Preparation of rivaroxaban nanocrystals and in vitro - in vivo assays

The aim of this thesis is to solve the dose-proportionality problem encountered in high doses as a result of low solubility of rivaroxaban (RXB) which is a direct factor Xa inhibitor and a Biopharmaceutical Classification System Class II drug. To increase the solubility of RXB, its nanocrystal formulations were prepared and their physicochemical characterizations were examined. Pluronic F 127 and Pharmacoat 603 were used as the stabilizers to prepare nanosuspensions with a combination of ultra turrax, ball mill and high pressure homogenization methods. With nanocrystal technology, the particle size is reduced, the in vitro dissolution and permeability coefficient is increased. The presence of crystal structure and the chemical structure of RXB have been found to be preserved. The nanosuspension formulation with the best particle size distribution, in vitro dissolution profile and permeability results was applied by oral gavage to rabbits at doses of 3 mg / kg, 10 mg / kg and 15 mg / kg. Plasma RXB levels were determined by LC / MS / MS method. The area under the curve and the maximum plasma concentration parameters were evaluated in terms of dose proportionality. The results obtained from simple linear regression, analysis of variance and equivalence criterion methods showed that dose proportionality between 3 mg-15 mg and 10 mg -15 mg doses were achieved.