Indian Patents. 224632:AN IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE CEPHALOSPORIN

Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE CEPHALOSPORIN
Abstract	The present invention relates to an improved process for the preparation of crystalline cephalosporin, more particularly cefoperazone sodium of formula (I) in pure form.

Full Text	Field of the invention The present invention relates to an improved process for the preparation of crystalline cephalosporin, more particularly cefoperazone sodium of formula (I) in pure form. Description of the prior art Cefperazone is an semi-synthetic cephalosporin with broad activity against resistant Gram negative bacteria, widely used in clinic due to its effectiveness in the cases of severe infections of skin, high and lower respiratory tract, central nervous system and genital-urinary system, cefoperazone is usually administered parenterally as the sodium salt which is available both in the amorphous and crystalline form. Cefoperazone sodium is disclosed in GB 1,508,071 as an amorphous solid and crystalline form is disclosed in US patent NO. 4,458,070 and 4,456,753. In general crystalline form of cefoperazone sodium is more stable than amorphous form since the former having higher purity, stability and lower hydroscopicity. In U.S pat. No 4,456,753 & 4,458,070 discloses a process for the preparation of crystalline cefoperazone sodium, the former one involves the usage of acetone/water mixture and the latter involves the usage of acetone/water/dichloromethane. Both processes yield sodium cefoperazone in the form of free needle microcrystals hence filtrations or centrifuge takes more time. WO 01/79210 discloses a process for the preparation of cefoperazone sodium using acetone/water/lower alcohol. KR 9600359 discloses a process for the preparation of cefoperazone sodium using THF/water/acetone/MIBK. Objectives of the invention The main objective of the present invention is to an improved process for the preparation of crystalline cefoperazone sodium of formula (I) in pure form. Another objective of the present invention is to provide a process for the preparation of crystalUne cefoperazone sodium of formula (I), which is easy to implement on commercial scales. Still another objective of the present invention is to provide a process for the preparation of crystalline cefoperazone sodium of formula (I), which is easy to filter. Still another objective of the present invention is to provide a process for the preparation of crystalline cefoperazone sodium of formula (I) in good yield and high purity. Summary of tlie invention: Accordingly, the present invention provides an improved process for the preparation of crystalline cefoperazone sodium of formula (I), the said process comprising the steps of: (i) dissolving cefoperazone acid in a solvent at a temperature in the range of 10oCto 50°C, (ii) adjusting pH of the solution to 5.5 to 7.0 with a solution containing source of sodium ions, and (iii) adding a mixture of two solvents selected from acetone/ethyl acetate, acetone/methyl acetate to precipitate crystalline cefoperazone sodium. Detailed description of the invention In an embodiment of the present invention, the solvent employed in step (i) is selected from acetone, THF, ethyl acetate, methanol, water and the like or mixtures thereof. In another embodiment of the present invention, the sodium ion source used in step (ii) is selected from sodium acetate, sodium lactate, sodium 2-ethyl hexonate, sodium bicarbonate, sodium hydroxide, sodium carbonate and the like or mixtures thereof. In still another embodiment of the present invention the preferable pH in step (ii) are 6.0 to 6.5. In another embodiment of the present invention, the solvent used in step (ii) to dissolve sodium ion source is selected from water, methanol, ethyl acetate and the like or mixtures thereof. In yet another embodiment of the present invention, the preferable mixture of solvent employed in step (iii) is acetone/ethyl acetate. In another embodiment of the present invention the mixture of two solvents can be added either in single addition or controlled addition so as to get crystalline cefoperazone sodium. In yet another embodiment of the present invention crystalline cefoperazone sodium obtained is sterile. In yet another embodiment of the present invention, the starting material cefoperazone acid is prepared according to the procedures available in the prior art. The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint and affords good quality of crystalline cefoperazone sodium of the formula (I). Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is illustrated with the following example, which should not be construed as limiting the scope of the invention. Example 1: Preparation of Cefoperazone sodium To acetone (225 ml) cefoperazone acid (75 gm) followed by sodium bicarbonate solution (9 gm in 113 ml water) were added at 20 °C and stirred 10 minutes. To the clear solution activated carbon was added stirred 10 minutes. Carbon was filtered and the solution was passed through 0.2-micron filter in sterile area. To the solution a mixture of acetone (1890 ml) and ethyl acetate (285 ml) were added in 3 lots. The solid obtained was filtered, washed with acetone dried to get the title compound (73-75 gm) in pure form. Claims: 1. A process for the preparation of crystalline cefoperazone sodium of formula (I), which comprising the steps of: i) dissolving cefoperazone acid in a solvent at a temperature in the rangeof l0°C to 50°C, ii) adjusting pH of the solution to 5.5 to 7.0 with a solution containing source of sodium ions, and iii) adding a mixture of two solvents selected from acetone/ethyl acetate, acetone/methyl acetate to precipitate crystalline cefoperazone sodium. 2. The process as claimed in claim 1, wherein the solvent employed in step (i) is selected from acetone, THF, ethyl acetate, methanol, water or mixtures thereof. 3. The process as claimed in claim 1, wherein the sodium ion source employed in step (ii) is selected from sodium acetate, sodium lactate, sodium 2-ethyl hexonate, sodium bicarbonate, sodium hydroxide, or sodium carbonate 4. The process as claimed in claim 1, wherein the preferable pH in step (ii) is 6.0 to 6.5. 5. The process as claimed in claim 1, the preferable mixture of solvent employed in step (iii) is acetone/ethyl acetate. 6. The process as claimed in claim 1, wherein the crystalline cefoperazone sodium obtained is sterile.

