Intensification of Processes for the Production of Active Pharmaceutical Ingredients: Increase in Safety and Sustainability

Fine chemical compounds and so-called "specialties" are generally synthesized through batch or semi-continuous processes. This is largely because such syntheses often involve complex and highly exothermic reactions, to be performed in semi-batch reactors for safety and/or selectivity reasons. An effective way to reduce costs and improve the reproducibility of such batch processes is to transform them into their continuous counterparts to reduce volumes and investment costs, while increasing the inherent safety of the process thanks to fewer hold-ups. The “shift to continuous” allows to reduce both the overall process times, with a general decrease in operating costs, and the content of solvents used as thermal flywheels, thanks to the greater efficiency of the heat exchange systems. All these aspects are defined as process intensification. In this work, the intensification of the production process of N-(4-nitro, 2-phenoxyphenyl) methanesulfonamide (NIM) by nitration in glacial acetic acid of N-(2-phenoxyphenyl) methanesulfonamide (FAM) will be proposed. Starting from the original semi-batch recipe two different continuous configurations will be proposed: a series of tubular reactors and a series of continuous reactors with complete mixing, in both cases with intermediate injections. The solvent content (glacial acetic acid) has been drastically reduced (from 82.5% to 50% by weight) to increase the levels of environmental sustainability of the synthesis. The high exothermicity of the process and the extremely rapid reaction kinetics were two fundamental aspects which had to be considered in the transition to the continuous process of the new formulation with reduced solvent content. For this reason, an ad hoc procedure was developed which allows the semi-batch recipe to be transformed into a corresponding one conducted in a tubular reactor with continuous lateral injections; this reactor was then discretized in the two reactor configurations mentioned above. The results obtained have shown how it is possible to obtain the desired product with practically unitary conversions using: a) a series of 4 isoperibolic tubular reactors, each with 4 discrete lateral feeds; b) a series of 5 mixed reactors with discrete side feeds. In both cases, the correct distribution of both the flow rate fed between the reactors in series and the temperatures of the cooling fluid (defined on the basis of the procedure developed for the passage of the process from discontinuous to continuous) was decisive for obtaining the desired performance. The series of tubular reactors was found to be optimal from the point of view of thermal control of the process, confirming that a series of tubular reactors is to be preferred in terms of safety compared to its counterpart with mixed reactors.