The use of ultrasound in the crystallization process of an active pharmaceutical ingredient

Abstract

In this research, ultrasound was used in the crystallization process as an alternative to conventional spontaneous crystallization and seeding crystallization. The study was implemented on an active pharmaceutical ingredient ticagrelor, where the influence of ultrasound on its physical properties was evaluated. Process parameters of spontaneous crystallization, seeding crystallization and ultrasound-assisted crystallization were extensively studied while the pros and cons of each were adequately exposed. Compared to spontaneous crystallization and seeding crystallization ultrasound-assisted crystallization has significantly improved fundamental crystallization parameters: nucleation, the growth of crystals and filtration time. At the same time, the tendency of particles to agglomerate was reduced, which lead to the avoidance of energy and time-consuming process of final product deagglomeration, often problematic in conventional crystallization. In addition, different physical properties of ticagrelor were reached and evaluated, for instance, morphology, particle size distribution and different polymorphic forms. Polymorphic forms I, II and III were efficiently produced in a repeatable, robust and optimal way. Ultrasound-assisted crystallization was proved to have a beneficial effect on the crystallization process of API, even on the industrial scale, and can successfully replace spontaneous crystallization and seeding crystallization.

Keywords: Active pharmaceutical ingredient; Crystallization; Physical properties; Ticagrelor; Ultrasound.