The origin of delayed polymorphism in molecular crystals under mechanochemical conditions

Abstract

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

Controlling polymorphism in molecular cocrystals by variable temperature ball milling

“…Atoms are coloured as: carbon (grey), oxygen (red) and nitrogen (blue). Please do not adjust margins Please do not adjust margins Following from our previous work, 13 we investigate here whether mechanochemically driven polymorphism can be controlled through changes in the equilibrium milling temperature. A 1:1 cocrystal of isonicotinamide (INA) and glutaric acid (GLU) was selected as a model system, Figure 1, which has one known polymorphic form (Form I) 27 that can be obtained by liquid assisted grinding (LAG).…”

“…For a polymorphic transformation to occur, a given crystal form must be driven over an energy barrier. This can be done for example by introducing defects into the crystal structure 13 or by increasing the equilibrium system temperature. To indirectly assess the effects of material activation (defect formation) on the polymorphism of INA:GLU, we explored neat grinding with one stainless steel ball (10 mm, 4.04 ± 0.02 g) at three milling frequencies (input energies), namely 50 Hz, 35 Hz, and 20 Hz (Figure 3a).…”

“…6 Many factors can influence the outcome of a mechanochemical transformation, including the material of the milling jar, 8,9 the presence of additives (liquid or solid), 7,10 and the type or intensity of mechanical treatment. [11][12][13][14] While reaction temperature has been routinely applied to control solution chemistry, its use as a control parameter for mechanochemical transformations remains less common, [15][16][17][18][19][20] and poorly understood. Early evidence suggests that equilibrium milling temperatures can be used in combination with milling intensity to enhance mechanochemical reactivity and increase reaction yields.…”

The mechanochemical excitation of crystalline LiN3

“…3 TRIS X-ray powder diffraction has been widely used to follow the formation and consumption of crystalline phases as a function of milling time, [4][5][6][7] and it has recently provided insights into the role of structural defects in activating mechanochemical transformations. 8,9 By using TRIS X-ray absorption spectroscopy 10 and optical fluorescence spectroscopy 11 changes in the electronic structure of matter can be followed during mechanochemical transformations. Additionally, vibrational [12][13][14][15][16] and NMR spectroscopies 17 provide insight into the evolution of molecular structure during milling.…”

“…By using TRIS thermometry, various authors have shown that over the course of a mechanochemical reaction, milling jars rarely exceed a few degrees. 9,19 Such findings have questioned the role of temperature as an underlying driving force in mechanochemical transformations.…”