MXPA99002586A - A crystalline substance of cefditoren pivoxyl and the production of the same - Google Patents

Abstract

As a novel substance is provided a new, crystalline substance of Cefditoren pivoxyl which has a high purity and an enhanced thermal stability on storage. This crystalline Cefditoren pivoxyl may be prepared by a process comprising a step of dissolving amorphous substance of Cefditoren pivoxyl in an anhydrous, first organic solvent capable of dissolving said amorphous substance 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 solutioncontaining 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.

Description

A crystalline substance of Cefditoren pivoxil and the production thereof TECHNICAL FIELD This invention relates to a new crystalline substance of Cefditoren pivoxil and also refers to new processes for the production of the new crystalline substance of Cefditoren pivoxil. Cefditoren pivoxil is an orally administrable prodrug belonging to an antibacterially active antibiotic of the cephalosporin type and is a compound generally referred to as pivaloyloxymethyl ester of 7- [(z) -2- (2-aminothiazole-4- il) -2-methoxyiminoacetamido] -3- [(z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4-carboxylic acid.

PREVIOUS TECHNIQUE OF THE INVENTION Cefditoren is a cefem compound which is represented by the following formula (A): and it is referred to as (+) - (6R, 7R) -7- [(z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoaceta ido] -3- [(z) -2- ( 4-Methylthiazol-5-yl) -etheni-1] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. This cefe compound of generic name "Cefditoren" is also designated as 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] acid ] -3-cephem-4-carboxylic acid (non-isomer, cis-isomer) in Japanese Patent No. 1698887 (Japanese Patent Publication "Koko u" N2 Hei-3-64503 published October 7, 1991), the US Patent No. 4,839,350 and European Patent No. 0175610. A pivaloyloxymethyl ester of Cefditoren, in which the 4-carboxyl group has been converted to ester with the pivaloyloxymethyl group for the purpose of improving the absorption capacity of the cefem compound through the Digestive tubes after oral administration thereof, is the aforementioned prodrug known by the generic name of "Cefditoren pivoxil" and is represented by the following formula (B): and which has a chemical name "2,2-dimethylpropionyl-oxymethyl ester of (-) - (6R, 7R) -7- [(z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] ] -3- [(z) -2- (4-Methylthiazol-5-yl) ethenyl] -8-oxo-5-thia-l-azabicyclo- [4.2.0] oct-2-ene-2-carboxylic acid " . Cefditoren pivoxil is known as a light yellow powder that has a melting point of 127 to 129 ° C (see the "Merck Index", 12th Edition, page 317).

Cefditoren has a low toxicity for mammals but shows a much wider antibacterial spectrum against gram-positive bacteria and gram-negative bacteria. The Cefditoren pivoxil is, in itself, antibacterially inactive but is useful as an orally administrable pro-drug and can be converted into the antibacterially active Cefditoren in the digestive tubes of mammals, with the cleavage of the ester-forming pivaloyloxymethyl group thereof. Cefditoren and Cefditoren pivoxil are known as highly excellent therapeutic agents that have been used extensively for therapeutic treatments and preventive treatments of bacterial infections caused by a variety of gram-positive bacteria and gram-negative bacteria. These produced Cefditoren pivoxil products which are currently commercially available are generally found exclusively in the form of an amorphous and powdered substance. This amorphous substance of Cefditoren pivoxil is generally prepared by a method in which a reaction solution containing synthesized Cefditoren pivoxil is mixed with isopropyl ether to precipitate an amorphous powder of Cefditoren pivoxil and this amorphous powder of Cefditoren pivoxil is dissolved in methanol, and in which the resulting solution of Cefditoren pivoxil in methanol is added to aqueous isopropanol to precipitate an amorphous powder of Cefditoren pivoxil and this amorphous powder is subsequently recovered (see, for example, Example 2 of US Patent No. 4,839,350 and European Patent Ns 0175610). Thus, to date, no crystalline substance or other form of Cefditoren pivoxil is known or obtained, as far as we know. The known amorphous substance of Cefditoren pivoxil has been widely used as an excellent antibiotic medicament, as specified above, but it is not yet a fully satisfactory drug since it is not stable to a sufficient degree when stored at an elevated temperature and under highly humid In addition, it has been found that the presently commercially available amorphous substance of Cefditoren pivoxil, generally having a purity of 94% to 95.5% for the Cefditoren pivoxil component when analyzed by means of liquid chromatography on a gel column. of reverse phase silica according to that detected with the absorption of ultraviolet rays. Accordingly, there is a remarkable demand to provide a new product of this class of Cefditoren pivoxil which is much purer and much more stable than the known amorphous substance of Cefditoren pivoxil. There is also another demand to provide a new process that is capable of producing a highly pure product of Cefditoren pivoxil in an efficient commercial scale form.

PRESENTATION OF THE INVENTION We, the inventors present, have carried out extensive investigations in order to solve the aforementioned problems, and subsequently we have assumed that, if the Cefditoren pivoxil can be obtained in a crystalline form, this will be a much more stable pro. and highly pure. The present inventors, in this way, have made additional investigations in an attempt to pro a crystalline form of Cefditoren pivoxil. As a result of these additional investigations, we have now discovered that, when an amorphous substance of Cefditoren pivoxil dissolves once into a first anhydrous organic solvent, it can perfectly dissolve the amorphous cefditoren pivoxil in it, and when the resulting solution of Cefditoren pivoxil in the first mentioned organic solvent is concentrated to a red volume of the solution at a temperature not higher than 15 ° C by evaporating the first organic solvent under a red pressure, followed by mixing the resulting concentrated solution with a volume of one anhydrous alkanol containing from 1 to 5 carbon atoms, as a second organic solvent miscible with the first organic solvent, and then repeating several times the concentration of the solution and the mixture of the concentrated solution with additional quantities of the alkanol from 1 to 5. carbon atoms at a temperature not higher than 15 ° C, in the form to which is detailed below, to thereby prepare a concentrated solution containing 50 to 250 mg / ml of Cefditoren pivoxil dissolved in substantially only a second organic solvent, the alkanol, and when the resulting concentrated solution containing 50 to 250 mg / ml of Cefditoren pivoxil in the alkanol is subsequently mixed with a volume of water at a temperature not higher than 10 ° C, then the Cefditoren pivoxil can begin to be deposited in a crystalline particle form from the aforementioned concentrated solution and a complete crystallization of Cefditoren pivoxil can be achieved by stirring the aqueous mixture of the remaining solution with the deposited crystal particles, at a temperature of 10 ° C or lower, and a crystalline substance of Cefditoren pivoxil can be separated and cultured from the solution remaining (the liquid phase) by filtration or centrifugation.

