Application of Ball Milling for Highly Selective Mechanochemical Polymorph Transformations

Abstract

Milling is an important secondary processing technique in the manufacture of pharmaceuticals, primarily used as a particle size reduction process. Para-, meta-and ortho-aminobenzoic acid (PABA, MABA, OABA) and carbamazepine (CBZ) are pharmaceutically relevant compounds that can exist in different polymorphic forms with distinct packing motifs and thus different physicochemical properties. A comprehensive study of the effect of milling on the polymorphism of PABA, MABA, OABA and CBZ was carried out. Milling PABA in the presence of catalytic amounts of valeric acid or methanol yielded the -polymorph which is otherwise difficult to obtain in bulk quantities. Milling also proved to be a more convenient method for producing MABA form IV compared to previously reported procedures. Principal component analysis of the pair distribution function transformed X-ray powder diffraction spectra of ball-milled CBZ samples showed that the milling-induced polymorphic transformation strongly depends on the ball-to-powder ratio. Elusive CBZ form IV could be obtained in pure form by optimizing the milling conditions.

Heterogeneous Esterification from α-Hydroxy Ketone and Alcohols through a Tandem Oxidation Process over a Hydrotalcite-Supported Bimetallic Catalyst

“…These methods all need suitable solvents in the procedures, while a process employing mechanochemistry for preparation of solid catalysts provides merits including simplicity, swiftness, and solventless conditions. 27,28 In particular, mechanochemical energy generated from ballmilling (BM) is able to provide new chemical composition or chemical reactivity on as-synthesized catalysts. 29−32 More importantly, various defects in the as-synthesized catalyst are generated by the centrifugal force and friction during milling, which further significantly promotes its catalytic performance.…”

“…Heterogeneous catalysis based on solid catalysts is a significant process in organic transformations because of the ease of catalyst handling and recyclability of the catalysts. − The preparation of solid catalysts, such as frequently used supported catalysts, generally employs wet impregnation and coprecipitation. These methods all need suitable solvents in the procedures, while a process employing mechanochemistry for preparation of solid catalysts provides merits including simplicity, swiftness, and solventless conditions. , In particular, mechanochemical energy generated from ball-milling (BM) is able to provide new chemical composition or chemical reactivity on as-synthesized catalysts. − More importantly, various defects in the as-synthesized catalyst are generated by the centrifugal force and friction during milling, which further significantly promotes its catalytic performance.…”

Ball size or ball mass – what matters in organic mechanochemical synthesis?

“…Ball-milling of solid mixtures has proved to be an efficient approach to the synthesis of organic and coordination compounds, ranging from multi-component crystals to polypeptides. [1][2][3][4][5][6][7][8][9][10] In particular, it is becoming increasingly important for obtaining pharmaceutical solids. Mechanochemical methods are attractive as environmentally benign techniques, and often permit rapid and high yield transformations.…”

Tuning the Apparent Stability of Polymorphic Cocrystals through Mechanochemistry

“…At present, many factors are now known to influence mechanochemical polymorphism, including the addition of liquid additives, 34,47 seeds, 48 polymer additives, 49 milling temperature, 50 and ballto-powder ratio. 51 However, many important parameters, including milling jar and ball material, remain largely unexplored. Furthermore, although it is now well-known that ball milling parameters can affect polymorphic outcomes, the stability of mechanochemically produced solid forms remains underexplored.…”