engleski

Quantitative in situ monitoring of mechanochemical selectivity in pharmaceutical cocrystal polymorphs

Recent advancement in real-time and in situ monitoring of mechanochemical reactions based on the powder X-ray diffraction (PXRD) [1], Raman spectroscopy [2] and combination of two [3] revealed astonishing complexity of milling reactions, involving crystalline and amorphous intermediates and multi-step reaction mechanism. However, in situ quantitative reaction monitoring has been limited only to synchrotron PXRD for systems were crystal structures of all participating phases were known preventing kinetic analysis for systems with phases of unknown crystal structures. In this work, quantitative tandem in situ monitoring via PXRD and Raman spectroscopy of mechanochemical cocrystallization of active pharmaceutical ingredient nicotinamide (na) and benzoic acid (ba) revealed curious dynamical behaviour involving four new cocrystal phases, multiple phase transformations and reaction pathways. Crystal structures of phase I and II of na:ba cocrystal were solved from PXRD data, while crystal structure of phase III and IV still remain unknown. Neat grinding reaction initially yielded III which then transformed into I. With liquid assisted grinding (LAG), reaction pathways depended on the type, amount and functionality of the liquid used. Higher amounts of water and primary alcohols stabilized III, while their lesser amounts stabilized I. In all cases III or I were preceded by II. Higher volumes of alcohols initially formed IV which rapidly transformed to II. Using different volumes of hexane the same reaction pathway was observed as in neat grinding, but in the case of addition of small volume of acetonitrile I formed directly from reactants. With higher volumes of acetonitrile I was preceded with IV and II. For formation of IV liquids with hydrogen bonding capabilities are necessary while hydroxyl moiety seem crucial for stabilization of III.

in situ ; mechanochemistry ; quantitative analysis ; selectivity ; pharmaceutical cocrystals

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