Hesperidin from Citrus Processing By-Products: Integrated Strategies from Extraction to Downstream Separation

The extraction of functional organic compounds from natural products has become an important focus of current research. Citrus fruits are among the most widely produced fruits worldwide and have attracted increasing attention because of their pleasant flavor and rich content of bioactive compounds. Hesperidin, the focus of this review, is a representative flavonoid glycoside that is abundant in citrus fruits and their processing by-products. Owing to its unique molecular structure and physicochemical properties, hesperidin frequently coexists with structurally similar flavonoids. This similarity makes its separation and purification particularly challenging. Although many studies have reported different methods for the extraction and purification of hesperidin, most of them concentrate on individual techniques. Systematic analyses of how upstream extraction strategies affect downstream separation efficiency are still limited. In this review, separation strategies for hesperidin are systematically discussed, covering the entire process from extraction to downstream purification. The focus shifts from isolated separation methods to a strategy-oriented design. Special attention is given to how different extraction approaches influence matrix complexity, and, consequently, the difficulty of subsequent separation steps. Downstream separation technologies, including adsorption, liquid–liquid partitioning, crystallization, and chromatography, are compared from the perspectives of separation mechanisms and process integration. Based on a comparative analysis of crystallization, phase partitioning, membrane processing, adsorption, and chromatographic techniques, this review discusses the typical process roles of different separation strategies. Solubility-driven crystallization and membrane-based clarification are identified as more suitable for large-scale processing, whereas adsorption and chromatography are more appropriate as enrichment and polishing steps, respectively. In addition, key control points for green extraction–separation integration are identified, including solvent recyclability, matrix complexity control, and early-stage load reduction. This work aims to provide a practical reference for the sustainable and scalable separation of flavonoid glycosides from citrus by-products.