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:
PROCESS FOR PREPARATION OF PHARMACEUTICAL COMPOSITION COMPRISING CEFDINIR OR SALTS THEREOF
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 a process for preparation of pharmaceutical composition comprising cefdinir or pharmaceutically acceptable salts thereof alongwith pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention relates to a process for preparation of pharmaceutical composition comprising cefdinir or pharmaceutically acceptable salts thereof alongwith pharmaceutically acceptable excipients.
Cefdinir, an extended-spectrum third generation semi-synthetic cephalosporin, is meant for oral administration and characterized by broad antibacterial spectrum against gram-positive and gram-negative bacteria. It is commercially available under the trade name of Omnicef®. Chemically Cefdinir is [(-) 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 (Formula I). Cefdinir is indicated for the treatment of patients with mild to moderate infections like community acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis /tonsillitis and uncomplicated skin and skin structure infections caused by susceptible strains of microorganisms.

US Patent No. 4,559,334 provides a process for preparation of cefdinir in amorphous form by lyophilization.
US Patent No. 4,935,507 provides a crystalline Form A of cefdinir and process for preparation thereof.
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PCT Application 2004104010 relates to a crystalline form of cefdinir and processes for producing the crystalline cefdinir. Also relates to the preparation of crystalline form of cefdinir, referred to as 'Form R' and pharmaceutical compositions that include the 'Form R'.
PCT Application 2005100368 relates to amorphous 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer), methods for its preparation, and pharmaceutical compositions comprising amorphous7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-vinyl-3-cephem - 4-carboxylic acid (syn isomer).
However, there remains a need for new processes in preparing pharmaceutical composition of cefdinir that provides ease of manufacturing and cost effectiveness. The present inventors while working on the development of cefdinir oral pharmaceutical composition, have surprisingly found that the pharmaceutical composition of cefdinir or salt thereof can be prepared by granulating Cefdinir with a solution of Polyoxyl 40 stearate in suitable organic solvent followed by blending the granules with suitable pharmaceutical excipients. Alternatively pharmaceutical composition of cefdinir can also be prepared by blending cefdinir with granules of calcium carboxymethyl cellulose wherein the granules can be prepared by using solution of Polyoxyl 40 stearate in suitable organic solvent. Also, it was surprisingly found that the cefdinir composition prepared by above two processes exhibits similar dissolution profile as that of commercially available OMNICEF® capsules and after 10 minutes 90% or more of cefdinir is released in 900 ml of 6.8 pH phosphate buffer at 50 rpm.
In one of the aspects of present invention there is provided a process for preparing pharmaceutical composition comprising cefdinir or pharmaceutical^ acceptable salts thereof wherein the said process involves the step of
a) granulating cefdinir with suitable solublization or wetting agent and organic solvent
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b) blending granules of step a) with pharmaceutical^ acceptable excipients
In yet another aspect of the present invention there is provided a process for preparing pharmaceutical composition comprising cefdinir or pharmaceutically acceptable salts thereof wherein the said process involves the step of
a) granulating carboxymethylcellulose calcium with suitable solubilization or wetting agent and organic solvent
b) blending the granules of step a) with cefdinir and pharmaceutically acceptable excipients
c) compacting the blend of step b) followed by converting compacts into granules
d) blending the granules of step c) with pharmaceutically acceptable excipients
The pharmaceutical composition comprises of cefdinir as an active ingredient. The pharmaceutical composition comprises of Intragranular and Extragranular material. The Intragranular material comprises of granules of Cefdinir prepared by wet granulation using a solution of Polyoxyl 40 stearate in suitable organic solvent. The extragranular material comprise of calcium carboxymethyl cellulose and magnesium stearate. Intragranular material comprising granules of Cefdinir is blended with extragranular material. The obtained blend can be filled into hard gelatin capsule shell.
The pharmaceutical composition can also be prepared by another process wherein the pharmaceutical composition comprises of Intragranular and Extragranular material. The Intragranular material comprises of granules of calcium carboxymethyl cellulose, cefdinir and magnesium stearate. The granules can be prepared by wet granulation using a solution of Polyoxyl 40 stearate in suitable organic solvent. The Intragranular material is compacted using roll compacter and then compacts are converted into suitable sized granules using oscillating granulator. The obtained Intragranular material is blended with
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extragranular material comprising magnesium stearate. The obtained blend can be filled into hard gelatin capsule shell.
The capsule obtained by above two processes exhibits a dissolution profile such that after 10 minutes 90% or more of cefdinir is released in 900 ml of 6.8 pH phosphate buffer at 50 rpm. The said capsule also exhibits similar dissolution profile as that of OMNICEF® (commercially available cefdinir capsules). The pharmaceutical composition is meant for oral administration.
The pharmaceutical composition can be granule, powder, sachet, capsule or compressed to form tablets.
Suitable solubilization or wetting agent may be one or more of Polyoxyethylene fatty acid esters, e.g. polyoxyl 40 stearate, polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj, polyoxyethylene fatty acid esters known and commercially available under the trade name Cetiol, PEG-54 Hydrogenated Castor Oil, and the like.
Suitable organic solvent may be one or more of Isopropyl Alcohol, Methylene chloride, chloroform, acetone, n-propanol and the like.
The pharmaceutically acceptable excipients can be selected from a group comprising of one or more of fillers, lubricants, disintegrants, glidants and the like.
Suitable filler may be selected from a group comprising one or more of lactose, carboxymethylcellulose calcium, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, sorbitol, powdered sugar and the like.
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Suitable lubricants may be selected from a group comprising one or more of talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, sodium benzoate and the like.
Suitable disintegrant may be one or more of carboxymethylcellulose calcium, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidants may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
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
Table 1: Composition of Cefdinir Capsules

