Mechanochemistry offers a unique opportunity to modify and manipulate crystal forms, often providing new products as compared with conventional solution methods. While promising, there is little known about how to...

Mechanochemistry has become a valuable method for the synthesis of new materials and molecules, with a particular strength for screening and preparing multicomponent crystals. In this work, two novel cocrystals of pyrazinamide (PZA) with pimelic acid (PA) were prepared mechanochemically. Their formation was monitored in real time by in situ synchrotron powder X-ray diffraction. Control over the polymorphic form was obtained through the selective choice of liquid additive via liquid assisted grinding. Slurry experiments and dispersion-corrected density functional theory calculations suggest that Form I is the thermodynamically stable form under ambient conditions. Upon aging, Form II converts to Form I. The stability of Form II upon aging was found to depend strongly on the milling duration, intensity, and material of the milling vessels. Longer or higher energy milling drastically increased the lifetime of the Form II product. For the first time, this work also demonstrates that the choice of milling jar can have a decisive effect on the aging stability of a bulk polymorphic powder. In contrast to material prepared in steel milling vessels, the preparation of Form II in Perspex (PMMA) vessels increased its lifetime 3-fold. These findings offer a new dimension to garnering control over mechanochemical cocrystallization and demonstrate the critical importance of the careful and timely ex situ screening of ball mill grinding reactions. This will be of importance for potential industrial applications of mechanochemical cocrystallization where understanding polymorph longevity is crucial for the development of a robust preparative protocol.

Control over ball milling transformations is needed before the transformative potential of mechanochemical processing can be realized. Many parameters are known to affect the outcome of mechanochemical polymorphism, yet the energy of ball milling is itself often overlooked. We here demonstrate how milling energy can exert significant influence over the polymorphic outcome of ball mill grinding and be used to control the overall reaction profile. Milling energy exerts its effect on the reaction profile by changing the rate at which structural defects form in crystalline phases. These defects destabilize a crystal to drive the system step-by-step towards polymorphic transformation. Our results demonstrate decisively that careful design and interpretation of ball milling experiments are necessary to obtain control over mechanochemical polymorphism

The mechanochemical formation of the ionic cocrystals of glucose (Glc) and sodium salts Glc 2 NaCl•H 2 O (1) and Glc 2 NaX (X = Br (2), I (3)) is presented. Products are formed by co-milling Glc with three sodium salts (NaCl, NaBr, NaI). The ionic cocrystals were obtained under both neat grinding and liquid-assisted grinding conditions, the later found to accelerate the reaction kinetics. The crystal structures of the ionic cocrystals ( 2) and (3) were solved from powder X-ray diffraction data. The structure solution contrasts with the structure of Glc 2 NaCl•H 2 O (1) where the electron density at three halide crystallographic sites is modeled as of being the intermediate between water molecule and a chloride ion. The reaction pathways of the three ionic cocrystals were investigated in real time using our tandem approach comprising a combination of in situ synchrotron powder X-ray diffraction and Raman spectroscopy. The results indicate the rapid formation of each cocrystal directly from their respective starting materials without any intermediate moiety formation. The products were further characterized by DTA-TG and elemental analysis.