A five-year dive in the realm of crystal engineering with water-soluble vitamins in addressing biopharmaceutical bottlenecks.

Crystal engineering through co-crystallisation offers a robust strategy for modulating the physicochemical properties and bioavailability of poorly soluble active pharmaceutical ingredients. A thoughtful selection of GRAS status co-formers is critical, as their molecular interactions govern the stability and solubility behaviour of the resulting solid-state architecture. Recently, the integration of nutraceuticals as co-formers has emerged as a promising, safe, and cost-effective approach within crystal engineering. Factors such as the type of functional group for hydrogen bonding, pKa, physicochemical compatibility, solubility, and molecular size need to be considered during co-crystal formation. This review provides a comprehensive summarisation of co-crystals synthesised using nicotinic acid, nicotinamide and ascorbic acid as primary co-formers with supportive case studies in the past five years. Comparative evaluation demonstrated that nicotinamide possesses remarkable versatility and co-crystallisation potential, yielding the highest number of successfully characterised co-crystal systems among the studied vitamins, owing to its favourable ΔpKa characteristics, amide functional group-mediated hydrogen-bonding capability, structural adaptability, and strong supramolecular synthon-forming tendency. Despite advances, research gaps persist, including limited data on their stability, scale-up challenges, and extensive in vivo performance of these co-crystals. Future perspectives emphasise the need for harmonised regulatory frameworks to facilitate the clinical translation and industrial adoption of these advanced nutraceutical crystalline forms.