Combining DoE and MASE: a winning strategy for the isolation of natural bioactive compounds from plant materials

The successes achieved in pursuing a nature-aided drug discovery (NADD) program are many and well-known, but it is still considered a second-order approach. Biomass extraction is a fundamental and critical step in the NADD process and often requires a high volume of usually organic and not eco-compatible solvents and a prolonged time. Optimization of such procedures could drastically decrease the costs required for the NADD process, also considering waste management. For this reason, many extraction techniques have been developed, among which one of the most diffused is microwave assisted solvent extraction (MASE). The MASE procedure is well suited for use in the drug discovery phase from natural sources. Still, there are several factors to consider, and the one-factor-at-a-time (OFAT) approach risks limiting the advantages the technique provides. The way to make it truly green is to couple MASE with DoE, even if this winning combination is limited. Consistently, we analyze the 10-year literature (2013-2022), reporting a critical discussion about DoE applied to set up MASE protocols for the extraction of metabolites (both performed with traditional solvents and with ionic and eutectic solvents) and essential oils. MASE is well suited for use in the nature-aided drug discovery, but the OFAT approach risks limiting the advantages offered by the technique. The way to make it truly green is to couple MASE with DoE, although this coupling is still limited.