Theoretical Feedback Control Scheme for the Ultrasound-Assisted Continuous Antisolvent Crystallization of Aspirin in a Tubular Crystallizer

Abstract

Ultrasound-assisted crystallization is a promising process for the production of crystals within a size distribution width. Toward the direction of attaining high-quality crystals, this article proposes and assesses a theoretical feedback control scheme that can be applied in a continuous tubular crystallizer. In this crystallizer, the antisolvent crystallization of aspirin (a pharmaceutical ingredient) in water (an antisolvent) and ethanol (a solvent) takes place under ultrasound. Initially, a dynamic model is developed and includes the aspirin concentration variations while also taking into account temperature modifications in the inlet. After model validation, a PI control scheme is finely tuned, implemented theoretically, and critically assessed at the (i) trajectory control of the crystal length (average size), (ii) alleviation of suddenly emerged disturbances (e.g., solvent flow rate, inlet temperature), and (iii) a combination of worst-case operating scenarios. As identified, the proposed controller can offer a practical platform that can be readily applied to different scales and geometries in continuous tubular crystallizers operating with ultrasound. During all simulations, the produced crystals maintained high quality.

Ultrasound-assisted continuous crystallization of metastable polymorphic pharmaceutical in a slug-flow tubular crystallizer

“…In recent years, ultrasound-assisted technology has been widely used in the pharmaceutical industry [19] , [20] . Savvopoulos et al [21] proposed and evaluated a theoretical feedback control scheme for ultrasound-assisted aspirin continuous anti-solvent crystallization in a tubular crystallizer. They determined that ultrasound-assisted crystallization was an effective method for preparing crystals with size distribution width [22] , [23] , [24] .…”