A PROCESS FOR PREPARING AN AMORPHOUS CEFUROXIME AXETIL HAVING A LOW MELTING POINT BACKGROUND OF THE INVENTION This invention relates to a process for preparing an amorphous cefuroxime axetil having a low melting point, more particularly, in which a solid medium including cefuroxime axetil homogeneously is prepared and wherein water is added at lower temperature than the melting point of the solid medium to give an amorphous cefuroxime axetil having low melting point and high bioavailability in high purity and in high yield.

Description of the Prior Art "An amorphous cefuroxime axetil having a low melting point" means that an amorphous cefuroxime axetil has the melting point of 94 - 96°C and belongs in Al between amorphous Al and amorphous A" designated on Acta Polon. Pharm.-Drug research Vol. 52, No 5, pp 397 - 401, 1995.

Cefuroxime is a valuable antibiotics which has a broad spectrum activity against gram-positive and gram-negative microorganisms and is used widely in clinical practice since it's well tolerated in the mammalian body.

However, when cefuroxime is administered orally, it is poorly absorbed in the gastro-intestinal tract and exist in sera and urine in low concentration, and hence cefuroxime is administered not orally but paranterally. Therefore, there has been a need for new cefuroxime preparation which can be easily absorbed in the gastro-intestinal tract following oral administration.

It is very important for the oral-adrnirnstration of the cephalosporin compounds, including cefuroxime, to maximize the absorption of antibiotic in the gastro-intestinal tract and to minimize the amount of antibiotic-remaining

in it, hence resulting in high bioavailability. The antibiotic which is not absorbed will be ineffective for its clinical use and may cause side-effects in the gastro-intestinal tract. Meanwhile, when carboxyl group of cefuroxime is esterified appropriately, the absorability of the cefuroxime in the gastro- intestinal tract is increased remarkably and the esterfying group is hydrolysed by enzymes existing in serum and body tissues to give the antibiotically active parent acid. Cefuroxime axetil is one of the most important compound among the esterified cefuroxime compounds. Cefuroxime axetil is named as <BR> <BR> <BR> <BR> 1-acetoxyethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(pur-2-yl)-2- (methoxyimino)acetamido] cef-3-m-4-carboxylate (syn isomer) and is useful for the treatment of a variety of diseases or infections caused by pathogenic bacteria through oral or rectal administration.

It was reported by British Patent No. 1,571,683 that cefuroxime axetil is produced in either crystal or amorphous form.

In addition, cefuroxime axetil di? trent from previous cephalosporin compounds in its character has better bioavailability and chemical stability in amorphous form than those in crystal form. The process for preparing an amorphous cefuroxime axetil was applied for patents(European Patent No.

107,276, Korean Patent No. 42,097) Cefuroxime axetil possesses an asymmetric carbon atom at the 1 position of 1-acetoxyethyl group and the compound can hence exist in the form of R- or S-isomer or mixtures of them. In the case of amorphous cefuroxime acetil, the mixture of R- and S-isomers has a higher bioavailability and an improved solubility than amorphous R-isomer or Sisomer alone. In mixing ratio of R-isomer and S-isomer, the molar ratio of R-isomer to S-isomer may be ranged 0.9:1 to 1.1:1, preferably 1:1(European Patent No. 107,276, Korean Patent No. 42,097).

In addtion, amorphous cefuroxime axetil is differ in physical and chemical characteristics depending on the preparation process(Acta Poloniac Pharmaceutica-Drug Research, Vol. 52, No. 5, pp397 - 401, 1995). An amorphous cefuroxime axetil has the m.p. of 94 96 96°C when it is prepared by rapid solvent evaporation method but it has the m.p. of 135 - 138 C when prepared by solvent precipitation method which precipitates the cefuroxime axetil by adding cefuroxime axetil solution into stirring another polar solvent.

The difference such as the m.p. causes the change of physical properties, and then its change causes difference in its bioavailability. Consequently, the amorphous cefuroxime axetil having a melting point of 94 96 96°C shows the most superior bioavailability.

There are several prior art such as spray drying, roller drying, solvent precipitation and lyoplilization. (European Patent No. 107,276, Korean Patent No. 42,097). First, spray-drying, which removes solvent through rapid solvent evaporation after spraying solution, is the most desirable method for the preparation of amorphous cefuroxime axetil among the patented methods. llowever, spray-drying method has many disadvantages in its use. That is, it needs conlplicated installation of equipment and cannot remove the impurities included in either starting material or formed newly in the process and may possess some crystal form with substantial amounts of amorphous cefuroxime axetil depending on its condition of the process.

