Penciclovir-FumaricAcid (2:1) Cocrystal: CrystalStructure, Hirshfeld Surface Analysis, and Release Behavior

Abstract Penciclovir (PCV), a nucleoside antiviral drug, exhibits extremely low oral bioavailability (<5%), which makes it difficult to achieve effective plasma concentrations. To address this limitation, a novel pharmaceutical cocrystal of PCV with fumaric acid (FA) was successfully prepared via a suspension method. The newly formed crystalline phase was identified and characterized by X-ray diffraction, DSC, and FT-IR spectroscopy. Molecular electrostatic potential calculations and Hirshfeld surface analysis were further employed to investigate the hydrogen-bonding assembly motifs and intermolecular interactions within the cocrystal. In vitro release experiments show that the PCV-FA cocrystal exhibited a slower and more sustained release behavior of PCV under both pH 1.2 and pH 7.4 media compared with the parent drug. In addition, accelerated stability studies revealed that no significant crystal phase transformation occurred after storage at 40 °C/75% RH for 3 months, indicating good solid-state stability. This work demonstrates that cocrystallization with fumaric acid successfully modulates the dissolution behavior of PCV through the formation of a robust hydrogen-bonding network. The structural analysis provides new insights into the structure–property relationships of antiviral drug cocrystals, offering a valuable reference for crystal engineering studies.