Polymorphism and stability of ibuprofen/nicotinamide cocrystal: The effect of the crystalline synthesis method

Abstract

The development over the past decade of design strategies for cocrystal preparation have led to numerous methods for the synthesis of cocrystal without take care of their influence on the precise structure and stability of cocrystalline states. On the other hand the mechanism of cocrystal formation remains widely unclear, especially the identification of the type of interactions mostly responsible for the cocrystalline stability. The present study focuses on the influence of the crystalline synthesis method on the polymorphism of cocrystals was analyzed from the preparation of S-ibuprofen/nicotinamide and RS-ibuprofen/nicotinamide cocrystals by co-milling, slow solvent evaporation and crystallization from the melt. X-ray diffraction and Raman spectroscopy experiments have shown that the polymorphic form of the cocrystals obtained by recrystallization from the melt (Form A) is different from that prepared by milling and by slow evaporation in solution (Form B). It was shown that both isothermal and non-isothermal recrystallizations from the melt blending are observed via a transient metastable micro/nano structure of form A. Additionally, it was observed that form A transforms into Form B upon heating via very weak changes in the hydrogen bond network. The crystallization in form A from the melt, instead of form B by other methods, was explained by the difficulty to form a supramolecular organization too far energetically from that existing in the melt. This study shows the crucial role of supramolecular H-bonding on the formation mechanism of cocrystals and how does the synthesis method of cocrystals change the supramolecular organization and the related structure of cocrystals.

Keywords: Cocrystals; H-bonds; Isothermal and non-isothermal crystallization; Low- and high-frequency Raman spectroscopy; Physical stability; Powder X-ray diffraction.