HU196602B - Process for producing acid-addition salts of 7-square brackets open alpha-(aminothiazol-4-yl)-alpha-/z/-methoxy-imino-acetamido square brackets closed -3-square brackets open (1-methyl-1-pyrrolidino)-methyl square brackets closed -3-cefem-4-carboxilate, as well as dry mixtures thereof formed with bases and suitable for producing injectable solutions - Google Patents

Abstract

The invention relates to a process for the preparation of a mixture of certain temperature-stable crystalline cephalosporin salts and a pharmaceutically acceptable non-toxic organic or inorganic base. In the process according to the invention, the abovementioned constituents are mixed in proportions such that, after the mixture has been distilled off with water, up to the injectable concentration, a p H value of about 3.5 to about 7 is achieved. The physical mixtures obtainable according to the invention can be stored without difficulty and sold in solid form. In addition, they can easily be converted into injectables by simply adding water.

Description

The present invention relates to a process for the preparation of novel thermostable semisynthetic cephalosporin salts; the preparation of these salts has not been described in prior literature. The invention also relates to the preparation of pharmaceutical compositions containing said salts as active ingredients.

Aburaki et al., U.S. Patent No. 4,406,899. in U.S. Patent No. 7,101,340, 7- [α- (2-aminothiazol-4-yl) n / N-methoxylaminoacetanido] -3 - [(1-methyl-1-pyrrolidino) methyl] -3-cephem-4 The zwitterionic form of carboxylate is also mentioned, the corresponding acid addition salts (which are present in the zwitterionic form of the injectable formulations) are also mentioned, and it is pointed out that the zwitterionic form has a broader spectrum of activity than the active substances ceftazidime and cefotaxime.

However, the cephalosporins described by Aburaki et al. Are stable in injectable formulations for only a few hours, and the zwitterionic form, even in the form of a dry powder, is unstable even at room temperature and for 1 week when stored at elevated temperatures (e.g. 45 ° C and above). lose at least 30% of their activity; therefore, such formulations require special sealed packaging and / or storage under refrigeration, and are therefore less favorable in packaging and storage than the said ceftazidime and cefotaxime active ingredients.

Although acid addition salts are mentioned by Aburaki et al., The cited patent does not disclose how they can be prepared, nor does it disclose that any of these salts has good stability in the form of a dry powder.

Kessler et al., "Comparison of New Cephalosporin, BMY 28142, with Otlier BroadSpectrum 0-1 Actam Antibiotics" (Comparison of New BMY Cephalosporin with Other Broad-spectrum 0-1 Actam Antibiotics), Antimicrobial Agents and Chemotherapy, 27 (2), 207- 216, Feb. 1985, mention is made of the sulfate salt of the antibiotic, but it is not described how it is produced and it is not claimed that this salt exhibits good stability at room temperature or in the form of dry powder at higher temperatures.

It has been found that 7- [α- (2-aminothiazol-4-yl) -? - N -methoxyiminoacetamido | Certain crystalline acid addition salts of 3 - [(1-methyl-1-pyrrolidino) methyl] -3-ccccin-4-carboxylate in dry powder form exhibit excellent stability at room temperature and higher stability than the aforementioned zwitterionic form. As used herein, the term "dry powder" is intended to mean that the material has a moisture content of less than 5% by weight.

Said acid addition salts include 7- [α- (2-amino-thiazol-4-yl) -N- (N-methoxyiminoacetamido) -3- (1-methyl-1-pyrrolidino) methyl] -3 -cephem-4-carboxylate is the sulfuric acid salt, the dinitrate, the monohydrochloride and the dihydrochloride acid addition salts, and the orthophosphoric acid addition salts containing from 1.5 to 2 moles of orthophosphoric acid per mole of salt, e.g. and solvates of said salts. The term "crystalline" is used herein in the sense that the material exhibits at least some degree of characteristic ordering of the molecules. While the sulfate, dinitrate, dihydrochloride, and orthophosphate acid addition salts are clearly crystalline (as evidenced by the double refraction under the polarizing microscope) and show the exact ordering of the molecules, the monobldrate acid addition salt only has some regularity as evidenced by the weak birefringence under the polarizing microscope), this material therefore does not exhibit a predictable exact molecular order and can therefore only be classified as "weakly" crystalline. As used herein, the term "crystalline" is used to mean not only the crystalline salts, but also the monohydrate acid addition salt which appears to be "slightly" crystalline.

The acid addition salts of the present invention, when prepared as an injectable solution, exhibit zwitterionic treatment; this zwitterionic structure is illustrated by formula (I) in the attached drawing.

