Effect of pH, temperature and native cyclodextrins on aqueous solubility of baricitinib

Baricitinib is a novel drug recommended in 2017 for the treatment of rheumatoid arthritis and other inflammatory diseases. The application of baricitinib can be restricted by its poor aqueous solubility. In this work, it was demonstrated that solubility of baricitinib is pH dependent. Baricitinib is very slightly soluble at pH 4-12 and freely soluble in the acidic and strongly alkaline media due to the ability to protonation and dissociation, respectively. Native cyclodextrins were used to improve the physicochemical properties of baricitinib. For the first time, host-guest complexes of baricitinib with alpha-, beta- and gamma-cyclodextrins were investigated by means of H-1 NMR, capillary electrophoresis and solubility methods. The stoichiometric composition and thermodynamic parameters of complex formation of baricitinib with cyclodextrins in the different buffers were obtained. Simultaneous determination of the binding constants of b-cyclodextrin with different ionized forms of BCN was performed by means of the capillary electrophoresis technique. The influence of cyclodextrin structure and ionization state of baricitinib on the inclusion complex formation was analyzed. The effect of cyclodextrins on solubility and membrane permeability of baricitinib was revealed. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

Baricitinib's solubility was found to be pH dependent, with slight solubility at pH 4-12 and better solubility in acidic and strongly alkaline media. The use of cyclodextrins improved the physicochemical properties of baricitinib, and the formation of host-guest complexes was studied. The influence of cyclodextrin structure and baricitinib's ionization state on complex formation and the impact of cyclodextrins on solubility and membrane permeability were analyzed.