Title of Invention	PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC
Abstract	The present invention relates to highly soluble form of a cephalosporin antibiotic. More particularly, the present invention relates to highly soluble of cefuroxime axetil of the formula (I).

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Field of the Invention The present invention relates to highly soluble form of a cephalosporin antibiotic. More particularly, the present invention relates to highly soluble of cefuroxime axetil of the formula (I). The present invention also relates to a process for the preparation of highly soluble form of a cephalosporin antibiotic. More particularly, the present invention relates to a process for the preparation of highly soluble of cefuroxime axetil of the formula (I). Background of the Invention Cefuroxime is chemically known as (6R,7R)-3-carbamoyloxymethyl-7->(Z)-2-(fur-2-yl)- 2-methoxyiminoacetamido-3-cephem-4-carboxylic acid and is disclosed in US patent No. 3,974,153. Cefuroxime has a good spectrum of antibacterial activity, extending both to gram positive and gram negative microorganisms. Cefuroxime cannot be used as such for oral administration, because it is not absorbed and does not enter the body fluid circulation. Cefuroxime axetil is a promedicament for oral administration having high stability against p-lactamase producer strains. In this respect, once the ester has been absorbed and has entered the body fluid circulation, it is hydrolyzed to release cefuroxime, which is actually responsible for the antibacterial activity. Cefuroxime axetil is disclosed in US patent No. 4,267,320. British Patent 1,571,683 discloses the preparation of cefuroxime axetil in crystalline form by precipitation from a solution of ethyl acetate with diethyl ether or diisopropyl ether. The commercially available cefuroxime axetil is in substantially amorphous form, as described and claimed in US patent No. 4,562,181, which states that "the crystalline product (a crystal) does not possess the best balance of properties for commercial use" whereas "the substantially amorphous form has a higher bioavailability following oral administration than the crystalline form. U.S. Pat. No. 4,820,833 describes a process for preparing a highly pure, substantially amorphous form of cefuroxime axetil comprising preparing a highly pure solution of cefuroxime axetil and spray drying said solution to recover highly pure, substantially amorphous cefuroxine axetil. US patent No. 5,013,833 describes the preparation of amorphous cefuroxime axetil by solvent precipitation of the product dissolved in an organic solvent (or a mixture thereof in water). The solvents used in these patents are the organic solvents include ketones, alcohols, acetonitrile, tetrahydrofuran, dioxane, esters, chlorinated solvents, or a homogeneous mixture of at least two such solvents. The precipitation processes referred to in US patent No. 5,013,833 while producing cefuroxime axetil substantially in amorphous form have a number of disadvantages such as use of very large volumes of a solvent such as dichloromethane (40 ml/g) and diisopropyl ether (32.5 ml/g), which by their toxicity and possibility of explosive peroxide formation may render the process not commercially feasible. us patent No. 5,847,118 discloses a method of preparing amorphous cefuroxime axetil which comprises dissolving crystalline cefiiroxime axetil in a solvent such as formic acid, the solvent being present in an amount just sufficient to dissolve the crystalline cefiiroxime axetil, and later adding the resulting cefiiroxime axetil solution to water. US patent No. 6,384,213 describes a process for the preparation of a pure amorphous form of cefuroxime axetil which involves dissolving crystalline cefiiroxime axetil in acetic acid including at least 5% v/v water and recovering said amorphous form of cefiiroxime axetil from the solution by the addition of additional water, the solution being added all at once to the additional water being present in a volume which is sufficient to precipitate said amorphous cefiiroxime axetil. The above process for the preparation of cefiiroxime axetil produces amorphous form with low yield because of poor solubility of crystalline cefiiroxime axetil in the solvents mentioned in the above patents. It has now been surprisingly found that by precipitating the new form of cefiiroxime axetil in acetone or acetone/DMF mixture substantially increases the solubility of cefiiroxime axetil, which resulted in increased yield of amorphous cefiiroxime axetil. Objective of the present invention The main of objective of the present invention is to provide a highly soluble form of cefiiroxime axetil. Yet another objective of the present invention is to provide a process for the preparation of amorphous form of cefiiroxime axetil from highly soluble form. Another objective of the present invention is to provide a process for the preparation of amorphous cefiiroxime axetil with good yield and purity. The present invention also provides a process for the preparation of highly soluble form of cefuroxime axetil of formula (I), which comprises : i). obtaining a solution of cefuroxime axetil in acetone or acetone/DMF mixture, ii). cooling the solution to -35 to -10 °C, iii). adding the resulting solution to water at 2 