The broad spectrum efficacy of the zwitterionic compound against various pathogenic organisms is described in Aburaki et al., U.S. Patent 4,406,899. U.S. Pat. thus, aqueous compositions of the acid addition salts prepared by the process of the present invention have the same broad spectrum efficacy.

Aqueous formulations of the acid addition salts of the present invention are obtained by the simple addition of these salts to sterile water to produce solutions which, when administered intravenously to rabbits, cause unacceptable irritation and, when administered intramuscularly, cause pain in animals. The sulfuric acid salt and the dinitrate acid addition salt have poor solubility and therefore insufficient solubility to make conventional injectable formulations. It has been found that these objectionable properties of said salts can be eliminated when used in a physical mixture with a pharmaceutically acceptable non-toxic organic or inorganic base, i.e. in the form of a simple mixture of the two solids; the mixture is prepared at a ratio such that the composition, when diluted with water, has a pH of about 3.5 to about 7 and the solution has a zwitterion activity between 1 mg / ml and 400 µg / ml, generally about 250 mg / ml (high pressure determined by chromatography).

Of the crystalline acid addition salts obtainable by the process of the present invention, 3 crystalline sulfuric acid addition salts are preferred, since they have a low water solubility (25 mg / ml) which allows crystallization from the aqueous medium in high yield with little loss.

The crystalline sulfuric acid addition salt is readily prepared by the following steps:

a) preparing an aqueous mixture of 1. at least 1 molar equivalent of sulfuric acid and 2. zwitterionic zephem derivative,

196,602 used in an amount such that the concentration in the aqueous mixture is greater than 25 mg / ml;

b) crystallizing the sulfuric acid addition salt, and

c) isolating the crystalline sulfuric acid addition salt obtained.

The crystalline salts of the invention (hereinafter referred to simply as "salts") exhibit excellent stability at room temperature and exhibit a loss of activity (as determined by thin layer chromatography) of 1% at room temperature for 1 month; After one month of storage at 45-56 ° C, their loss of activity (as determined by thin layer chromatography) is less than 15%.

Particularly preferred among such salts is the sulfuric acid addition salt. Its loss of activity is less than 10% after storage for one month at 45-56 ° C. Particularly preferred is the low water solubility of the sulphate (about 25 mg / ml), which allows crystallization from water with minimal loss.

The dinitrate acid addition salt is also of low water solubility (about 60 mg / ml) and therefore this salt can be crystallized from water with little loss.

Monohydrochloride, dihydrochloride, and sesquiv or diorthophosphoric acid addition salts have a water solubility of greater than 200 mg / ml and are preferably crystallized from organic solvents rather than water to obtain good yields.

The crystalline acid addition salts of the present invention are prepared as follows:

As mentioned above, the sulfuric acid addition salt 35 can be prepared by the following steps:

a) preparing an aqueous mixture of 1. at least 1 molar equivalent of sulfuric acid and 2. zwitterionic zephem derivative in an amount such that it is present in the 40 mixture at a concentration greater than 25 mg / ml,

b) allowing the salt to crystallize, finally

c) isolating the crystallized sulfuric acid addition salt. 45

Preferably, the zwitterionic cefem derivative in step a) is used in an amount ranging from about 100 mg / ml to 200 mg / ml and step b) is carried out in an aqueous solvent-free aqueous medium. Generally, in step a), sulfuric acid is not used in an amount greater than 2 molar equivalents. In step a), the zwitterionic zephem derivative is used in an amount such that its gg concentration in the mixture is less than 500 mg / ml.

Step (a) is carried out either in such a way that e.g. To the 1 N sulfuric acid solution is added the solid zwitterionic compound with vigorous stirring to form a solution, or else θθ can be achieved by first dissolving the solid zwitterionic compound in water and then slowly adding the khanic acid solution with stirring.

In step (b), crystallization is conveniently initiated by the addition of a seed crystal, followed by stirring, preferably for 15 minutes to 2 hours. Preferably, the crystallization step is carried out in an organic solvent-free aqueous medium; under these conditions, the product is generally more than 98% pure. Although the presence of an organic solvent, such as acetone, promotes crystallization and increases the crystalline salt yield by reducing the solubility of the sulfuric acid addition salt formed in the crystallization medium, it also facilitates the precipitation of impurities resulting in a crystalline product. If the zwitterionic cephem derivative is used in an amount such that its concentration in the mixture is less than 25 mg / ml, an organic solvent, preferably acetone, must be added to the crystallization medium to ensure a satisfactory yield of the crystalline salt. If acetone is used for this purpose, it is preferably used in an amount of 0.5 to 10 volumes per volume of aqueous crystallization medium.