Sr. No. Ingredients Qty/ Capsule (mg) %
Intragranular Ingredients
1. Cefdinir 300.0 83.33
2. Polyoxyl 40 stearate 0.250 0.070
3. Isopropyl Alcohol qs —
Extragranular Ingredients
4. Calcium Carboxymethyl cellulose 54.750 15.21
5. Magnesium Stearate 5.000 1.40
Total 360.0 100.00
Procedure: The pharmaceutical composition comprise of Intragranular and extragranular Ingredients. The Intragranular ingredients comprise of Cefdinir granules that were prepared by granulating cefdinir with a solution of Polyoxyl 40
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Stearate in isopropyl alcohol. The Intragranular ingredients were blended with extragranular ingredients comprising calcium carboxymethyl cellulose magnesium stearate. The obtained granules were filled into hard gelatin shell.
EXAMPLE 2
Table 2: Composition of Cefdinir Capsules

Sr. No. Ingredients I Qty/ Capsule (mg) %
Intragranular Ingredients
1. Calcium Carboxymethyl cellulose 54.00 15.00
2. Polyoxyl 40 stearate 1.000 0.28
3. Isopropyl Alcohol qs —
4. Cefdinir 300.0 83.33
5. Magnesium Stearate 3.000 0.833
Extragranular Ingredients
6. Magnesium Stearate 2.000 0.55
Total 360.0 100.00
Procedure: The pharmaceutical composition comprise of Intragranular and extragranular Ingredients. The Intragranular Ingredients comprises of granules of calcium carboxymethyl cellulose, cefdinir and magnesium stearate. The granules of calcium carboxymethyl cellulose were prepared by wet granulation using a solution of Polyoxyl 40 stearate in isopropyl alcohol. The Intragranular ingredients were compacted using roll compacter and then compacts were converted into suitable sized granules using oscillating granulator. The obtained granules were blended with extragranular material comprising magnesium stearate. The obtained blend was filled into hard gelatin capsule shell.
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TABLE 3: Drug release data of Cefdinir capsules prepared as per the formula given in table 1 and 2 alongwith the drug release data of Omnicef® capsule.

Time (min) Omnicef® capsule % Drug released Example 1 % Drug released Example 2 % Drug released
0 0 0 0
10 91.5 94.0 91.0
20 96.1 97.7 95.0
30 98.5 100.5 96.0
45 99.8 101.7 97.0
60 100.4 104.6 96.0
For determination of drug release, USP Type 2 Apparatus, 50 rpm is used wherein 900ml of phosphate buffer pH 6.8 is used as a medium.
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WE CLAIM:
1. A process for preparing pharmaceutical composition comprising cefdinir or
pharmaceutically acceptable salts thereof wherein the said process involves
the step of
a) granulating cefdinir with suitable solubilization or wetting agent and organic solvent
b) blending granules of step a) with pharmaceutically acceptable excipients
2. A process for preparing pharmaceutical composition comprising cefdinir or
pharmaceutically acceptable salts thereof wherein the said process involves
the step of
a) granulating carboxymethylcellulose calcium with suitable solubilization or wetting agent and organic solvent
b) blending the granules of step a) with cefdinir and pharmaceutically acceptable excipients
c) compacting the blend of step b) followed by converting compacts into granules
d) blending the granules of step c) with pharmaceutically acceptable excipients

3. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein the solubilization or wetting agent is one or more of Polyoxyl 40 stearate, polyoxyethylene fatty acid esters.
4. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein organic solvent is one or more of isopropyl alcohol, methylene chloride, chloroform, acetone, n-propanol.
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5. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein pharmaceutical^ acceptable excipients is selected from a group comprising of one or more of filler, lubricant, disintegrant, glidant.
6. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein the said composition is meant for oral administration.
7. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein the said composition exhibits a dissolution profile similar to Omnicef® capsules in 900 ml of 6.8 pH phosphate buffer at 50 rpm.
8. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein the said composition exhibits a dissolution profile such that after 10 minutes 90% or more of cefdinir is released in 900 ml of 6.8 pH phosphate buffer at 50 rpm.
9. A process for preparing pharmaceutical composition as per claim 1 and 2, wherein the said composition is powder, granule, sachet, capsule, tablet.
Dated this ™ day of August, 2006
For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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