FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR THE PURIFICATION OF DIACEREIN.

2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad - 431210 (M.S.) India
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved and economical process for purification of Diacerein.
The following specification particularly describes the invention and the manner in which it is to be performed.



FIELD OF THE INVENTION
The present invention prov'des an improved and economical process for purification of Diacerein.
BACKGROUND OF THE INVENTION

Diacerein of Formula I is chemically known as 4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid and is indicated for the treatment of osteoarthritis. It acts by inhibiting interieukin-1.
o
.COOH
Y Y
o o
Formula I
Journal of Chemical Society (Transactions), 1909, 1085-1095) reported a process for the preparation of Diacerein. U.S. Patent No. 5670695 and European patent Nos. 0243698, 0520414 and 0636602 also disclose preparation of Diacerein from aloin.
U.S. Patent No. 5986129 discloses a process for the preparation of Diacerein starting from substituted diphenyl ketones.
Several other patents e.g. United States Patent Nos. 5,391,775, 5,393,898, 6,596,764 and 6,624,192 discloses a process for the preparation of Diacerein from rhein-9-anthrone-8-glucoside.
EP 0636602, 1567474, 00928781 U.S. Patent 5756782, 5670695 U.S Application 2007037992 & 20060135797 and PCT application PCT/EP 00/03691 & WO 01/96276
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discloses methods of purification of Diacerein in order to reduce the content of aloe-emodine impurity in Diacerein.
Other means of purification of diacerein are disclosed in EP 1669344 and US Patent 4,950,687. The salification of diacerein and extraction with organic solvent afford pure Diacerein.
Aloe-emodine (1,8-dihydroxy-3-hydroxymethyl-anthracinone) and triacetyl aloe-emodine are the major impurity associated with Diacerein. Aloe-emodine is a cathartic compound and possesses mutagenic properties. There are several processes have been reported in prior art for preparing Diacerein with minimum level of aloe-emodine impurity. This impurity is formed due to incomplete oxidation of acetylated-aloin with chromium trioxide.
While working on the purification process of Diacerein, inventors have come up with a simple purification process of Diacerein wherein the aloemodine content is below 2ppm in the finish product. Crystallization is one of the means to achieve the desired purity of Diacerein and keep the Aloemodine impurity level below 2 ppm. The inventors have developed a single step recrystallization process wherein Diacerein is recrystallize in a suitable solvent to obtain pure Diacerein with aloemodine content below 2 ppm.
In one of the aspect provided herein a process for purification of Diacerein includes the step of:
(a) Dissolving crude diacerein in suitable solvent,
(b) isolating pure decerein form the reaction mixture thereof.
The Diacerein has a purity of more than 99.5 % and combined aloe-emodine and triacetyl aloe-emodine content of less than 2 parts per million (ppm).
The inventors have also developed a pharmaceutical compositions that contain Diacerein having a purity of more than 99.5 % and combined aloe-emodine and triacetyl aloe-emodine content of less than 2 ppm with an admixture of one or more pharmaceutically acceptable carrier, excipient or diluents.
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Crude diacerein, having the combined aloe-emodine and triacetyl aloe-emodine content of more than 5 ppm, can be obtained from any of the process reported in the prior art. The so obtained crude Diacerein can be purified in several ways. It can be slurry washed with a suitable solvent or can be recrystallised from a suitable organic solvent to remove the impurities. It can also be treated with activated charcoal to remove coloring impurities. The Diacerein can be precipitated by cooling of the reaction mixture or removal of the solvent under reduced pressure or by addition of the antisolvent in to reaction mass or vice versa. The isolated Diacerein is dry at temperature 60-70 deg to for the removal of solvent and volatile impurities.
The suitable organic solvent comprises protic polar solvent, an aprotic polar
solvent, or a mixture of a protic polar solvent and an aprotic polar solvent.
For example polar protic solvent, polar aprotic, protic solvent which may include of methanol, ethanol, isopropanol , n-propanol , Acetone, Dimetyl suphoxide, Dimethyl acetamide, Dimethyl formamide, water, and the like may be used as single or in mixture of to purify Diacerein.
The anti-solvent is characterized by the fact that the Diacerein is insoluble, practically insoluble or very slightly soluble in the anti-solvent. The terms insoluble, practically insoluble or very slightly soluble have their ordinary meanings as defined in United States Phamacopoeia 2002. The resultant mass can be gradually cooled to about 0-35°C and filtered to get the pure Diacerein.
The isolation may be achieved by general techniques like filtration, decantation, centrifugation or evaporation of a solution.
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The Diacerein obtained by the process of present invention having purity more than 99.5 % and combined aloe-emodine and triacetyl aloe-emodine impurity content of less than 2 parts per million.
The purity of Diacerein is measured using HPLC. Diacerein thus obtained can be used for the preparation of various pharmaceutical compositions with therapeutic effective amount of and one or more pharmaceutically acceptable carrier, excipient or diluents.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Purification of Diacerein: Example 1:
Charged Diacerein (50 gm; Aloe emodine + Tri acetyl aloe-emodine content-9.6 ppm) and dimethylsulfoxide (500 ml) in a round bottom flask and heat the mixture at 50-60°C to get clear solution. The reaction mixture is added into pre cooled water of 10 °C (1.45 L) reaction mass is stirred at same temperature for one hour and stirred for 2 hours at room temperature. The precipitated product is filtered, washed and dried.
Yield - 48 g
Impurity profile-
Aloe-emodine + Triacetyl aloe-emodine-1.9 ppm
Purity-99.82 %
Example 2:
Charged Diacerein (50 gm; Aloe emodine + Tri acetyl aloe-emodine content-10 ppm) dimethylsulfoxide (400 ml) and acetone (100 ml) in a round bottom flask and heat the
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mixture at 50-60°C to get clear solution. The reaction mixture is added into pre cooled water of 10 °C (1.5 L) reaction mass is stirred at same temperature for one hour and stirred for 2 hours at room temperature. The precipitated product is filtered, washed and dried.
Yield - 47g
Impurity profile-
Aloe-emodine + Triacetyl aloe-emodine-1.4 ppm
Purity-99.76 %
Example 3:
Charged Diacerein (120 gm; Aloe emodine + Tri acetyl aloe-emodine content-14 ppm); was suspended in dimethylacetamide (240 ml) at 70-80 °C for one hour and suspended material was cooled to room temperature and stirred at 0-5 °C for one hour. Suspended solid was filtered, washed and dried.
Yield-96 gm
Purity-99.79%
Aloe emodine +Triacetyl aloe-emodine content 0.4 ppm
Example 4:
Charged Diacerein (100 gm; Aloe emodine + Tri acetyl aloe-emodine content-11 ppm); was suspended in dimethylacetamide (240 ml) and methanol (100 ml) at 70-80 °C for one hour and suspended material was cooled to room temperature and stirred at 0-5 °C for one hour. Suspended solid was filtered, washed and dried.
Yield-91 gm
Purity-99.86%
Impurity profile-Aloe emodine +Triacetyl aloe-emodine content 0.7 ppm
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We Claim:
1. A process for purification of Diacerein comprising:
(a) dissolving crude Diacerein in suitable solvent,
(b) isolating pure Diacerein form the reaction mixture thereof.

