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: NOVEL FORM OF CEFDINIR.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to novel, stable form of cefdinir, method for preparation, and pharmaceutical compositions thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.
The present invention relates to novel, stable form of cefdinir, method for preparation, and pharmaceutical compositions thereof.
[(-) 6R, 7R]-7-((Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido)-3-vinyl-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid commonly termed as cefdinir of Formula I is third generation semi-synthetic cephalosporin for oral use, characterized by broad antibacterial spectrum against gram-positive and gram-negative bacteria. In particular cefdinir shows excellent antibacterial activity against Streptococci and Staphylococci.


N-K O
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US Patent No. 4,559,334 provides a process for preparation of cefdinir in amorphous form by lyophilization. The amorphous form produced in turn is highly hygroscopic and therefore very difficult to formulate.
US Patent No. 4,935,507 provides a crystalline Form A of cefdinir and process for preparation thereof. Form A of cefdinir is reported to be having specific X-Ray diffraction (XRD) pattern.
US Application No. 20030204082 provides crystalline form of cefdinir having a specific XRD pattern.
US Application No. 20040210049 provides crystalline acid addition salts of cefdinir specifically sulphate and mesylate salt.
US Application No. 20040242556 provides crystalline form of cefdinir designated as Form B having a specific XRD pattern. Said form B is prepared from crystalline form A by first forming the trifluoroacetic acid salt followed by basification with ammonia.
US Patent No. 6,350,869 (PCT Application No. WO 98/45299) describes a process for preparation of crystalline dicyclohexylamine (DCHA) salt of cefdinir and monohydrate form of cefdinir. However, characterization data of the crystalline salt or monohydrate form of cefdinir is not provided in the '869 Patent.
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Several PCT Applications detail crystalline salts of cefdinir which are either useful as intermediates in preparation of cefdinir or can be used as broad-spectrum antimicrobials. WO 02/98884 (crystalline sulphate, tosylate and mesylate salt of cefdinir); WO 04/16623 (crystalline salts of acetyloximino cefdinir / methylcarbonyloxyimino cefdinir) and WO 04/56835 (crystalline phosphate salts).
PCT Application No WO 03/50124 describes crystalline cefdinir potassium monohydrate and process for preparation thereof. The application further details utilization of the potassium salt of cefdinir in monohydrate form as potential antimicrobial agent.
Indian Patent Application No. 1508/Del/2004 describes a crystalline Form B of cefdinir having a specific XRD, DSC and FTIR spectrum, which is essentially different from the one provided by US Application No 20040242556.
The present invention provides novel, stable form of cefdinir, method for preparation, and pharmaceutical compositions thereof.
A first aspect of the present invention provides Form I of cefdinir.
A second aspect of the present invention provides Form I of cefdinir having characteristic XRD pattern as depicted in Figure 1 of the accompanied drawing.
A fourth aspect of the present invention provides Form I of cefdinir having bound moisture content of 4 % w/w or less.
A fifth aspect of the present invention relates to a process for preparation of Form I of cefdinir wherein the said process comprises of
a) dissolving cefdinir or salt thereof in first organic solvent
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b) adding a second organic solvent characterized by the fact that cefdinir is insoluble, slightly soluble or practically insoluble in the said organic solvent, in the solution of step a) or vice versa,
c) isolating Form I of cefdinir from the reaction mixture obtained thereof.
Cefdinir is dissolved in first organic solvent. The selection of first organic solvent is characterized by the fact that it has solubility for cefdinir. The said organic solvent optionally includes dimethylformamide or formic acid and the like. The reaction mass is treated with a second organic solvent, characterized by the fact that cefdinir is insoluble, slightly soluble or practically insoluble in the said organic solvent but is miscible with first organic solvent, The said second organic solvent includes but not limited to isopropyl alcohol, ethyl acetate, toluene, n-butanol, acetone and the like. Pure cefdinir is obtained from the reaction mass, which can be isolated and dried suitably.
