Advanced Sample Preparation Techniques for Multi-Residue Analysis in Food and Health Research

The simultaneous determination of multiple organic compounds in complex food and biological matrices is increasingly essential for ensuring food safety, understanding bioactive nutrient dynamics, and assessing chronic exposure to contaminants. This review provides a comprehensive evaluation of modern sample preparation strategies, including Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS); Solid-Phase Extraction (SPE); Dispersive Solid-Phase Extraction (d-SPE); Solid-Phase Microextraction (SPME); and Liquid–Liquid Extraction (LLE), for their applicability in extracting diverse classes of organic compounds ranging from pesticides, mycotoxins, to phytochemicals and environmental residues. Each technique was assessed for recovery efficiency, selectivity, matrix effect minimization, and integration with Gas Chromatography–Tandem Mass Spectrometry (GC-MS/MS) and Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS), which are widely applied in food safety, environmental, and biomedical monitoring. Comparative analysis highlights that QuEChERS-based approaches offer rapid, solvent-saving workflows suitable for fruits, vegetables, and grain-based samples, whereas SPE and SPME exhibit superior performance in trace-level analysis of biofluids and lipid-rich matrices. The review further emphasizes the critical role of tailored sample preparation in improving data reliability and supporting downstream applications in dietary exposure assessment, functional food development, and food-medicine homology research. These findings reinforce the need for robust, matrix-adaptable, and automation-compatible preparation protocols to advance the analytical precision in food as medicine studies and contribute to public health strategies based on nutritional therapeutics.