Continuous Crystallization Using Ultrasound Assisted Nucleation, Cubic Cooling Profiles and Oscillatory Flow

Arne Vancleef,Leen C J Thomassen,Leen Braeken,Ward De Beuckeleer,Tom Van Gerven

doi:10.3390/pr9122268

Abstract

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.

Highlights

Crystallization is an important unit operation in the pharmaceutical industry that determines downstream processes and the bioavailability of the pharmaceutical ingredient in the human body
Tubular crystallizers are continuous crystallizers that are of interest because of their narrow residence time distributions, small working volumes and excellent heat transfer, allowing conditions that favor small particle sizes and narrow particle size distributions [1,2]
Tubular crystallizers have shown to allow control over the particle size [3,4,5] and they accommodate a large range of obtainable crystal sizes [6]

Summary

Introduction

Crystallization is an important unit operation in the pharmaceutical industry that determines downstream processes and the bioavailability of the pharmaceutical ingredient in the human body. The sonicated tubular crystallizer made by Kreimer et al could work for 2 h with ultrasound compared to 30 min without ultrasound, by optimizing the conditions they managed to increase the operating time to 5 h Another promising solution is a slug flow with two liquid phases as shown by Rossi et al and Nagasawa and Mae as it prevents contact between the wall and the crystals, experiments proving this are still lacking [11,12,13]. Liquid-gas slug flows have shown promising results [14], it is still unclear under which conditions these crystallizers can omit fouling and for how long as crystals still come in contact with the wall All these solutions introduce new problems in the form of complexity and scalability

Methods

Discussion

Conclusion