In this way, the present inventors have succeeded in obtaining this crystalline substance of Cefditoren pivoxil having a high purity of 97% to 98% for the Cefditoren pivoxil component and can show a remarkably higher storage stability at an elevated temperature, in comparison with the known amorphous substance of Cefditoren pivoxil. This crystalline substance of Cefditoren pivoxil obtained is now in orthorhombic form as measured by an X-ray powder diffractometer and a single-crystal X-ray diffractometer, and this crystalline substance of Cefditoren pivoxil consists of simple crystals that possess a density of 1.21 to 1.23 g / cm3. This crystalline substance of Cefditoren pivoxil also has a melting point of 206.2 ° C to 215.7 ° C with decomposition, as evaluated from the thermal absorption peak shown in the heat flow curve that was determined by testing the crystalline substance in a differential tracking calorimeter. It is considered that this crystalline substance of Cefditoren pivoxil that owns the orthorhombic form and that possesses the physical-chemical characteristics before mentioned, must be a new substance, since it was not known in the past any pro or substance of Cefditoren pivoxil that shows the characteristics particular physical-chemical properties indicated above.

In addition, the present inventors have now discovered that the new crystalline substance of Cefditoren pivoxil currently obtained is tasteless for the tongue when placed on the tongue, the opposite of the known amorphous substance of Cefditoren pivoxil which usually has an unpleasant bitter taste for the language, when provided orally (see the internationally published specification No. WO 97/13516 of PCT Application No. PCT / JP 96/02967). This invention has now been achieved on the basis of the aforementioned discoveries of the present inventors.

Therefore, in a first aspect of this invention, a crystalline substance of Cefditoren pivoxil, namely pivaloyloxymethyl ester of 7- [(z) -2- (2-aminothiazole-4-) acid, is offered as a novel substance. il) -2-methoxyiminoacetamido] -3- [(z) -2- (4-me ylazol-5-yl) ethenyl] -3-cephem-4-carboxylic acid, characterized in that the aforementioned crystalline substance of Cefditoren pivoxil is Orthorhombic form and has a melting point with decomposition at a temperature in the range of 206.2 ° C to 215.7 ° C as assessed from the thermal absorption peak shown in the heat flux curve of the aforementioned substance determined with a Differential scanning calorimeter, because a single crystal of the aforementioned crystalline substance has a density of 1.21 to 1.23 g / cm3 and contains 4 molecules of Cefditoren pivoxil within a unitary crosslinking of the single crystal, because the aforementioned crystalline substance has a purity of 97 % to 98% for the component e of Cefditoren pivoxil as measured by liquid chromatography using a reversed-phase silica gel column and detecting by absorption of ultraviolet rays, and because the aforementioned crystalline substance has a higher thermal stability than the known amorphous substance of Cefditoren pivoxil . It is preferred that the crystalline substance of Cefditoren pivoxil have a purity of 97.7% or greater for the Cefditoren pivoxil component. Several samples of the new crystalline substance of Cefditoren pivoxil supplied according to the first aspect of this invention were taken and analyzed by means of an X-ray powder diffractometer, and it was subsequently discovered that the data of the X-ray powder diffractometer of the crystalline substance tested by Cefditoren pivoxil show the diffraction peaks at the following diffraction angles: about 9.7 degrees, about 10.8 degrees, about 11.4 degrees, about 12.1 degrees, about 13.6 degrees, about 15.6 degrees, about 16.2 degrees, about 17.4 degrees, about 19.0 degrees, about 19.5 degrees, about 20.1 degrees, about 20.8 degrees, about 21.5 degrees, about 25.2 degrees, about 29.9 degrees and about 33.0 degrees.

It should be added that the known amorphous substance of Cefditoren pivoxil does not show any diffraction peak when it is tested by the same X-ray powder diffractometer as mentioned above. In addition, a single crystal was taken as a sample of the crystalline product of Cefditoren pivoxil that was produced in Example 1 shown below, and the crystal structure of this single crystal was investigated using a single-crystal X-ray diffractometer ( Model AFC-5R, a product of Rigaku-Denki Company, Ltd., Japan). As a result, it was discovered that the only crystal tested by Cefditsren pivoxil possesses substantially the crystallographic characteristics that are tabulated in Table 1 below. Table 1 Crystallographic data of a single crystal of Cefditoren pivoxil Crystalline system: Orthorrhythmic shape > ica Constants of the grid: a = 14.02 6Á, b = 18. 438Á, c = 11.815Á, a = 90 °, ß = 90 °,? = 90 ° Spatial group: P2? P2? P2 1 Ns of molecules within a single ret. Unit number: 4 Crosslinking capacity: 3055 Á3 Density: 1.22 g / cm3 on average R value: 4% The aforementioned crystallographic data of the single crystal of Cefditoren pivoxil currently reveal that a molecule of Cefditoren pivoxil present in a lattice of a crystal unit takes the conformation molecular structure of the molecule as illustrated in Figure 1 of the appended illustrations. From the above data, it was further revealed that the stereo-chemistry in the half of the oxime and the stereochemistry in the 3-position of the Cefditoren pivoxyl compound having the crystalline form are obviously of the Z-configuration, and therefore, they are of the configuration without and of the configuration Z, respectively, which indicates that the crystalline substance of Cefditoren pivoxil as obtained according to this invention, must undoubtedly be an ester of pivaloyloxymethyl acid. - [(z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [(z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4- crystalline carboxylic As described above, the new crystalline substance of Cefditoren pivoxil according to this invention possesses an improved storage stability in comparison with the known amorphous form of Cefditoren pivoxil. In order to test the thermal stability in the storage of the new crystalline substance of Cefditoren pivoxil according to this invention, compared to the known amorphous form of Cefditoren pivoxil, a sample of the crystalline Cefditoren pivoxil was used which was produced in the Example 1 specified later, as well as a sample of the amorphous pivoxyl Cefditoren that was produced by mixing a solution of amorphous pivoxyl Cefditoren in methanol with an aqueous isopropanol to precipitate an amorphous powder of this compound, and separating and drying this powder under a reduced pressure. These samples were placed separately in sealed dry containers and stored for 1 month, for 2 months and for 4 months at 60 ° C and at 40 ° C, respectively. After these storages, the samples were analyzed by a liquid chromatographic method and the percentages of the residual amount of Cefditoren pivoxil left in the stored samples from the area below the absorption peak that was shown in the obtained chromatograms were evaluated. It is assumed that the initial content of Cefditoren pivoxil in the test samples was 100% at the start of storage. The results of the test obtained are summarized in Tables 2 and 3 below.

