Patent ID: 6486149
Filing Date: 2002-11-26
Classification: A61K,A61P,C07D,Y10S

Abstract:
A process for the preparation of a yellow-colored powdery composition consisting essentially of particles which each are formed of a homogeneous mixture of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with a water-soluble high-molecular weight additive, and which particles have a uniform, internal texture within each particle, characterized in that the process comprises a step of dissolving an orthorhombic crystalline substance of Cefditoren pivoxil in an acidic aqueous solution which contains a water-soluble high-molecular weight additive made of either a water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose and methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol dissolved at a concentration of 0.05% to 1% (weight/weight basis), and said acidic aqueous solution also contains hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0.1NËœ12N of the acid, so that the amount of Cefditoren pivoxil dissolved in said acidic aqueous solution is in the range of 10 times to 130 times based on the entire weight of said water-soluble high-molecular weight additive contained in said acidic aqueous solution, resulting in an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular weight additive and the acid dissolved therein, a step of subsequently neutralizing the acidic aqueous solution by adding slowly thereto an aqueous solution selected from the group consisting of an aqueous solution of sodium or potassium hydroxide, an aqueous solution of sodium or potassium hydrogen carbonate, an aqueous solution of sodium or potassium carbonate and an aqueous solution of ammonium hydroxide, singly or in combination, while maintaining said acidic aqueous solution at a temperature of 10Â° C. or below under stirring, and with the amount of said basic sodium or potassium compound or ammonium hydroxide to be added to said acidic aqueous solution being so adjusted that the resulting reaction solution after the neutralization has a pH value of 6.5Ëœ7.1, and a step of continuing during the neutralization reaction the stirring of the aqueous solution containing Cefditoren pivoxil at a temperature of 10Â° C. or below, to bring about co-precipitation of Cefditoren pivoxil and the water-soluble high-molecular weight additive simultaneously from the aqueous solution, a step of collecting by filtration or centrifugation, the deposited precipitate from the resulting neutralization reaction mixture, a step of washing the collected precipitate with an aqueous solution of a water-soluble high-molecular weight additive made of the same substance as that of the first-mentioned water-soluble high-molecular weight additive and containing said additive dissolved in said solution at a concentration of 0.5%Ëœ10% (weight/weight basis), while at least a portion of said water-soluble high-molecular weight additive used in the washing aqueous solution is transferred from the washing aqueous solution of the water-soluble high-molecular weight additive onto the surfaces of the particles of said precipitate, and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of the particles each formed of the homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with the above-mentioned water-soluble high-molecular weight additive present in a proportion of 0.5%Ëœ5% based on the weight of the Cefditoren pivoxil substance.