Abstract

The growing emphasis on sustainable natural product development has sparked interest in green extraction methods that are both efficient and environmentally friendly. This review explores how Design of Experiments (DOE), particularly when applied through Design Expert® software, plays a central role in optimizing phytochemical extraction. By comparing various techniques—such as microwave-assisted, ultrasound-assisted, enzyme-assisted, and supercritical fluid extraction—the review highlights how DOE improves yield, reduces solvent use, and shortens extraction time. Case studies show that methods like central composite and Box–Behnken designs can enhance extraction efficiency by up to 500 % while maintaining compound integrity. Beyond optimization, the review emphasizes the integration of risk assessment tools (e.g., HACCP, FMEA) into DOE workflows, supporting consistency and regulatory compliance under Quality by Design (QbD) principles. It also introduces green and white analytical chemistry metrics (AGREE, GAPI, etc.) to evaluate environmental impact and method performance. Altogether, this article provides practical insights into how DOE-driven strategies can support low-emission, scalable, and regulation-ready herbal extraction within the broader shift toward Pharmacy 4.0 and climate-conscious bioprocessing.