Table 2 Table 3 From the results of Tables 2 and 3 above, it is observed that the crystalline substance of Cefditoren pivoxil according to this invention is capable of possessing a residual amount of 99% Cefditoren pivoxil even after storage for 4 months to 40 minutes. ° C and also after storage for 2 months at elevated temperatures of up to 60 ° C, indicating that the residual amount of Cefditoren pivoxil does not decrease substantially for a long time after storage of the crystalline pivoxyl Cefditoren under ordinary conditions at ambient temperatures , and that the crystalline pivoxyl Cefditoren of this invention has a better thermal stability than the known amorphous pivoxyl Cefditoren. Next, the production of the crystalline substance of Cefditoren pivoxil according to this invention will be described. Speaking concisely, the crystalline substance of Cefditoren pivoxil can be produced by such a process that it is characterized by including a step of dissolving an amorphous substance of Cefditoren pivoxil within a first anhydrous organic solvent capable of dissolving the Cefditoren pivoxil perfectly therein. in comparison with an alkanol of 1 to 5 carbon atoms, and a step of subsequently replacing the component of the first organic solvent of the resulting solution in a gradual manner by means of some proportions of an anhydrous alkanol of 1 to 5 carbon atoms as a second organic solvent, so that the solution prepared first of Cefditoren pivoxil in the first organic solvent is mixed with a proportion of an anhydrous alkanol (the second organic solvent), the resulting mixture is concentrated at a reduced volume by the evaporation of the first and the second organic solvent thereof under a pressure re ducida, whereby a concentrated solution of Cefditoren pivoxil is formed in a mixed solvent that includes a smaller proportion of the first organic solvent and a larger proportion of the alkanol (the second organic solvent), this concentrated solution is mixed once more with a further amount of the alkanol and then re-concentrated by evaporating the first and second organic solvent, while repeatedly mixing the concentrated solution with an additional amount of alkanol and the concentration of the solution that was diluted with the alkanol added, in such a way that a solution containing, at a given concentration of 50 mg - 250 mg / ml, the Cefditoren pivoxil dissolved in the solvent made only or almost solely from the mentioned alkanol, and whose process is characterized also to include the additional step of mixing this last solution of Cefditoren pivoxil in the sole solven of alkanol formed in this manner, with a proportion of water at a temperature not higher than 10 ° C, to cause the solid particles of Cefditoren pivoxil to begin to deposit in the aforesaid solution, and an additional step of incubating with stirring the solution containing the solid particles deposited in this way, at a temperature of 0 ° C to 10 ° C for a time of 10 minutes to 48 hours, in such a way that all the solid particles deposited crystallize completely in the crystalline form of Cefditoren pivoxil. More particularly, in a second aspect of this invention, there is provided a process for the preparation of a crystalline substance of Cefditoren pivoxil having the orthorhombic form, which includes the successive conduction of the fwing steps from one to eight: in a first step, dissolving an amorphous substance of Cefditoren pivoxil in a first anhydrous organic solvent, in which the Cefditoren pivoxil is much more soluble than in an alkanol containing 1 to 5 carbon atoms and which is miscible with the alkanol of 1 - 5. carbon atoms, to obtain in this way a solution containing 10 mg to 50 mg of the cefditoren pivoxil dissolved by 1 ml of the resulting solution of Cefditoren pivoxil in the first organic solvent, in a second step, mix the resulting solution of Cefditoren pivoxil in the first organic solvent with an anhydrous alkanol containing from 1 to 5 carbon atoms as a second organic solvent, in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxil dissolved in the mixture resulting from the mentioned solution of Cefditoren pivoxil in the second organic solvent at a concentration of 5 mg to 40 mg of the cefditoren pivoxil dissolved by 1 ml of the aforesaid mixture, in a third step, concentrate the resulting solution of Cefditoren pivoxil in the first and the second organic solvent mixed as they were obtained in the second step, at a temperature of -5 ° C to 15 ° C by evaporating the organic solvents of the aforementioned solution under a reduced pressure, to provide a concentrated solution containing 50 mg / ml to 250 mg / ml of the cefditoren pivoxil dissolved, in a fourth step, The concentrated solution obtained in this way in the third step with an additional 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 pivoxil dissolved in the The resulting mixture of the aforementioned concentrated solution with the additional volume of the alkanol, at a concentration of 25 mg to 125 mg of the cefditoren pivoxil dissolved by 1 ml of the aforesaid mixture, in a fifth step, concentrate the resulting solution of Cefditoren pivoxil diluted this way with the additional volume of the alkanol in the fourth step, at a temperature of -5 ° C to 15 ° C by evaporating the solvents of the aforementioned solution under a reduced pressure, to produce a concentrated solution containing 50 mg / ml to 250 mg / ml of Cefditoren pivoxil dissolved in the solvent, made entirely or almost entirely from alkanol menc. In a sixth step, mix the concentrated solution obtained in the fifth step gradually with water of a volume from 1 to 20 times greater than the volume of the above concentrated solution at a temperature of 0 ° C to 10 ° C, for making that him Cefditoren pivoxil begin to deposit as crystals, in a seventh step, stir the resulting mixture of the aforementioned concentrated solution with water and the deposited crystals, as obtained in the sixth step, at a temperature of 0 ° C to 10 ° C for a sufficient time to carry out a complete crystallization of the Cefditoren pivoxil, and in an eighth step, separate and culture the crystalline pivoxyl Cefditoren from the remaining solution by filtration or centrifugation, followed by drying the substance of Cefditoren crystalline pivoxil cultured under reduced pressure. In the process according to the second aspect of this invention, it is preferred that the first organic solvent used in the first step be selected from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofurans, dioxane, acetonitrile, an ester of low alkyl of acetic acid, in particular methyl acetate, ethyl acetate and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of these, and that the alkanol as the second organic solvent used in the second step and the fourth step, is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, sec-amyl alcohol and tere-amyl alcohol, as well as the mixed solvents of two or more of these. In the process according to the second aspect of this invention, it is also preferred that the third step and the fifth step of concentrating the Cefditoren pivoxil solution in the solvent (s) be carried out at a temperature of 0 °. C at 10 ° C under a reduced pressure of 10 - 50 Torr (measurement). In this process, it is possible to omit the sixth step of mixing the concentrated solution obtained in the fifth step with water, but the concentrated solution obtained in the fifth step is immediately stirred at a temperature of 0 ° C to 10 ° C for a time sufficient to carry out a complete crystallization of the Cefditoren pivoxil, and the resulting crystals are separated and subsequently cultured by filtration or centrifugation and then dried under reduced pressure.

