Cocrystals of Favipiravir: Improved Physicochemical Properties and Solution Stability Study

Favipiravir (FPV) is used in the treatment of viral influenza, but it faces challenges due to its moderate solubility and poor tabletability. As an oral drug, it is necessary to develop a drug candidate that can improve its solubility and bioavailability. In addition, solution instability is one of the challenging issues of FPV cocrystals that should be noticed. On the premise of maintaining the solution stability, we aim to improve the solubility and tabletability through the preparation of FPV cocrystals to provide good alternative drugs. Herein, besides FPV-PHBA, we report the preparation and characterization of three new cocrystals of FPV with 3-hydroxybenzoic acid (FPV-3HBA, 1:1), 3,5-dihydroxybenzoic acid (FPV-3,5DHBA, 1:1), and also a cocrystal-hydrate with 3,4-dihydroxybenzoic acid (FPV-3,4DHBA-H2O, 1:1:1). All the cocrystals were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Hirshfeld surface (HS) analysis, and molecular electrostatic potential surface (MEPS) analysis. Furthermore, we evaluated the solubility, tabletability, hygroscopicity, and accelerated stability of the cocrystals and explored the relationship between their structure and properties. The cocrystals exhibited a 6-fold increase in solubility and improved tabletability while maintaining good stability under certain temperature and humidity conditions. The hygroscopicity of the FPV cocrystals slightly increased to 2%, which still meets the storage requirements. However, during the dissolution of FPV-3HBA or FPV-3,5DHBA cocrystals, high supersaturation levels led to the dissociation of these cocrystals, indicating poor solution stability, which may hinder the achievement of the desired bioavailability for FPV. To address this issue, we introduced polyvinylpyrrolidone (PVP), which significantly inhibited the dissociation of the cocrystals by interacting with their surfaces. Our research has presented promising FPV candidate drugs and thoroughly investigated the solution stability of the highly soluble FPV cocrystals.