Also, the yield is low or not constant as varied between 50.6 and 90%.

Secondly, roller-drying is the method which evaporizes the solvent rapidly from solution at the surface of roller and has the similar disadvantages as spray-drying. In addition, it needs complicated facilities and manipulation and cannot remove impurities included in either starting material or newly formed. It is very inconvenient to be industrialization

because the product should be taken out from roller.

Spray drying and roller drying are the rapid evaporation methods that remove the solvent from solution by evaporizing the solvent rapidly.

Thirdly, solvent precipitaion is the method that precipitates the product by mixing solution with different polarity of solvents and it has following disadvatages. It can include crystal form with substantial amounts of amorphous form depending on its condition of preparation and its yield is low or not constant as 68.3 to 91.7%. Moreover, the solution should be added slowly in the process of precipitation to protect from coagulation, and it needs sensitive processes such as blowing gas continuously or mixing with various solvents.

Finally, lyophilization is the method which produces the product through sublimation of the solid which includes the cefuroxime axetil homogeneously at a temperature lower than the m.p. of solid. It has many disadvantages as follows. This method needs expensive and complicated facilities and can not remove the impurities included in starting material.

And it needs extra purification process in which the products are broken into small pieces and sieved and (Irieti again after lyophilizing for appropriate hours because it's very difficuit to renlove the solvent completely by this method.

SUMMARY OF THE INVENTION We, inventors, have long been associa ted with the research for the easy preparation of amorphous cefuroxime axetil having a low m.p. and a high bioavailability. From our research we have established the method for preparing easily amorphous cefuroxime axetil of Al type having a low m.p. as follows. The solid including the cefuroxime axetil homogeneously is

prepared and water is added into the solid at a temperature lower than m.p. of the solid medium and stirred to afford amorphous cefuroxime axetil precipitate, which was filtered, washed and dried at reduced pressure to give the desired product.

Therefore, the object of this invention is to provide the process of preparing amorphous cefuroxime axetil having a low m.p., a high purity and also high bioavailability.

This invention relates to a process for preparing the amorphous cefuroxime axetil having a low melting point, characterized by comprising the following steps of (a) Step for preparing the fused solution including cefuroxime axetil homogeneously by adding crystal cefuroxime axetil alone or the mixture of crystal and amorphous cefuroxime axetil to a melted solid medium maintained at higher temperature than the melting point of itself; (b) Step for preparing a solid including cefuroxime axetil homogeneously by cooling the said fused solution to lower temperature than a (c) Step for preparing a precipitate of amorphous cefuroxime axetil having a low melting point by adding water at lower temperature than a melting point of the solid medium into the said solid; and (d) Step for recovering the said precipitate.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to preparing amorphous cefuroxime axetil having a low m.p. and high bioavailability from crystal cefuroxime axetil alone or the mixture of crystal and amorphous cefuroxime axetil.

First, after the fused solution is prepared from the solid medium by keeping a higher temperature than the m.p. of the solid medium, crystal cefuroxime or the mixture of crystal and amorphous cefuroxime axetil are dissolved in the solution. At this time, it is desirable to choose the solid medium which has relatively high m.y. at between 0 and 25° and can mix with water. If the m.p. of the solid medium is lower than O"C, coagulation may be occurred when water is added at lower temperature than the m.p. of the solid medium. If the m.p. of the solid medium is higher than 25°C, it's inconvenient because the solid should be heated to be dissolved and then can be used.

A medium material of liquid phase which can be used for the solid medium in this invention -nay be dimethylsulfoxide, dioxane or t- butylalcohol, preferably 4 imeth ' lsulThxid e or dioxane.

The solid medium including the cefuroxime axetil homogeneously is obtained by cooling the used medium material to lower temperature than the m.p. of the solid medium. At this time, if the cooling temperature is kept higher than the m.p. of the solid medium, the medium material in liquid phase is mixed with water rapidly to give the rapid precipitation of cefuroxime axetil resulting in coagulation and it is difficult to recover the precipitate in the next process in which water is added.

