Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM OF CEFDINIR
Abstract	The present invention provides process for the preparation of crystalline Form B of 7(3-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid of Formula I, wherein Mi+ is selected from Na+, K+, NH4"1"; with acid to produce acid addition salt, followed by treating with base in a solvent to produce compound of Formula I.

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FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of crystalline Form B of 7(3-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid of Formula I BACKGROUND OF THE INVENTION 7β-[(Z)-2-(2-Amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid is generically known as Cefdinir. Cefdinir is effective against both gram-positive and gram-negative bacteria and has been found to have good stability towards p-lactamases. It is particularly effective against S. aureus, which has shown resistance to other oral cephalosporins. Cefdinir is used in the treatment of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis, community aquired pneumonia caused by H. influenzae and unaccomplished skin and skin-structure infections caused by S. aureus and S. pyogenus. Cefdinir is marketed as capsules and suspension for oral administration under the brand name Ominicef®. Cefdinir was first disclosed by Takaya et. al. in U.S. Patent No. 4,559,334. This patent describes a synthesis and isolation of Cefdinir in Example-14 and 16. However, there is no information about the crystal nature of the product obtained therein. In subsequent patent US 4,935,507, it is disclosed that Cefdinir obtained as per the method described in Examples-14 and 16 of US '334 patent is a "crystalline like amorphous product, not a crystalline product," which has several disadvantages in that "it is bulky, not pure, unstable and insufficient in filtration rate." These properties render the material not particularly amenable for pharmaceutical preparations, unstable and difficult to use in a large-scale production. US 4,935,507 discloses methods of producing crystalline Cefdinir Form A, which has better filtration rate, high purity and stable Cefdinir suitable for pharmaceutical preparation, which is prepared by treating amorphous Cefdinir with sodium bicarbonate solution and the resulting aqueous solution was subjected to column chromatography and then adjusting the pH between 1-2 at 35-40°C, followed by cooling to obtain Cefdinir crystal A. Alternatively, amorphous Cefdinir was dissolved in methanol and to this solution added water at 35°C, stirred and allowed to stand at room temperature to obtain Cefdinir crystal A. Although US 4,935,507 claims crystalline Form A, advantages have yet to be realized by other, heretofore undiscovered, forms of Cefdinir. These are now provided by the present invention US 2004-0242556 discloses a new crystalline form of Cefdinir having moisture content in the range of about 5.5-7%, but typically 6-7%, (determined by the Karl Fisher (KF) method) amounting closely to sesquihydrate and is herein referred to as Cefdinir crystal B. which is a stable, nontoxic, non-solvate crystalline modification of Cefdinir. Cefdinir prepared by any of the above-described processes may contain anti-isomer, polymeric impurities or by-products originating from production processes or storage, which gives Cefdinir with low purity and assay. Pure Cefdinir preparation involves repeated crystallizations and loss of yield. We have now found that, in the process of the present invention, if aqueous solution of salt of 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir) is passed through ion-exchange resin and then converting into acid addition salt of Cefdinir followed by converting Cefdinir crystal B, which is substantially free of polymeric impurities and in high yield. OBJECTIVE OF INVENTION The main objective of the present invention is to provide a simple and effective process for the preparation of crystalline Cefdinir crystal B with high purity and good yields on a commercial scale. SUMMARY OF THE INVENTION Accordingly, the present invention relates to an improved process for the preparation of crystalline Form B of 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid of Formula I, which comprises, (i) treating crude 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (I) with base in a solvent to produce a salt of Formula II, wherein M+ is selected from Na+, K+, NH4+ (ii) passing the queous solution of compound of Formula II through nonionic adsorption resin column, followed by treatment with acid to produce acid addition salt of 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid of Formula III, wherein M2 is selected from trifluoroacetic acid, methanesulfonic acid, acetic acid, p-toluenesulfonic acid, phosphorous acid, sulfuric acid or dicyclohexylamine, (iii) treating the compound of Formula III with a base in a solvent to produce highly pure Cefdinir crystal B of Formula I. DETAILED DESCRIPTION OF THE INVENTION Crude 7P-[(Z)-2-(2-amino-44hiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (II) is prepared according to the procedure described in our pending US application US 2004/0242557. Crude 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (I) is treated with a base selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, ammonium hydroxide or a mixture thereof in a solvent selected from water, ethanol, methanol, acetonitrile, or mixtures thereof at a temperature of about 0°C to about 25°C, preferably 10-15°C. The pH of the solution should be 6.5 to 8, preferably 6.9 to 7.2, so that the solution becomes homogenous and no solid remains in solution. The aqueous solution of salt of compound of Formula (II) is passed through a column packed with non-ionic adsorption resin selected from Diaion HP-20 and the resulting eluate is heated to about 30 to 50°C, preferably 35-40°C and then treated with acid selected from sulfuric acid, hydrochloric acid, formic acid or a mixtures thereof to adjust the pH to 2.5 to 3.0 to produce a purified Cefdinir. Purified Cefdinir is treated with an acid selected from acetic acid, methane sulfonic acid, p-toluene sulfonic acid, phosphoric acid etc., in a solvent selected from water, acetonitrile, acetone or mixtures thereof at a temperature of about 20°C to about 50°C preferably 30°C to about 35°C, then cool the reaction mass to 0 to about 25°C, preferably 10-15°C, the precipitated product is filtered to produce the acid addition salt of Cefdinir of Formula III. Compound of Formula III is suspended in water and adjusted the pH to 2.5 to 3.5, preferably 3.0 to 3.2 using base selected from ammonium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, preferably with ammonium hydroxide at a temperature of about 5°C to 35°C, preferably at 15-20°C to produce highly pure Cefdinir crystal B. Crystal B exists as a sesquihydrate, as mentioned in our co-pending US application US 2004/0242556. The following examples to prepare Cefdinir crystal B illustrate the nature of the invention and are provided for illustrative purpose only and should not be construed to limit the scope of the invention: Example 1: Preparation of 7p-[(Z)-2-(2-amino-4-thiazolyl)-24iydroxyiminoacetamido]-3- vinyl-3-cephem-4-carboxyIic acid crystal B: Step A: Purification of 7p-[(Z)-2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir): The crude Cefdinir (175 g) was suspended in water (1090 ml) and cooled to 10-12°C. pH of this solution was adjusted to 6.9-7.2 with 10% w/w ammonium hydroxide solution (50 ml) till the solid gets dissolved. The solution containing ammonium salt of Cefdinir was passed through a column packed with Diaion HP-20 resin (500 g). The product was eluted with cold water (3000 ml) at 0 to 10°C. The elute was heated to 35-40°C and adjusted the pH to 2.5-3.0 with 10% sulfuric acid (53 ml) at 35-40°C. The precipitated product was filtered, washed with DM water (750 ml). Step B: Preparation of phosphoric acid salt of 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir-H3PO4 salt): Cefdinir obtained from step A (5 g) was suspended in acetonitrile (100 ml) at 25-30°C and orthophosphoric acid (2.48 g) was added in 10 min. The resulting mixture containing product was stirred at 25°C for 30 min, filtered the reaction mass, washed with acetonotrile (50 ml) and dried at 40-45°C under vacuum to obtain the title compound as white crystalline powder (yield 6 g: mp: 165°C). !H NMR in DMSO-dfi 5 in ppm : 2.40 (2, 3H, methyl); 3.58-3.87 (ABq, 2H, SCH2); 5.22-5.24 (d, 1H, 6-H); 5.32-5.35 (d, 1H, CH= CH2); 5.58-5.64 (d, 1H, CH= CH2); 5.77-5.81 (dd, 1H, 7-H); 6.86 (s, 1H, thiazolyl); 6.88-6.98 (dd, 1H, CH= CH2); 9.73-9.76 (d, 1H, CONH); 12.26 (bs, 1H,-C=N-OH). Step B: Preparation of crystalline Form B of 7 β -[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir Crystal B): Phosphoric acid salt of Cefdinir (5 g), was suspended in DM water (100 ml) at 25-30°C and cooled to 16°C. pH was adjusted to 3.0-3.2 with aqueous ammonia solution at 15-20°C. The resulting slurry was cooled to 2-5°C and stirred for 1 hr to complete the crystallization. Solid was filtered and washed with water (50 ml). Dried the product to obtain the title compound as off-white powder (yield: 3 g, water content: 6.38 %w/w). Example 2: Step A: Preparation of dicyclohexylamine