Full Text

Field of the invention
The present invention relates to an improved process for the preparation of crystalline cephalosporin, more particularly cefoperazone sodium of formula (I) in pure form.
Description of the prior art
Cefperazone is an semi-synthetic cephalosporin with broad activity against resistant Gram negative bacteria, widely used in clinic due to its effectiveness in the cases of severe infections of skin, high and lower respiratory tract, central nervous system and genital-urinary system, cefoperazone is usually administered parenterally as the sodium salt which is available both in the amorphous and crystalline form.
Cefoperazone sodium is disclosed in GB 1,508,071 as an amorphous solid and crystalline form is disclosed in US patent NO. 4,458,070 and 4,456,753. In general crystalline form of cefoperazone sodium is more stable than amorphous form since the former having higher purity, stability and lower hydroscopicity.
In U.S pat. No 4,456,753 & 4,458,070 discloses a process for the
preparation of crystalline cefoperazone sodium, the former one involves the usage
of acetone/water mixture and the latter involves the usage of
acetone/water/dichloromethane. Both processes yield sodium cefoperazone in the
form of free needle microcrystals hence filtrations or centrifuge takes more time.
WO 01/79210 discloses a process for the preparation of cefoperazone sodium using acetone/water/lower alcohol. KR 9600359 discloses a process for the preparation of cefoperazone sodium using THF/water/acetone/MIBK.

Objectives of the invention
The main objective of the present invention is to an improved process for the preparation of crystalline cefoperazone sodium of formula (I) in pure form.
Another objective of the present invention is to provide a process for the preparation of crystalUne cefoperazone sodium of formula (I), which is easy to implement on commercial scales.
Still another objective of the present invention is to provide a process for the preparation of crystalline cefoperazone sodium of formula (I), which is easy to filter.
Still another objective of the present invention is to provide a process for the preparation of crystalline cefoperazone sodium of formula (I) in good yield and high purity.
Summary of tlie invention:
Accordingly, the present invention provides an improved process for the preparation of crystalline cefoperazone sodium of formula (I),

the said process comprising the steps of:
(i) dissolving cefoperazone acid in a solvent at a temperature in the range of
10oCto 50°C,
(ii) adjusting pH of the solution to 5.5 to 7.0 with a solution containing source
of sodium ions, and
(iii) adding a mixture of two solvents selected from acetone/ethyl acetate,
acetone/methyl acetate to precipitate crystalline cefoperazone sodium.

Detailed description of the invention
In an embodiment of the present invention, the solvent employed in step (i) is selected from acetone, THF, ethyl acetate, methanol, water and the like or mixtures thereof.
In another embodiment of the present invention, the sodium ion source used in step (ii) is selected from sodium acetate, sodium lactate, sodium 2-ethyl hexonate, sodium bicarbonate, sodium hydroxide, sodium carbonate and the like or mixtures thereof.
In still another embodiment of the present invention the preferable pH in step (ii) are 6.0 to 6.5.
In another embodiment of the present invention, the solvent used in step (ii) to dissolve sodium ion source is selected from water, methanol, ethyl acetate and the like or mixtures thereof.
In yet another embodiment of the present invention, the preferable mixture of solvent employed in step (iii) is acetone/ethyl acetate.
In another embodiment of the present invention the mixture of two solvents can be added either in single addition or controlled addition so as to get crystalline cefoperazone sodium.
In yet another embodiment of the present invention crystalline cefoperazone sodium obtained is sterile.
In yet another embodiment of the present invention, the starting material cefoperazone acid is prepared according to the procedures available in the prior art.
The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint and affords good quality of crystalline cefoperazone sodium of the formula (I).

