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Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, we designed and built an automated two-stage mixed suspension mixed product removal (MSMPR) crystallization platform for a model compound (carbamazepine, CBZ) that exhibits multiple polymorphs. The crystallization process includes the integration of PAT tools (online Raman microscopy and focused beam reflectance microscopy, FBRM) for real-time monitoring. A series of case studies were done to evaluate the performance of the continuous system and PAT tools. Specifically, the drawing schemes, slurry transport, and variations on process variables are considered as the three key risk areas for continuous crystallization process development. Our proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program coded in LabVIEW, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM). To the best of our knowledge, this is also the first study on continuous crystallization of carbamazepine for form III and its polymorphic transition (between form II and form III).

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Covalent coupling of Ru(II) light absorbers to a Rh(III) electron collecting site through polyazine bridging ligands affords photocatalytic production of H(2) in the presence of visible light and a sacrificial electron donor. A robust photocatalytic system displaying a high turnover of the photocatalyst has been developed using the photoinitiated electron collector [{(bpy)(2)Ru(dpp)}(2)RhBr(2)](5+) (bpy=2,2'-bipyridine; dpp=2,3-bis(2-pyridyl)pyrazine) and N,N-dimethylaniline in DMF/H(2)O. Studies have shown that increased [DMA], the headspace volume, and the use of DMF solvent improves the systems performance and stability providing mechanistic insight into the deactivation routes of the photocatalytic system. Photolysis of the system at 460 nm generates 20 mL of H(2) in 19.5 h with a maximum Φ=0.023 based on H(2) produced and an overall Φ=0.014 and 280 turnovers of the photocatalyst. The photocatalytic system also displays long-term photostability with 30 mL of H(2) generated and 420 turnovers in 50 h under the same conditions. Prolonged photolysis provides 820 mol H(2) per mole of catalyst.