276921 Coupling of Crystallizers for Efficient Enantioseparation - Comparison of Two Different Process Strategies

Tuesday, October 30, 2012: 3:17 PM
Crawford West (Westin )
Matthias Johannes Eicke, Physical and Chemical Foundations of Process Engineering, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany, Guillaume Levilain, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany, Martin Peter Elsner, Georg-Simon-Ohm University of Applied Sciences, Nuremberg, Germany and Andreas Seidel-Morgenstern, Physical and Chemical Foundations of Process Engineering, Max-Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany

Chiral molecules can be a particular challenge when used in drugs because of the existence of their stereoisomers. Although both enantiomers are merely mirror images, they can show drastically different effects in living organisms, which are chiral themselves and thus able to distinguish between the two molecules. Owing to this, it is essential to obtain enantiomers in their pure form. A wide array of methods has been studied and brought to application which on the one hand is concerned with the direct synthesis and on the other hand focuses on a more engineering biased approach that is, the separation of the racemate using well-known as well as novel techniques.

This contribution takes on the engineering route and puts the application of preferential crystallization (PC) as a separation technique at its center. It is well known that a racemic solution containing both enantiomers at equal proportions can be subcooled and still remain in a state where only the liquid phase exists. This phenomenon, called metastability, applies to other solutions as well but it is the key for applying PC. Within this region of kinetic inhibition it is possible to grow seed crystals of only one enantiomer. At some point however, the unseeded species will undergo nucleation and contaminates the product. In order to prevent this, the process must be stopped and the product has to be removed from the mother liquor. Certainly, this leads to great limitations with respect to yield because a considerable amount of product is still left in the dissolved state.

An improvement is possible for systems that crystallize as conglomerates such as DL-threonine/H2O. It has been shown that two crystallizers coupled via a constant exchange of crystal free solution and seeded with opposite enantiomers can overcome these limitations [1, 2].

Recently more work has been done by the authors to further improve coupled PC. Different polythermal modes of operation have been investigated theoretically indicating the possibility for significant enhancements with respect to yield and productivity. Furthermore, a variant of coupled PC originally described in [3] has been investigated in detail both theoretically and experimentally for the model system DL-threonine/H2O. The scheme of the process is depicted in Figure 1.

Figure 1: Operating principle for the connection of selective crystallization and dissolution.

Contrary to the first strategy, where both tanks are seeded with the respective pure enantiomers, this variant requires only one type of homochiral seeds. One crystallizer (Tank 1) holds a supersaturated racemic solution to which the preferred enantiomer E1 is added in solid form. The other crystallizer (Tank 2) contains a saturated racemic solution with the same concentration to which solid racemate is added. Since the temperature in Tank 1 is below saturation level the seeds will grow reducing the level of supersaturation. Due to the exchange of clear solution a transient undersaturation with respect to E1 will appear in Tank 2, leading to a selective dissolution of this enantiomer from the solid racemate. In this case preferential crystallization is happening in one tank while a selective dissolution in the other leads to a purification of the supplied racemate with respect to the second enantiomer E2. The process thus yields two pure molecules while only one is needed as an investment.

This contribution will focus on how coupling crystallizers can help to make enantioseparation more efficient. The core will be a comparison of both process strategies with respect to their productivity but also their strengths and weaknesses. Further insight will be given by complementing experimental results with simulation studies directed at the influence of different process parameters.

1.         Elsner, M.P., G. Ziomek, and A. Seidel-Morgenstern, Efficient Separation of Enantiomers by Preferential Crystallization in Two Coupled Vessels. AIChE Journal, 2009. 55(3): p. 640-649.

2.         Elsner, M.P., G. Ziomek, and A. Seidel-Morgenstern, Simultaneous preferential crystallization in a coupled batch operation mode. Part II: Experimental study and model refinement. Chemical Engineering Science, 2011. 66(6): p. 1269-1284.

3.         Merck & Co. Inc., Resolution of Racemic Mixtures of Optically Active Enantiomorphs. Patent DE1543238, 1965.

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