Cocrystallization of Amantadine Hydrochloride with Resveratrol: The First Drug–Nutraceutical Cocrystal Displaying Synergistic Antiviral Activity

In order to highlight the advantages of the nutraceutical resveratrol (RVA) in perfecting the in vitro/in vivo properties of amantadine hydrochloride (ATHC), to realize advantageous complementarities between the two components and thus fill gaps in a drug–nutraceutical cocrystal with synergistically antiviral efficacy, a cocrystallization strategy of bidirectional coupling optimization has been developed. In this strategy, ATHC's advantage of high water solubility is used to enhance RVA's dissolubility and bioavailability, thereby activating its auxiliary antiviral effect, and meanwhile the excessive solubility of ATHC is properly reduced. The perfected antiviral activity of RVA, in return, contributes cooperativity with ATHC in antiviral efficacy, achieving a synergistic effect for the cocrystal. Using this strategy, the first antiviral drug–nutraceutical cocrystal, ATHC-RVA has been prepared and structurally characterized. The in vitro/in vivo property evaluations conducted both by theoretical and experimental methods reveal 152 and 9.64 times improvements, respectively, in the solubility and bioavailability of RVA, and the risk of toxic effects caused by the excessive solubility of ATHC is reduced through a slower release. Especially, the antiviral synergy of ATHC and RVA is significantly increased with CI < 1, exhibiting a potential to overcome drug resistance. All these benefits open a new pathway for the development of synergistic antiviral pharmaceutical cocrystals through cocrystallization techniques.