Continuous production of single enantiomers at high yields by coupling single column chromatography, racemization, and nanofiltration
Highlights
► A proposed reactor-separator-recycle process improves significantly yield and performance of enantiomer productions. ► Single column chromatography is an efficient and flexible alternative to more complex process configurations. ► Simple shortcut methods facilitate fast design and performance evaluation. ► For the first time an experimental implementation of such concept in fully coupled operation is reported.
Introduction
Preparative chromatography is a powerful technology applied in various fields for resolving difficult separation problems. A difficult task that is particularly relevant in the pharmaceutical industry, is the production of single enantiomers at high purity. These are often produced via a classical chemical synthesis of the racemate, that is, the 50:50 mixture of the two enantiomers of a component. Since usually only one enantiomer is of therapeutic interest, this requires a subsequent separation of the racemate.
Such separation is challenging and expensive due to the extreme chemical similarity of the enantiomers. Various classical techniques are established, for example, crystallization, dynamic kinetic resolution, or chromatography. Besides this also hybrid separations that combine chromatography and crystallization with recycles were proposed for improving process performance [1], [2], [3], [4], [5]. However, due to the racemic composition of the starting material, the overall yield of enantioseparations is inherently limited to 50% only. This limitation can be overcome if an isomerization reaction, viz. racemization, of the undesired enantiomer can be included. Different corresponding concepts utilize crystallization, e.g. [6], chromatography e.g. [7], [8], or both [9]. As regards chromatography, a particular focus has been on the continuous simulated moving bed (SMB) technology. One research direction is devoted to reactive SMB processes and such with side reactors [8], [10], [11]. These concepts are particularly suited for low purity requirements. An improved performance for higher product purity, as is typical for enantiomeric products, can be achieved by SMB reactors with internally distributed reaction and separation [12], [13].
An alternative to the above approaches are reactor-separator-recycle systems. In such process chromatography is used to separate the desired enantiomer in required purity from the undesired form. The undesired enantiomer is subjected to a racemization reaction, which delivers, in equilibrium, again a racemic mixture. Together with some fresh racemic feed this mixture is recycled back to the chromatographic separation. Since chromatography causes a significant dilution, it is useful to perform a partial solvent removal before recycling the reaction product. Obviously, such concept can improve the yield of an enantiomer production up to 100%.
Bechtold et al. [8] suggested a corresponding process for enantiomer productions using SMB chromatography, an enzymatic racemization and membrane filtration for solvent removal. They proposed it also for other biotransformations. Recently Wagner et al. [14] documented a first successful experimental implementation in fully coupled operation for the production of a rare sugar, increasing the yield drastically from 25% to almost 100%. As regards enantiomer productions, several theoretical studies were performed [7], [8], [12], [15]. In particular in [5] possible economic benefits were underlined by cost savings of almost 50% for industrially relevant problems. However, so far a fully coupled implementation seems not reported.
In this work we extend the scope of this concept by using a conventional single column for the chromatographic separation. This can be an attractive alternative to SMB-based processes due to significantly lower investment costs and process complexity, respectively. Furthermore, this approach has a much higher flexibility since it allows removing additional impurities by defining corresponding waste fractions. Racemization can be performed by a homogeneous, heterogeneous, or enzymatic reaction, while solvent removal is preferably conducted by membrane filtration. It is worth noting that, to the best of our knowledge, so far only a batch-wise “decoupled” experimental implementation of a similar process based on evaporation and an additional crystallization was performed [9].
When aiming at a more attractive realization in fully coupled operation, the discontinuous nature of single-column chromatography complicates process design. The interconnections reduce the degree of freedom and prohibit an independent design of the units. Due to the distinct nonlinear dynamics of the periodically operated chromatography in combination with a recycle, a detailed design will require a correspondingly detailed dynamic model. However, simple methods for basic design are certainly also desired, since they facilitate a fast evaluation of achievable performance that might justify the efforts of a detailed design.
To address these questions, in the next section shortcut design methods are developed that require as input only a single chromatogram without the need for a detailed model of the complete process. Such model is developed subsequently for further design studies. In the following section the design methods are applied for evaluating the achievable process performance, and process dynamics are investigated using the detailed model. The final section demonstrates experimental feasibility of the process in fully coupled operation for an enantiomeric model system, as well as applicability of the design methods.
Section snippets
Process configuration
For a realization of the fundamental concept discussed above we apply the setup in Fig. 1. The enantiomers are separated using a single chromatographic column. The column's effluent is fractionated into a product fraction containing the desired target enantiomer in purified form, and a recycle stream comprising an excess of the undesired enantiomer. The recycle is sent directly to the racemization reactor. Here we consider a homogeneous racemization reaction in a stirred tank reactor. The
Theoretical investigations
Below the performance of the complete process is evaluated using the developed design methods. Furthermore the dynamic process behavior is investigated to critically assess the applicability of the design methods. In the investigations we apply a purity requirement of 98% for the target enantiomer 1. In the calculations we use the experimental parameters of the model system chlorthalidone (see “Setup 2” in Section 4).
Experimental setup and materials
The model substance used in this work is the racemic pharmaceutical ingredient chlorthalidone (CTD) that has a molecular weight 339 g/mol (purchased from Molekula, Gillingham, UK).
For the process combination the setup in Fig. 7 was used. The process was controlled and monitored via RS232 ports using a MatLab script developed for this purpose. Two 16-port valves after the column served for sampling chromatograms and for fraction collection during operation of the complete process. Note that
Conclusions
A process concept has been proposed that increases the yield of the production of single enantiomers. The process, which combines single column chromatography, racemization and nanofiltration, was validated successfully in theoretical and experimental investigations. The concept is found attractive since it is relatively simple and more flexible in comparison to using more complex technologies like simulated moving bed chromatography.
Simple shortcut design methods were developed that allow a
Acknowledgements
The authors gratefully acknowledge the support of the Max Planck Institute for Dynamics of Complex Technical Systems in Magdeburg, Germany; in particular by A. Kienle and A. Seidel-Morgenstern. Parts of this project were supported by the European Commission within the collaborative research project INTENANT (FP7-NMP2-SL2008-214129), the German Academic Exchange Service (DAAD), and the Academy of Finland.
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