2. The process of claim 1 wherein, suitable solvent is protic polar solvent, an aprotic polar solvent, or a mixture of a protic polar solvent or a mixture of aprotic solvent or a mixture of protic polar solvent and an aprotic polar solvent.
3. The process of claim 2 wherein the protic polar solvent is a lower alkanol.
4 The process of claim 3 wherein the protic polar solvent is methanol, n propanol or iso propanol.
5. The process of claim 2 wherein the aprotic polar solvent is N,N dimethylformamide, acetonitrile, dimethylsulfoxide, N,N-dimethyl acetamide , acetone.
6. The process of Claim 5 wherein the aprotic polar solvent is N, N dimethylsulphoxide.
7. The process of claim 1 wherein a mixture of protic or and aprotic polar solvents is used.
8. The process of Claim 2 wherein the isolation is done by pouring the reaction mass into water.
9. The purity of pure diaerein is more than 99.5 % with combined content of aloe-emodine and triacetyl aloe-emodine in pure diacerein is not more than 2ppm.
10. Pharmaceutical compositions comprising treaputic effective amount of Diacerein having a purity of more than 99.5 % and combined aloe-emodine and triacetyl aloe-emodine content of less than 2 ppm prepared by the process of claim 1; and one or more pharmaceutical^ acceptable carrier, exciepient or diluents.
Dated this _th day of Jul 2008 For Wockhardt Limited

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