In the seventh step of the process according to the first aspect of this invention, the mixture of the concentrated solution of Cefditoren pivoxil dissolved with water and the deposited crystals of Cefditoren pivoxil which have been produced in the sixth step of the process, is stirred to a temperature from 0 ° C to 10 ° C for a sufficient time to carry out a complete crystallization of the Cefditoren pivoxil. The stirring can be carried out by means of a mechanical stirrer or under an ultrasonic irradiation. The term "carrying out a complete crystallization of Cefditoren pivoxil" indicates that the amorphous solid particles of the cefditoren pivoxil that may have been deposited, if any, can be converted to a crystalline form during the agitation of the aforementioned mixture in order to avoid that the final product of the Cefditoren crystalline pivoxil be contaminated with a trace amount of the amorphous Cefditoren pivoxil, and also that the dissolved pivoxil Cefditoren present in the solution be deposited to a total degree or a maximum degree as much as possible. Once the crystalline substance of Cefditoren pivoxil has been successfully obtained according to the process of the second aspect of this invention, the crystalline substance of Cefditoren pivoxil can be produced by a different process using the mentioned crystalline substance of Cefditoren pivoxil as a seed crystal and includes some steps of the process of the second aspect of this invention. In a third aspect of this invention, therefore, there is provided a process for the preparation of a crystalline substance of Cefditoren pivoxil having the orthorhombic form, which includes the successive conduction of the following steps (a) to (i): (a) ) carrying out the process of the second aspect of this invention as described above, in order thus to obtain a crystalline substance of Cefditoren pivoxil having the orthorhombic form, (b) to place the crystalline substance of Cefditoren pivoxil obtained in this manner as a seed crystal in a solution containing 10 mg / ml to 50 mg / ml of Cefditoren pivoxil which has been prepared by dissolving an amorphous substance of Cefditoren pivoxil in a first anhydrous organic solvent as defined above, (c) incubating the solution of Cefditoren pivoxil in the first organic solvent and including subsequently therein the seed crystal of the Cefditoren pivoxil added in the previous step (b), at a temperature of 0 ° C to 50 ° C for a time of 10 minutes to 48 hours, preferably at a temperature of 0 ° C at 20 ° C for a time of 20 hours to 40 hours, to cause the crystalline substance of the Cefditoren pivoxil to begin to be deposited from the aforesaid solution. (d) concentrating the Cefditoren pivoxil solution with the seed crystal incubated in this way in the previous step (c), at a temperature of -5 ° C to 15 ° C by evaporating the first organic solvent thereof under a reduced pressure, to thereby produce a concentrated solution containing 50 mg / ml to 250 mg / ml of the dissolved Cefditoren pivoxil and the seed crystal of the remaining Cefditoren pivoxil in it, (e) mix the concentrated solution of Cefditoren pivoxil which contains the remaining seed crystal in the form obtained in the previous step (d), with the anhydrous alkanol having from 1 to 5 carbon atoms as the second organic solvent in a proportion thereof necessary to reduce the concentration of the dissolved pivoxyl Cefditoren at a concentration of 25 mg / ml to 125 mg / ml of Cefditoren pivoxil dissolved in the mixture resulting from the aforementioned concentrated solution of Cefditoren pivoxil with the alkanol which still contains the remaining seed crystal of Cefditoren pivoxil, (f) concentrate the resulting mixture of the concentrated solution of Cefditoren pivoxil with the alkanol as obtained in the previous step (e), at a temperature of -5 ° C to 15 ° C through the evaporation of the first organic solvent and the alkanol thereof under a reduced pressure, to thereby produce a concentrated solution containing the cefditoren pivoxil dissolved in its concentration of 50 mg / ml to 250 mg / ml and the remaining seed crystal of the Cefditoren pivoxil, (g) mix the concentrated solution including the dissolved Cefditoren pivoxil and the remaining seed crystal in the form obtained in the previous step (f), with water at a volume of 1 to 20 times greater than the volume of the aforementioned concentrated solution of Cefditoren pivoxil, at a temperature of 0 ° C to 10 ° C, to thereby facilitate a crystalline substance of Cefditoren pivoxil to be deposited from the resulting mixture of the above-mentioned concentrated solution of Cefditoren pivoxil with water, (h) stirring the resulting aqueous mixture of the solution containing the dissolved Cefditoren pivoxil, water and the crystalline substance deposited from Cefditoren pivoxil, as obtained in the previous step (g) , at a temperature of 0 ° C to 10 ° C for a time of 20 hours to 40 hours, to carry out in this way a complete crystallization of the Cefditoren pivoxil, and (i) to separate and cultivate the crystals obtained in the previous step (h), of the remaining solution, followed by the drying of the cultured crystals under reduced pressure. In the process according to the third aspect of this invention, it is preferred that the solution of Cefditoren pivoxil in the first anhydrous organic solvent to be added with the seed crystal of Cefditoren pivoxil in step (b) is a solution that has been prepared by dissolving the amorphous substance of Cefditoren pivoxil in an organic solvent selected from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, a low alkyl ester of acetic acid, in particular methyl acetate, ethyl acetate and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of these, and that the alkanol used in step (e) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, sec-amyl alcohol and tere-amyl alcohol, as well as the mixed solvents of two or more of these. In this process, it is also preferred that step (c) of incubating the solution of the Cefditoren pivoxil containing the seed crystal, as well as steps (d) and (f) of concentrating the Cefditoren pivoxil solution, are carried out at a temperature not higher than 10 ° C. The crystalline substance of Cefditoren pivoxil, according to the first aspect of this invention, can also be produced by another process that includes much smaller steps than in the processes of the second and third aspects of this invention, using as seed crystal a Cefditoren crystalline pivoxil in the form in which it was prepared above. In a fourth aspect of this invention, there is provided a process for the preparation of a crystalline substance of Cefditoren pivoxil having the orthorhombic form, which includes consecutively carrying out the following steps (i) to (iv): (i) a step of effecting the process of the first aspect of the invention, to thereby obtain a crystalline substance of Cefditoren pivoxil having the orthorhombic form, (ii) a step of placing the crystalline substance of Cefditoren pivoxil obtained in step (i) , as a seed crystal in a solution of Cefditoren pivoxil which has been prepared by dissolving an amorphous substance of Cefditoren pivoxil at a concentration of 10 mg / ml to 50 mg / ml in an anhydrous organic solvent selected from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, a low alkyl ester of acetic acid, in particular methyl acetate, acetates of ethyl and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of these, and that the alkanol as the second organic solvent used in the second step and the fourth step, is selected from methanol , ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, sec-amyl alcohol and tere-amyl alcohol, as well as the mixed solvents of two or more of these. (iii) a step of stirring the resulting mixture of the Cefditoren pivoxil solution in the organic solvent with the Cefditoren pivoxil seed crystal as obtained in step (ii), at a temperature not higher than 50 ° C, during a sufficient time to facilitate the crystallization of the Cefditoren pivoxil in the solution, and (iv) to separate and culture the crystalline substance deposited from Cefditoren pivoxil from the remaining solution by filtration or centrifugation, followed by the drying of the cultured crystals of Cefditoren pivoxil under a reduced pressure.

