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Research Project: Genetic Improvement of Crop Plants for Use with Low Quality Irrigation Waters: Physiological, Biochemical and Molecular Approaches

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Title: Preparative separation of high-purity dihydroartemisinic acid from artemisinin production waste by combined chromatography

Author
item LIU, SHUOQIAN - Hunan Agricultural University
item Ferreira, Jorge
item TIAN, DONGMING - Hunan Agricultural University
item TANG, YUWEI - Hunan Agricultural University
item LIU, LIPING - Hunan Agricultural University
item YANG, WEI - Hunan Agricultural University
item LIU, ZHONGHUA - Hunan Agricultural University
item TIAN, NA - Hunan Agricultural University

Submitted to: Chemical and Pharmaceutical Bulletin
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/22/2017
Publication Date: 12/28/2017
Citation: Liu, S., Ferreira, J.F., Tian, D., Tang, Y., Liu, L., Yang, W., Liu, Z., Tian, N. 2017. Preparative separation of high-purity dihydroartemisinic acid from artemisinin production waste by combined chromatography. Chemical and Pharmaceutical Bulletin. 66(3):319-326. https://doi.org/10.1248/cpb.c17-00927.
DOI: https://doi.org/10.1248/cpb.c17-00927

Interpretive Summary: Malaria is the major killing parasitic disease in the world, killing mostly children under the age of five. Currently, malaria is resistant to most quinine-derived drugs, but is treated successfully by artemisinin-based combination therapies (ACT). Artemisinin (ART) is produced by the plant Artemisia annua and is required for the production of ACT. Currently, the price or ACT is still unaffordable by the majority of people living in malaria-stricken areas. ACT prices can decrease if artemisinin yield per cultivated area can increase. Dihydroartemisinic acid (DHAA), a direct plant precursor of artemisinin (ART), is produced by the plant at concentrations similar, or superior, to ART but is discarded as waste after the commercial extraction of ART. In order to make full use of the ART production waste (APW) and to increase ART yield, we have developed an efficient and scalable method that leads to high-purity DHAA from APW by combining anion-exchange chromatography with silica-gel column chromatography. These technologies use separation columns made of special polymers or resins that adsorb DHAA while letting undesirable compounds go through. Then, special solvents can desorb DHAA in a highly-purified form. We have tested the adsorption and desorption characteristics of DHAA on ten anion-exchange resins and identified a resin with the highest capacity of adsorption and desorption for DHAA. Subsequently, further purification of DHAA by silica-gel column chromatography was achieved, and a purity of up to 98% (w/w) was obtained for DHAA. Finally, a scaled-up separation of DHAA from APW was performed and the results validated the method developed in this study. This work presents for the first time a preparative isolation of high- purity DHAA from APW with a final yield of 2.59%. This technology can significantly increase the final yield of ART per plant and per hectare via transformation of DHAA to ART in vitro, and has the potential to lower the prices of ART as raw material for anti-malarial drugs.

Technical Abstract: In order to make full use of artemisinin production waste and thus to reduce the production cost of artemisinin, we developed an efficient and scalable method to isolate high-purity dihydroartemisinic acid from artemisinin production waste by combining anion-exchange resin with silica-gel column chromatography. The adsorption and desorption characteristics of dihydroartemisinic acid on 10 types of anion-exchange resin were investigated, and the results showed that the 717 anion-exchange resin exhibited the highest capacity of adsorption and desorption to dihydroartemisinic acid. Adsorption isotherms were established for the 717 anion-exchange resin and they fitted well with both Langmuir and Freundlich model. Dynamic adsorption and desorption properties of 717 anion-exchange resin were characterized to optimize the chromatographic conditions. Subsequently, the silica-gel column chromatography was performed and dihydroartemisinic acid with a purity of up to 98% (w/w) was obtained. Finally, the scale-up experiments validated the preparative separation of high-purity dihydroartemisinic acid from industrial waste developed in the present work. This work presented for the first time an isolation of dihydroartemisinic acid with a purity of 98% from Artemisia annua (A. annua) by-product, which adds more value to this crop and has the potential to lower the prices of anti-malarial drugs.