Process intensification in flow chemistry using micro and millidevices: Numerical simulations of the syntheses of three different intermediate API compounds for diabetes mellitus drug production

Abstract

Microreactor Technology (MRT) appears as an interesting alternative for process intensification, including the development of continuous synthesis of fine chemicals and Active Pharmaceutical Ingredients (API). The inherent proposal of MRT is to reduce the scale-up time by simply increasing the number of microreactors in parallel, the numbering-up concept using optimal designed micro or millidevices. Among the API, rosiglitazone and lobeglitazone are derivatives of thiazolidine-2,4-dione (TZD), which is used as a building block, for molecules with biological activity, sensitive to insulin and, thus, with its administration the body makes better use of the insulin it produces, being an important structural element in medicinal chemistry, especially for type 2 diabetes mellitus, one of the biggest concerns in the health area worldwide, affecting nowadays more than 180 million people. The numerical assessment of MRT for various API synthesis related to type 2 diabetes mellitus drugs indicates its comparable or superior performance compared to traditional batch process. Specifically, proposed micromixer designs facilitate successful scale-up to milliscale while maintaining microscale performance, with significantly lower pressure drops than commercial Asia microreactors. The proposed flow distributors offer good performance in ensuring uniform distribution across outlets due to their conical shape design and laminar flow regime, with low pressure drops. The flow distributor with eights outlet is preferred for higher flow rates due to its superior performance, minimizing the pressure drops. Efficient flow rate and molar concentration control at each reactor unit can be ensured by using one distributor for each reactant's feed stream. This approach guarantees accurate concentration, flow rate control and ideal residence time, ultimately facilitating higher total throughput for scale-up. The potential use of micromixer actuators lies in its ability to maintain or enhance performance while transitioning from micro to milli-scale, offering promising alternatives for process intensification and scale-up in pharmaceutical synthesis, particularly for medications targeting type 2 diabetes mellitus.