Polymorphism of the antiviral agent clevudine

Abstract

Polymorphism of the antiviral drug clevudine is addressed here for the first time. Three polymorphs were isolated and investigated in order to establish their structural relationships as well as their aqueous solubilities and thermodynamic stabilities. Forms 1, 2 and 3 crystallize in the monoclinic space group P2₁ with 4, 2 and 8 molecules per unit cell respectively. Extensive H-bonding occurs in all three crystals, leading to stacked layers in Forms 1 and 3, while Form 2 contains close-packed columns of clevudine molecules. A combination of hot stage microscopy, differential scanning calorimetry, variable-temperature PXRD and the observation of solvent-mediated transformations, enabled assignment of relevant phase transitions as well as the construction of a schematic energy-temperature diagram, which reflects enantiotropic relationships, with Form 2 as the stable form below ∼175 °C. Possible implications of the results in the context of further development and expected widespread use of this antiviral are discussed.