Synthon-driven polymorphism in the favipiravir–theophylline cocrystal

Abstract

Screening polymorphs in active pharmaceutical ingredients (APIs) and evaluating their stability aspects are crucial for selecting the desired crystalline form that exhibits optimal solid-state properties. In this study, we report and discuss the elusive nature of the second form (form II) of the favipiravir–theophylline cocrystal. This form was obtained only once and never appeared again despite extensive crystallisation efforts. In contrast, the previously identified form I has consistently emerged under a wide range of crystallisation experiments. This observation prompted us to investigate the underlying structural, thermal and energetic characteristics of the system. Single-crystal X-ray diffraction revealed distinct structural differences between the two forms; form I exhibits a homosynthon, whereas form II contains a heterosynthon between favipiravir and theophylline. Variations in synthons impart distinct crystal packing arrangements to each form. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to assess thermal behaviour and phase transitions. The results indicate that form I is the thermodynamically stable polymorph, while form II represents the kinetic polymorph. Furthermore, lattice energy calculations and Hirshfeld surface analysis confirm the greater stability of form I. Despite the favourable synthon energy associated with the heterosynthon in form II, form I is favoured due to its overall higher lattice stabilisation energy. Additionally, packing efficiency and crystal density calculations showed that form I has a higher packing index, which contributes to its enhanced stability over form II. This study highlights the intricate kinetic-thermodynamic balance governing polymorphic landscapes and provides valuable insights into the phenomenon of disappearing polymorphs in the favipiravir–theophylline cocrystal.