A key enabler for the future success of continuous manufacturing in pharmaceutical and fine chemical production processes is the control of product quality. Since approx. 90% of all small molecular active pharmaceutical ingredients produced involve a crystallization step, a holistic view on its process chain is crucial in order to ensure a defined particle size distribution, high purity, and specific polymorphic form. Different concepts for small-scale continuous crystallization are available, improving the product qualities in comparison to batch. Continuous solid–liquid separations, on the other hand, are rather scarce. Therefore, we designed and characterized an innovative continuous vacuum screw filter (CVSF) for solid–liquid separation, washing, and drying of suspensions in a small scale (up to 10 g of solid per minute). This contribution shows the general working principle of the CVSF as well as a systematic investigation of varying operating parameters on the particle size distribution (PSD), residual moisture, and residence time distribution of the solid phase. As a model system, l-alanine/water is used. The results show that the PSD can be entirely maintained while ensuring a narrow residence time distribution of the solid phase with axial dispersion numbers between 18.7 and 76.2. The residual moisture is for all experiments in a good range of 20–25%. Furthermore, it could be shown that the operability is possible over 8 h. Summarizing, the modular setup of the CVSF offers a maximized flexibility and thus rapid adaptability to changing market demands and product requirements.

Catalyst recycling is the key toward the sustainable application of homogeneously catalyzed reactions whereby integrated processes with selective product crystallization allow high selectivity under mild conditions and subsequent purification of the product without the need for any auxiliary. In this work, we develop and implement a five-step strategy toward selective product crystallization as a tool for recycling of a homogeneous catalyst using the example model reaction of methoxycarbonylation of methyl-10-undecenoate using commercially available catalyst and ligand. The strategy includes targeted investigations on the reaction regarding the stability and productivity of the catalyst but also on the crystallization, regarding catalyst leaching, product purity, and recovery, to finally develop an integrated process. Implementation of this target-oriented approach allows for increasing catalyst productivity to a cumulated turnover number ∑TON 4600 after five recycling runs and obtaining a recovery of isolated product of 82% with 98% purity of the desired linear diester.

A novel apparatus concept for integrated, small-scale continuous filtration, washing, and drying is presented. The continuous vacuum screw filter (CVSF) allows obtaining dried and free-flowing product particles from the continuously fed suspension. While the first study presented the CVSF concept in detail and focused on the characterization with respect to the product quality control and solid-phase residence time distribution (RTD S ) during sole filtration, the modular extension with washing modules and a vacuum-induced (pre-) drying setup is now presented here. For this purpose, a wash module was designed and implemented. The influence of single-stage and two-stage washing on the particle size distribution (PSD) and RTD S was investigated for the L-alanine/water model system. Single-stage washing increased the particle size of d 90,3 by 120 μm (+19%) due to a higher agglomeration degree, while using two-stage washing could completely preserve the particulate properties of the inlet suspension. To identify favorable operating conditions for efficient (pre-) drying, the effect of varying throughputs and mean residence times on the residual moisture of the product particles was quantified. High filling degrees (>30%) and increased mean residence times (>11 min), in combination with two-stage washing and efficient vacuum-induced airflow, ensured completely isolated, free-flowing, and almost dry particles with residual moistures of 1% and an entire maintenance of the PSD. Measurements of the RTD S showed a slight broadening due to the wash liquid used, still ensuring a narrow RTD S and thus almost plug-flow-like behavior. In summary, the CVSF offers unique features, such as its modularity and rapid start-up behavior, providing a promising concept for integrated continuous particle isolation from suspensions.

Selective product crystallization for separation and recycling of homogeneous catalysts represents one novel promising method to develop sustainable chemical processes. This specific application holds two main challenges: (1) In the crystallization and subsequent filtration and washing process, isolation of a pure crystalline product is required to obtain the maximum quantity of catalyst in the filtrate for recycling, and (2) the entire process must be operated in an inert atmosphere to maintain the catalytic activity of oxygen-sensitive species. Key to the isolation of a pure product is precise control of the crystallization process, which is realized in this work by gassing-induced nucleation using inert argon. Assuming that the nucleation step is crucial for the control of particle properties of the crystalline product and the related efficiency of downstream separation by filtration and washing, we systematically investigated the effect of controlled nucleation by gassing on these quantities using the oleo-chemical model system, 1,12-dimethyl dodecanedioate/methanol. The experimental results verify that by gassing with argon, the nucleation step can be initiated at lower supersaturation compared to uncontrolled cooling crystallization with spontaneous nucleation despite the comparably small metastable zone width of the investigated model system in the range of 1–3 K. It is further demonstrated that consequently less nuclei are formed that grow to larger product crystals, which can be more efficiently separated from the mother liquor in the filtration and washing step, reducing the mother liquor leaching to the isolated product to nearly 100 ppm. Finally, it is verified that gassing crystallization with argon offers a considerable benefit for the isolation of a pure crystalline product while maintaining inert operating conditions required for recycling of oxygen-sensitive catalysts.

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