Cocrystals of Two Co-Occurring Plant Metabolites: Purification with Synergistic Potentiation and Bioavailability- A Tale of Two Case Studies

Abstract

Abhijit G. Banerjee

This study reviews advances in the design and application of co-crystals derived from plant metabolites as enhanced antimalarial agents. Co-crystallization, involving the combination of a bioactive plant-derived compound (e.g., quinoline derivatives, artemisinin) with a suitable co-former such as hydroxy aromatic acids or other bioactive molecules, has been shown to improve solubility, stability, bioavailability, and therapeutic potency without altering the active pharmaceutical ingredient’s chemical identity. Examples include aminoquinoline–hydroxybenzoic acid co- crystals, which display lower IC50 values against chloroquine-resistant Plasmodium falciparum, and artemisinin-based co-crystals that achieve 21–26-fold increases in solubility and enhanced in vivo efficacy. Synergistic formulations, such as artemisinin with flavonoid-rich extracts, exploit complementary mechanisms of action to increase parasite inhibition and potentially delay resistance. Novel systems, including 11-aza-artemisinin co-crystals, show improved solubility and preclinical promise. Additionally, alkaloid–anthraquinone co-crystals, exemplified by the rhein–matrine system, demonstrate up to 50-fold improved dissolution and higher oral bioavailability through hydrogen bonding and supramolecular organization. These multi-mechanistic hybrids enhance pharmacokinetic profiles, tablet ability, and stability, broadening the pharmaceutical potential of plant-derived compounds. Collectively, plant metabolite-based co- crystals represent a valuable strategy for overcoming solubility-limited bioactivity, improving antimalarial efficacy, and addressing drug resistance challenges.

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