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.
The present invention is illustrated with the following example, which should not be construed as limiting the scope of the invention.
Example 1:
Preparation of Cefoperazone sodium
To acetone (225 ml) cefoperazone acid (75 gm) followed by sodium bicarbonate solution (9 gm in 113 ml water) were added at 20 °C and stirred 10 minutes. To the clear solution activated carbon was added stirred 10 minutes. Carbon was filtered and the solution was passed through 0.2-micron filter in sterile area. To the solution a mixture of acetone (1890 ml) and ethyl acetate (285 ml) were added in 3 lots. The solid obtained was filtered, washed with acetone dried to get the title compound (73-75 gm) in pure form.

Claims:
1. A process for the preparation of crystalline cefoperazone sodium of formula
(I),
which comprising the steps of:
i) dissolving cefoperazone acid in a solvent at a temperature in the
rangeof l0°C to 50°C, ii) adjusting pH of the solution to 5.5 to 7.0 with a solution
containing source of sodium ions, and iii) adding a mixture of two solvents selected from acetone/ethyl
acetate, acetone/methyl acetate to precipitate crystalline
cefoperazone sodium.
2. The process as claimed in claim 1, wherein the solvent employed in step (i) is selected from acetone, THF, ethyl acetate, methanol, water or mixtures thereof.
3. The process as claimed in claim 1, wherein the sodium ion source employed in step (ii) is selected from sodium acetate, sodium lactate, sodium 2-ethyl hexonate, sodium bicarbonate, sodium hydroxide, or sodium carbonate
4. The process as claimed in claim 1, wherein the preferable pH in step (ii) is 6.0 to 6.5.
5. The process as claimed in claim 1, the preferable mixture of solvent employed in step (iii) is acetone/ethyl acetate.

6. The process as claimed in claim 1, wherein the crystalline cefoperazone sodium obtained is sterile.

Documents:

0242-che2003 claims duplicate.pdf

0242-che2003 description (complete) duplicate.pdf

242-che-2003-abstract.pdf

242-che-2003-claims.pdf

242-che-2003-correspondnece-others.pdf

242-che-2003-correspondnece-po.pdf

242-che-2003-description(complete).pdf

242-che-2003-form 1.pdf

242-che-2003-form 19.pdf

242-che-2003-form 5.pdf

abs-242-che-2003.jpg

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Patent Number

224632

Indian Patent Application Number

242/CHE/2003

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

Date of Filing

24-Mar-2003

Name of Patentee

ORCHID CHEMICALS & PHARMACEUTICALS LTD

Applicant Address

ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI-600 034,

Inventors:

#	Inventor's Name	Inventor's Address
1	GAUTAM KUMAR DAS	GEETHA APARTMENTS, 33, RUKMINI ROAD, KALAKSHETRA COLONY, BESANTNAGAR, CHENNAI 600 090,
2	PRAMOD NARAYAN DESHPANDE	5-TEMPLE GLADE APARTMENTS, 41-D, BEACH ROAD, KALAKSHETRA COLONEY, BESANT NAGAR, CHENNAI 600 090,
3	RAJENDRA JANARDAN SARANGDHAR	PLOT NO. 8, (OLD)/NEW NO. 19, ELEGANT APARTMENTS, DR. VASUDAVE NAGAR EXTENSION, THIRUVANMIYUR CHENNAI -600 041,
4	SRINIVASAN SHANMUGAN	17, SUBRAMANYA NAGAR INDUSTRIAL ESTATE, PUDUKKOTTAI 622004,
5	THAMBIDURAI MARAPPA GOUNDAR	8/188, EB COLONY, PERUMA PALAYAM, SRI VASAVI COLLAGE (PO) ERODE (TK) 638316,

PCT International Classification Number

A61K31/545

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA