Leflunomide, an immunosuppressive disease-Modifying antirheumatic drug, is sparingly soluble in aqueous solutions. The aim of this work was to propose the suitable excipients for the enhancement of aqueous solubility of leflunomide. The ability of different cyclodextrins, biopolymers and (hydroxypropyl-(beta-cyclodextrin + biopolymer) mixtures to improve the leflunomide solubility due to complex formation was examined by phase solubility and spectroscopy methods. It was found that (beta-cyclodextrin and its hydroxypropylated and methylated derivatives form stable 1:1 complexes with leflunomide and considerably increase the drug solubility. Influence of cyclodextrin structure on the thermodynamics of binding with leflunomide was analyzed. In comparison with cyclodextrins, solubilizing effect of polymers such as polyvinylpyrrolidone (PVP K16-18 and K29-32), polyethylene glycol (PEG 1000) and hydroxypropylmethylcellulose was considerably lower. Among polymers under consideration only PVP K29-32 displays a noticeable solubilizing efficiency due to its ability to complex formation with leflunomide through hydrogen bonding. It was demonstrated that formation of the ternary complexes cyclodextrin/leflunomide/polymer does not occur and synergetic effect of cyclodextrins and polymers is rather weak. (C) 2016 Elsevier B.V. All rights reserved.