to 45 °C and iv). drying the product at 35-45 °C, to yield highly soluble form of cefuroxime axetil. Detailed description of the invention In yet another embodiment of the present invention, the highly soluble form of cefuroxime axetil is useful for the preparation of amorphous form of cefuroxime axetil. In yet another embodiment of the present invention, the highly soluble form of cefuroxime axetil can also be prepared from the mother liquor of crystalline cefuroxime axetil. In an embodiment of the present invention, the new form of cefuroxime axetil is prepared either by adding water to acetone or acetone/DMF solution containing X lie pieoeiii iiivt;iiLi\Jii lo piwviu-t^Li \jy uiti v^A.aiii]Jiu3 ^ivv^ii uwnjw, wiiiv^ii ait^ piviviut^u by way of illustration only and should not be considered to limit the scope of the invention. Example 1 Crystalline cefuroxime axetil (10 g) was charged to a 50 ml round bottomed flask containing 1:1 (v/v) mixture of DMF and acetone (17 ml) under dry conditions. The solution was stirred at room temperature and cooled to -25 to -30 °C in 10 minutes. This solution was added to water (323 ml) stirred at 0-2 °C dropwise over 5 minutes. The resulting solution was stirred for 30 minutes at 5 °C, filtered the product and washed with chilled water (100 ml) and dried at 40 °C under vacuum to yield cefuroxime axetil (8.5 g, m/c = 0.91 %). Example 2 Crystalline cefuroxime axetil (10 g) was charged to a 50 ml round bottomed flask containing 1:1 (v/v) mixture of DMF and acetone (25 ml) under dry condition. The solution was stirred and cooled to -25 to -30 °C in 10 minutes. This solution was added to water (495 ml) stirred at 0-2 °C dropwise over 5 minutes and stirred further for 30 minutes at 5 °C, filtered the product, and washed with chilled water (100 ml) and dried at 40 °C under vacuum to yield highly soluble form of cefuroxime axetil (8.3 g, m/c = 0.97 %). Example 3 Acetyl bromide and acetaldehyde with dimethyl acetamide was charged at -5 to 10 °C and stirred for 10 hrs. Cefuroxime acid (100 g) dissolved in DMAc was added to the above solution at 10-15 °C. To the reaction mass sodium carbonate was added and stirred at the same temperature for 1 hr. After completion of the reaction, the reaction mass was transferred to a mixture of ethyl acetate and water. The ethylacetate layer (100 g) containing cefuroxime axetil was taken in 250 ml round bottomed flask fitted with distillation assembly and distilled the solvent at 35-37 °C under vacuum. Dissolved the residue (20.1 gm) thus obtained in a 1:1 (v/v) mixture of DMF and acetone (34 ml) under dry condition. The solution was stirred well and cooled to -25 to -30 °C in 10 minutes. This solution was added into water (646 ml) stirred at 0-2 °C dropwise over 5 minutes. Stirred for 30 minutes at 5 °C, filtered the product, and washed with chilled water (100 ml). This precipitate was added into water (100 ml), stirred for 30 minutes at room temperature and filtered. Washed the precipitate with water (50 ml) and dried at 40 °C under vacuum to yield highly soluble form of cefuroxime axetil (5.8 g, m/c = 0.73 %). Example 4 Acetyl bromide and acetaldehyde with dimethyl acetamide was charged at -5 to 10 °C and stirred for 10 hrs. Cefuroxime acid (100 g) dissolved in DMAc was added to the above solution at 10-15 °C. To the reaction mass sodium carbonate was added and stirred at the same temperature for 1 hr. After completion of the reaction, the reaction mass was transferred to a mixture of ethyl acetate and water. The ethylacetate layer (100 g) containing cefuroxime axetil was taken in a 250 ml round bottomed flask fitted with distillation assembly and distilled the solvent at 35-37 °C under vacuum. The residue thus obtained (10.5 gm) was kept under high vacuum (2-3 mm of Hg) for 30 minutes and dissolved in a 1:1 (v/v) mixture of DMF and acetone (17 ml) under dry condition. The solution was stirred well and cooled to -25 to -30 °C in 10 minutes. This solution was added in to water (663 ml) stirred at 0-2 °C dropwise over 5 minutes. The reaction mixture was stirred for 30 minutes at 5 °C, filtered the product and washed with chilled water (100 ml). This precipitate was added into water (200 ml), stirred for 30 minutes at room temperature and filtered. Washed the precipitate with water (50 ml) and dried at 40 °C under vacuum to yield highly soluble form of cefuroxime acid (6.0 g, m/c = 1.00 %). We claim : 1. Highly soluble form of cefuroxime axetil of formula (I), 2. A process for the preparation of highly soluble form of cefuroxime axetil of formula (I), which comprises : i). obtaining a solution of cefuroxime axetil in acetone or acetone/DMF mixture, ii). cooling the solution to -35 to -10 °C, iii). adding the resulting solution to water at 2 to 45 °C and iv). drying the product at 35-45 °C, to yield highly soluble form of cefuroxime axetil. 3. The process as claimed in claim 2, wherein the step (iii) is carried out by adding water to acetone or acetone/DMF solution. 4. The process as claimed in claim 2, wherein the step (iii) is carried out by adding acetone or acetone/DMF solution to water. 5. The process as claimed in claim 2, wherein the highly soluble form of cefuroxime axetil is used for the preparation of amorphous form of cefuroxime axetil.

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