Unveiling propylene glycol as a green alternative solvent in reversed-phase HPLC: first report on the rapid assay of acetaminophen–caffeine tablets

Propylene glycol (PG), a generally recognized as safe ingredient widely used in pharmaceuticals, cosmetics, and food products, has not previously been investigated as a green solvent for high-performance liquid chromatography (HPLC). This study reports the first application of PG as an organic modifier in reversed-phase HPLC. A simple, eco-friendly, and efficient isocratic method was developed for the simultaneous determination of acetaminophen and caffeine in combination tablets, with effective separation of the impurity 4-aminophenol. Using a 10-cm C18 column and a mobile phase comprising 25 % (v/v) PG in water, adjusted to pH 4.0 with glacial acetic acid, at 50 °C and a flow rate of 2.0 mL/min, complete separation was achieved within 2 min under a backpressure below 200 bar and detection at 275 nm. The method was fully validated and provided results consistent with the United States Pharmacopeial method. Greenness evaluation using AGREE and GAPI tools confirmed superior environmental performance, with a BAGI score of 85.0, demonstrating high practicality. Owing to low volatility, flammability, and toxicity, along with water miscibility, UV transparency, biodegradability, and renewable sourcing, PG represents a green and sustainable alternative to conventional volatile HPLC solvents without compromising analytical performance or reliability.