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AssigneeMeiji Seika Kaisha, Ltd.
InventorsKiyoshi Yasui, Masahiro Onodera, Masamichi Sukegawa, Tatsuo Watanabe, Yuichi Yamamoto, Yasushi Murai, Katsuharu Iinuma
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A crystalline substance of Cefditoren pivoxyl is provided which has a high purity and enhanced thermal stability on storage. This crystalline Cefditoren pivoxyl may be prepared by a process comprising a step of dissolving an amorphous form of Cefditoren pivoxyl in an anhydrous, first organic solvent capable of dissolving said amorphous form well therein, and steps of replacing the first organic solvent component of the resulting solution by an anhydrous alkanol of 1 to 5 carbon atoms as a second organic solvent, in such a manner that the firstly prepared solution of Cefditoren pivoxyl in the first organic solvent is mixed with a volume of the alkanol and then is concentrated below 15° C. under reduced pressure, and so on. Thereby, the process proceeds so as to produce a solution containing 50 mg/ml to 250 mg/ml of Cefditoren pivoxyl dissolved in the alkanol alone. From the latter solution, crystals of Cefditoren pivoxyl are induced to deposit by addition of water at a temperature of 0-10° C. The resulting admixture of the concentrated solution of Cefditoren pivoxyl in alkanol with added water and the deposited Cefditoren pivoxyl is then agitated 10° C. or below, to effect a complete crystallization of Cefditoren pivoxyl.
A crystalline substance of Cefditoren pivoxyl, namely 7-[(Z)-2-(2-aminothiazol) -2-methoxyiminoacetamido]-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° C. to 215.7° C. as evaluated from the peak of thermal absorption shown in the heat flow curve of said substance determined by a differential scanning calorimeter, that a single crystal of said crystalline substrate has a density of 1.21 to 1.23 g/cm3 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 as measured by a liquid chromatography with using a reverse phase silica gel column and by detecting with ultra-violet ray absorption at 230 nm, and that said crystalline substance has a higher thermal stability as determined at a temperature of 60° for two months or at a temperature of 40° for four months than the known amorphous substance of Cefditoren pivoxyl.
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