Process for isolating artemisinin from Artemisia annua

Details Process for isolating artemisinin from Artemisia annua Process for isolating artemisinin from Artemisia annua

2002-03-27

2004-02-03

Tate, Christopher R. (Department: 1654)

Drug, bio-affecting and body treating compositions

Plant material or plant extract of undetermined constitution...

Containing or obtained from artemisia

C424S774000, C514S450000, C514S452000, C549S276000, C549S348000

Reexamination Certificate

active

06685972

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the isolation of artemisinin, an antimalarial agent from the herb of the
Artemisia annua
plant, comprising of extracting the herb with ethanol, partitioning of the extract between water and hexane, followed by evaporative crystallization of artemisinin from hexane phase to produce substantially pure artemisinin.
BACKGROUND AND PRIOR ART OF THE INVENTION
Artemisinin (Qinghaosu) is a sesquiterpene lactone endoperoxide having potent antimalarial activity (Klayman D L, 1985, Science 228, 1049). Clinical studies on artemisinin and its semisynthetic derivatives such as artemether, artesunate and arteether have been used in the treatment of malaria, including severe complicated-, multiple drug resistant- and cerebral-malaria. As being structurally different from commonly used antimalarials the problem of resistance and cross-resistance (that is now seriously limiting the effectiveness of such drugs) is not observed for artemisinin and its derivatives. Recently, methods have been reported for chemical synthesis of artemisinin but large scale economical synthesis is still not possible. Thus, plant
Artemisia annua
remains the sole source of artemisinin for the industry. The present invention provides a rapid, simple and economical method for the isolation of artemisinin from plant
Artemisia annua.
Ancient methods (Klayman D L, Lin A J, Acton N, Scovill J P, Hoch J M, Milhous W K & Theoharides A D, 1984, Jour of Natural Products 47:715-717 and Rucker G, Mayer R & Manns D, 1986, Planta Medica, 3 : 245) involved the extraction of plant material with the petroleum ether followed by chromatographing the relatively crude extract on silica gel. The column was eluted with a mixture of 7.5% ethyl acetate in chloroform to obtain pure artemisinin. Later Singh A, Vishwakarma R A, Husain A, 1988, Planta Medica 64, 475-476 reported extraction of plant parts with n-hexane followed by chromatographing the extract on silica gel column. In this case elution was performed with the mixture of ethyl acetate and hexane. In these process major disadvantage was that the procedure depend upon chromatographing a relatively crude extract on silica gel. This needs large solute to adsorbent ratio 1:44, which is expensive.
Another method of artemisinin extraction involves the extraction of plant material with hexane, followed by partitioning the extract between hexane and acetonitrile followed by chromatographing the acetonitrile phase on silica gel (ElFerali F S, ElSohli H N, 1990, U.S. Pat. No. 4,952,603). Slow extraction of artemisinin in hexane needs hot percolation for longer duration, while for partitioning step, acetonitrile being relatively costly relatively costly solvent, increases cost of production for artemisinin. Another disadvantage of this method is that for obtaining artemisinin column chromatography is unavoidable. Yet another disadvantage is that artemisinic acid being predominant, it tends to elute with artemisinin, thus affecting the purity of artemisinin.
Jain D C, Tandon S, Bhakuni R S, Siddique M S, Kahol A P, Sharma R P, Kumar S, Bhattacharya A K, 1999, U.S. Pat. No. 5,955,084 suggests a process for simultenous production of artemisinin and essential oil from the plant
Artemisia annua
. In this process basic methodology for artemisinin extraction involves the extraction of plant material with hexane, followed by partitioning the extract between hexane and acetonitrile followed by chromatographing the acetonitrile phase on silica gel. Additionally the method suggests the extraction of essential oil from the residual marc by hydro-distillation and also describes a method for isolation of artemisinic acid and its conversion in to artemisinin. Overall the process disclosed is a complex amalgamation of several chemical reactions. However certain problems remained untouched such as the process being time consuming and costly affair because of using the hexane as extraction solvent, partitioning the extract between hexane and acetonitrile followed by chromatography.
A process for extracting aretannuin from
Artemisia annua
was reported by Zhang J, Fan D and Ma X (1994) Patent No. CN 1092073 A, which involve leaching the leaves of
Artemisia annua
with aqueous ethanol (<70% concentration) followed by extracting the leaching liquid with gasoline containing 30% of benzene or ethyl acetate in a continuous extracting device. Gasoline extract was then treated with activated carbon to decolorize followed by concentrating and crystallizing the artemisinin using ethanol. In this process large volumes of aqueous ethanol are needed to be fractionated with gasoline containing 30% benzene or ethyl acetate to make the ethanol clean for recycling. This lead to the transfer of most of the compounds extracted in ethanol:water mixture in to the gasoline and benzene mixture. Concentrating the gasoline mixture followed by crystallization of aretimisinin using ethanol results in crystallization. Use of commercial grade benzene during the processing is not suitable because of their possible toxic effects. The process used a mixture of solvents during transfer, which can not be re-used further.
Wheatley G W and Chapman T B, 2001, U.S. Pat. No. 6,180,105 disclosed another method for artemisinin production which involves extraction of the dry herb of
Artemisia annua
using liquid carbon dioxide and allowing the carbon dioxide to evaporate from the resultant mixture. This method is dependent on liquid carbon dioxide, which is obtainable only from liquid carbon dioxide preparing plant (a very costly device).
A reference may also be made to the Applicant's U.S. Pat. No. 5,995,084 which describes a process for the simultaneous production of artemisinin and essential oil from the plant
Artemisia annua
. In the aforesaid invention, artemisinic acid is separated from the artemisinin before it is treated with base.
Also, a reference may be made to the Applicants co-pending application Ser. No. 09/538,892 wherein an agricultural method for maximizing the artemisinin yield of the plant
Artemisia annua
is described. However, this application concentrates upon the agricultural method of scheduling the growing of the plant rather at the process for extraction of artemisinin.
The Applicant's The extraction with n-hexane petroleum ether are mostly used solvents, which take more time for extraction, and require hot percolation. These solvents are hazardous in nature. Subsequently most of the methods used chromatography to obtain artemisinin, which is a major cause for higher cost of production.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a simple, rapid, cost effective and practical method for the isolation of artemisinin from plant
Artemisia annua
without using chromatography, which yields artemisinin in substantial quantities and purity obviating the drawbacks of the prior art.


REFERENCES:
patent: 5413928 (1995-05-01), Weathers et al.
patent: 5955084 (1999-09-01), Jain et al.
patent: 6180105 (2001-01-01), Wheatley et al.
patent: 1092073 (1994-09-01), None

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