Enhancing the Oral Bioavailability of an Antiviral Drug Acyclovir by Crystal Engineering of Novel Pharmaceutical Cocrystals

Acyclovir (ACV), a cornerstone in the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections, exhibits poor oral bioavailability (15–30%) owing to its low solubility and permeability. Administration of the drug in higher doses is required to achieve the required therapeutic efficacy; however, dose escalation may increase the risk of adverse side effects in patients. In this manuscript, pharmaceutical cocrystallization strategy is employed to enhance the physicochemical properties of the drug and its oral bioavailability. A robust hydrogen bond motif, carboxylic acid-aminopyrimidine, is utilized to facilitate the cocrystallization of acyclovir with carboxylic acid-bearing coformer molecules. Two cocrystals with gallic acid (ACVGAM, monohydrate & ACVGAD, dihydrate) and a cocrystal with gentisic acid (ACVGEN, partial hydrate) are identified and characterized by SCXRD, PXRD, DSC, TGA, HSM, IR, and NMR techniques. Crystal structure analysis reveals that gallic acid cocrystals are sustained by acid-amide heterosynthon while the gentisic acid cocrystal is stabilized by acid-aminopyrimidine heterosynthon besides having the hydroxyl-imidazole interactions. Cocrystals exhibit enhanced dissolution and solubility profiles of the drug in acidic, basic, and neutral media. PAMPA studies indicate that the cocrystals have a positive effect on permeability, resulting in 1.4- to 3-fold enhancements as compared to ACV. Pharmacokinetic studies in Sprague–Dawley rats demonstrate improved pharmacokinetic parameters for ACVGAM and ACVGEN cocrystals with achievement of ∼35% higher oral bioavailability (AUC) compared to ACV form. Moreover, the T max values for ACVGAM and ACVGEN are notably shorter (0.50 h), suggesting a faster onset of action compared with ACV (0.92 h). These results strongly support the superiority of cocrystals over the parent drug acyclovir highlighting their potential for improved therapeutic efficacy and may offer better treatment for HSV and VZV infections.