Simultaneous preferential crystallization in a coupled batch operation mode. Part II: Experimental study and model refinement
Introduction
Enantiomerism is a widespread phenomenon observed for a multitude of substances utilized as drugs. This phenomenon can confer entirely different biochemical properties (in a chiral environment, which is ubiquitous in the human body) to molecules that are somehow quite similar except that their mirror image is not superimposable. Typically, enantiomers are rather readily available in racemic composition, i.e. equal amounts of both enantiomers, after a conventional, symmetric chemical synthesis. The recognition of differences in the pharmacological activity of enantiomeric molecules has induced the necessity to administer them as an isolated enantiomer (eutomer) in order to ensure the desired optimum therapeutic effect. However, this need of manufacturing enantiopure substances affects not only the pharmacological industry but other industrial sectors likewise such as agrochemical, petroleum, food, cosmetic and fragrance industries, all of which are increasingly concerned with the development of efficient techniques to produce enantiopure products. Driven by the impending, more restrictive policies of regulatory authorities, enantioseparation has become a flourishing field of research for more than twenty years which still continues to grow. The interest in isolation of pure enantiomers at the preparative and industrial level is undeniably crucial and motivates the effort for sustained development of new methods and intensification of those already established. In order to achieve enantiopure components, two basic approaches can be applied: enantioselective synthesis or otherwise conventional symmetric synthesis with subsequent chiral separation (Ahuja, 1997). If the general applicability and the process costs are taken into consideration, then the second approach is often much more attractive (Franco and Minguillón, 2001) since after the symmetric synthesis, for the resolution classical chiral separation techniques (crystallization, chromatography, membrane processes) as well as some special integrated hybrid process alternatives can be applied (Ströhlein et al., 2003, Kaspereit et al., 2005, Fung and Ng, 2006, Bechtold et al., 2006, Petruševska-Seebach et al., 2009, Würges et al., 2009a, Würges et al., 2009b). Lately, Flood (2008) summarized the most significant resolution methods for amino acids underscoring crystallization processes. Most of these methods are of course not restricted to amino acids; in fact they are widely applicable also to any chiral substance. Among all enantioseparation methods, enantioselective Preferential Crystallization (PC) is an attractive and inexpensive method since auxiliaries and reagents, other than a solvent are not required. The excellent treatise by Jacques et al. (1994) and the recently published overview by Coquerel (2007) give detailed information about the modus operandi in principle as well as benefits and drawbacks of PC.
In particular, the separation of mixtures which reveal a typical conglomerate phase diagram (cf. Fig. 1), i.e. a physical mixture of enantiopure crystals, by PC holds great potential. Such systems in initially supersaturated solution tend to reach an equilibrium state, i.e. the eutectic point in which the now saturated liquid phase showing solubility concentration according to the crystallization temperature will be comprised of equal amounts of both enantiomers and the solid phase will be composed of a mixture of crystals of both enantiomers. Notwithstanding, before approaching this state, it is possible to preferentially produce just one of the enantiomers after seeding with homochiral crystals. Seeding with the preferred enantiomer at the beginning of the process is essentially used to inoculate the supersaturated solution whereby the growth (and secondary nucleation) of these enantiomeric crystals is predominantly initialized (Jacques et al., 1994). Contrary to accepted opinion an initial excess of that enantiomer being crystallized is indeed beneficial but not mandatorily necessary for resolution (Elsner et al., 2005). Decisive for the outcome of this kinetically controlled PC in metastable solutions is a crystallization rate difference between both enantiomers. However, it is worth mentioning that the initially generated supersaturation of the solution and, therefore, the finally attainable yield of enantiopure solid phase are limited since crossing the metastable zone into the labile region, where spontaneous primary nucleation of the unwanted enantiomer may occur additionally, must be avoided. In general, the supersaturation of the target enantiomer (as well as other experimental conditions) has to be controlled not only due to the prevention of primary nucleation with the inherent occurrence of the counter enantiomer but also concerning the minimization of secondary nucleation which may have an unfavorable impact on the Crystal Size Distribution (CSD) of the gained product and therefore on the efficiency of the downstream processes, such as filtration and washing. Both requirements, high enantiopurity and large as well as well-shaped crystals with a narrow CSD, are determined primarily by the kinetics of the single mechanistic steps. Hence, for successful operation of PC the importance of combining thermodynamic with kinetic knowledge cannot be overemphasized.
