Supramolecular engineering of an azelaic acid-nicotinamide cocrystal for dual anti-inflammatory and brightening efficacy.

An [AzA][Nic] cocrystal was engineered through supramolecular synthon design between azelaic acid ([AzA]) and nicotinamide ([Nic]) to overcome intrinsic [AzA] bioavailability limitations. Single-crystal X-ray analysis and DFT calculations revealed that the N1⋯O4-H4 hydrogen bond and electrostatic complementarity drive molecular reorganization into a distinctive cocrystal architecture. This supramolecular restructuring induces critical conformational shifts of [Nic] and [AzA], leading to a 9.6-fold enhancement in the aqueous solubility of [AzA] (from 2.4 to 23 mg mL-1) and a reduced HOMO-LUMO gap to 8.159 eV (vs. 9.926 eV for [AzA]) with stronger electron-donating/accepting capabilities and multiple active sites, which facilitates the bioactivity and bioavailability of [AzA]. Computational docking demonstrated the cocrystal's superior PPARγ binding (ΔGbinding = -153.5 kJ mol-1) and stable complex formation (evidenced by reduced Rg and SASA), mechanistically explaining its ability to suppress pro-inflammatory cytokines (TNF-α/IL-8/PGE-2) and reduce melanin levels in vitro. Clinical validation of 3 wt% essence confirmed significant human skin brightening (increase in L/ITA°, p < 0.01) and depigmentation (decrease in M, p < 0.05). This work establishes cocrystallization as a transformative supramolecular strategy for optimizing dermatological activities by utilizing synergistic structure-bioactivity relationships.