An innovative approach for the recovery of nobiletin, hesperidin, and other phytochemicals from tangerine leaves (Citrus reticulata) by-products using a solvent mixture based on natural compounds.

Citrus reticulata leaves, rich in phytochemicals, are underutilized by-products with sustainable valorization potential under Green Chemistry principles. This study developed an eco-friendly solvent combining thymol (Thy), oxalic acid (OA), and ethanol (EtOH) to extract nobiletin and hesperidin guided by COSMO-RS and high-intensity ultrasound (HIUS). The optimum solvent composition (0.9 % oxalic acid, 24.1 % thymol and 75 % EtOH) achieved higher yields of nobiletin (0.38 mg mL-1), hesperidin (0.74 mg mL-1) than pure EtOH (0.30 mg mL-1 of nobiletin and 0.64 mg mL-1 of hesperidin). HPLC-DAD-MS/MS and GC-MS analyses revealed that the optimized extract had a more complex phytochemical profile with a richer composition than the EtOH extract. Furthermore, optimized Thy-OA-EtOH extract exhibited superior bioactivity, with enhanced antioxidant capacity and neuroprotective effects (IC50: 334.40 mg mL-1) compared to HIUS-EtOH (IC50: 1482.20 mg mL-1). This study highlights the potential of natural compound mixtures with HIUS for extracting phytochemicals from citrus leaves for food and pharmaceutical applications.