Abstract
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.
Highlights
Crystallization of active pharmaceutical ingredients (API) is an important unit operation for the pharmaceutical industry that impacts downstream processes and the bioavailability of the API
The results indicate that the ultrasound-assisted nucleation process is presumably dominated by secondary nucleation
The particle size remains constant over time, which indicates that the crystals exiting the nucleator all had the same residence time and that there is no hold up, as this would cause a size increase in the particles exiting the nucleator
Summary
Crystallization of active pharmaceutical ingredients (API) is an important unit operation for the pharmaceutical industry that impacts downstream processes and the bioavailability of the API. Crystallization research has been focusing on the transition from batch to continuous processing in order to reduce production costs and improve product quality. Within this transition, an important goal control over the particle size distribution during the crystallization without the need for subsequent milling operations to reduce the crystal size. Controlling the nucleation stage is crucial for the final particle size distribution. While continuous seeding is an interesting alternative for continuous nucleators, the usage of seeds results in particles larger than the seeds, which limits particle size control [5]
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