Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients

Abstract

A continuously operated tubular crystallizer system with an inner diameter of 2.0 mm has been successfully operated. It allows the crystallization of active pharmaceutical ingredients (APIs) under controlled conditions. Acetylsalicylic acid (ASA) which was crystallized from ethanol (EtOH) was used as the model substance. An ethanolic suspension of ASA-seeds was fed into the tubular crystallizer system, where it was mixed with a slightly undersaturated ASA-EtOH solution that was kept at an elevated temperature in its storage vessel. Supersaturation was created via cooling and the seeds grew to form the product crystals. This work mainly focuses on the proof-of-concept and on the impact of the flow rates on the product crystals and the crystal size distribution (CSD). All other parameters including concentrations, temperatures, and loading of seeds were kept constant. Higher flow velocities generally resulted in reduced number and volume mean diameters, due to reduced tendency of agglomeration and decreased time for crystal growth due to shorter residence times of the suspension in the tube. Generally, all experiments unmistakably led to shifting of volume density distributions toward significantly larger values for product crystals in comparison to the seeds and were capable of yielding product masses in a g/min scale.

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

“…3,4 Generally, there are two types of continuous crystallizers that are most investigated, viz., the tubular and the stirred-tank designs. 5 Regardless of recycling, these two designs help to achieve idealised flow patterns, namely the plug-flow 6 and the mixed-suspension mixed-product removal (MSMPR)…”

Continuous Suzuki—Miyaura reactions with novel Ce—Sn—Pd oxides and integrated crystallization as continuous downstream protocol

“…Furthermore, particle formation in flow-through devices with inner diameters of few centimeters has been reported. Our group published several studies focusing on the controlled growth of crystals by selecting precise cooling trajectories in continuous-flow crystallizers [15][16][17][18].…”

Separation units and equipment for lab-scale process development

“…Continuously seeded cooling crystallization can suppress undesired nucleation events or the formation of crystals of an undesired morphology. Thus, a stable steadystate operation is feasible and scaling/clogging issues can be reduced [49,92,103]. The current work focuses on the development of a device for continuous seed crystal generation by abrasion from larger parent or product crystals, followed by a mechanical classification of the desired crystal fraction.…”