Inorganic salts of topiroxostat: metastable tautomeric form and improved pharmaceutical performance†

Abstract

Tautomerism is a phenomenon where a compound may exist in two or more interconvertible structural isomers (known as tautomers) that are generally different in terms of the relative position of one hydrogen atom. Tautomeric pharmaceuticals have more potential solid forms, thereby expanding the range of options for modulating their physicochemical properties in the solid state. All crystal structures of topiroxostat (TOP) polymorphs solved previously and in this contribution reveal that the TOP molecule monotonically exists in the 2H-tautomeric form. After salt formation with hydrochloric acid (TOP–HCl–H₂O) or sulfuric acid (TOP–H₂SO₄ form I and form II), the protonated 3H-tautomeric form was observed. Compared with TOP, all three salt forms demonstrated improved dissolution performance and TOP–HCl–H₂O also displayed satisfactory moisture stability. It is noteworthy that hydrochloric acid and sulfuric acid are the most commonly used salt formers for commercial pharmaceuticals. The proven safety of the counterions and improved pharmaceutical performance of TOP salts highlight their potential for further pharmaceutical applications.