Urea Cocrystals for Sustainable Agriculture: Linking Supramolecular Design with Rhizosphere Function and Nutrient Use Efficiency

Abstract Urea, containing 46% nitrogen by weight, remains the most widely used nitrogen-based fertilizer in the world. However, 40 to 70% of the applied urea nitrogen is lost through ammonia volatilization, nitrate leaching, and nitrous oxide emissions. Enhanced efficiency fertilizers, such as polymer-coated urea and nano urea, improve nutrient release and use efficiency, but their effects on soil rhizosphere remain comparatively less studied. Urea-based cocrystals represent a supramolecular crystal engineering approach for next-generation fertilizer design. This review examines crystallographic, physicochemical, and biological factors that establish structure−property−function relationship along with coformer selection and its effect on agronomic performance. Lattice energy, synthon geometry, and crystal packing influence dissolution rate, hygroscopicity, and thermal stability of cocrystals. The R22(8) amide-acid heterosynthon commonly acts as a primary motif, and coformer characteristics influence nitrogen release. Cocrystal dissolution may also deliver bioactive coformers to the rhizosphere at controlled concentrations, potentially influencing microbial communities. Ionic cocrystals, such as CaSO4.4urea and urea.ZnCl2.KCl (ZnKU) may provide multinutrient benefits within a single crystalline lattice. Overall, urea cocrystals represent a promising platform for regulating nutrient release, reducing nitrogen losses, and delivering essential micronutrients along with rhizosphere interactions. This review identifies key research gaps, a roadmap for integrating artificial intelligence (AI)-based coformer discovery, scale-up, and field validation for commercial deployment.