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.

Equipment and Separation Units for Flow Chemistry Applications and Process Development

“…In general, continuous crystallization is performed in two basic apparatuses, namely, on the one hand in the continuously stirred tank (CST), especially the mixed-suspension, mixedproduct-removal (MSPMR) [26][27][28][29][30], and on the other hand in the plug flow (PF) [31][32][33][34][35][36][37][38]. There are many variants of both types, which are described in literature [39,40].…”

The Future of Pharmaceutical Manufacturing Sciences

“…Modeling of such systems has been reported in the literature . Continuous filtration and washing (API finish), although well established in other process industries at a large scale have received less attention on a small scale suitable for API manufacturing and in the GMP environment.…”

“…289 Modeling of such systems has been reported in the literature. 290 Continuous filtration and washing (API finish), although well established in other process industries at a large scale have received less attention on a small scale suitable for API manufacturing and in the GMP environment. Unlike small-molecule APIs, continuous biopharmaceutical manufacturing, including the corresponding purification technology, is still in its infancy.…”

Crystal shape and size control using a plug flow crystallization configuration

“…Initially, we model a continuous plug flow crystallizer with 5 segments for the production of lysozyme crystals through kinetic Monte Carlo (kMC) simulation methods in the way described in Kwon et al (2013) using the rate equations originally developed by Durbin and Feher (1991). A seeding strategy is used to decouple the nucleation from the crystal growth processes (Liu et al, 2010;Eder et al, 2011;Besenhard et al, 2014;Ferguson et al, in press). Furthermore, an upper bound of the supersaturation level is imposed as a constraint so that the system is enforced to stay in the metastable regime where the degree of primary nucleation is negligible (Shi et al, 2005).…”