Patent EA-001526-B1 (EA)
Title: A crystalline substance of cefditoren pivoxyl and the production of the same
Inventor: YASUI KIYOSHI
IPC: C07D501/14
Filed: 1997-09-19
Abstract: 1. A crystalline substance of Cefditoren pivoxyl, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, characterized in that said crystalline substance of Cefditoren pivoxyl is of orthorhombic form and has a melting point with decomposition at a temperature in a range of 206.2 degree C to 215.7 degree C , that a single crystal of said crystalline substance has a density of 1.21 to 1.23 g/cm 3 and contains 4 molecules of Cefditoren pivoxyl within a unit lattice of the single crystal, that said crystalline substance has a purity of 97% to 98% for the Cefditoren pivoxyl component, has a higher thermal stability than the known amorphous substance of Cefditoren pivoxyl. 2. A crystalline substance of Cefditoren pivoxyl as claimed in claim 1, further characterized in that an X-ray powder diffractometer data of said crystalline substance of Cefditoren pivoxyl shows peaks at the following diffraction angles: approximately 9.7 degree, approximately 10.8 degree, approximately 11.4 degree, approximately 12.1 degree, approximately 13.6 degree, approximately 15.6 degree, approximately 16.2 degree, approximately 17.4 degree, approximately 19.0 degree, approximately 19.5 degree, approximately 20.1 degree, approximately 20.8 degree, approximately 21.5 degree, approximately 25.2 degree, approximately 29.9 degree and approximately 33.0 degree, and that the single crystal of said crystalline substance has substantially the following crystallographic features: Crystalline system: Orthorhombic form Lattice constants: a=14.026. angstrom , b=18.438. angstrom , c=11.815.  angstrom ,  alpha.=90 degree , beta.= 90 degree , .gamma.= 90 degree  Space group: P21 P21 P21, Number of molecules within a single unit lattice: 4 Lattice capacity: 3055.  angstrom   Density: 1.22 g/cm<3> on average, R value: 4%. 3. A crystalline substance of Cefditoren pivoxyl according to claim 1, which has a purity of 97.7% or higher for the Cefditoren pivoxyl component. 4. A process for the preparation of a crystalline substance of Cefditoren pivoxyl having the orthorhombic form according to claim l, which comprises conducting successively the following first to eighth steps: dissolving an amorphous substance of Cefditoren pivoxyl in an anhydrous, first organic solvent in which Cefditoren pivoxyl is much more soluble than in an alkanol containing 1 to 5 carbon atoms and which is miscible with said alkanol, thereby to obtain a solution containing 10 mg to 50 mg of the dissolved Cefditoren pivoxyl per 1 ml of the resulting solution of Cefditoren pivoxyl in the first organic solvent, mixing the resulting solution of Cefditoren pivoxyl in the first organic solvent with an anhydrous alkanol containing 1 to 5 carbon atoms as a second organic solvent in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxyl dissolved in the resulting mixture of said solution of Cefditoren pivoxyl with the second organic solvent, to a concentration of 5 mg to 40 mg of the dissolved Cefditoren pivoxyl per 1 ml of said resulting mixture, concentrating the resulting solution of Cefditoren pivoxyl in the mixed first and second organic solvents as obtained in the second step, at a temperature of -5 degree C to 15 degree C by evaporation of the organic solvents from said solution under a reduced pressure, to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the dissolved Cefditoren pivoxyl, mixing the concentrated solution so obtained in the third step with a further volume of an alkanol of 1 to 5 carbon atoms used as the second organic solvent in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxyl dissolved in the resulting mixture of said concentrated solution with the further volume of the alkanol, to a concentration of 25 mg to 125 mg of the dissolved Cefditoren pivoxyl per 1 ml of said resulting mixture, concentrating the resulting solution of Cefidtoren pivoxyl so diluted with the further volume of the alkanol in the fourth step, at a temperature of -5 degree C to 15 degree C by evaporation of the solvents from said solution under a reduced pressure, to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the Cefditoren pivoxyl dissolved in the solvent entirely or substantially entirely made of said alkanol, mixing the concentrated solution obtained in the fifth step with water of a volume of 1-fold to 20-folds greater than the volume of the above concentrated solution at a temperature of 0 degree C to 10 degree C, to make Cefditoren pivoxyl to start to deposit as crystals, agitating the resulting mixture of the above mentioned concentrated solution with water and the deposited crystals as obtained in the sixth step, at a temperature of 0 degree C to 10 degree C for a time sufficient to effect