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.
A continuous tubular crystallizer system with an inner diameter of 2.0 mm and an overall length of 27 m was used to generate acetylsalicylic acid seeds in situ from ethanolic solution via cooling and ultrasound irradiation and to grow the crystals in the tubing with a controlled temperature trajectory. In order to minimize the residence time distribution, air bubbles were introduced into the system to generate a segmented gas-slurry flow. The narrow residence time distribution and the tight temperature control in the small tubing due to the large surface to volume ratio resulted in relatively narrow crystal size distributions of the product. Generally, all experiments clearly demonstrated significant crystal growth for the product crystals in comparison to the seeds and yielded product masses on the g/min scale. Furthermore, it was demonstrated that the size of the product can be easily controlled via fines removal by dissolution due to rapid heating and varying the mass of seeds per mL of solution.
Protein crystals have many important
applications in many fields,
including pharmaceutics. Being more stable than other formulations,
and having a high degree of purity and bioavailability, they are especially
promising in the area of drug delivery. In this contribution, the
development of a continuously operated tubular crystallizer for the
production of protein crystals has been described. Using the model
enzyme lysozyme, we successfully generated product particles ranging
between 15 and 40 μm in size. At the reactor inlet, a protein
solution was mixed with a crystallization agent solution to create
high supersaturations required for nucleation. Along the tube, supersaturation
was controlled using water baths that divided the crystallizer into
a nucleation zone and a growth zone. Low flow rates minimized the
effect of shear forces that may impede crystal growth. Simultaneously,
a slug flow was implemented to ensure crystal transport through the
reactor and to reduce the residence time distribution.
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