In the context of PC it is noticeable that effort has been put on the investigation of considerable chemical aspects with emphasis on equilibrium phase diagrams (Jacques et al., 1994, Collet, 1999, Beilles et al., 2001, Pallavicini et al., 2004, Pallavicini et al., 2008, Tulashie et al., 2008, Bredikhina et al., 2008). Only a few contributions can be found in the literature which deal with the process itself: Profir and Matsuoka (2000) analyzed for instance PC of DL-threonine in order to elucidate the phenomena of purity decrease in later stages of the resolution process. Extensive experimental work in the field of PC has been conducted by Coquerel and co-workers (Ndzié et al., 1997, Beilles et al., 2001, Dufour et al., 2001, Coquerel, 2007) with respect to two different operation modes: seeded isothermal PC and auto-seeded programmed polythermal PC (AS3PC). Recently, Wermester et al. (2008) proposed the utilization of a non-chiral base for the auto-seeded programmed polythermal PC of modafinic acid in order to improve the yield.
Although kinetic data such as crystal growth and nucleation rates are absolutely essential for design methods, it is remarkable that the number of publications devoted to quantify kinetic aspects within the scope of PC is still small (Elsner et al., 2005, Wang and Ching, 2006, Angelov et al., 2008, Wang et al., 2008, Czapla et al., 2009). Wang and Ching (2006) have shown how thermodynamic and kinetic aspects can be exploited in order to plan adequate temperature trajectories controlling the critical supersaturation in batch operation for preferential crystallization of 4-hydroxy-2-pyrrolidone in propan-2-ol.
However, the theoretical background of conventional crystallization processes embracing all kinetic facets like crystal growth rate, nucleation rate, etc. which is also the basis for PC has been established by several researchers (Mullin, 1993, Mersmann, 2001). In the last decades, crystallization processes have been studied more in detail from a chemical engineering perspective to indicate the advantages of controlling and manipulating the supersaturation, i.e. concentration and/or crystallization temperature, in batch crystallization. Mullin and Nývlt (1971) investigated for example the influence of a cooling profile on the final Crystal Size Distribution (CSD). Jones and Mullin (1974) attempted to apply an optimal cooling profile in order to improve the CSD of the product. Since usually nucleation rates exhibit significant uncertainties, recently, Bakar et al. (2009) have focused on in situ nuclei formation (by addition of antisolvent or decrease of crystallization temperature) as well as fines removal (by addition of solvent or increase of crystallization temperature) detected by a Focused Beam Reflectance Measurement (FBRM) probe in order to shape the crystal size distribution of the product. In a skillful manner they have demonstrated that their approach by Direct Nucleation Control (DNC) provides a robust crystallization control strategy without any knowledge of the nucleation and/or dissolution rates. An integrated crystallization system taking into account downstream processes like filtration and drying of the solid phase was the subject of the work published by Wibowo et al. (2001). Of course, all these issues play also an important role in developing new methods and novel processes for PC. Finally, it is worth pointing out that in order to meet certain product demands, i.e. product purity, yield and CSD, some sophisticated, model-based control strategies which one can find in the literature for conventional batch crystallization (Vollmer and Raisch, 2006, Hermanto et al., 2007, Nagy, 2009) should be also applied to PC after some modification, in order to ensure unchanging product quality and to achieve certain (optimized) product specifications.
Elsner et al. (2005) published a study with regard to a model-based process improvement concerning PC where an effective equipment arrangement was analyzed both theoretically and experimentally. The main topic was the analysis of a cyclic operation mode which allows increasing the process productivity. An optimization of the initial conditions for this PC process with a cost relation as an objective function was done at first by Angelov et al. (2006). Later on, a control problem with regard to maximizing the amount of attainable preferred enantiomer with purity of at least 95% by determining an optimal temperature profile was investigated theoretically by the same authors (Angelov et al., 2008). In addition, Bhat and Huang (2009) recently identified different regimes of interest during PC within a four objective optimization framework using a genetic algorithm in which the average crystal size as well as the productivity was maximized, whereas both the batch time and the coefficient of variation at the desired purity were minimized.
The mathematical modeling of preferential crystallization requires high precision as is illustrated by Qamar et al. (2008) where several different numerical schemes were assessed for a PC model. The comparison shows clear advantages (i.e. low numerical dispersion and high computational efficiency) of the high resolution finite volume schemes and the Method of Characteristics (MOC) for the current problem.
In comparison to the simple batch and cyclic operation mode, an alternative configuration of coupled crystallizers (cf. Fig. 2) where both enantiomers are crystallized simultaneously appears to be an even more promising concept for conglomerate forming systems in terms of outperforming productivity as well as purity (Elsner et al., 2007, Qamar et al., 2009, Elsner et al., 2009). The theoretical analysis of this newly proposed crystallizer configuration has been studied in part I of this work (Elsner et al., 2007) where the influence of various process variables with regard to process productivity and final product properties was described. Additionally, the main idea and a preliminary feasibility study for this coupled mode can be found in Elsner et al. (2009).