BRIEF DESCRIPTION OF THE ACCOMPANYING ILLUSTRATIONS Figure 1 represents the molecular conformation or steric structure of the crystalline pivoxyl Cefditoren of this invention, which has been elucidated from the analysis of the crystal structure of a single crystal by a single-crystal X-ray diffractometer. Figure 2 shows a pattern of the X-ray powder diffraction data of a crystalline substance of Cefditoren pivoxil that was obtained in Example 1 given below in accordance with this invention. Figure '3 shows a curve of the heat flux with respect to temperature (° C), which was determined by testing the crystalline substance of Cefditoren pivoxil Example 1 with a differential tracking calorimeter. Figure 4 shows a pattern of the X-ray powder diffraction data of a crystalline substance of Cefditoren pivoxil which was obtained in Example 4 according to this invention. Figure 5 shows a curve of the heat flux with respect to temperature (° C), which was determined by testing the crystalline substance of Cefditoren pivoxil of Example 4 with a differential scanning calorimeter. Figure 6 shows a pattern of X-ray powder diffraction data of a crystalline substance of Cefditoren pivoxil that was obtained in Example 6 given below in accordance with this invention. Figure 7 shows a curve of the heat flux with respect to temperature (° C), which was determined by testing the crystalline substance of Cefditoren pivoxil of Example 6 with a differential scanning calorimeter. Figure 8 shows a pattern of the X-ray powder diffraction data of a crystalline substance of Cefditoren pivoxil that was obtained in Example 7 according to this invention. Figure 9 shows a curve of the heat flux with respect to temperature (° C), which was determined by testing the crystalline substance of Cefditoren pivoxil of Example 7. Figure 10 shows a pattern of the powder diffraction data of X-rays of a crystalline substance of Cefditoren pivoxil which was obtained in Example 8 provided subsequently according to this invention. Figure 11 shows a curve of the heat flux with respect to temperature (° C), which was determined by testing the crystalline substance of Cefditoren pivoxil of Example 8 with a differential scanning calorimeter. Figure 12 shows a pattern of the X-ray powder diffraction data of a crystalline substance of Cefditoren pivoxil that was obtained in Example 9 according to this invention. Figure 13 shows a curve of the heat flux with respect to temperature (° C), which was determined by testing the crystalline substance of Cefditoren pivoxil of Example 9 with the differential scanning calorimeter.

BEST MODE FOR CARRYING OUT THE INVENTION The production of crystalline pivoxyl Cefditoren by the novel processes of this invention is now illustrated with reference to the following Examples 1 to 9, to which this invention is not limited. Examples 1-3 are illustrative examples for carrying out the process according to the second aspect of this invention. Example 4 is an illustrative example for carrying out the process according to the third aspect of this invention. Examples 5 to 9 are illustrative examples for carrying out the process according to the fourth aspect of this invention. Example 1 An amorphous substance (10 g) of Cefditoren pivoxil, namely pivaloyloxymethyl ester of 7- [(z) -2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3- [( z) -2- (4-Methylthiazol-5-yl) ethenyl] -3-cephem-4-carboxylic acid, was dissolved in ethyl acetate (400 ml) at room temperature (at 10 ° C). The resulting solution containing the cefditoren pivoxil dissolved at a concentration of 25 mg / ml ethyl acetate was subsequently mixed with anhydrous ethanol (60 m) at a temperature of 5 ° C or less, to prepare a solution containing 217 mg / ml of Cefditoren pivoxil in the mixture of ethyl acetate and ethanol (in total 460 ml). This solution was concentrated to a volume of 80 ml by evaporating the ethyl acetate and the ethanol under a reduced pressure of 20 Torr (in measure), keeping the temperature of the mentioned solution below 1 ° C. The concentrated solution obtained in this way had a concentration of 125 mg / ml of cefditoren pivoxil dissolved in a mixture of a larger proportion of ethanol and a smaller proportion of ethyl acetate. This concentrated solution was mixed with an additional quantity of anhydrous ethanol (80 ml) below 10 ° C, to prepare a solution containing 62.5 mg / ml of Cefditoren pivoxil dissolved in a mixed solvent that included a higher proportion of ethanol and a minor ethyl acetate. The latter solution was subsequently concentrated to a volume of 80 ml by evaporating the solvents under a reduced pressure of 20 Torr, maintaining the temperature of the solution at a temperature not higher than 10 ° C. In this way, a concentrated solution containing 125 mg / ml of Cefditoren pivoxil in ethanol could be obtained as substantially the only solvent present in the aforementioned solution. The solution obtained in this manner containing 125 mg / ml of Cefditoren pivoxil in anhydrous ethanol was mixed with water (140 ml) at a temperature not higher than 10 ° C, allowing the Cefditoren pivoxil to be deposited as crystalline particles in the resulting mixture . The resulting mixture containing the pivoxyl Cefditoren deposited therein was subjected to stirring overnight at the same temperature as mentioned above (ie, below 10 ° C), such that the Cefditoren pivoxil was subjected to a crystallization complete The crystals formed in this way were separated from the remaining solution by means of filtration and then dried under reduced pressure, yielding pale yellow crystals (9.5 g) of Cefditoren pivoxil at a purity of 98%. Figure 2 of the accompanying drawings shows a pattern of the mentioned X-ray powder diffraction data of the above crystalline product of Cefditoren pivoxil obtained in this Example 1, which was measured using an X-ray powder diffractometer (Geiger-Flex Model) 2027, an apparatus supplied by Rigaku-Denki Co., Ltd., Japan) with a CuK-o beam. at a voltage of 40 kilovolts and an electric current of 30 milliamps. The pattern of Figure 2 reveals that the product of Cefditoren pivoxil of this Example 1 was in crystalline form. Figure 3 of the accompanying drawings shows a curve of the heat flux (in milliwatts) with respect to the temperature (° C) of the aforementioned product of crystalline pivoxyl Cefditoren of Example 1, which was determined with a differential scanning calorimeter (a apparatus manufactured by Perkin-Elmer Co. Ltd., USA) at a temperature rise rate of 10 ° C per minute. The curve of Figure 3 shows that a peak of thermal absorption appeared at 214,835 ° C, indicating that the crystalline pivoxyl Cefditoren product of this Example 1 had a melting point of 214.8 ° C with decomposition. Table 4 below tabulates these diffraction angles in the X-ray powder diffraction data of Figure 2, in which the diffraction peaks are shown, as well as the relative intensities of these diffraction peaks. The relative intensities of the diffraction peaks were evaluated assuming that the intensity value of a maximum diffraction peak totals 1000.

Table 4 Value of the diffraction angle exhibiting the diffraction peaks in the X-ray powder diffraction data shown in Figure 2, and values of the relative intensities of the diffraction peaks.

