Supercritical CO2 extraction of artemisinin from Artemisia annua plant and the biotechnological production of artemisinin precursors: A dual-focus review

Artemisinin, a vital compound renowned for its potent antimalarial properties, has garnered significant attention due to its therapeutic importance and critical role in combating malaria. The extraction process is essential in recovering artemisinin from Artemisia annua L. plant. Supercritical carbon dioxide (scCO₂) extraction has emerged as a highly effective and eco-friendly technique, offering improved efficiency, selectivity, and greener processing than conventional solvent-based methods. Despite this advancement, plant-derived artemisinin faces challenges in meeting global demand due to naturally low yields, seasonal variation, and agricultural limitations. Biotechnological advances have enabled the microbial production of artemisinin precursors, such as artemisinic acid and amorphadiene, which can be chemically or enzymatically converted into artemisinin, providing a scalable and sustainable production route. Despite the significance of both approaches, existing literature often treats them in isolation. Therefore, this work provides a comprehensive review, integrating scCO₂ extraction technologies with microbial-based fermentation strategies for producing artemisinin and its precursors. Key parameters influencing scCO₂ extraction efficiency, such as CO₂ flow rate, temperature, co-solvent use, and pressure, are analyzed alongside fermentation bioprocess factors such as strain selection, pH, dissolved oxygen levels, carbon sources, and fermentation modes. By evaluating these complementary strategies, this review provides a holistic perspective aimed at improving artemisinin production yield, for accessibility and sustainability, ensuring a reliable global supply. It concludes by highlighting current challenges and proposing future directions necessary for optimizing the integrated production pipeline of artemisinin and its precursors.