6 research outputs found
Separation of Chiral Active Pharmaceutical Ingredients:A First Step towards Continuous Preferential Crystallization in the Pharmaceutical Industry
Separation of Enantiomers by Preferential Crystallization: Mathematical Modeling of a Coupled Crystallizer Configuration
Separation of Enantiomers by Preferential Crystallization: Mathematical Modeling of a Coupled Crystallizer Configuration
A mathematical
model describing the separation of enantiomers by
simultaneous preferential crystallization in a coupled crystallizer
configuration is developed. The model was validated against experimental
data for a chemical model compound, the conglomerate forming system
of asparagine monohydrate in water. The kinetic parameters required
were taken from available literature sources and simulations compared
to experimental data. Simulations were found to be in good agreement
with experimental data. Additional model simulations suggest that
the separation process can be improved by increasing the mean residence
time of the liquid phase in the crystallizers, and the mass of seeds
supplied. Reducing the size of seed crystals will also lead to an
improved separation. The model can also be used to simulate the performance
of the crystallization process for a racemic compound forming system.
The racemic compound and the pure enantiomer can be separated simultaneously
in each crystallizer, having sufficient enrichment of the pure enantiomer
in the feed solution. The model can also be extended to represent
a fully continuous separation process taking into account the continuous
supply of enantiopure seed crystals and liquid feed solution and the
continuous removal of solid product and mother liquor
Separation of Enantiomers by Continuous Preferential Crystallization: Experimental Realization Using a Coupled Crystallizer Configuration
The
experimental realization of a continuous preferential crystallization
process, consisting of two mixed-flow crystallizers coupled via crystal-free
liquid exchange streams and with only the liquid phases operating
continuously, is addressed. Experiments in triplicate, using the conglomerate-forming
system of dl-asparagine monohydrate in water, were conducted,
and the achievement of nearly racemic composition of the liquid phase
in the crystallizers was verified. An experiment was also carried
out using seed crystals of a smaller average particle size than used
in the reference experiments. Successful enantioseparation by crystal
growth, with the repeatability being within ±10% deviation, was
obtained. However, slow crystal growth, due to a low surface integration
rate, led to a negligible consumption of the desired enantiomer added
in the feed solution, resulting in low productivities. Productivities,
yields, and purities of solid products were influenced by the morphological
differences in the seed crystals. Due to irregularly shaped seed crystals,
increase in the productivities and yields were achieved in the L-Tank.
Lower purities of solid products from the L-Tank compared to purities
of the solid products from the D-Tank were obtained. This could be
due to surface nucleation of d-asparagine monohydrate, ascribed
to the surface structure of the seeds of l-asparagine monohydrate
supplied. Improvements in productivity, yield, and purity in the L-Tank,
for the same process duration, were realized using seed crystals of
lower average particle size having a smoother surface structure. The
main advantages compared to other separation processes are low capital
cost, high crystal purity and yield, ease of upscaling, increased
safety, and reduced environmental impact due to reduction in the amount
of solvent used. The application is currently limited to conglomerate-forming
systems, but the separation concept may open new possibilities for
process improvements regarding enantioseparation of racemic compound-forming
systems as well