a complete crystallization of Cefditoren pivoxyl, and 5. A process according to claim 4, in which the first organic solvent used in the first step is chosen from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl iso-butyl ketone, tetrahydrofuran, dioxane, acetonirile, a lower alkyl ester of acetic acid, particularly methyl acetate, ethyl acetate, and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of them, and the alkanol as the second organic solvent used in the second step and fourth step is chosen from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, n-amyl alcohol, iso-amyl alcohol, sec-amyl alcohol and tert-amyl alcohol, as well as mixed solvents of two or more of them. 6. A process according to claim 4, in which the third step and fifth step of concentrating the solution of Cefditoren pivoxyl in the solvent(s) is conducted at a temperature of 0 degree C to 10 degree C under a reduced pressure of 10 to 50 Torr (guage). 7. A process for the preparation of a crystalline substance of Cefditoren pivoxyl having the orthorhombic form according to claim l, which comprises conducting successively the following first to seven steps: dissolving an amorphous substance of Cefditoren pivoxyl in an anhydrous, first organic solvent in which Cefditoren pivoxyl is much more soluble than in an alkanol containing 1 to 5 carbon atoms and which is miscible with said alkanol, thereby to obtain a solution containing 10 mg to 50 mg of the dissolved Cefditoren pivoxyl per 1 ml of the resulting solution of Cefditoren pivoxyl in the first organic solvent, mixing the resulting solution of Cefditoren pivoxyl in the first organic solvent with an anhydrous alkanol containing 1 to 5 carbon atoms as a second organic solvent in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxyl dissolved in the resulting mixture of said solution of Cefditoren pivoxyl with the second organic solvent, to a concentration of 5 mg to 40 mg of the dissolved Cefditoren pivoxyl per 1 ml of said resulting mixture, concentrating the resulting solution of Cefditoren pivoxyl in the mixed first and second organic solvents as obtained in the second step, at a temperature of -5 degree C to 15 degree C by evaporation of the organic solvents from said solution under a reduced pressure, to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the dissolved Cefditoren pivoxyl, mixing the concentrated solution so obtained in the third step with a further volume of an alkanol of 1 to 5 carbon atoms used as the second organic solvent in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxyl dissolved in the resulting mixture of said concentrated solution with the further volume of the alkanol, to a concentration of 25 mg to 125 mg of the dissolved Cefditoren pivoxyl per 1 ml of said resulting mixture, concentrating the resulting solution of Cefidtoren pivoxyl so diluted with the further volume of the alkanol in the fourth step, at a temperature of -5 degree C to 15 degree C by evaporation of the solvents from said solution under a reduced pressure, to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the Cefditoren pivoxyl dissolved in the solvent entirely or substantially entirely made of said alkanol, immediately after the fifth step agitating the concentrated solutions obtained in the fifth step at a temperature of 0 degree C to 10 degree C for a time sufficient to effect a complete crystallization of Cefditoren pivoxyl, and subsequent separating and harvesting the crystals by filtration and then dried under reduced pressure. 8. A process for the preparation of a crystalline substance of Cefditoren pivoxyl having the orthorhombic form according to claim 1, which comprises conducting successively the following step (a) to step (i): (a) placing the so obtained crystalline substance of Cefditoren pivoxyl as a seed crystal in a solution containing 10 mg/ml to 50 mg/ml of Cefdiroren pivoxyl which has been prepared by dissolution of an amorphous substance of Cefditoren pivoxyl in an anhydrous, first organic solvent as defined in claim 4, (b) incubating the solution of Cefditoren pivoxyl in the first organic solvent and further containing therein the seed crystal of Cefditoren pivoxyl added in the above step (a), at a temperature of 0 degree C to 50 degree C for a time of 10 minutes to 48 hours, (c) concentrating the solution of Cefditoren pivoxyl with the seed crystal so incubated in the above step (b), at a temperature of -5 degree C to 15 degree C by evaporation of the first organic solvent therefrom under a reduced pressure, thereby to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the dissolved Cefditoren pivoxyl and the seed crystal of Cefditoren pivoxyl remaining therein, (d) mixing the concentrated solution of Cefditoren pivoxyl containing the remaining seed crystal as obtained in the above step (c) with an anhydrous alkanol of 1 t