Cocrystals of Penciclovir with Hydroxybenzoic Acids: Synthesis, Crystal Structures, and Physicochemical Evaluation

Penciclovir, a potent and selective inhibitor of herpes viruses, cannot be formulated in oral preparations as it shows low oral bioavailability (5-10%) due to its poor solubility and/or poor permeability, thus greatly limiting its clinical application. To improve the solubility, five cocrystals of penciclovir with 3,5-dihydroxybenzoic acid (PCV/35DHBA), gallic acid (PCV/GA and PCV/GA center dot H2O), and 4-hydroxycinnamic acid (PCV/4HCA and PCV/4HCA center dot H2O) were successfully obtained via liquid-assisted grinding and/or slurry methods. The new cocrystal phases were fully characterized by spectroscopy, thermal analysis, and X-ray diffraction techniques, including the single crystal structure determination of PCV/35DHBA, PCV/GA center dot H2O, and PCV/4HCA center dot H2O. The dissolution studies demonstrated that the solubility and/or dissolution rates of PCV/35DHBA, PCV/GA, and PCV/GA center dot H2O were significantly improved, whereas that of PCV/4HCA and PCV/4HCA center dot H2O were remarkably reduced compared to the free drug. The DVS measurements and accelerated ICH condition tests confirmed that all cocrystals except PCV/4HCA center dot H2O were stable enough to endure standard processing steps. Therefore, PCV/35DHBA, PCV/GA, and PCV/GA center dot H2O have the potential to be developed as efficient oral formulations of PCV, as they exhibit significantly improved solubility with enough stability.