It is desirable to cool the solid medium to lower temperature than the <BR> <BR> <BR> <BR> m.p. of the solid medium by a temperature differenc of 5 to 25°C. When the medium is cooled at lower lemperature than the m.p. of the medium by a temperature difference of less than 5°C, a small amount of the solid medium can be mixed together in liquified state and coagulation can be occurred due to the excellerated solubility of the solid medium when precipitate is trying to be obtained by adding water. in addition, when the solid medium is cooled

at lower temperature than the m.p. of the medium by a temperature difference more than 25°C, precipitate is possibly not formed because the solid medium is not solubilized smoothly. This is because that, when water is added in the next process, water is frozen at the surface of the solid medium being contacted. It is not economical because it's expensive to keep a low cooling temperature.

In the following process is a precipitate formed by adding water into a solid medium kept a cooling temperature of the above and following by stirring. It is desirable at this time to keep water being added to the solid medium at lower temperature than the m.p. of it. If water being added is kept at higher temperature than the m.p. of the solid medium, some coagulation can be occurred by being-increased of the solubility of the solid medium into water. Adding water maintained at a temperature between 0°C and 5° is most desirable. It is convei-,ient and hence advantageous to use <BR> <BR> <BR> <BR> water of a temperature !Xstweer £) and b 5° because it can be prepared easily by adding water to ice without special adjustment of temperature.

In the process of precipitate-forming, it is desirable to add water 15 20 times by volume as much as solid medium used and to stir with a speed of 600 ~ 1000 rpm for 10 to O minutes.

The precipitate formed is filtered at reduced pressure and sequentially washed with water and hexane, and dried under vaccum for about 20 hours at 40~60°C.

Through the preparing process described as the above, amorphous cefuroxime axetil having a low m.p. is obtained reproducibly in higher than 95% yield. According to the result analysed by HPLC, amorphous cefuroxime axetil having a low m.p. obtained by the process of this invention is the absolutely pure product having its purity higher than 97%, and the mole

ratio of R-isomer to S-isomer i.; 1:0.9 to 1:11 and is shown as desirable. In addition, amorphous cefuroxime axetil of this invention has a m.p. of 94 96"C as a range showing a best bioavailability.

This invention of new process which is completely different from the prior art, has the advantages of producing an exclusively amorphous cefuroxime axetil in high yield through easy and simple manipulation.

As shown in the above, this invention is completely different from the prior art in that the product is obtained by dissolving it in water with keeping the solid medium in solid state at lower temperature than its m.p.. The prior art as the above-mentioned includes roller-drying and spray drying method which give the procuct by removing the solvent rapidly after evaporation of solvent, and solvent precipitate metilott which produces the product by mixing the solution with another different polarity of solvent.

The freezing precipitation according to this invention is completely new method in principle which has lever been introduced in any method before. In addition to this, this invention docsn't require special equipments or facilities, and uses a cheap water as a main solvent, whilst rapid solvent removing techinque for the rapid removal of solvent needs special equipment, and lyophilization method needs special equipment for keeping the reduced pressure for the sublimation of solvent, too. And this invention also has advantage of providing exclusively amorphous cefuroxime axetil having a low m.p. in high purity nnd in high yield as well as a high bioavailability, whilst solvent precipitate can produce the amorphous cefuroxime axetil having a high m.p. or small amounts of crystal foj n.

This invention is described in more detail by the following examples, but the claim is not limited to these examples.

In addition, the crystal cefuroxime axetil used in the following

examples was prepared in high purity by following the procedure of the Brithish Patent No. 1,571,683.

EXAMPLE 1 Crystal cefuroxime axetil (2g, mixture of R- and S-isomer) was dissolved in dimethylsulfoxide(7 mL) and cooled to ()°C to freeze. Water(110 <BR> <BR> <BR> <BR> mL) at S 5°C was added and stirred for 15 minutes. The resulting precipitate was separated by filteration nd washed sequentially with H20(50 mL), cyclohexane, then dried for 20 hours at 50 C under vacuum to produce 1.9 g of amorphous cefuroxime axetil.

