Title of Invention

PROCESS FOR THE PREPARATION OF STERILE CEPHALOSPORIN

Abstract

The present invention relates to a process for the preparation of a sterile cephalosporin antibiotic. The present invention more particularly relates to an improved process for the preparation of sterile cephalosporin of general formula (I) or its solvates, hydrates or salts. wherein R3 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl; R2 represents

Full Text

Field of the invention The present invention relates to a process for the preparation of a sterile cephalosporin antibiotic. The present invention more particularly relates to an improved process for the preparation of sterile cephalosporin of general formula (I) or its solvates, hydrates or salts. Description of tlie prior art The cephalosporins constitute an important class of semisynthetic antibiotics that have proved highly useful in treating bacterial infections in man. It is well known that for parenteral administration the said antibiotic must be prepared in sterile condition. The sterile product must be free of microoganisms and insoluble particulates, the process used in preparing it must embody Good Manufacturing Practices ("GMP") that will produce and maintain the required quality of the product in terms of sterility and therapeutic effectiveness. Freeze-drying is an old and often used process for removing a solvent from a solute. Water is the solvent generally utilized in a freeze-drying process. Other solvents can be employed but are limited to those, which become solid in the range of temperatures which can be practically employed in the process and which will sublime under vacuum. The conventional procedure for freeze-drying antibiotics and other pharmaceuticals involves the following steps: 1) preparation of solution of non-sterile compound 2) filtering through a sterilizing filter 3) lyophilisation to produce solid. While the process is cumbersome, expensive and slow, it provides a method for removing a solvent without damaging heat labile solutes. US patent 5,707,634 discloses a process for the preparation of sterile cephalosporin, which involves (1) dissolving the solid to be finely divided in a liquid carrier solvent to form an injection solution and (2) adding the injection solution of step (1) to a volume of anti-solvent such as carbon dioxide, ethane, ethylene, nitrous oxide, fluoroform, dimethyl ether, propane, butane, isobutanes, propylene, chlorotrifluormethane, sulfur hexafluoride, bromotrifluoromethane, chlorodifluoromethane, hexafluoroethane, or carbon tetrafiuoride sufficient to precipitate or crystallize the solid. The usage of anti-solvent makes the process expensive. JP 02069483 discloses a process for purification of cephalosporinic compound having quatemary ammonium salt substitution at 3^^ position using DMSO. U.S. Pat. No. 4,263,253 discloses a process for sterilizing solids, e.g., pharmaceutical active ingredients, by dissolving the non-sterile solid in a gas under supercritical conditions, and then passing the resulting solution through a sterilizing filter to provide a sterile fluid gas/solid mixture. For commercial application this process is not suitable. We have now found an improved process for the preparation of the compound of formula (I), which is simple and has advantages over the processes described in the above-mentioned prior art documents. Objectives of the invention The main objective of the present invention is to provide a process for the preparation of sterile cephalosporin of general formula (I). Another objective of the present invention is to provide a process for the preparation of compounds of formula (I), which avoid time consuming freeze-drying process and also easy to implement on commercial scales. Still another objective of the present invention is to provide a process for the preparation of compounds of formula (I) in good yield and high purity. Summary of the invention: Accordingly, the present invention relates to an improved process for the preparation of sterile cephalosporin of general formula (I) or its solvates, hydrates or salts, wherein R\ and R2 are described earlier, which comprises: (i) dissolving the non-sterile compound of formula (I) or its salts, hydrates or solvates in an organic acid at a temperature in the range of-10°C to 50°C, (ii) filtering the solution through a sterile filter into a previously sterilized container in a sterile area, and (iii) precipitating the compound of formula (I) or its salts, hydrates or solvates at a temperature in the range of-10 °C to 50 °C. Detailed description of the invention In an embodiment of the present invention the salts of compound of formula (I) may be selected from hydrochloride, sulfate, hydroiodide, formate, acetate, perchlorate, TFA salt and the like. In still another embodiment of the present invention the precipitation in step (iii) is done either by adding solvent and/or by adjusting pH. In yet another embodiment of the present invention the organic acid employed for precipitation is selected from acetic acid, propanoic acid, formic acid, methane sulphonic acid and the like or mixtures thereof In still another embodiment of the present invention the solvent employed for precipitation is selected from acetone, water, methanol, IPA, t-butanol, ethyl methyl ketone, diethyl ketone, pentan-3-one, cyclohexanone, methyl isobutyl ketone, iso butanol, and the like or mixters thereof In still another embodiment of the present invention the pH of solution is adjusted using ammonia, sodium bicarbonate, sodium hydroxide, sodium carbonate and the like. In another embodiment of present invention the technology given in this invention can be applied to wide range of cephalosporin compounds such as cephaloridine, cefsulodin, cefalonium, cefpirome, ceftazidime, cefclidin, cefozopran, cefepime, etc. In another embodiment of the present invention the starting material for the present invention can be prepared according to the procedures reported in prior art. The present invention is exemplified by the following examples, which are provided for illustration only and should not be construed to limit the scope of the invention. Example 1: Preparation of Sterile Cefalonium sulphate: To DMW, cephalothin sodium and sodium iodide was added followed by isonicotinamide was added. Heated the reaction mixture till completion of reaction and isolated the product as sulfate salt. To aqueous acetic acid (500 ml), non-sterile cefalonium sulfate (100 gm) was added and stirred till dissolution. The solution was filtered through 0.2-micron filter under sterile condition. To filtrate sterile water was added at 35-38 °C, and pH of the solution was adjusted 4.90.The reaction mixture was cooled to 18-20 °C. The solid obtained was filtered, washed with water and acetone and dried under vacuum to get pure sterile cefalonium. Example 2, Preparation of Sterile Cepirome sulphate: To aqueous acetic acid (975 ml), non-sterile cepirome sulfate (100 gm) was added and stirred till dissolution. The solution was filtered through 0.2-micron filter under sterile condition. To filtrate, acetone (5 It) was added at 24-26 °C. The reaction mixture was cooled to 18-20 °C. The solid obtained was filtered, washed with water and acetone and dried under to get pure sterile cepirome sulphate (90 gm). Claims 1) A process for the preparation of sterile cephalosporin of general formula (I) or its solvates, hydrates or salts wherein R3 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Re represents hydrogen or (Cp C6)alkyl; R2 represents the said process comprising the steps of: (i) dissolving the non-sterile compound of formula (I) or its salts, hydrates or solvates in an organic acid at a temperature in the range of-10°C to 50°C, (ii) filtering the solution through a sterile filter into a previously sterilized container in a sterile area; and (ii) precipitating the compound of formula (I) or its salts, hydrates or solvates at a temperature in the range of-10°C to 50°C. 2) The process as claimed in claim 1, wherein the organic acid is selected form acetic acid, propanoic acid, formic acid or methane sulphonic acid. 3) The process as claimed in claim 1, wherein the precipitation step (iii) is done by adding solvent and/or by adjusting pH. 4) The process claimed in claim 2, wherein the solvent employed for precipitation is selected from acetone, water, methanol, IPA, t-butanol, ethyl methyl ketone, diethyl ketone, pentan-3-one, cyclohexanone, methyl isobutyl ketone, iso butanol and the like or mixtures there of. 5) The process as claimed in claim 2, wherein the pH of solution adjusted using ammonia, sodium bicarbonate, sodium hydroxide or sodium carbonate. Dated this eighteenth (18^^) day of September 2003 for Orchid Chemicals & Pharmaceuticals Ltd.,

Documents:

750-mas-1996 complete specification as granted.pdf

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758-che-2003-abstract.pdf

758-che-2003-claims.pdf

758-che-2003-correspondnece-others.pdf

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

758-che-2003-form 1.pdf

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