Traditional pharmaceutical manufacturing is based on a complex supply chain that is vulnerable to spikes in demand and interruptions. Continuous pharmaceutical production in compact modules is a potential solution that allows for drug manufacturing when and where it is needed with significantly shorter lead times. As part of the Pharmacy on Demand (PoD) initiative, we demonstrate the potential for end-to-end manufacturing of multiple drug substances in reconfigurable devices, under common industrial constraints, and within a challenging manufacturing time frame. A new set of refrigerator-sized modules was constructed for the synthesis, isolation, and formulation of several drugs, with focus on achieving high manufacturing throughputs, and allowing for the production of pharmaceutical tablets. Their operation is demonstrated with the synthesis and formulation of USP-compliant tablets of diazepam, diphenhydramine hydrochloride, and ciprofloxacin hydrochloride, as well as liquid formulations of lidocaine hydrochloride and atropine sulfate.

We present a 3D metal printing showerhead mixer to blend effectively two reagent streams into a confined mixing volume. Each stream is pre-distributed to multiple channels to increase the contact area in the mixing zone, which enables high mixing performance with smaller pressure drop. The showerhead mixer shows excellent mixing performance owing to its ability to intersperse rapidly the two streams as characterized by the diazo coupling reactions and CFD simulations. Experimental results demonstrate superior performance of the showerhead mixer compared to two common commercial micro T-mixers, especially in low Reynolds number regime. CFD results are employed to i) help understand the mixing mechanism, ii) reproduce the experimental observations, and iii) inform the design specifications for optimal performance. Good agreement between experiments and simulations is achieved. The final design includes multiple sidefed inlets for improved mixing performance of the showerhead mixer, as suggested by the validated CFD models.

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The crystallization of the two polymorphs of l-glutamic acid (LGA) is carried out in a continuous crystallization process, and its performance according to different criteria is evaluated. The study aims at identifying suitable operating conditions for producing either αLGA or βLGA with a high polymorphic purity. To this end, we investigate the process both from a theoretical perspective and through experiments using either a single stirred-tank crystallizer or a cascade of two stirred-tank crystallizers in series. In terms of theory, we extend the MSMPR-based steady-state stability analysis of Farmer et al. (AIChE J.20166235053514) by accounting for the possibility of a nonrepresentative withdrawal of the solid phase from the crystallizer. Additionally, the process is simulated using population balance equations, thereby investigating the effect of operating conditions on polymorphic purity, yield, and productivity. Guided by the model-based conclusions, we identified suitable operating conditions and experimentally tested them. The experimental campaign has demonstrated that βLGA could be successfully and continuously produced in both process configurations according to the theory with performance as expected, whereas that was not possible for αLGA. The difference between the two stems from different operational challenges, whose consequence is that steady-state operation is attained in the case of βLGA but not in that of αLGA. In the former case, the needle-like βLGA crystals, which exhibit no agglomeration, tend to be only slightly oversampled; in the latter case, the prismatic αLGA crystals undergo major agglomeration and hence are very difficult to suspend and effectively withdraw from the crystallizer.

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