Structural Insightsinto the Resveratrol-PiperazineCocrystal Forms Enabling the Cocrystallization Process Developmentfrom Solution

The aim of this study was to structurally characterize resveratrol-piperazine cocrystal forms using the single-crystal X-ray diffraction technique. Two resveratrol-piperazine cocrystals, designated solvent-free form (RP1) and tetrahydrofuran solvated form (RP2), were successfully synthesized with a solvent-based method. The crystal structure of the anhydrate cocrystal is similar to the non-disordered structure reported in the literature, but it exhibits a disordered piperazine molecule. Notably, this disorder leads to small variations in the unit cell parameters compared to the non-disordered structure, thus generating a distinct crystal structure as such. Nevertheless, this new, disordered structure identified in the single crystal is an intermediate form that readily transforms into the non-disordered structure upon mechanical processing. The non-disordered anhydrate is stable upon storage at elevated temperature and relative humidity, while the solvate is unstable under the same accelerated conditions and transforms into the anhydrate cocrystal. Additionally, the solvent molecules are not bonded in the solvated crystal structure and thus desolvation is readily achieved via slurry at elevated temperatures in an antisolvent. This desolvation behavior makes the solvated cocrystal a suitable intermediate for producing the more stable anhydrate cocrystal. To summarize, this study provides a comprehensive understanding of the resveratrol-piperazine cocrystallization process by revealing the detailed structural characteristics of the cocrystal forms. Furthermore, it provides a proof of concept for developing a solution cocrystallization process able to achieve resveratrol purification and simultaneously provide a cocrystal product with enhanced aqueous solubility.