Reaction systems and process variants

Reaction systems and process variants

Continuous production of anti-malarial medicines

Artemisinin and its derivatives are currently the basis for the most effective medicines to cure malaria. In recent years, however, the high price for artemisinin as well as huge price fluctuations resulted in shortages of artemisinin-based therapies and gave rise for vast counterfeiting of the drugs. In order to make these medications more widely available the production process of artemisinin needs to be improved and innovated.

The main source of artemisinin is the extraction of the plant Artemisia annua, which contains only max. 1.4 wt-% of the target compound in the dried matter. Our approach to make the production process more cost-efficient is to increase the yield of artemisinin obtained from the extraction by utilizing dihydroartemisinic acid (DHAA) – the biological precursor to artemisinin. DHAA is contained in significant amounts in the plant and can be converted to additional artemisinin in a selective partial synthesis. Thus, an efficient production process for artemisinin can be achieved by coupling extraction with selective partial synthesis followed by an separation unit (figure 1) for the final purification.

Abbildung 1: Overall process concept for the continuous production of artemisinin

In the extraction step our research focuses on the simultaneous isolation of artemisinin and dihydroartemisinic acid from dried leaves by countercurrent solid-liquid extraction. The process is studied theoretically by a stage equilibrium cell model in order to predict and identify suitable operations condtions for the extraction. These conditions will be used for experimental investigation with a self-designed and custom built screw-extruder.

In the reaction step the DHAA obtained in extraction can be converted to artemisinin via a photooxidation followed by an acid-catalyzed reaction sequence. To initiate the photooxidation, a photoactive compound is required which transfers absorbed light energy to triplet oxygen forming highly reactive singlet oxygen. We showed that chlorophyll, a second byproduct of the extraction, can be utilized to initiate the photooxidation [2] making the addition of other, often toxic photocatalysts unnecessary. Thus, artemisinin can be synthesized out of crude extract of A. annua by treating it just with oxygen, acid and visible light. The partial synthesis is investigated in close collaboration with the group of Prof. P.H. Seeberger and Dr. Kerry Gilmore of the Max Plank Institute for Colloids and Interfaces, Golm.

For the purification of artemisinin from reaction mixture without prior extraction, efficient combinations of chromatography and crystallization processes have been studied. 3-zone SMB chromatography with a capture step and seeded cooling crystallization were coupled successfully providing artemisinin at required purity constraints (>99.5%) and acceptable yield (Purity = 99.9%, Yield = 61.5%). Future work will be dedicated to adapt the developed methods to purify artemisinin from enriched extract.


[1] Münzberg, S., Vu, T. G., Seidel-Morgenstern,A., (2018) Generalizing Countercurrent Processes: Distillation and Beyond, Chemie Ingenieur Technik, 90 (11), pp. 1769-1781
[2] Triemer, S., Gilmore, K., Vu, T.G., Seeberger, P.H., Seidel-Morgenstern, A., (2018) Literally Green Chemical Synthesis of Artemisinin from Plant Extracts, Angewandte Chemie International Edition, 57 (19), pp. 5525-5528
[3] O'Brien, A. G., Horvath, Z., Lévesque, F., Lee, J. W., Seidel-Morgenstern, A., Seeberger, P. H., (2012) Continuous Synthesis and Purification by Direct Coupling of a Flow Reactor with Simulated Moving-Bed Chromatography. Angewandte Chemie International Edition, 51 (28), pp. 7028-7030
[4] Horvath, Z., O'Brien, A. G., Seeberger, P. H., Seidel-Morgenstern, A., (2014) Design and optimization of coupling a continuously operated reactor with simulated moving bed chromatography. Chemical Engineering Journal , 251, pp. 355-370
[5] Gilmore K., Kopetzki, D., Lee J.W., Horváth Z., McQuade D.T., Seidel Morgenstern A., Seeberger P.H., (2014) Continuous synthesis of artemisinin-derived medicines, Chem. Comm, 50, pp. 12652-12655
[6] Horvath Z., Horosanskaia E., Lee J. W., Lorenz H., Gilmore K., Seeberger P.H., Seidel-Morgenstern, A., (2015) Recovery of artemisinin from a complex reaction mixture using continuous chromatography and crystallization, Organic Process Research & Development, 19 (6), pp. 624-634

Coupled enantioselective resolution and enzymatic racemization

Keywords: enantioselective HPLC, preferential crystallization, enzymatic racemization, mathematical modelling.

While significant improvement is made in enantioselective resolution techniques, such processes suffer a major drawback in their 50% yield constraint, as the unwanted by-product enantiomer is typically discarded after the separation. An attractive solution is the subsequent recycling of the by-product enantiomer by racemization. The racemization reaction converts the by-product into a racemic mixture of both enantiomers, which can be separated again, resulting in a significant yield increase.

Fig. 1: General process scheme for coupled enantiomer production processes.

Racemization reaction

Racemization can be performed chemically, but this process often includes high temperatures, extreme pH values or is very slow. An eco-friendly alternative is the use of enzymes as biocatalyst, which not only accelerate the racemization reaction but in general also operate at moderate conditions, allowing an easier coupling with the resolution units.

Coupling options

In this group, model molecules are separated with enantioselective liquid chromatography (LC) and with preferential crystallization (PC) followed in both cases a by-product racemization with an immobilized racemase. The process with LC was studied for resolving the mandelic acid enantiomers using a mandelate racemase. For comparison, the coupled process with PC was tested for resolution of the enantiomers of the conglomerate forming amino acid asparagine coupled with an amino acid racemase catalyzed reaction. Suitable initial operating conditions for the process couplings were identified empirically for the single process units as well as for the coupled processes. 

Fig. 2: Schematic illustration of coupled enantioselective batch chromatography and enzymatic racemization.

Fig. 3: Schematic illustration of coupled preferential batch crystallization and enzymatic racemization.

Enzyme immobilization

The enzyme production is often time consuming and can be expensive. Therefore, the enzyme is immobilized to enable reuse. Suitable immobilization procedures were developed for both enzymes. The amino acid racemase was purified with metal ion affinity chromatography and immobilized on Lifetech amino-activated resin. Due to its high activity, the crude extract of mandelate racemase was directly immobilized on Eupergit CM by Sigma-Aldrich.


Process simulation

Simulations based on mathematical models and experimental parameters were used for a deeper process understanding and to investigate the influence of operating conditions on the key performance indicators. In both cases the coupling not only increased the coupled process yield, but also its the purity and productivity. All obtained information were evaluated to find optimal conditions and to identify the potential of the two variants of the coupled process for resolution of enantiomers of other chiral compounds.


[1] Wrzosek, K., García Rivera, M. A., Bettenbrock, K., Seidel‐Morgenstern, A., (2016) Racemization of undesired enantiomers: Immobilization of mandelate racemase and application in a fixed bed reactor. Biotechnology journal, 11(4), pp. 453-463
[2] Carneiro, T., Bettenbrock, K., Lorenz, H., Seidel-Morgenstern, A. (2016) Combination of Preferential Crystallization and Racemization – First Results. In Proceedings of BIWIC 2016; Magdeburg, pp. 173-178
[3] Wrzosek, K., Harriehausen, I., Seidel‐Morgenstern, A., (2018) Combination of enantioselective preparative chromatography and racemization: Experimental demonstration and model based process optimization, Organic Process Research & Development [Accepted]
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