FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
PROCESS FOR THE PURIFICATIONTION OF CHLOROTHIAZIDE SODIUM


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 invention provides the process for purification of chlorothiazide sodium by treating chlorothiazide with sodium source in methanol. The process involves the formation of chlorothiazide sodium methanol solvate and converting the solvate into chlorothiazide sodium.
The following specification particularly describes the invention and the manner in which it is to be performed.

I

4. DESCRIPTION
The invention provides the process for purification of chlorothiazide sodium by treating chlorothiazide with sodium source in methanol. The process involves the formation of chlorothiazide sodium methanol solvate and converting the solvate into chlorothiazide sodium.
Chlorothiazide of Formula I is chemically known as 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is commercially available under the trade name DIURIL®.
DIURIL® is indicated for the adjunctive therapy in edema associated with congestive heart failure, renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs.

FORMULA I
U.S. Patent No. 2,809,194 discloses synthesis of chlorothiazide.
U.S. Patent No. 3,160,629 discloses the synthesis of chlorothiazide by oxidation of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide with potassium permanganate.


Several other processes are known in the art for preparation of chlorothiazide in U.S. Patent No. 2,965,675, U.S. Patent No. 2,937,169, British patent No. 0,826,923 and French Patent No. 1,271,021.
The inventors have developed the process for purification of chlorothiazide sodium by treating chlorothiazide with sodium source in methanol. The process involves the formation of chlorothiazide sodium methanol solvate and converting the solvate into chlorothiazide sodium.
The chorothiazide sodium solvate showed different XRPD pattern than the chlorothiazide sodium. The chlorothiazide sodium obtained by the process of the invention has purity 99.5 % or more when measured by HPLC.
In one of the aspect of invention there is provided a process for preparation of chlorothiazide sodium methanol solvate wherein the process includes steps of,
a) treating chlorothiazide with sodium source in methanol,
b) isolating the product from the reacton mass thereof.
The chlorothiazide is obtained by the process known in the art via U.S. Patent No. 2,809,194. The process involves the dissolution of chlorothiazide in methanol and treating the reaction mixture with sodium source in methanol. Subsequent removal of the solvent from the reaction mixture under reduced pressure and the product is isolated by addition of suitable solvent.
Sodium source term defined here as sodium hydroxide, sodium methaoxide or sodium 2-ethyl hexonoate solution in methanol.
Chlorothiazide sodium solvate with methanol XRPD pattern is shown in Fig.1 and has purity 99% or more when measured by HPLC wherein moisture content is 5.2 to 6.0%.

DSC of chlorothiazide sodium solvate with methanol is shown in Fig 2.
In another aspect of the invention provides the process for the preparation of solvate free chlorothiazide sodium. The process includes steps of:
a) contacting chlorothiazide sodium methanol solvate in methanol
b) isolated the product from reaction mixture thereof.
The process involves the dissolution of chlorothiazide sodium solvate in methanol and removal of solvent at atmosphere pressure. The chlorothiazide sodium is isolated by addition of alkanol solvents or ester solvents in the reaction mixture. The XRPD pattern of chlorothiazide sodium is shown in Fig 3 and its DSC is shown in Fig 4.
The suitable solvent includes alkanol and ester solvents such as isopropanol, isobutanol, ethyl acetate or the mixture thereof.
The term isolated includes the isolation of the product by filtration decantation after removal of the solvent or addition of suitable solvent.
The invention is further illustrated by the following example which is 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 invention.
Example 1: Chlorothiazide Sodium Methanol Solvate
To the solution of chlorothiazide (85 gm) and methanol (200 ml) was added methanolic sodium hydroxide solution (11.80 gm sodium hydroxide; in 350 ml of methanol) to obtain clear solution. The solution was concentrated under reduced pressure and isopropyl alcohol (250 ml) was added. The reaction mixture is
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further stirred for 30-40 min for complete precipitation of product. The precipitated product was filtered, washed and dried to yield chlorothiazide sodium methanol solvate.
Yield : 84 gm
Purity = 99.8% (by HPLC)
Moisture content = 5.37%
Example 2: Chlorothiazide Sodium
The chlorothiazide sodium methanol solvate (10 gm) was dissolved in methanol (80 ml) to get clear solution. The solution was stirred at room temperature for 20-30 minute followed by removal of methanol under atmosphere pressure to get the syrupy mass. In the syrupy mass ethyl acetate (50 ml) was added followed by partial removal of ethyl acetate precipitates the product. The reaction mixture was further stirred for 20- 30 minutes, precipitated product is filtered, isolated and dried to yield chlorothiazide sodium. Yield = 8.4 gm Purity = 99.89% (by HPLC) Moisture content = 1.38
Example 3: Preparation of chlorothiazide sodium.
To the solution of chlorothiazide (100 gm) in methanol (250 ml) was added methanolic sodium hydroxide solution (14 gm sodium hydroxide; in 400 ml of methanol) to obtain clear solution. The solution concentrated at atmospheric pressure and product is completely precipitated by addition of ethyl acetate (400 ml). The precipitated product was filtered, washed and dried to yield chlorothiazide sodium Yield: 100 gm Purity = 99.8% (by HPLC)
Moisture content = 1.14 %


We claim:
1. A process for preparation of chlorothiazide sodium methanol solvate
wherein the process comprises of,
a) treating chlorothiazide with sodium source in methanol,
b) isolating the product from the reaction mass thereof.

2. The process of claim 1, wherein sodium sources are one of sodium hydroxide, sodium methoxide or sodium 2-ethyl hexanoate.
3. The process of claim 1, wherein the methanol is removed under reduced pressure and the product is isolated by addition of alkanol and or ester solvent
4. The process of claim 3, wherein alkanol and ester solvent are one or mixture of isopropanol, isobutanol, ethyl acetate.
5. A chlorothiazide sodium methanol solvate.
6. The chlorothiazide methanol solvate of claim 5, wherein the XRD is shown in fig 1.
7. The chlorothiazide methanol solvate of claim 5, wherein, moisture content is 5.3-5.8%.
8. A chlorothiazide sodium methanol solvate having purity 99.0% or more when measured by HPLC.
9. A process for preparation of solvate free chlorothiazide sodium wherein process comprises of;
a) contacting chlorothiazide sodium methanol solvate in methanol
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b) isolated the product from reaction mixture thereof.
1O.The process of claim 8, wherein the methanol is removed at atmospheric pressure and the product is isolated by addition of alkanol and or ester solvent.