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Mechanochemistry is an effective, environmentally benign, and facile method for the synthesis of new crystal forms. 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 mechanochemical reactivity and selectivity. Control over ball milling transformations is needed before the transformative potential of mechanochemical processing can be realized. 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 absorption spectroscopy, NMR, Raman spectroscopy, and thermography. Here we will discuss our recent results investigating the formation of polymorphic cocrystals thereby elucidating the influence of milling parameters (solvent, temperature, time) 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. 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 investigations of milling reactions offer a new approach to tune and optimize mechanochemical processes.
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 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.
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.