Subsequently, the unique crystals of the crystalline pivoxyl Cefditoren product of this Example 1 were taken and the crystallographic characteristics of the single crystal were measured by means of a single-crystal X-ray diffractometer (Model AFC-5R, manufactured by Rigaku-Denki Co ., Ltd., Japan). The single crystal had the orthorhombic shape and had a density of 1.22 g / cm3 as measured by a conventional method. The results obtained from the measurement are summarized in Table 1 provided above. Examples 2-3 The procedures of Example 1 were repeated using • methanol instead of ethanol. The procedures of Example 1 were repeated one more time using isopropanol instead of ethanol. In these two tests of the experiments, pale yellow crystals of Cefditoren pivoxil were obtained in yields of 7.6 g and 7.8 g, respectively. It was found that the products of the two cultures of the crystalline pivoxyl Cefditoren were orthorhombic in shape and had a purity of 98% and a purity of 97%, respectively. Example 4 An amorphous substance (10 g) of Cefditoren pivoxil. it was dissolved in ethyl acetate (400 ml) at room temperature (at 10 ° C). To the resulting solution containing the cefditoren pivoxil dissolved at a concentration of 25 mg / ml of ethyl acetate was added 0.02 g of a previously prepared crystalline substance of Cefditoren pivoxil obtained in Example 1, as the seed crystal.

The solution of Cefditoren pivoxil in ethyl acetate containing the aggregated seed crystal was incubated at 10 ° C for 40 hours under mechanical agitation. After this incubation, this solution was concentrated to a volume of 40 ml under a reduced pressure of 20 Torr, keeping the temperature of the solution below 10 ° C. The concentrated solution obtained in this way contained 250 mg / ml of the cefditoren pivoxil dissolved in ethyl acetate together with the seed crystal. This concentrated solution in ethyl acetate was subsequently mixed with ethanol (60 ml) to prepare a solution containing 100 mg / ml of Cefditoren pivoxil in a mixture of ethyl acetate and ethanol, together with the seed crystal. The latter solution was again concentrated to a volume of 40 ml under a reduced pressure of 20 Torr, keeping the temperature of the solution below 10 ° C, such that a concentrated solution containing 250 mg / ml of Cefditoren was formed. pivoxil dissolved in ethanol as substantially the sole solvent and containing the seed crystal therein. The concentrated solution obtained in this manner was mixed with water (140 ml) at a temperature not higher than 10 ° C, so that the crystalline solid particles of Cefditoren pivoxil would begin to deposit in the resulting mixture. This mixture was stirred overnight at a temperature not higher than 10 ° C in order that the crystalline pivoxyl Cefditoren was deposited from the solution in a full degree. The deposited crystalline particles of Cefditoren pivoxil were separated from the remaining solution (the liquid phase) by filtration and then dried under reduced pressure, yielding 9.5 g of Cefditoren pivoxil as pale yellow crystals. Figure 4 of the accompanying drawings shows a pattern of the mentioned X-ray powder diffraction data of the crystalline product of Cefditoren pivoxil obtained in this Example 4, which were measured in the same manner as in Example 1. Figure 5 the accompanying drawings show a curve of the heat flux (in milliwatts) with respect to the temperature (° C) of the crystalline pivoxyl Cefditoren product of Example 4, which was determined by testing this product with a differential scanning calorimeter thereon as in Example 1. The curve in Figure 5 shows that a peak of thermal absorption appeared at a temperature of 212,482 ° C, which indicates that the Cefditoren crystalline pivoxil product of Example 4 had a melting point of 212.4 ° C with decomposition. The crystalline pivoxyl Cefditoren product of this Example 4 had a purity of 98.0%, as analyzed by a liquid chromatography on a reverse phase silica gel column. Example 5 The amorphous substance (10 g) of Cefditoren pivoxil was dissolved in ethyl acetate (400 ml) to prepare a solution containing 25 mg / ml Cefditoren pivoxil dissolved in ethyl acetate. To this solution was added seed crystal (0.02 g) of Cefditoren pivoxil which had been previously prepared. The resulting solution of Cefditoren pivoxil containing the aggregated seed crystal was subsequently stirred at room temperature (at 10 ° C) under ultrasonic irradiation. During this agitation, the crystallization of Cefditoren pivoxil was carried out. The crystals formed in this manner were separated from the remaining liquid phase of the solution by filtration and dried under reduced pressure to yield pale yellow crystals of Cefditoren pivoxil in a production of 7 g. The product of crystalline pivoxyl Cefditoren obtained in this Example had a purity of 98% according to what was analyzed by liquid chromatography. In addition, this crystalline pivoxyl Cefditoren product showed a pattern of X-ray powder diffraction data and a curve of heat flux with respect to temperature (° C), which are the same as those shown in Figures 4 and 5 of the accompanying illustrations, respectively. Example 6 The procedures of Example 5 were repeated using acetone instead of ethyl acetate. A crystalline substance of Cefditoren pivoxil was obtained in a production of 6.5 g and a purity of 97.8%. The X-ray powder diffraction data of this Cefditoren pivoxyl crystalline product were measured in the same manner as in Example 1 and are shown in Figure 6 of the accompanying drawings. In addition, this crystalline pivoxyl Cefditoren product was tested with the differential scanning calorimeter in the same manner as in Example 1, and in Figure 7 of the accompanying drawings the resulting curve of the heat flow with respect to the temperature as determined for this product. The curve in Figure 7 indicates that this crystalline pivoxyl Cefditoren product had a melting point of 215.6 ° C with decomposition. Example 7 The procedure of Example 5 was repeated using methanol instead of ethyl acetate. A crystalline substance of Cefditoren pivoxil was obtained in a production of 8 g and a purity of 97.5%.

X-ray powder diffraction data of this Cefditoren crystalline pivoxil product was measured in the same manner as in Example 1 and shown in Figure 8 of the accompanying drawings. In addition, this crystalline pivoxyl Cefditoren product was tested with the differential tracking calorimeter in the same manner as in Example 1, and in Figure 9 of the accompanying drawings the resulting curve of the heat flux with respect to the temperature as determined for this product. The curve in Figure 9 indicates that this crystalline pivoxyl Cefditoren product had a melting point of 206.2 ° C with decomposition. Example 8 The procedures of Example 5 were repeated using methylene chloride instead of ethyl acetate. A crystalline substance of Cefditoren pivoxil was obtained in a production of 6 g and a purity of 97%. The X-ray powder diffraction data of this Cefditoren crystalline pivoxil product were measured in the same manner as in Example 1 and are shown in Figure 10 of the accompanying drawings. In addition, this Cefditoren crystalline pivoxil product was tested with the differential scanning calorimeter in the same manner as in Example 1, and in Figure 11 of the accompanying drawings the resulting curve of the heat flux with respect to the temperature as determined for this product. The curve in Figure 11 indicates that this crystalline pivoxyl Cefditoren product had a melting point of 214.3 ° C with decomposition. Example 9 The procedure of Example 5 was repeated using acetonitrile instead of ethyl acetate. A crystalline substance of Cefditoren pivoxil was obtained in a production of 7 g and a purity of 97.5%. The X-ray powder diffraction data of this Cefditoren pivoxyl crystalline product were measured in the same manner as in Example 1 and are shown in Figure 12 of the accompanying drawings. In addition, this crystalline pivoxyl Cefditoren product was tested with the differential tracking calorimeter in the same manner as in Example 1, and in Figure 13 of the accompanying drawings the resulting curve of the heat flow with respect to the temperature as determined for this product. The curve in Figure 13 indicates that this crystalline pivoxyl Cefditoren product had a melting point of 214.8 ° C with decomposition.

