Ultrasonic‐assisted phytochemical extraction using hydrophobic natural deep eutectic solvents: from solvation energy prediction to process optimization

Abstract BACKGROUND Green solvents provide sustainable alternatives to conventional organic solvents, reducing environmental and health hazards. This study investigates ultrasound‐assisted extraction of phytochemicals from Aegle marmelos leaves using the hydrophobic natural deep eutectic solvent AD12 (acetic acid:n‐decanoic acid, 1:2). Parameter optimization, solvent recovery, and reusability are explored in this study. RESULTS Process intensification using response surface methodology identified optimal ultrasonic‐assisted extraction conditions: 400 rpm, 8 min pulsed ultrasonication (13 W), and 10 mL/g solvent‐to‐feed. Under these optimized conditions, the total extractive yield reached 42.90 ± 4.4 mg/g, while the total alkaloid and phenolic contents were 0.75 ± 0.14 and 1.27 ± 0.15 mg/g, respectively. Alkaloids were best recovered under mild conditions (13 W, 5 min, 14 mL/g), whereas phenolics required higher power (130 W, 5 min, 10 mL/g) for best recovery. Solvent recovery was optimized using a three‐stage pulsed ultrasonic protocol (10 min per stage, 130 W) with a 20 mL/mL deionized water‐to‐filtrate ratio, recovering 83.5 ± 0.02% decanoic acid and 31.25 ± 2.45 mg/g total extractive yield. AD12 retained >95% efficiency over five reuse cycles, confirming stability and recyclability. Further, extraction efficiency of three phytochemicals—aegeline, rutin, and marmelosin—showed a clear dependence on solute–solvent interactions in AD12 and ethanol. Alchemical free‐energy perturbation calculations of solvation free energies closely matched HPLC‐measured extractability, confirming AD12's superior capacity for aegeline and rutin, while ethanol favored marmelosin. This highlights the predictive value of solvent‐based computational modeling for targeted phytochemical extraction. CONCLUSION Hydrophobic natural deep eutectic solvent AD12 enables selective, efficient, and reusable phytochemical extraction. Solvent‐based prediction coupled with ultrasonic‐assisted process intensification provides a rational approach for optimized recovery and scalable bioprocess design. © 2025 Society of Chemical Industry (SCI).