Continuous crystallization in tubular crystallizers is of particular interest to the pharmaceutical industry to accurately control average particle size, particle size distribution, and (polymorphic) shape. However, these types of crystallizers require fast nucleation, and thus, short induction times at the beginning of the flow process, which is challenging for larger and complex organic molecules. High shear and/or the presence of bubbles were identified to influence the nucleation behavior. This work investigates the effects of both high-shear mixing and ultrasound on the anti-solvent crystallization of paracetamol in acetone-water. Both devices generate intense amounts of shear and gas bubbles. Generally, the results show that increasing input power decreases the induction time significantly for both the rotor-stator mixer and ultrasound probe. However, the induction time is almost independent of the supersaturation for the ultrasound probe, while the induction time significantly increases with decreasing supersaturation for the rotor-stator mixer. In contrast, the particle size distribution for the rotor-stator mixer is independent of the supersaturation, while increasing supersaturation decreases the particle size for the ultrasound probe.
Ultrasound has proven to be an important tool for controlling nucleation in continuous tubular crystallizers. However, insufficient information is available about the parameters controlling the nucleation rate in a continuous ultrasonic process. Previous research has studied parameters related to the nucleation rate, but has not measured the nucleation rate directly or continuously. In this work, the nucleation rate is measured continuously and inline to solve this problem and achieve a better process understanding. The results indicate that the ultrasound-assisted nucleation process is presumably dominated by secondary nucleation. Additionally, the supersaturation, residence time and flow rate have a strong influence on the nucleation rate. On the other hand, the influence of the ultrasonic power is crucial but levels off once a certain amount of power is reached. The static pressure in the system determines the effective ultrasonic power and is therefore also important for the nucleation rate. Finally, maintaining an equal power per unit of volume and an equal residence time by increasing the tubing diameter seems to be a good scale-up method. These results will improve understanding of ultrasonic tubular crystallizers and how to control them.
Continuous tubular crystallizers have the potential to reduce manufacturing costs and increase product quality. However, designing tubular crystallizers is a complex and challenging task as crystallization is a complex, multiphase process with a propensity for fouling and clogging. While several designs have been proposed to overcome these issues, these designs are either unproven or poorly scalable and complex. In this work a continuous crystallizer is designed and evaluated to mitigate these issues. The tubular crystallizer combines a novel method to obtain a cubic cooling profile to control the supersaturation, ultrasound to induce nucleation and oscillatory flow to improve mixing and minimize fouling and sedimentation. The results show that the crystallizer was able to operate for more than 4 h without clogging, with high yields and a narrow particle size distribution. The design proposed here is therefore considered a viable approach for continuous crystallizers.
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