INDUSTRIAL APPLICABILITY As described hereinabove, according to this invention it has become feasible to obtain, in the form of a new substance, a crystalline substance of Cefditoren pivoxil having a higher purity than and having a higher thermal stability under storage of the known amorphous substance of Cefditoren pivoxil. The new crystalline substance of Cefditoren pivoxil obtained in accordance with this invention has advantages for being used as a bulk material which is used to prepare an orally administrable antibiotic medicament having a broad antibacterial spectrum. In addition, new processes have been provided to prepare the crystalline substance of Cefditoren pivoxil, which can be carried out efficiently on a commercial scale.

Claims (11)

1. CLAIMS 1. A crystalline substance of Cefditoren pivoxil, namely pivaloyloxymethyl ester of 7- [(z) -2- (2-amino-thiazol-4-yl) -2-methoxy iminoaceta ido] -3- [(z ) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4-carboxylic acid, characterized in that the aforementioned crystalline substance of Cefditoren pivoxil is orthorhombic in shape and possesses a melting point with decomposition at a temperature in the range from 206.2 ° C to 215.7 ° C as evaluated from the thermal absorption peak shown in the heat flux curve of the mentioned substance determined with a differential scanning calorimeter, because a single crystal of the aforementioned crystalline substance possesses a density of 1.21 to 1.23 g / cm3 and contains 4 molecules of Cefditoren pivoxil within a unitary crosslinking of the single crystal, because the aforementioned crystalline substance has a purity of 97% to 98% for the component of Cefditoren pivoxil as measured by a liquid chromatography uti A column of reversed phase silica gel is detected and detected by the absorption of ultraviolet rays, and because said crystalline substance has a thermal stability higher than the known amorphous substance of Cefditoren pivoxil.
2. 2. A crystalline substance of Cefditoren pivoxil as set forth in claim 1, further characterized in that the data of the X-ray powder diffractometer of the mentioned crystalline substance of Cefditoren pivoxil show the peaks at the following diffraction angles: approximately 9.7 degrees about 10.8 degrees, about 11.4 degrees, about 12.1 degrees, about 13.6 degrees, about 15.6 degrees, about 16.2 degrees, about 17.4 degrees, about 19.0 degrees, about 19.5 degrees, about 20.1 degrees, about 20.8 degrees, about 21.5 degrees, about 25.2 degrees, approximately 29.9 degrees and approximately 33.0 degrees. and because the only crystal of the aforementioned crystalline substance possesses substantially the following crystallographic characteristics: Crystalline system: Orthorhombic form Crosslinking constants: a = 14.026Á, b = 18.438Á, c = 11.815Á, = 90 °, ß = 90 °, ? = 90 ° Space group: P2X P21 P2? Number of molecules within a single unitary grid: 4 Reticulated capacity: 3055 Á3 Density: 1.22 g / cm3 on average R value: 4%
3. 3. A crystalline substance of Cefditoren pivoxil as indicated in Claim 1, which has a purity of 97.7% or greater for the Cefditoren pivoxil component.
4. 4. A process for the preparation of a crystalline substance of Cefditoren pivoxil having the orthorhombic form according to Claim 1, which includes the successive conduction of the following steps from one to eight: in a first step, dissolving an amorphous substance of Cefditoren pivoxil in a first anhydrous organic solvent, in which the Cefditoren pivoxil is much more soluble than in an alkanol containing from 1 to 5 carbon atoms and which is miscible with the alkanol mentioned, to obtain in this way a solution containing from 10 mg to 50 mg of the cefditoren pivoxil dissolved by 1 ml of the resulting solution of Cefditoren pivoxil in the first organic solvent, in a second step, mix the resulting solution of Cefditoren pivoxil in the first organic solvent with an anhydrous alkanol containing 1 to 5 carbon atoms as a second organic solvent, in a proportion of the same as necessary to reduce the concentration of Cefditoren pivoxil dissolved in the mixture resulting from the mentioned solution of Cefditoren pivoxil in the second organic solvent at a concentration of 5 mg to 40 mg of the cefditoren pivoxil dissolved by 1 ml of the aforesaid mixture, in a third step, concentrate the resulting solution of Cefditoren pivoxil in the first and the second organic solvent mixed as they were obtained in the second step, at a temperature of -5 ° C to 15 ° C by evaporation of the organic solvents of the above solution under reduced pressure, to provide a concentrated solution containing from 50 mg / ml to 250 mg / ml of the dissolved cefditoren pivoxil ,. in a fourth step, mixing the concentrated solution obtained in this way in the third step with an additional 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 pivoxil dissolved in the resulting mixture of the aforementioned concentrated solution with the additional volume of the alkanol, at a concentration of 25 mg to 125 mg of the cefditoren pivoxil dissolved by 1 ml of the aforesaid mixture, in a fifth step, concentrate the resulting solution of Cefditoren pivoxil thus diluted with the additional volume of the alkanol in the fourth step, at a temperature of -5 ° C to 15 ° C by evaporating the solvents of the aforesaid solution under a reduced pressure, to produce a concentrated solution containing 50 mg / ml to 250 mg / ml of Cefditoren pivoxil dissolved in the solvent, prepared in its entirety or almost in its entirety in pairs After the mentioned alkanol, in a sixth step, mix the concentrated solution obtained in the fifth step with water of a volume from 1 to 20 times greater than the volume of the above concentrated solution at a temperature of 0 ° C to 10 ° C. , to cause the Cefditoren pivoxil to begin to deposit as crystals, in a seventh step, to stir 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 °. C at 10 ° C for a sufficient time to carry out a complete crystallization of the Cefditoren pivoxil, and in an eighth step, separate and cultivate the crystalline pivoxyl Cefditoren from the remaining solution by filtration or centrifugation, followed by drying the substance of Cefditoren crystalline pivoxil cultured under reduced pressure.
5. 5. A process according to Claim 4, wherein the first organic solvent used in the first step is selected from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, a low alkyl ester. of acetic acid, in particular methyl acetate, ethyl acetate and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of these, and that the alkanol as the second organic solvent used in the Second step and the fourth step is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, sec-amyl alcohol and terephthalic alcohol. amyl, as well as the mixed solvents of two or more of these.
6. 6. A process according to claim 4, wherein the third step and the fifth step of concentrating the solution of Cefditoren pivoxil in the solvent (s) are carried out at a temperature of 0 ° C to 10 ° C. under a reduced pressure of 10 - 50 Torr (measurement).
