Selection and Assessment of Bio‐Based Solvent in Biocatalysis: Application to Lipase‐Catalyzed Synthesis of Caffeic Acid Phenethyl Ester

Biocatalysis offers a sustainable alternative for chemical synthesis, but some enzymes, like lipases, still require conventional organic solvents, which are often flammable, toxic, and unsuitable for food or pharmaceutical applications. In this study, we present a systematic approach consisting of solvent selection, design of experiments optimization, and mass transfer analysis. As a case study, caffeic acid phenethyl ester (CAPE), a pharmacologically active compound derived from propolis, can be synthesized enzymatically. In this study, the Novozym 435-catalyzed esterification of caffeic acid and phenethyl alcohol was optimized using p-cymene, a bio-based solvent. To increase productivity, a system combining p-cymene as a solvent and dimethyl sulfoxide (DMSO) as a cosolvent was chosen. The optimal synthesis conditions were found to be 27 mM caffeic acid, 1460.5 mM phenethyl alcohol, and 73°C, achieving a 75.57% CAPE yield. Both external and internal mass transfer effects on the reaction rate were assessed. This study demonstrates the potential of using biocatalysts and green solvents for the sustainable synthesis of CAPE.