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The dynamic behavior of two coupled continuously operated crystallizers connected through exchange pipes and equipped with a fines removal system is theoretically analyzed. It is an extension of our recent work on continuous enantioselective preferential crystallization in a single vessel. A high resolution finite volume scheme is applied to solve the model in the crystal size coordinate, while an ODE-system in the time coordinate is solved by a fourth order Runge-Kutta method. The influences of different seeding and operating strategies on the process are studied systematically. To assess the quality of the process several goal functions are used, such as purity, productivity, yield and mean crystal size of the target enantiomer. Continuous and periodic seeding concepts are compared. The goal functions considered provide clear evidence about the significant potential of this new process. To prove advantages of the coupled process, corresponding results are compared with those for a single crystallizer.

This contribution investigates the effects of different seeding strategies and residence time characteristics on the dynamics of a Mixed Suspension Mixed Product Removal (MSMPR) crystallizer equipped with a fines dissolution unit. For the first time continuous preferential enantioselective crystallization is investigated. The fines dissolution is included as recycle streams around the MSMPR crystallizer. Moreover, primary heterogeneous and secondary nucleation mechanisms along with size-dependent growth rates are taken into account. A semi-discrete high resolution finite volume scheme (FVS) is employed for discretizing the derivatives with respect to the length coordinate. The resulting ordinary differential equations (ODEs) are solved by a Runge–Kutta method of order four. Several numerical case studies are carried out. The results support process design and optimization.

A systematic procedure for synthesizing the multi-stage crystallization process was developed for resolution of enantiomeric mixtures involving solid solutions in the crystalline phase. The model compound investigated was citalopram oxalate, which revealed a complete solid solution in the solid phase. The counter-current multi-stage batch crystallization was suggested to isolate the target enantiomer from enantiomerically enriched mixtures. The solid–liquid equilibria in the presence of a solvent and the distribution diagrams were quantified and used in designing the crystallization process and defining adequate processing conditions. Different flowsheet schemes were considered and compared with respect to the process performance. The design procedure was verified by the experimental separation of enantiomeric mixtures of citalopram.

In the previous part of this series a parametric study was presented to assess theoretically the performance of a novel crystallizer configuration. Complementary, the present work addresses a comprehensive, systematic experimental examination accompanied by an analysis of some relevant process parameters (mass of seeds, CSD of seeds, starting point for the mother liquor exchange, process duration) of two general concepts for preferential crystallization in which the amino acid threonine dissolved in water was used as a model system. In the first step of investigations, the impact of these process parameters was studied for conventional single batch crystallization. The experimental results are discussed and compared with the theoretical ones. Moreover, a configuration consisting of two coupled crystallization vessels was investigated. The specific manipulation of the concentration profiles of each enantiomer in solution as well as of the temperature profiles was found to be suitable to enhance the process performance. This is reflected by higher achievable process productivities and higher product purities.

In this work, an efficient numerical method is introduced for solving one-dimensional batch crystallization models with size-dependent growth rates. The proposed method consist of two parts. In the first part, a coupled system of ordinary differential equations (ODEs) for the moments and the solute concentration is numerically solved to obtain their discrete values in the time domain of interest. These discrete values are also used to get growth and nucleation rates in the same time domain. To overcome the issue of closure, a Gaussian quadrature method based on orthogonal polynomials is employed for approximating integrals appearing in the ODE system. In the second part, the discrete growth and nucleation rates along with the initial crystal size distribution (CSD) are used to construct the final CSD. The expression for CSD is obtained by applying the method of characteristics and Duhamel's principle on the given population balance model (PBM). The proposed method is efficient, accurate, and easy to implement in the computer. Several numerical test problems of batch crystallization processes are considered. For a validation, the results of the proposed technique are compared with those obtained using a high resolution finite volume scheme.

This work is concerned with the modeling and simulation of population balance equations (PBEs) for combined particulate processes. In this study a PBE with simultaneous nucleation, growth, aggregation and breakage processes is considered. In order to apply the finite volume schemes (FVS) a reformulation of the original PBE is introduced. This reformulation not only help us to treat the aggregation and breakage processes in a manner similar to the growth process in the FVS but also in deriving a stable numerical scheme. Two numerical methods are proposed for the numerical approximation of the resulting reformulated PBE. The first method combines a method of characteristics (MOC) for growth process with an FVS for aggregation and breakage processes. The second method purely uses a semidiscrete FVS for all processes. Both schemes use the same FVS for aggregation and breakage processes. The numerical results of the schemes are compared with each other and with the available analytical solutions. The numerical results were found to be in good agreement with analytical solutions.

This contribution addresses the design and investigation of two hybrid enantioseparation processes including an enzymatic racemization step in order to enhance the overall performance. Complementary to part I where the manufacturing and the characterization of an amino acid racemase (EC 5.1.1.10) was emphasized [Wurges, K., Petrusevska, K., Serci, S., Wilhelm, S., Wandrey, C., Seidel-Morgenstern, A., Elsner, M.P., Lutz, S., 2009. Enzyme-assisted physicochemical enantioseparation processes—part I: production and characterization of a recombinant amino acid racemase. J. Mol. Cat. B (in print), online available: doi:10.1016/j.molcatb.2008.10.006.], the work presented in this paper tends more towards developing a data base for potential process schemes for the manufacture of selected amino acids. The first proposed process concept (P-I) couples preferential crystallization (PC) and racemization for the production of l -asparagine ( l -Asn) using racemic mixture of dl -asparagine (conglomerate-forming system) as a starting material, while the second concept (P-II) integrates chromatography and racemization for the preparation of l -methionine ( l -Met) starting with racemic mixture of dl -methionine (compound-forming system). As mentioned in part I, a racemization unit, where the unwanted enantiomer will be converted into racemate, is incorporated into the hybrid processes for the sake of 100% yield, theoretically. Besides the basic investigation according to the solid–liquid equilibria, PC and chromatography, the focus of this paper is mainly on the kinetic studies of the racemization reaction. Initially, the solubility ternary phase diagrams of both examined systems were determined, leading into the idea of combination of the proposed process schemes. For P-I the concept of PC of l -Asn was experimentally proven and the kinetics of the racemization was examined for d - and l -Asn in water using purified lyophilizate (PL). Concerning P-II, for the chromatographic unit the impact on the separation of dl -Met on eremomycin based stationary phase using KPi buffer and MeOH as mobile phase was evaluated in terms of resolution and selectivity at three different temperatures by varying the content of methanol (MeOH) in the mobile phase and the pH. The experiments for determination of the racemization kinetics were done for a compromised parameter set using crude lyophilizate (CL). In both cases a Michaelis–Menten three-step model was used to describe the enzymatic reaction.

