Recovery of Artemisinin from a Complex Reaction Mixture Using Continuous Chromatography and Crystallization

Abstract

Artemisinin, a secondary metabolite of sweet wormwood, is the basis for the production of the most effective antimalarial drugs. Since the amount of artemisinin currently produced from plants is not sufficient to treat the worldwide malaria cases, an effective semisynthetic method was developed recently that is capable of producing artemisinin from dihydroartemisinic acid (DHAA). DHAA is a byproduct obtained during the extraction of artemisinin from plant leaves. The photocatalytic reaction to convert DHAA to artemisinin can be performed continuously in a tubular reactor using toluene as a solvent. The reactor effluent contains besides artemisinin the photocatalyst (dicyanoanthracene) and several compounds that are structurally similar to artemisinin, including unreacted DHAA starting material. To isolate artemisinin from the reaction mixture, two separation techniques were applied, crystallization and chromatography. The solid obtained by seeded cooling crystallization was highly enriched in artemisinin but contained also traces of the photocatalyst. In contrast, using a variant of continuously operated multicolumn simulated moving bed (SMB) chromatography, which splits the feed into three fractions, we were able to recover efficiently the photocatalyst in the raffinate stream. The extract stream provided already almost pure artemisinin, which could be finally further purified in a simple crystallization step

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…113,114 Following the synthesis of Artemisinin, first an SMB chromatographic separation brought the product mixture to 92% purity, then crystallization from the concentrated mixture provided the pure API in 99.9% purity. 115 …”

Continuous Synthesis and Purification by Coupling a Multistep Flow Reaction with Centrifugal Partition Chromatography

“…In‐line work‐up can remove co‐products while it cannot eliminate by‐products that are structurally related to the desired product. High purity can be achieved by final‐product purification by multicolumn chromatography, simulated moving bed (SMB) chromatography, catch‐and‐release chromatography, crystallization, or recrystallization, although these methods have their drawbacks. Crystallization usually requires semi‐batch processing, and catch‐and‐release chromatography can only be categorized as a truly continuous purification method when automated switching between multiple columns is employed .…”

“…Crystallization usually requires semi‐batch processing, and catch‐and‐release chromatography can only be categorized as a truly continuous purification method when automated switching between multiple columns is employed . The operation of SMB chromatography is technically complex; furthermore, it utilizes expensive solid adsorbents, and challenging separations may require additional crystallization …”

Continuous Synthesis and Purification by Coupling a Multistep Flow Reaction with Centrifugal Partition Chromatography

“…In‐line work‐up can remove co‐products while it cannot eliminate by‐products that are structurally related to the desired product. High purity can be achieved by final‐product purification by multicolumn chromatography, simulated moving bed (SMB) chromatography, catch‐and‐release chromatography, crystallization, or recrystallization, although these methods have their drawbacks. Crystallization usually requires semi‐batch processing, and catch‐and‐release chromatography can only be categorized as a truly continuous purification method when automated switching between multiple columns is employed .…”