Recent Advances in Sample Preparation and Analytical Detection of Sulfonamide Residues in Milk: A Critical Review

Abstract

Sulfonamides (SAs) are a class of synthetic broad-spectrum antibiotics commonly used to treat bacterial infections in dairy cattle. Improper use can lead to drug residues being excreted into milk, posing a serious threat to public health. Current efforts in veterinary drug residue detection are directed toward rapid, efficient, and multi-residue methods. This critical review systematically evaluates sample pretreatment and analytical detection techniques for sulfonamide residues in milk. PubMed, Web of Science, CNKI, and Wanfang databases were searched up to May 2025. After screening, 55 studies were included. The advantages and disadvantages of different methods are compared: chromatographic methods (HPLC and LC-MS/MS) offer high sensitivity (detection limits 0.05-0.10 μg/kg) and structural confirmation, but require expensive instrumentation and time‑consuming pretreatment (>60 min/sample). Biosensors and surface-enhanced Raman spectroscopy (SERS) respond quickly (<10 min) and are suitable for on-site testing, yet they suffer from lower stability, limited multiplexing capacity, and matrix‑induced false positives. Major limitations of current methods include matrix effects, emulsification rates above 25% in liquid-liquid extraction, poor quantification ability of immunoassays (RSD >15%), and detection limits above 10 μg/kg for most rapid tests. In practice, conventional chromatography remains the gold standard for confirmatory analysis, while biosensors and immunoassays serve as complementary tools for large-scale or field screening. Future research should focus on improving matrix robustness, multiplex detection capability, and portability of emerging technologies.