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- Mechanochemistry (11)
- In situ (5)
- Cocrystal (3)
- Milling (3)
- XRD (3)
- cocrystal (3)
- Polymorphs (2)
- benzamide (2)
- theophylline (2)
- API molecule (1)
Organisationseinheit der BAM
- 6 Materialchemie (2)
- 6.3 Strukturanalytik (2)
The successful mechanochemical syntheses of three cadmium phenylphosphonates indicates that mechanochemistry is ideally suited for synthesizing metal phosphonates. With this powerful synthesis tool it is possible to synthesize rapidly and efficiently both known and novel phosphonates. The Crystal structures of the two new compounds, and, were solved from PXRD data. They contain monodeprotonated phenylphosphonate and neutral phenylphosphonic acid ligands. The synthesis pathways of all three compounds were investigated in situ. A diffusion mechanism is corroborated by our findings.
Intermediates could be detected and identified. The kinetically favored product (3) could always be detected during the syntheses. The thermodynamic stability of the compounds and the stoichiometric ratio of the starting materials are the two directing factors for the synthesis of the final products.
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.
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.
The driving forces triggering the formation of co-crystals under milling conditions were investigated by using a set of multicomponent 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 co-crystals including the coformer anthranilic acid. The results of the competitive milling reactions indicate that the formation of co-crystals driven by intermolecular recognition are influenced and inhibited by kinetic aspects including the formation of intermediates and the stability of the reactants.
The combination of two analytical methods including time-resolved in situ X-ray diffraction (XRD) and Raman spectroscopy provides a new opportunity for a detailed analysis of the key mechanisms of milling reactions. To prove the general applicability of our setup, we investigated the mechanochemical synthesis of four archetypical model compounds, ranging from 3D frameworks through layered structures to organic molecular compounds. The reaction mechanism for each model compound could be elucidated. The results clearly show the unique advantage of the combination of XRD and Raman spectroscopy because of the different information content and dynamic range of both individual methods. The specific combination allows to study milling processes comprehensively on the level of the molecular and crystalline structures and thus obtaining reliable data for mechanistic studies.
Synthesis, structure determination, and formation of a theobromine: oxalic acid 2:1 cocrystal
(2015)
The structure and the formation pathway of a new theobromine : oxalic acid (2 : 1) cocrystal are presented. The cocrystal was synthesised mechanochemically and its structure was solved based on the powder X-ray data. The mechanochemical synthesis of this model compound was studied in situ using synchrotron XRD. Based on the XRD data details of the formation mechanism were obtained. The formation can be described as a self-accelerated ('liquid like') process from a highly activated species.
Benzamide has been known for its polymorphism for almost 200 years.Three polymorphic forms are described. To date,itwas only possible to crystallizeametastable form in amixture together with the thermodynamically most stable form I. Acomplete transformation of form Iinto the metastable form III by mechanochemical treatment has been achieved. Catalytic amounts of nicotinamide seeds were used to activate the conversion by mechanochemical seeding. NMR experiments indicated that the nicotinamide molecules were incorporated statistically in the crystal lattice of benzamide form III during the conversion. The transformation pathway was evaluated using in situ powder X-ray diffraction.
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 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.