engleski

Quantitative in situ monitoring of mechanochemical polymorph selectivity

Development of real-time and in situ techniques for monitoring of mechanochemical reactions based on synchrotron powder X-ray diffraction (PXRD)[1], Raman spectroscopy[2] and combinations of two[3] enabled unique insights into reaction paths and dynamics. However, quantitative reaction monitoring has been limited to PXRD only for systems that involve phases with known crystal structure. In this work, tandem approach enabled quantification of cocrystallization of benzoic acid (ba) and active pharmaceutical ingredient nicotinamide (na) in reaction that involves multiple phase transition and reaction pathways. Crystal structures of phases I and II of na:ba cocrystal were solved from PXRD data while structure of phase III and IV still remain unknown. With careful choice of liquids for liquid assisted grinding (LAG) polymorph selectivity is achieved. Volume, functionality and polarity of liquid direct the reaction pathway and mechanism also the final product. Higher volumes of primary alcohols stabilize phase III, while lower prefers phase I. Both final products form from intermediate phase II which is stabilized with methanol or water. Neat grinding yields phase I but with phase III as intermediate. The same reaction path is observed with various volumes of n hexane. With acetonitrile reaction path and final product differs depending on the volume used. Phase IV is observed only as fleeting intermediate before it transforms to phase II and liquids with hydrogen bonding capabilities seem to be crucial for its formation while hydroxyl moiety are necessary for stabilization of phase III.

in situ monitoring, mechanochemistry, mechanochemical reactivity, quantitative methods, kinetics, polymorph selectivity

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