7. 7. A process according to claim 4, wherein the sixth step of mixing the concentrated solution obtained in the fifth step with water is omitted, but the concentrated solution obtained in the fifth step is immediately stirred at a temperature of 0 ° C. at 10 ° C for a sufficient time to carry out a complete crystallization of the Cefditoren pivoxil, and the resulting crystals are separated and subsequently cultured by filtration or centrifugation and then dried under reduced pressure.
8. 8. A process for the. Preparation of a crystalline substance of Cefditoren pivoxil having the orthorhombic form according to Claim 1, which includes the successive conduction of the following steps (a) to (i): (a) carrying out the process in accordance with what is indicated in Claim 4, in order thus to obtain a crystalline substance of Cefditoren pivoxil having the orthorhombic form, (b) to place the crystalline substance of Cefditoren pivoxil obtained in this manner as a seed crystal in a solution containing 10 mg / ml to 50 mg / ml Cefditoren pivoxil which has been prepared by dissolving an amorphous substance of Cefditoren pivoxil in a first anhydrous organic solvent as defined in Claim 4, (c) incubating the Cefditoren pivoxil solution in the first organic solvent and subsequently including therein the seed crystal of the Cefditoren pivoxil added in the above step (b), at a temperature of 0 ° C to 50 ° C for a time from 10 minutes to 48 hours, preferably at a temperature of 0 ° C to 20 ° C for a time of 20 hours to 40 hours, to cause the crystalline substance of the Cefditoren pivoxil to begin to be deposited from the aforesaid solution, ( d) concentrating the Cefditoren pivoxil solution with the seed crystal incubated in this way in the previous step (c), at a temperature of -5 ° C to 15 ° C by evaporating the first organic solvent therefrom under a pressure reduced, to thereby produce a concentrated solution containing 50 mg / ml to 250 mg / ml of the dissolved Cefditoren pivoxil and the seed crystal of the remaining Cefditoren pivoxil in it, (e) mix the concentrated solution of Cefditoren pivox ilo containing the remaining seed crystal in the form obtained in the previous step (d), with the anhydrous alkanol of 1 to 5 carbon atoms as the second organic solvent in a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxil dissolved at a concentration of 25 mg / ml to 125 mg / ml of Cefditoren pivoxil dissolved in the resulting mixture of the above-mentioned concentrated solution of Cefditoren pivoxil with the alkanol still containing the remaining seed crystal of Cefditoren pivoxil, (f) concentrating the resulting mixture of the concentrated solution of Cefditoren pivoxil with the alkanol as obtained in the previous step (e), at a temperature of -5 ° C to 15 ° C by evaporation of the first organic solvent and the same alkanol a reduced pressure, to thereby produce a concentrated solution containing the cefditoren pivoxil dissolved at its concentration of 50 mg / ml to 250 mg / ml and the crystal Remaining emilla of Cefditoren pivoxil, (g) mix the concentrated solution including the dissolved Cefditoren pivoxil and the remaining seed crystal in the form obtained in the previous step (f), with water at a volume of 1 to 20 times higher than the volume of the aforementioned concentrated solution of Cefditoren pivoxil, at a temperature of 0 ° C to 10 ° C, to thereby facilitate a crystalline substance of Cefditoren pivoxil being deposited from the resulting mixture of the aforementioned concentrated solution of Cefditoren pivoxil with water, (h) stirring the resulting aqueous mixture of the solution containing the dissolved cefditoren pivoxil, water and the crystalline substance deposited from Cefditoren pivoxil, as obtained in the previous step (g), at a temperature of 0 ° C at 10 ° C for a time of 20 hours to 40 hours, in order to carry out in this way a complete crystallization of Cefditoren pivoxil, and (i) to separate and cultivate the crystals obtained in step previous (h.), of the remaining solution, followed by the drying of the cultured crystals under reduced pressure.
9. 9. A process according to Claim 8, wherein the solution of Cefditoren pivoxil in the first anhydrous organic solvent to be added with the seed crystal of Cefditoren pivoxil in step (b) is a solution that has been prepared by dissolving of the amorphous substance of Cefditoren pivoxil in an organic solvent selected from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, a low alkyl ester of acetic acid, in particular methyl acetate, acetate of ethyl and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of these, and that the alkanol used in step (e) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, sec-amyl alcohol and tere-amyl alcohol, as well as the mixed solvents of two or more of these.
10. A process according to Claim 8, wherein step (c) of incubating the solution of the Cefditoren pivoxil containing the seed crystal, as well as steps (d) and (f) of concentrating the Cefditoren pivoxil solution, are carried out at a temperature not higher than 10 ° C.
11. 11. A process for the preparation of a crystalline substance of Cefditoren pivoxil having the orthorhombic form according to Claim 1, which includes consecutively carrying out the following steps (i) to (iv): (i) a step of carrying out the process of Claim 4, to thereby obtain a crystalline substance of Cefditoren pivoxil having the orthorhombic form, (ii) a step of placing the crystalline substance of Cefditoren pivoxil obtained in step (i), as a crystal of seed in a solution of Cefditoren pivoxil that has been prepared by dissolving an amorphous substance of Cefditoren pivoxil at a concentration of 10 mg / ml to 50 mg / ml in an anhydrous organic solvent selected from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, a low alkyl ester of acetic acid, in particular methyl acetate, ethyl acetate and n-acetate propyl, methylene chloride and chloroform, as well as mixed solvents of two or more of these, and that the alkanol as the second organic solvent used in the second step and the fourth step, is selected from methanol, ethanol, n-propanol, isopropanol , n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, sec-amyl alcohol and tert-amyl alcohol, as well as the mixed solvents of two or more of these. (iii) a step of stirring the resulting mixture of the Cefditoren pivoxil solution in the organic solvent with the Cefditoren pivoxil seed crystal as obtained in step (ii), at a temperature not higher than 10 ° C, during a sufficient time to facilitate the crystallization of the Cefditoren pivoxil in the solution, and (iv) to separate and culture the crystalline substance deposited from Cefditoren pivoxil from the remaining solution by filtration or centrifugation, followed by drying the cultured crystals of Cefditoren pivoxil under a reduced pressure.