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Control of ball milling conversions is required before the full potential of mechanochemical processing can be realized. It is well known that many parameters affect the outcome of mechanochemical polymorphism, but the energy of ball milling itself is often overlooked. We show here how this parameter alone can exert a significant influence on the polymorphic outcome of ball mill grinding by allowing the selective isolation of two polymorphic forms in their pure form under the same grinding conditions. Furthermore, we show how apparent mechanochemical equilibria can be deceptive. Our results clearly demonstrate the need for careful design and interpretation of ball milling experiments beyond current thinking.
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.
Mechanochemistry has become a sustainable and attractive cost-effective synthetic technique, largely used within the frame of crystal engineering. Cocrystals, namely, crystalline compounds made of different chemical entities within the same crystal structure, are typically synthesized in bulk via mechanochemistry; however, whereas the macroscopic aspects of grinding are becoming clear, the fundamental principles that underlie mechanochemical cocrystallization at the microscopic level remain poorly understood. Time-resolved in situ (TRIS) monitoring approaches have opened the door to exceptional detail regarding mechanochemical reactions. We here report a clear example of cocrystallization between two solid coformers that proceeds through the formation of a metastable low melting binary eutectic phase. The overall cocrystallization process has been monitored by time-resolved in situ (TRIS) synchrotron X-ray powder diffraction with a customized ball milling setup, currently available at μ Spot beamline at BESSY-II, Helmholtz-Zentrum Berlin. The binary system and the low melting eutectic phase were further characterized via DSC, HSM, and VT-XRPD.
Tuning and controlling the solid-state photophysical properties of organic luminophore are very important to develop next-generation organic luminescent materials. With the aim of discovering new functional luminescent materials, new cocrystals of 9-anthracene carboxylic acid (ACA) were prepared with two different dipyridine coformers: 1,2-bis(4-pyridyl)ethylene and 1,2-bis(4-pyridyl)ethane. The cocrystals were successfully obtained by both mechanochemical approaches and conventional solvent crystallization. The newly obtained crystalline solids were characterized thoroughly using a combination of single crystal X-ray diffraction, powder X-ray diffraction, Fourier-transform infrared spectroscopy, differential thermal analysis, and thermogravimetric analysis. Structural analysis revealed that the cocrystals are isostructural, exhibiting two-fold interpenetrated hydrogen bonded networks. While the O–H···N hydrogen bonds adopts a primary role in the stabilization of the cocrystal phases, the C–H···O hydrogen bonding interactions appear to play a significant role in guiding the three-dimensional assembly. Both π···π and C–H···π interactions assist in stabilizing the interpenetrated structure. The photoluminescence properties of both the starting materials and cocrystals were examined in their solid states. All the cocrystals display tunable photophysical properties as compared to pure ACA. Density functional theory simulations suggest that the modified optical properties result from charge transfers between the ACA and coformer molecules in each case. This study demonstrates the potential of crystal engineering to design solid-state luminescence switching materials through cocrystallization.
Mechanochemistry is an effective, environmentally benign, and facile method for the synthesis of new multicomponent crystal systems. Different milling parameters are known to affect the mechanisms and rates of product formation: milling frequency, milling time, filling degree of the milling jar, ball diameter and vessel size, degree of milling ball filling, and material of jars. The increasing interest in mechanochemistry is contrasted by a limited mechanistic understanding of the mechanochemical reactivity and selectivity. Different analytical methods and their combinations have been developed for the time resolved in situ monitoring of mechanochemical transformations, including powder X-ray diffraction, X-ray adsorption spectroscopy, NMR, Raman spectroscopy, and thermography.1 Here we will discuss our recent results investigating the formation of (polymorphic) cocrystals2–3 and metal-organic frameworks,4 thereby elucidating the influence of milling parameters and reaction sequences on the formation mechanism and kinetics. For the mechanochemical chlorination reaction of hydantoin normalizing the kinetic profiles to the volume of the milling ball showed clearly that milling reaction kinetics are conserved.6 Here physical kinetics dominate reaction rates in a ball-milling transformation. Attempting to interpret such kinetics in purely chemical terms risk misinterpreting the results. Our results indicate that time-resolved in situ investigation of milling reactions offer a new approach to tune and optimize mechanochemical processes.