For analysis, design and model-based control of crystallization processes typically population balance models or reduced models derived therefrom are used. Usually the kinetic parameters in these models are determined analyzing measured concentration trajectories and/or particle size distributions using parameter estimation procedures. In the case of preferential crystallization of enantiomers the analysis of experiments is complex since there are two “competing” crystal populations. In this field often batch processes are performed using seeds of the desired enantiomer. Currently, it is in particular challenging to quantify and optimize a new concept: e.g. the so-called “ a uto s eeded p rogrammed p olythermal p referential c rystallization” (“as3pc” [Coquerel, G., Petit, M.-N., Bouaziz, R., 2000. Method of resolution of two enantiomers by crystallization. United States Patent, Patent number: 6,022,409]). In order to design and optimize this process the temperature dependent kinetic constants for crystal growth, nucleation and dissolution have to be known. In this work a reduced model for this auto seeded process is presented. The general identifiability of the model parameters is investigated along with some suggestions on how to reparameterize the kinetic terms involved. The values of the identified key parameters are estimated using conventional least square optimization using experimental data determined for the model system threonine/water. Parameter confidence and cross correlation are discussed and finally the model is validated using experiments not used for parameter estimation.

This article introduces a technique for reconstructing crystal size distributions (CSDs) described by well-established batch crystallization models. The method requires the knowledge of the initial CSD which can also be used to calculate the initial moments and initial liquid mass. The solution of the reduced four-moment system of ordinary differential equations (ODEs) coupled with an algebraic equation for the mass gives us moments and mass at the discrete points of the given computational time domain. This information can be used to get the discrete values of size independent growth and nucleation rates. The discrete values of growth and nucleation rates along with the initial distribution are sufficient to reconstruct the final CSD. In the derivation of current technique the Laplace transformation of the population balance equation (PBE) plays an important role. The proposed technique has dual purposes. Firstly, it can be used as a numerical technique to solve the given population balance model (PBM) for batch crystallization. Secondly, it can be used to reconstruct the final CSD from the initial one and also vice versa. The method is very efficient, accurate and easy to implement. Several numerical test problems of batch crystallization processes are considered here. For validation, the results of the proposed technique are compared with those from the high resolution finite volume scheme which solves the given PBM directly.

This article describes batch-wise preferential crystallization separation of mixtures of L- and D-threonine. The use of online polarimetry combined with refractometry and microscopic investigation of the solid phase provides information on the crystallization kinetics. Results obtained for different crystallization conditions (supersaturation, temperature and enantiomeric excess) in a batch crystallizer are presented. Based on these results, a non-linear dynamic model has been developed. The control problem is to determine an optimal temperature profile which will result in a maximum amount of product with required quality. In this dynamic optimization problem B-splines have been used for interpolation of the temperature profile.

The intention of this paper is the theoretical analysis and optimization of preferential crystallization of enantiomers performed simultaneously in two batch crystallizers which are coupled. An exchange of the liquid phases may increase the overall crystallization kinetics and that might lead to a higher productivity. In this study, the amino acid threonine dissolved in water was used as a model system. Taking experimentally estimated parameters describing the crystallization thermodynamics as well as kinetics into consideration, a simplified mathematical description based on population balance model was established for the simulation of the time changes of liquid phase composition during the preferential crystallization process. Based on this simplified model the above mentioned crystallizer configurations has been optimized and investigated concerning the maximum attainable productivity.

In this paper a detailed experimental study on the application of continuous stripping mode foam fractionation to separate a model surfactant–protein mixture was performed with emphasis on the competitive adsorption behaviour and transport processes of surfactant–protein mixtures in the rising foam column. Bubble size measurements of the foamate showed that at steady state conditions the bubbles rising from the liquid pool were stabilised by BSA. However at the top of the column the recovery of Triton X−100 in the foamate (75–100%) was always greater than the recovery of BSA (13–76%) for all foam fractionation experiments. The enrichment of BSA remained at almost unity for experiments with high feed concentrations of both components and low air flow rates, and only increased when the recovery of Triton X−100 reached 100%. Thus it was concluded that Triton X–100 displaced the adsorbed BSA from the surface. The surface activity and diffusivity of the two components was determined from surface tension and nuclear magnetic resonance (NMR) measurements. These results illustrated that competitive adsorption behaviour was due to the greater maximum surface pressure (2.05 times) and diffusivity (19.6 times) of Triton X−100 than BSA. In addition to investigating the effect of foam fractionation process parameters on the separation of mixed systems, the results from the characterisation studies of surface adsorption and foam properties provided insight and deeper understanding of the competitive adsorption behaviour of surfactants and proteins in a foam fractionation process.