Red betel leaves (Piper ornatum N.E.Br.) contain various secondary metabolites with potential antioxidant activity. This study aimed to determine the optimum maceration conditions for red betel leaf extraction using Response Surface Methodology (RSM) with a Box-Behnken Design (BBD). The investigated factors included ethanol concentration (50%, 70%, and 96%), maceration time (24, 48, and 96 hours), and material-to-solvent ratio (1:5, 1:10, and 1:15). Antioxidant activity was evaluated using the ABTS method and expressed as IC₅₀ values. Data analysis was performed using Design-Expert 13 through ANOVA and desirability function. The ABTS assay was conducted at 730 nm with an operating time of 30–32 minutes, and the quercetin calibration curve showed R² = 0.9968. Experimental IC₅₀ values ranged from 37.43 to 90.79 ppm. The quadratic model was adequate with R² = 0.9030 and insignificant Lack of Fit (p = 0.9654). Optimization produced the best conditions at 50% ethanol, 96-hour maceration, and a 1:15 ratio, with predicted IC₅₀ of 36.70 ppm and desirability value of 1.000. Phytochemical screening identified alkaloids, flavonoids, tannins, saponins, and triterpenoids, indicating very strong antioxidant potential.
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