A continuously operated tubular crystallizer system with an inner diameter of 2.0 mm has been successfully operated. It allows the crystallization of active pharmaceutical ingredients (APIs) under controlled conditions. Acetylsalicylic acid (ASA) which was crystallized from ethanol (EtOH) was used as the model substance. An ethanolic suspension of ASA-seeds was fed into the tubular crystallizer system, where it was mixed with a slightly undersaturated ASA-EtOH solution that was kept at an elevated temperature in its storage vessel. Supersaturation was created via cooling and the seeds grew to form the product crystals. This work mainly focuses on the proof-of-concept and on the impact of the flow rates on the product crystals and the crystal size distribution (CSD). All other parameters including concentrations, temperatures, and loading of seeds were kept constant. Higher flow velocities generally resulted in reduced number and volume mean diameters, due to reduced tendency of agglomeration and decreased time for crystal growth due to shorter residence times of the suspension in the tube. Generally, all experiments unmistakably led to shifting of volume density distributions toward significantly larger values for product crystals in comparison to the seeds and were capable of yielding product masses in a g/min scale.

A continuous tubular crystallizer system with an inner diameter of 2.0 mm and an overall length of 27 m was used to generate acetylsalicylic acid seeds in situ from ethanolic solution via cooling and ultrasound irradiation and to grow the crystals in the tubing with a controlled temperature trajectory. In order to minimize the residence time distribution, air bubbles were introduced into the system to generate a segmented gas-slurry flow. The narrow residence time distribution and the tight temperature control in the small tubing due to the large surface to volume ratio resulted in relatively narrow crystal size distributions of the product. Generally, all experiments clearly demonstrated significant crystal growth for the product crystals in comparison to the seeds and yielded product masses on the g/min scale. Furthermore, it was demonstrated that the size of the product can be easily controlled via fines removal by dissolution due to rapid heating and varying the mass of seeds per mL of solution.

This study investigates the effects of seed loading on the mean crystal size of the model substance, acetylsalicylic acid, crystallized from ethanol in a continuously seeded tubular crystallizer. A hot, highly concentrated ethanolic acetylsalicylic acid solution was mixed with an acetylsalicylic acid-ethanol seed suspension. Subsequent cooling of the slurry in the tubing promoted supersaturation and hence crystal growth. The tubular shape of the 15 m-long crystallizer with an inner diameter of 2 mm enabled narrow residence time distributions of the crystals in the pipe and excellent temperature control in the radial direction and along the tubing. Crystals entering the crystallizer had both identical growth conditions in each section and about the same time for crystal growth. Narrow crystal size distributions were achieved with decreasing differences in the volume-mean-diameter sizes of the seed and product crystals as seed loadings increased. Decreasing the seed size had a similar effect as increasing the seed loading, since in that case the same amount of seed mass resulted in more individual seed particles. Altering the arrangement of the coiled crystallizer with respect to spatial directions (horizontal, vertical) did not lead to a significantly different outcome. All experiments produced considerably larger product crystals in comparison to the seeds despite relatively short crystallization times of less than 3 min. Moreover, product mass gains of a few hundred percent at a g/min-scale were achieved. Similarities in product crystal samples taken at different times at the outlet of the crystallizer showed that steady-state conditions were rapidly reached in the continuous flow crystallization device.

Development of 3D printed stainless steel reactors for the oxidation of Grignard reagents in continuous flow.