Cocrystallization of amantadine hydrochloride with nutrient: Insights into directed self- assembly and optimized biopharmaceutical character by integrating theory and experiment

Abstract

In order to make full use of the advantages of phenolic acid nutraceutical p-coumaric acid (COA) in cocrystallizing with antiviral medication amantadine hydrochloride (ADH), further get innovative insights into assembling ADH-nutraceutical cocrystal and optimizing biopharmaceutical characters of ADH by combining experiment with theory, a novel cocrystal, ADH-COA, is prepared and structurally characterized. Single-crystal X-ray diffraction confirms that the cocrystal consists of COA and ADH molecules in a 1:2 ratio, building a three-dimensional supramolecular network strengthened by charge-assisted hydrogen bonds and tightly packed patterns, which is distinguished by two distinct conformations H-1 and H-2 arising from neutral COA molecules with different counter-ions of ADH within the lattice. These features endow the cocrystal with promoting charge dispersion and polarity reduction, resulting in 37.11 ∼ 41.39 % solubility reduction under different pH conditions versus raw ADH, contributing to mitigating side effects associated with excessive solubility of ADH. Such change of in vitro property, in turn, optimizes in vivo pharmacokinetics, showcasing the lengthened half-life and enhanced 1.45-fold bioavailability. Emphatically, these experimental findings are corroborated by DFT-based theoretical models, demonstrating some positive correlations between macroscopic properties and microstructures of the cocrystal. Thereby, the dual-optimization of in vivo/vitro properties of ADH allows to be fulfilled through the cocrystallization-driven strategy.