Continuous Monophasic Production of Pharmaceutical-Grade 5‑Hydroxymethylfurfural from Sugar Syrup

A continuous-flow, monophasic catalytic process for the direct production of 5-hydroxymethylfurfural (5-HMF) from sugarcane syrup was developed using a microreactor platform to enable sustainable, pharmaceutical-compatible manufacturing. In contrast to conventional mineral-acid or biphasic systems, green citric acid was employed as a sustainable catalytic alternative. Low-toxicity solventsdeionized water, acetone, n-propanol, and isopropanolwere systematically evaluated to balance reaction performance and downstream compatibility. The results were benchmarked against a conventional solvent system. Key process parameters, including reaction temperature, residence time, catalyst loading, organic-to-aqueous (O:A) ratio, initial syrup concentration, and salt addition, were investigated and optimized using response surface methodology. Under the optimized conditions (15 wt % citric acid, 170 °C, O:A ratio of 0.25:1, and a residence time of 80 min), a maximum 5-HMF selectivity of 43.9% was achieved in a monophasic acetone-based system. A simplified downstream strategy combining sequential selective adsorption with solvent evaporation enabled purification of 5-HMF to 99% purity without complex extraction or biphasic separation steps. Compared with related systems, superior production and purification performance was observed. By combining green catalysis, continuous microreactor processing, direct syrup utilization, and simplified downstream purification, the proposed strategy offers a promising pathway to pharmaceutical-grade 5-HMF production, with reduced separation complexity and enhanced process intensification.