Modelling and control of combined cooling and antisolvent crystallization processes

Abstract

Although for decades nearly all pharmaceuticals have been purified by crystallization, there have been a disproportionate number of problems associated with the operation and control of these processes. This paper provides an overview of the recent advances in model-based and model-free (direct design) approaches to control the crystallization of pharmaceuticals, treating both antisolvent and cooling crystallization. A model-based combined technique which simultaneously controls the antisolvent addition rate and the cooling profile is presented. A population balance model of the combined coolingantisolvent addition system is developed and a moments model is used in optimal control strategies with various objective functions. The simulation and experimental results show the advantages of the combined approach.

Crystallization by Antisolvent Addition and Cooling

“…It is possible to vary antisolvent addition rate and cooling rate simultaneously (Nagy et al, 2008), allowing to optimize crystal quality in industrial operations. The presented kinetic data as well as shape and size distribution measurement for antisolvent cooling crystallization corroborate its utilization in industrial operation.…”

“…Studying crystallization of paracetamol in isopropanol-water system in which water was added as antisolvent, Knox et al (2009) increased the yield from 78.4% to 93.5% when antisolvent was added before cooling. Nagy et al (2006Nagy et al ( , 2008 utilized the method of moments to model the combined cooling and antisolvent crystallization in order to obtain the optimum recipe for crystallizing lovastatin (a hypolipidemic agent in drugs) in acetone/water mixture and achieve a maximized crystal size. Compared to cooling-only strategy, antisolvent-only strategy improved the product mean size in 15%, while combined strategy improved the mean size in 22%.…”

“…Crystallization was evaluated utilizing Nýlvlt's method to calculate crystallization kinetics (Nývlt et al, 2001). …”

Modeling and Bayesian parameter estimation for semibatch pH‐shift reactive crystallization of l‐glutamic acid

“…Because the solution volume of a semibatch crystallizer is time varying, it is convenient to redefine the number density on the basis of the total operating volume of the system such that 6,16 f i 5n i V (15)…”

On the prediction of psd in antisolvent mediated crystallization processes based on fokker-planck equations

“…This method implies first principle assumptions, requiring a detailed knowledge of the physics and thermodynamics of the process. Some important contributions to this subject have been reported in the literature (e.g., Worlitschek and Mazzotti, 2004;Bakir et al, 2006;Nowee et al, 2008;Nagy et al, 2008). However, they demand a great deal of knowledge of the complex thermodynamic associated with the solute and solvent properties to be adequately incorporated in the population balances.…”