Process Modeling, Simulation, and Technoeconomic Evaluation of Separation Solvents for the Continuous Pharmaceutical Manufacturing (CPM) of Diphenhydramine

Abstract

Continuous Pharmaceutical Manufacturing (CPM) has been shown to provide significant process benefits, including cost savings and increased material efficiencies, over the currently implemented batch paradigm which very frequently implies poor heat transfer and mixing and high volumes of waste. The continuous flow synthesis of diphenhydramine, a first-generation antihistamine, has been demonstrated at the laboratory scale, featuring in-line synthesis and purification in both a carrier solvent and in a neat mixture. The present paper illustrates the development of a process model for the continuous upstream processing of diphenhydramine in order to demonstrate the feasibility and viability of continuous manufacturing. The model features the design of plug flow microreactors for the continuous flow synthesis of 100 kg per annum of diphenhydramine (the option of solventless/neat reactions has also been considered explicitly in all stages of our process analysis), heating requirements, and the comparison of ca...