(366a) Coupling of Crystallizers for Efficient Enantioseparation - Comparison of Two Different Process Strategies

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.