical methods and density functional theory calculations, was indispensable for identifying all the phases. Analyzing the results of in situ ball-milling, we established a stepwise mechanism for the formation of several 1:1 cocrystals via an intermediate 2:1 phase. The nature of the solvent in liquidassisted grinding was found to significantly affect the reaction rate and, in some cases, the reaction pathway.
The mechanochemical Knoevenagel condensation of malononitrile with p-nitrobenzaldehyde was studied in situ using a tandem approach. X-ray diffraction and Raman spectroscopy were combined to yield time-resolved information on the milling process. Under solvent-free conditions, the reaction leads to a quantitative conversion to p-nitrobenzylidenemalononitrile within 50 minutes. The in situ data indicate that the process is fast and proceeds under a direct conversion. After stopping the milling process, the reaction continues until complete conversion. The continuous and the stopped milling process both result in crystalline products suitable for single crystal X-ray diffraction.
The effect of the ball to reactant ratio on mechanochemical reaction times studied by in situ PXRD
(2017)
The effect of the reactant powder mass on reaction times for the mechanochemical formation of a soft matter model system was studied by in situ PXRD. The syntheses were performed at a constant ball mass in a shaker mill with and without glassy SiO2 as an inert additive. Reaction times decreased with the increase of the ball to reactant ratio (BRR). The kinetic influence of the SiO2 powder was excluded. The decrease in the reaction time with decreasing mass of reactants was related to the rise in the stress energy transferred to the powder by a higher ball impact. The BRR had no effect on the induction time. But the product conversion was accelerated by raising the BRR. While a certain temperature is needed for the activation of reactants in the induction phase, the conversion of soft matter reactants is rather controlled by impact than temperature.
A newly established in situ technique using Raman spectroscopy was employed for the detailed kinetic investigation of mechanochemical reaction pathways. This approach was applied for the systematic investigation of the direct influence of colliding balls on the reaction rate constants of a mechanochemical cocrystallization reaction. As a model reaction, the mechanochemical cocrystallization of felodipine and the coformer imidazole was investigated. Keeping the total ball mass constant by varying the number of milling balls, our study reveals that the impact of each single collision has a more significant influence on the reaction kinetics than expected.
Chemie kann so einfach sein: Zwei Pulver in eine Kugelmühle geben, kräftig schütteln und schon entsteht eine neue Verbindung. Dr. Franziska Fischer konnte durch Echtzeitüberwachung die Reaktionswege solcher mechanochemischen Synthesen aufdecken. Ihre Dissertation am Institut für Chemie der Humboldt-Universität und an der Bundesanstalt für Materialforschung und -prüfung leistet einen entscheidenden Beitrag zur Entwicklung umweltverträglicher und kosteneffizienter Synthesemethoden.
Synthesen in der Kugelmühle
(2016)
We present a first direct measurement of the temperature during milling combined with in situ Raman spectroscopy monitoring. The data reveal a low temperature increase due to the mechanical impact and clear temperature increases as a consequence of the reaction heat. Based on the data, temperature rises as postulated in the magma plasma and hot spot theory can be excluded for soft matter milling syntheses.
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.
Mechanochemistry is increasingly used as a ‘green alternative’ for synthesizing various materials including pharmaceutical cocrystals. Herein, we present the mechanochemical synthesis of three new cocrystals containing the API carbamazepine (cocrystals CBZ:Indometacin 1:1, CBZ:Benzamide 1:1, and CBZ:Nifedipine 1:1). The mechanochemical reaction was investigated in situ documenting a fast and complete reaction within one minute. Online NMR spectroscopy proved the direct influence of the dissolution behaviour of the coformers to the dissolution behaviour of the API carbamazepine. The dissolution behaviour of the organic cocrystals is compared to the behaviour of the pure drug indicating a general applicability of this approach for detailed cocrystal dissolution studies.