<i>In situ</i> investigation of controlled polymorphism in mechanochemistry at elevated temperature†

Mechanochemistry routinely provides solid forms (polymorphs) that are difficult to obtain by conventional solution-based methods, making it an exciting tool for crystal engineering. However, we are far from identifying the full scope of mechanochemical strategies available to access new and potentially useful solid forms. Using the model organic cocrystal system of nicotinamide (NA) and pimelic acid (PA), we demonstrate with variable temperature ball milling that ball milling seemingly decreases the temperature needed to induce polymorph conversion. Whereas Form I of the NA:PA cocrystal transforms into Form II at 90 °C under equilibrium conditions, the same transition occurs as low as 65 °C during ball milling: a ca 25 °C reduction of the transition temperature. Our results indicate that mechanical energy provides a powerful control parameter to access new solid forms under more readily accessible conditions. We expect this ‘thermo-mechanical’ approach for driving polymorphic transformations to become an important tool for polymorph screening and manufacturing

The origin of delayed polymorphism in molecular crystals under mechanochemical conditions

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 polymorphis

Unintended Rate Enhancement in Mechanochemical Kinetics by Using Poly(methyl methacrylate) Jars

Time-resolved in situ (TRIS) X-ray diffraction has changed how mechanochemical transformations are studied but requires the use of X-ray transparent jars often made from poly(methyl methacrylate) (PMMA). However, using PMMA jars can alter the apparent kinetics of mechanochemical polymorphism by an order of magnitude, questioning the interpretability of established TRIS methods. Our results suggest that rate enhancement in PMMA jars may not be dominated by chemical effects of the polymer, but rather a result of different equilibrium temperatures within the jar. These features must be better understood before control over mechanochemical reactions can be achieved

The origin of delayed polymorphism in molecular crystals under mechanochemical conditions

We show that mechanochemically driven polymorphic transformations can require extremely long induction periods, which can be tuned from hours to days by changing ball milling energy. The robust design and interpretation of ball milling experiments must account for this unexpected kinetics that arises from energetic phenomena unique to the solid state. Detailed thermal analysis, combined with DFT simulations, indicates that these marked induction periods are associated with processes of mechanical activation. Correspondingly, we show that the pre-activation of reagents can also lead to marked changes in the length of induction periods. Our findings demonstrate a new dimension for exerting control over polymorphic transformations in organic crystals. We expect mechanical activation to have a much broader implication across organic solid-state mechanochemistry

A Comparative Study of the Ionic Cocrystals NaX(α-d-Glucose)2_2 (X = Cl, Br, I)

The mechanochemical formation of the ionic cocrystals of glucose (Glc) and sodium salts Glc2NaCl·H2O (1) and Glc2NaX (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 Glc2NaCl·H2O (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