In this study, a flexible optimization approach is introduced to design an optimal biocompatible solvent for an extractive fermentation process with cell-recycling. The optimal process/solvent design problem is formulated as a mixed-integer nonlinear programming model in which performance requirements of the compounds are reflected in the objectives and the constraints. A flexible or fuzzy optimization approach is applied to soften the rigid requirement for maximization of the production rate, extraction efficiency and to consider the solvent utilization rate as the softened inequality constraint to the process/solvent design problem. Such a trade-off problem is then converted to the goal attainment problem, which is described as the constrained mixed-integer nonlinear programming (MINLP) problem. Mixed-integer hybrid differential evolution with multiplier updating method is introduced to solve the constrained MINLP problem. The adaptive penalty updating scheme is more efficient to achieve a global design