Yield: 95% HPLC analysis: Amorphous cefuroxime Axetil: 97.4% Ceph-2-em compound: 0.2% Impurities: 1.2% R-isomer/S-isomer ratio(HPLC): 1.02/1 Water content(Karl Filscher): 1.0% m.p.: 94~96°C NMR(DMSO-d6, ppm): 19 I .5(d, 3H), 2.()(d, 3H), 3.4 ~ 3.6(m, 2H), 3.9(s, 3H), 4.5 ~ 4.8(m, 2H), 5.2(m, 1H), 5.8(m, 1H), 6.5 ~ 6.7(m, 4H), 6.8~7.0(m, 1H), 7.8(m, 1H), 9.7(d, 1H) IR(KBr, cm-l): 3480 or 3210(NH, NH2 complex), 1782( -lactam), 1760(acetate), 1720(4-ester group), 1720 and 1594(carbamate), 1676 and 1534(7-a m i do) XRD(Shimadzu DX-1 power diffractometer): The sample was mounted at sample holder and diffraction peak was obtained at the speed 4 ' /min with 30kv, 30mA of Cuka line. At this time, the peaks were shown halo which is

typical for the amorphous forum. And hence the product was identified as an amorphous form with no crystal form.

EXAMPLE 2.

Crystal cefuroxime axetil (100g, mixture of R- and Sisomer) was dissolved in dimethylsulfoxide(350 mL) and cooled to 0°C to freeze.

Water(5.3 L) of 5°C was added and stirred for 20 minutes. The resulting precipitate was separated by filteration and washed sequentially with H20(2.5 L) and cyclohexane, then dried tor 20 hours at 50°C under vacuum to produce 95.6 g of amorphous cefuroxime axet@@.

Yield: 95.6% HPLC analysis: Amorphous cefuroxime Axetil: 97.0% Ceph-2-em compound: 0.3% Impurities: 1.3% R isomer/S isomer ratio(HPLC): 1.04/I Water content(Karl Filscher):1.1% m.p.:92~96°C NMR(DMSO-d6, ppm): c 1.5(d, 3H), 2.0(d, 3H), 3.4 ~ 3.6(m, 2H), 3.9(s, 3H), 4.5~4 8(m, 2H), 5.2(m, 1H), 5.8(m, 1H), 6.5~6.7(m, 4H), 6.8~7.0(m, 1H), 7.8(m, 1H), 9.7(d, 1H) IR(KBr, cm-l): 3480 or 321 0(NH, NH2 complex, 1782( -lactam), 1760(acetate), 1720(4-ester group). 1720 and 1594(carbamate), 1976 and 1534(7-amido) XRD(Shimadzu DX-1 power diffractometer): The sample was mounted at sample holder and differaction peak was obtained at the speed 4 @ /min with 30kv, 30mA of Cuka line. At this time. the peaks were shown halo which is

typical for the amorphous form. And hence the product was identified as an amorphous form with no crystal form.

EXAMPLE 3 Crystal cefuroxinle axetil (2g, mixture of R and S isomer) was dissolved in dioxane(6 mL) and cooled to 0°C t() freeze. Water(100 mL) at 5°C was added and stirred for 15 minutes. The resulting precipitate was separated by filteration and washed sequentially with H20(50 mL) and cyclohexane, then dried for 20 hours at 50°C under vacuum to produce 1.9 g of amorphous cefuroxime axetil.

Yield: 95.0% HPLC analysis: Amorphous cefuroxine Axetil: 96.8% Ceph-2-em compound: 0.3% Impurities: 1.4% R isomer/S isomer ratio(HPLC): 0.98/1 Water content(Karl Filscher): 1@% m.p.:95~97°C NMR(DMSO-d6, ppm): c 1.5(d, 3H), 2.0(d, 3H), 3.4 ~ 3.6(m, 2H), 3.9(s, 3H), 4.5 ~ 4.8(m, 2H), 5.2(m, 1H), 5.8(m, 1H), 6.5 ~ 6.7(m, 4H), 6.8 ~ 7.0(m, 1H), 7.8(m, 1H), 9.7(d, 1H) IR(KBr, cm-l): 3480 or 3210(NH, NH2 complex), 1782( -lactam), 1760(acetate), 1720(4-ester group), 1720 and 1594(carbamate), 1676 and 1534(7 -ainido) XRD(Shimadzu DX-1 power diffractometer): The sample was mounted at sample holder and diffraction peak was obtained at the speed of 4 ° /min with 30kv, 30mA of Cuka line. At this time, the peaks were shown halo which is typical for the amorphous form. And hence the product was identified as an amorphous form with no crystal form.

As mentioned in the above, tlle process according to this invention doesn't need special equipments for the rapid evaporation of solvent or for keeping the vacuum state to remove the solid medium by sublimation.

Water is used as a cheap solvent and it is especially useful for industrialization since it's possible to produce amorphous cefuroxime axetil having a low m.p., high purity, and hit yield as well as a high bioavailability.