Modeling a seeded continuous crystallizer for the production of active pharmaceutical ingredients

Abstract

The approximation of a well mixed reactor is prevalent when it comes to the modeling of a crystallization process. Since temperature, concentration, and mass content vary due to inhomogeneous mixing, this approximation is a very loose one. The continuously operated seeded tubular crystallizer system developed in our group overcomes obstacles like a slow response to changes in the outer parameters and inhomogeneous mixing. Therefore the applicable well mixed assumption facilitates detailed modeling of the crystallization process by means of population balance equations (PBE) coupled with mass and energy balances. Modeled results were validated by means of experiments. The amount of aggregation events during the crystallization could be quantified and it was proven that the growth of seeded crystals is almost exclusively responsible for solid mass uptake if the reactor is operated appropriately. The performed sensitivity analysis exposed which process settings should be maintained most accurately to avoid fluctuations in the product crystals’ quality attributes and to limit undesired nucleation events.