The aim of this study was to improve rivaroxaban water-solubility by cocrystal preparation and to understand this process. The screening with water-soluble coformers was performed via both mechanochemical and solution-mediated techniques. Two cocrystals of rivaroxaban with malonic acid and oxalic acid were prepared, and the structure of the cocrystal with oxalic acid was solved. Both cocrystals exhibit improved dissolution properties. The mechanism of the supersaturation maintenance was studied by in-situ Raman spectroscopy. The transformation into rivaroxaban dihydrate was identified as the critical step in the improved dissolution properties of both cocrystals. Moreover, the transformation kinetics and solubilization effects of the coformers were identified as responsible for the differences in the dissolution behavior of the cocrystals. In-vivo experiments proved that the use of cocrystal instead of form I of free API helped to increase the bioavailability ofrivaroxaban.

Department of Analytical Chemistry Faculty of Science Charles University Prague Czech Republic

Department of Chemical Engineering University of Chemistry and Technology Technická 3 166 28 Prague 6 Dejvice Czech Republic

Department of Chemical Engineering University of Chemistry and Technology Technická 3 166 28 Prague 6 Dejvice Czech Republic; Department of Structure Analysis Institute of Physics of the Czech Academy of Sciences Na Slovance 1999 2 182 00 Praha 8 Czech Republic

Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Zentiva k s U Kabelovny 130 10237 Prague 10 Czech Republic

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Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes

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