salt of 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir- DCHA salt): Cefdinir obtained from Example 1 step A (5 g) was suspended in acetone (50 ml) and water (5 ml) at 25-30°C and dicyclohexylamine (2.40 g) was added in one lot at 25°C and stirred for 15 min at 25-30°C. Acetone (25 ml) was added and stirred for 1 h at 25 °C. The resulting solid was filtered, washed with acetone (25 ml) and dried to get the title compound as off-white crystalline powder (yield 7.6 g m.p: 174-178°C). ]H NMR in PMSO-dfi 5 in ppm : 3.58-3.87 (ABq, 2H, SCH2); 5.22-5.24 (d, 1H, 6-H); 5.32-5.36 (d, 1H, CH-CH2); 5.59-5.64 (d, 1H, CH=CH2); 5.78-5.82 (dd, 1H, 7-H); 6.87 (s, 1H, thiazolyl); 6.87-6.98 (dd, 1H, CH=CH2); 9.73-9.75 (d, 1H, CONH); 12.25 (bs, 1H, -C=N-OH). Step B: Preparation of crystalline Form B of 7 β -[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir Crystal B): Dicyclohexylamine salt of Cefdinir (5 g) was dissolved in water (150 ml) at 25-30°C. The hazy solution was cooled to 18°C and adjusted the pH to 2.6 with 10% aqueous sulfuric acid at 18-20°C. The resulting slurry was stirred for 10 min, cooled to 2-5°C and further stirred for 1 hr to complete the crystallization. Solid was filtered, washed with water (2 X 25 ml) and dried to obtain title compound as off-white powder (yield: 3.7 g; Water content: 6.3% w/w). Example 3: Step A: Preparation of methanesulfonic acid salt of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxyIic acid (Cefdinir- Methane sulfonic acid salt): Cefdinir obtained from Example 1 step A (5 g) was suspended in acetonitrile (100 ml) 25-30°C and methane sulfonic acid (4.5 g) was added in 10 min at 35°C-40°C and stirred for 30 min at the same temperature. The resulting slurry was filtered, washed with acetonitrile (50 ml) and dried to get the title compound as off-white crystalline powder (yield 12 g m.p: 200-210°C). !H NMR in DMSQ-d. 5 in ppm : 1.11-1.96 (m, 10H, dicyclohexyl); 3.39-3.53 (ABq, 2H, SCH2); 4.96-5.00 (d, 1H? CH=CH2); 5.07-5.08 (d, 1H, 6-H); 5.18-5.24 (d, 1H, CH-CH2); 5.63-5.68 (dd, 1H, 7-H); 6.66 (s, 1H, thiazolyl); 6.96-7.06 (dd, 1H, CH=CH2); 9.42-9.45 (d, 1H,CONH). Step B: Preparation of crystalline Form B of 7 β -[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir Crystal B): Methane sulfonic acid salt of Cefdinir (3 g) was suspended in DM water (90 ml) and cooled to 15°C. pH was adjusted to 3.0 with 10% aqueous ammonia (2.5 ml). The slurry obtained was cooled to 5°C and stirred for 1 hr at the same temperature to comlete the crystallization. Solid was filtered, washed with water (30ml) and dried to obtain title compound as an off-white powder (yield: 2.3 g, water content: 6.08% w/w). Example 4: Step A: Preparation of sulfate salt of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir-sulfate salt): Cefdinir obtained from Example 1 step A (10 g) was suspended in acetonitrile (100 ml) and cooled to 15°C. Sulfuric acid (3 g) was added in 10 min and stirred for 30 min at 25-30°C. The resulting slurry was cooled to 5 °C and stirred for 1 hr to complete the crystallization. Solid was filtered, washed with acetonitrile (30 ml) and dried to obtain 12 g of title compound as a pale yellow coloured crystalline powder. (yield: 12 g m.p:176-182°C). !H NMR in DMSO-d* 5 in ppm : 3.52-3.58 (ABq, 2H, SCH2); 5.18-5.20 (d, 1H, 6-H); 5.29-5.33 (d, 1H, CH=CH2); 5.56-5.62 (d, 1H, CH=CH2); 5.77-5.81 (dd, 1H, 7-H); 6.67 (s, 1H, thiazolyl); 6.86-6.95 (dd, 1H, CH=CH2); 9.49-9.52 (d, 1H, CONH). Step B: Preparation of crystalline Form B of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir Crystal B): Cefdinir H2SO4 salt (3 g) was suspended in water (90 ml) and cooled to 15°C. pH was adjusted to 3.0 with aqueous ammonia (5 ml) at 15-20°C. The slurry obtained was cooled to 2-5°C and stirred for 30 min. Solid was filtered, washed with water (2 X 25 ml) and dried to obtain 2 g of title compound as an off-white powder (Yield: 2 g; water content: 6.83% w/w). WE CLAIM: 1. An improved process for the preparation of crystalline Form B of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid of Formula I, which comprises, hydrolysis of compound of Formula III with a base in a solvent and isolating crystal B of Formula I, wherein M2 is selected from methanesulfonic acid, acetic acid, p- toluenesulfonic acid, phosphorous acid sulfuric acid or dicyclohexylamine, 2. A process according to claim 1, wherein the base is selected from ammonium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. 3. A process according to claim 1, wherein the solvent is selected from water, acetonitrile, acetone or mixtures thereof.

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