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

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 candidate solvents for API purification via continuous liquid–liquid extraction. Original results indicate attractively small computed reactor volumes and considerable heating requirements for the given plant capacity. Chloroform emerges as a potent separation solvent in comparison to other candidate solvents, allowing the highest material efficiency (environmental factor of 3.43, total cost savings of 49.5%), but its high toxicity prohibits use for continuous manufacturing. Methylcyclohexane is the next strongest candidate separation solvent (environmental factor of 31.06, total cost savings of 37.3%) whose chemical properties render it significantly more acceptable for CPM implementation. The present study exhibits the potential for technological innovation via facilitating the transition from batch to continuous production methods in the pharmaceutical industry.