A sixth aspect of the present invention provides a pharmaceutical composition comprising Form I of cefdinir along with pharmaceutically acceptable carrier. The pharmaceutical compositions comprise of oral dosage forms such as tablets, capsules, liquid orals, suspensions and the like. Topical dosage forms such as creams, lotions, ointments and the like.
A seventh aspect of the present invention provides a method of treating bacterial infections comprising administering to a mammal in need thereof a therapeutically effective amount of Form I of cefdinir.
Figure 1 depicts XRD of Form I of cefdinir.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
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While the present invention has been described in terms of its specific embodiments, 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.
EXAMPLE 1 PREPARATION OF FORM I OF CEFDINIR
Cefdinir (10 g) was taken in dimethylformamide (25 ml) and stirred at ambient temperature to get the clear solution. The solution, so obtained was treated with isopropyl alcohol (750 ml). Filtered, dried at 40°C to get title compound. Moisture Content: 3.2 w/w.
EXAMPLE 2 PREPARATION OF FORM I OF CEFDINIR
Cefdinir (10 g) was taken in dimethylformamide (25 ml) and stirred at ambient temperature to get the clear solution. The reaction mass so obtained was treated with ethyl acetate (750ml). Filtered, dried at 40°C to get title compound. Moisture Content: 3.9 w/w.
EXAMPLE 3 PREPARATION OF FORM I OF CEFDINIR
Cefdinir (2.5 g) was taken in dimethylformamide (15 ml) and stirred at ambient temperature to get the clear solution. The reaction mass so obtained was treated with toluene (100 ml). Filtered, dried at 40°C to get title compound. Moisture Content: 2.3 w/w.
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EXAMPLE 4 PREPARATION OF FORM I OF CEFDINIR
Cefdinir (2.5 g) was taken in dimethylformamide (15 ml) and stirred at ambient temperature to get the clear solution The reaction mass so obtained was treated with n-butanol (100 ml). Filtered, dried at 40°C to get title compound. Moisture Content: 3.5 w/w.
EXAMPLE 5 PREPARATION OF FORM I OF CEFDINIR
Cefdinir imidazole salt (5 g) was taken in formic acid (5 ml) and stirred at ambient temperature to get the clear solution. The reaction mass so obtained was treated with acetone (250 ml). Filtered, dried at 40°C to get title compound. Moisture Content: 3.1 w/w.
EXAMPLE 6 PREPARATION OF FORM I OF CEFDINIR
Cefdinir (2.5 g) was taken in dimethylsulphoxide (5 ml) and stirred at ambient temperature to get the clear solution. The reaction mass so obtained was treated with isopropyl alcohol (180 ml). Filtered, dried at 40°C to get title compound. Moisture Content: 3.4 w/w.

WE CLAIM:
1. A process for preparation of Form I of cefdinir wherein the said process
comprises of
a) dissolving cefdinir or salt thereof in first organic solvent
b) adding a second organic solvent characterized by the fact that cefdinir is insoluble, slightly soluble or practically insoluble in the said organic solvent, in the solution of step a) or vice versa,
c) isolating Form I of cefdinir from the reaction mixture obtained thereof.
2. The process according to claim 1, wherein the first organic solvent include dimethylformamide/ dimethylsulphoxide or formic acid and the like.
3. The process according to claim 1, wherein the second organic solvent include isopropyl alcohol, ethyl acetate, toluene, n-butanol, acetone and the like.
4. Form I of cefdinir having characteristic XRD pattern as depicted in Figure 1.
5. Form I of cefdinir having moisture content of about 4% w/w or less.
6. A pharmaceutical composition comprising amorphous Form I of cefdinir along with pharmaceutically acceptable carrier (s) / excipient (s). The pharmaceutical compositions comprise of oral dosage forms such as tablets, capsules, liquid orals, suspensions and the like. Topical dosage forms such as creams, lotions, ointments and the like.
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7. A method of treating bacterial infections comprising administering to a mammal in need thereof a therapeutically effective amount of amorphous Form I of cefdinir.
8. The method according to claim 9, wherein the said mammal is human.
Dated this 1st day of June 2006
For Wockhardt Limited
(Yatendra Kumar) Authorized Signatory
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