Abstract
In this study, an AM-based continuous processing reactor system was designed, manufactured, and assembled on a laboratory scale for the generation of pharmaceutical substances with an improved process control. The developed AM-based (additively manufactured) continuous pharmaceutical reactor system for the synthesis of metronidazole derivatives aimed to optimize both the physical and the chemical processes with time savings. Using AM, we were able to build reactor subcomponents with complex designs and precise dimensions, which facilitated the precise control of the reaction parameters and reduced the amount of chemicals required compared to macroscale reactors. The assembly of the whole reactor system consisted of main reactor bodies, mixers, valves, heat exchangers, electrical motors, and a microcontroller system. The assembled reactor system revealed a continuous flow of reagents and ensured uniform mixing and reaction conditions, thereby increasing the process efficiency and product quality. Five metronidazole derivatives were synthesized via two continuous processes, involving metronidazole reduction and its subsequent reactions with terephthalic aldehyde and anthracen-9(10H)-one to form Schiff bases. The optimal conditions were determined as follows: compound A (72% yield, 120 min, 55 °C), compounds B and C (63% and 68% yield, respectively, 8 h, 65 °C), and compounds D and E (74% and 85% yield, respectively, 8 h, 45 °C).