We studied the influence of coformers flexibility on the supramolecular assembly of 5-substituted resorcinol. Two cocrystals of orcinol (ORL) with two dipyridine molecules, i.e. 1,2-di(4-pyridyl)ethane (ORLeBPE) and 1,2-di(4-pyridyl)ethylene (ORLeBPY), were prepared by mechanochemical synthesis and slow evaporation of solvent. The new crystalline solids were thoroughly characterized by single crystal Xray diffraction (SCXRD), powder X-ray diffraction analysis (PXRD), Fourier-transform infrared spectroscopy (FT-IR), differential thermal analysis (DTA), and thermogravimetric analysis (TGA). Structural determination reveals that in both cocrystals, the phenolepyridine, i.e. OeH/N(py) heterosynthon takes the main role in the formation of cocrystals. In ORLeBPE, the components form infinite 1D zig-zag chains, which are extended to 2D layer structure by inter-chain CeH/O interactions between BPE hydrogen atoms and hydroxyl oxygen atoms of ORL. In ORLeBPY, the components form a 0D fourcomponent complex. Formation of the discrete assemblies is attributed to the comparative rigid nature of BPY, which restricts the formation of an extended network.
The mechanism of ternary cocrystal formation, and the potential role of intermediate binary phases, has been debated for some time. We report here the first in situ real-time monitoring of two prototypic ternary cocrystals. Our results suggest that the question is more complicated than previously considered. The mechanism of mechanochemical ternary cocrystal formation depends on the milling conditions, here the milling frequency and addition of liquid. Binary phases can form under certain conditions, but do not act as intermediates in the formation of the ternary cocrystals. Rather, binary phases are competitive with the ternary phase, and their formation appears to compete with that of the ternary components. The presence of binary phases leads to an increase in the overall reaction time. The results reported here offer the first insights into the true complexities of mechanochemical multi-component synthesis of higher order multi-component crystals and demonstrate a new understanding of the influence of milling condition for the study of mechanisms and kinetics.
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.
We present an in situ PXRD investigation of the mechanochemical cocrystal formation of pyrazinamide with pimelic acid in two milling jar materials. DFT calculations of the two synthesized polymorphs suggest that the relative stability is based on a conformation change of pyrazinamide in the cocrystal.
Mechanochemistry has become a valuable method for the synthesis of new materials, especially for pharmaceutical cocrystals. The Advantages of fast reactions in high purity and yield face a lack of understanding the underlying mechanism. Therefore, in situ setups to study mechanochemical reactions have been established. Herein, we present an in situ investigation of the mechanochemical cocrystal formation of pyrazinamide (PZA) with pimelic acid (PM) using synchrotron XRD. Two new polymorphs of PZA:PM (1:1) were synthesized by milling the starting materials in milling jars of different materials. While Form I is only obtained using a steel jar, Form II can be obtained purely in jars made of Perspex. In situ XRD experiments reveal a direct formation of Form II in Perspex and an intermediate formation of Form II in steel jars converting to Form I upon further grinding. Heating experiments and DFT calculations predict that Form II is the thermodynamically more stable polymorph. Therefore, the reaction progress in the steel jar contradicts Ostwald’s rules of stages as the more stable Form II converts into the metastable Form I. Hence, mechanochemistry offers the possibility to synthesize new materials that cannot be obtained using conventional methods.
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.
Two isomorphous crystals are reported based on a naphthylvinylpyridine coformer. The crystals are mechanically flexible and exhibit photosalient response to UV irradiation. We therefore show how multiple mechanical phenomena can be simultaneously designed into a single material by cocrystallization.
Mechanochemistry provides polymorphs that are difficult to obtain by conventional solution-based methods. Based on the nicotinamide and pimelic acid cocrystal, we demonstrated that the ball size, frequency, and temperature are essential parameters. Our results indicate that fine-tuning the energy input during a mechanochemical reaction can provide control over polymorphism.