The aim of this work was to develop a simple, green and low-consumption method for the extraction of ganoderic acids. An in situ effervescence reaction-assisted mechanochemical extraction method was proposed, and the effects of independent variations in terms of sodium bicarbonate concentration, milling time, and liquid/solid ratio (mL/g) were investigated by means of a response surface methodology (RSM) Box-Behnken design (BBD). The highest yields of ganoderic acids were achieved by grinding a Ganoderma lucidum sample with sodium bicarbonate (372.60 mg/g) and citric acid for 0.87 min with a water to material ratio of 10.58 mL. The linear calibration ranges were from 0.01–5 μg/mL for the six analytes and had good linearity with a correlation coefficient of determination higher than 0.9991. In addition, the obtained LODs of the six target analytes were 1.46 − 2.97 ng/mL, and the LOQs calculated as ten times the signal-to-noise ratio were 4.88 − 9.90 ng/mL. The proposed method was successfully applied to the Ganoderma lucidum samples.
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