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This work investigates the application of static mixers (SMs) in precipitating environments as present in certain pharmaceutical processes, in which the undesired side effect of precipitation of the residual dissolved fraction leads to equipment fouling and process stability challenges. The tests were conducted using saturated suspensions mixed with an anti-solvent to challenge the system with a step change of solubility in the presence of seeds and SMs. Various equipment configurations such as co-axial vs perpendicular mixing, different equipment dimensions, plastic vs metal SM, or ultrasound (US) irradiation were investigated, and fouling probability and stability were analyzed for different precipitation rates by monitoring the pressure level. The process stability was highly influenced by the setup configuration. The most stable and satisfactory process was achieved by co-axial mixing of the fluids before the SM plus using US irradiation. With this setup a run time of 5 h was achieved, continuous processing beyond 5 h could be realized by parallel arrangement of SMs, in which the process is switched from one SM to another after a pressure threshold is triggered. Furthermore, the particle size in various feed and outlet suspensions was analyzed, and correlations between the amount of suspended particles and the particle growth were determined. The highest initial solids in the feed suspension (30 wt%) resulted in the smallest growth of the particles in the outlet suspension (d 50 increased by 17.7%) after anti-solvent addition.

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Continuous manufacturing of pharmaceuticals offers such benefits as production flexibility, reduced drug product costs, and improved product quality. Moving toward continuous manufacturing requires suitable small-scale equipment, either by development of new equipment or optimization of existing equipment. In primary manufacturing, particle properties are often altered during crystallization and have to be restored during subsequent processing. Drying a crystallized product is one of the most challenging steps, especially since attrition and agglomeration can occur. To that end, we investigated the drying behavior of a crystalline model compound with moisture levels of up to 10 wt % in a corotating twin-screw extruder. The feed mass flows on a piece of small-scale equipment used for pharmaceutical production varied between 0.5 and 2.0 kg/h. Experiments were conducted to evaluate the drying performance in various process settings. Because of a very narrow and consistent residence time distribution, extrusion drying has the potential for pharmaceutical compound drying. In our study, we successfully accomplished drying of a crystalline product with very little agglomeration and/or attrition in some process settings while preserving a crystal size similar to that of the raw material. The reduction in particle size occurred as a result of long residence times (low extruder screw speed) and a decrease in the residual moisture of the product. The aim of our work was to show the potential of extruder drying as a novel continuous manufacturing process for pharmaceuticals and to enable further process development.