Supplementing part I, in this contribution a comprehensive and systematic experimental investigation of PC performed in an isothermal coupled mode (Coupled Isothermal Batch Preferential Crystallization, CIB-PC) will be presented and checked against the standard isothermal single batch process (Simple Isothermal Batch Preferential Crystallization, SIB-PC). For the first time, we believe to be able to shed light on how some process parameters like mass of seeds, CSD of seeds, starting point for the mother liquor exchange and process duration influence the objective functions, i e. yield, productivity and purity, which have not been published so far for PC.
These two concepts will be illustrated by PC of threonine in water which is unambiguously known as a conglomerate forming system. In addition to the experimental results, a comparison with results obtained from a re-defined, detailed mathematical model will be shown. In contrast to part I this re-defined model involves the temperature-dependence of the thermodynamic as well as kinetic parameters which additionally enables the investigation of non-isothermal PC. Compared to the previous part the approach for the strongly heterogeneous, primary nucleation has been slightly modified and besides, the crystal growth anomaly which has been observed experimentally is now also included in the kinetic model. Finally, a Coupled Polythermal Batch Preferential Crystallization Mode (CPB-PC) with a certain temperature profile will be proposed to improve the process productivity.
Section snippets
Physical aspects: manipulation of concentration profiles in coupled PC
In simple Isothermal Batch Preferential Crystallization (SIB-PC) the preferred p-enantiomer is selectively separated from a supersaturated, racemic or p-enriched solution. If the supersaturation is maintained in the metastable region (i.e. regime where no spontaneous primary nucleation occurs which is a prerequisite for successful operation), after seeding with the p-enantiomer just this p-form will be preferably crystallized within a limited time period. Due to the high purity restrictions of
Material
Racemic mixture of DL-threonine (purity>98%) used as raw material for dissolving in water during these studies was supplied by Merck Schuchardt OHG, Hohenbrunn, Germany. Besides, for the preparation of the solutions ultrapure water was generated by Milli-Q® purification gradient system (Millipore Corporation, Molsheim, France) using a 0.22 μm Millipak® membrane filter. For the inoculation of the supersaturated solutions enantiopure seed crystals of L- and D-threonine, respectively (purity>98%,
Case study I: Simple Isothermal Batch Preferential Crystallization (SIB-PC) runs
In this section, the theoretical and the experimental investigation of the main process variables for the crystallization process in a simple isothermal batch mode will be presented. The influence on the productivity and product purity will be shown. To begin with, the authors would like to give a brief survey about the influence of the mass of seeds on the process performance.
Conclusions
In this work, the theoretical and experimental investigation of some essential process parameters for two different crystallizer configurations has been performed for the conglomerate system DL-threonine in water. For the simple isothermal batch PC the impact of mass of seeds as well as initial crystal size distribution of the seeds has been investigated experimentally, and compared to our model predictions. It has been proven that an increase of mass of seeds results in a higher mass of the
Nomenclature
- a
parameter for interfacial tension [-]
- a0
(fitted) parameter for log-normal distribution function [-]
- a1
(fitted) parameter for log-normal distribution function [m]
- a2
(fitted) parameter for log-normal distribution function [-]
- aASL
parameter for ASL3 approach [m−1]
- aprim
lumped constant within exponential term for primary heterogeneous nucleation [-]
- asat
temperature dependent parameter for solubility [-]
- AW
heat transfer surface area [m2]
- bsat
temperature dependent parameter for
Acknowledgments
The authors thank Luise Borchert and Jacqueline Kaufmann for their laboratory work and their help in performing the HPLC analyses. Thanks are also due to Markus Ikert for the characterization of the crystal surfaces of numerous samples by SEM.
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2013, Chemical Engineering ScienceCitation Excerpt :This technique is normally applied to conglomerates, a physical mixture of enantiomerically pure crystals. Several articles are available on preferential crystallization in batch mode, see for example Jacques et al. (1981), Collet (1999), Alvarez-Rodrigo et al. (2004), Elsner et al. (2005), Coquerel (2007), Czapla et al. (2009), and Elsner et al. (2011). Recently, Qamar et al. (2012) have adopted the concept of continuous mixed-suspension-mixed-product-removal (MSMPR) crystallizers (e.g. Randolph and Larson, 1988) to obtain pure enantiomers from racemic mixtures in a single crystallizer.