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Continuous processing gains importance in the fine chemical and pharmaceutical industries where crystallization is an important downstream operation. Seeded cooling crystallization of the L-alanine/water system was investigated under similar conditions, i.e., temperature interval, cooling rate, and seed material, both in a stirred batch vessel and in a continuous plug flow crystallizer in the coiled flow inverter (CFI) design with horizontal helical tube coils (ID = 4 mm) and frequent 90°bends of the coils. Short-cut calculations based on characteristic time scales and the Damkoḧler number allow for comparing the batch and continuous crystallization processes. The experimental results reveal crystal growth and growth rate dispersion to be dominating on the product crystal size distribution (CSD). However, at low flow rates of approximately 31 g min −1 , a moving sediment flow of the slurry was present in the CFI crystallizer, resulting in further size dispersion effects. Elevated flow rates of approximately 40 g min −1 resulted in a more homogeneous suspension flow and a product CSD comparable to batch quality. Simulation studies based on a population balance equation model strengthen the hypothesis of the solid phase residence time distribution (RTD S ) to be more spread in the moving sediment flow regime, leading to a wider product CSD.

Continuous manufacturing of fine chemical, life science, and pharmaceutical products is under recent investigation in R&D. As cooling crystallization is an important unit operation for purification of products, continuously operated, scalable devices are required for process development on lab-scale. A tubular crystallizer was developed, based on the coiled flow inverter design. Experimental characterization proved a narrow residence time distribution of the liquid phase close to ideal plug flow. Counter-current air cooling allows for adjusting linear and curved temperature profiles. Unseeded operation with the L-alanine (water) system demonstrated that nucleation has to be actively controlled to successfully apply intensified continuous cooling crystallization processes.

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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.

The reproducibility of product properties of normal batch cooling crystallizations is often insufficient. For a reliable design of product properties like the median diameter, it is essential to control the nucleation process. An innovative technology to induce nucleation during cooling crystallization is gassing. Therefore, quantification of the influence of gassing and process parameters is important. For this purpose, Design of Experiment approaches were used, investigating a linear cooling profile with constant cooling duration and quadratic cooling profiles with varied cooling duration. Succinic acid/water was used as the model system. The supersaturation where gassing is started was identified as most important design parameter using linear cooling profiles. Using quadratic cooling profiles, the median diameter can be mainly designed by adjusting the cooling duration. By the choice of the cooling profile and gassing supersaturation, it is possible to control the median diameter in a range between 300 and 750 μm. The results show also that independent from the cooling profile, gassing crystallization has an enlarging effect on the median diameter of product crystals. This effect can be used to reduce batch time for crystallization processes.

The quality of crystalline products, defined by e.g. purity or crystal size distribution (CSD), is primarily dominated by crystallization conditions but influenced by further downstream processes like solid-liquid separation and drying also. Through uncontrolled agglomeration within the crystallization process chain the purity or CSD can be negatively affected. Therefore, in context of process optimization, missing knowledge of the impacts on the final product can lead to product batches out of specification. To increase the understanding of agglomeration and to provide insight into the relevance of holistic process optimization the agglomeration behavior of L-alanine crystals is exemplarily quantified over the crystalline process chain. For the quantification the agglomeration degree (Ag) and the agglomeration degree distribution (AgD) are determined. The results show that the product quality achieved after crystallization is significantly affected by agglomeration during drying. Especially if washing after solid-liquid separation is omitted, a broadening of the CSD is observed. Moreover, the evaluation by the AgD indicates that the final product can be -despite similar characteristics of the CSD -highly different. Consequently, it can be concluded that the characterization of the product quality by the CSD alone is insufficient and the quantification of agglomeration is essential for process optimization.