Step c) is carried out by separating the crystalline salt formed, preferably by vacuum filtration, and washing the crystalline product remaining on the filter, for example, first with a mixture of acetone and water, then with acetone only (e.g. 10 volumes of 0.1 N sulfuric acid solution, followed by acetone (e.g. 1/4 volume), and then the washed crystalline product is dried, for example, in a vacuum dryer at 30-50 ° C for 4-20 hours.

The sulfuric acid addition salt preparation method described herein can also be used to purify the zwitterionic cefem derivative since the solubility of the sulfuric acid addition salt is lower than its zwitterionic chemical, and thus the zwitterionic compound can be purified without being solid during purification. in a zwitterionic form. If the desired sulfuric acid addition salt is then obtained to produce a substantially pure zwitterionic (free base form), this can be accomplished by dissolving the sulfuric acid addition salt in water with a pH of less than 6.5 barium hydroxide octahydrate. Ba (OH) j · 8H ₂ O is added in an amount equal to 90100% of the theoretical amount, the barium sulphate precipitated by this is removed by filtration and the filtrate containing the zwitterionic compound is dissolved or lyophilized to give the solid zwitterion free base or acetone is added to the solution to precipitate the amorphous steric ion which is then isolated by vacuum filtration, the solid remaining on the filter is washed, for example, with acetone and dried in vacuo; however, the free zwitterionic compound obtained in solution may also be used directly in solution. The sulfuric acid addition salt can also be converted to the free base by ion exchange, for example by using Dowex WGR weakly basic anion exchange resin and Dowex XU-40090.01 highly acidic cation exchange resin, and then separating the resulting free base by lyophilization.

Alternatively, the cationic ionic cefcm can be converted to crystalline dinitrate acid addition salt such that 1. at least 2 molar equivalents of nitric acid and 2. meg-35.

A corresponding amount of 196,602 zwitterionic cefem derivatives is mixed with the zwitterionic compound in an amount such that its concentration in the crystallization mixture is greater than 100 mg / ml and crystallization is initiated by the addition of seed crystal or by rubbing the vessel wall with a glass rod. diluted with propanol and cooled. The precipitated crystalline dinitrate acid addition salt is isolated, for example, by filtration and washed, for example, with a 50:50 by volume mixture of 2-propanol and water, then with 2-propanol, then with ether, and then dried under vacuum at 50 ° C for 2 hours.

The monohydrochloride acid addition salt may be prepared by dissolving the zwitterionic cephem derivative in hydrochloric acid containing 1 molar equivalent of hydrochloric acid, initiating crystallization by stirring on steel, stirring further, and separating the precipitated crystals, for example, by vacuum filtration. wash and dry under vacuum. Alternatively, the monohydrochloride acid addition salt can be formed from the dihydrochloride acid addition salt by suspending the dihydrochloride in dichloromethane, adding 1 molar equivalent of triethylamine to the slurry to form the monohydrochloride for example, vacuum filtration, washing with dichloromethane and drying in vacuo.

The crystalline dihydrochloride acid addition salt may be prepared by dissolving the zwitterionic cephem derivative in at least 2 molar equivalents of hydrochloric acid, initiating the crystallization of the salt by addition of acetone, and separating the precipitated crystals, for example, by vacuum filtration and washing with acetone. .

The monohydrochloride acid addition salt may be prepared by dissolving the zwitterionic cephem derivative in hydrochloric acid containing 1 molar equivalent of hydrochloric acid, initiating crystallization by stirring with acetone, stirring is continued, and the precipitated crystals are removed by, for example, vacuum filtration. wash and dry under vacuum. Alternatively, the monohydrochloride acid addition salt can be formed from the dihydrochloride acid addition salt by suspending the dihydrochloride in dichloromethane, adding 1 molar equivalent of triethylamine and then adding the monohydrochloride to give the , washed with dichloromethane and dried in vacuo.

The crystalline dihydrochloride acid addition salt may be prepared by dissolving the zwitterionic cephem derivative in at least 2 molar equivalents of hydrochloric acid, initiating the crystallization of the salt by addition of acetone, and separating the precipitated crystals, for example, by vacuum filtration and washing with acetone. .

The crystalline acid addition salt of di-orthophosphoric acid can be prepared by dissolving the zwitterionic compound in phosphoric acid solution containing at least 2 molar equivalents of phosphoric acid, adding acetone to the aqueous solution to initiate crystallization, and separating the precipitated crystals, e.g. wash and dry under vacuum. Crystalline sciqui-orthophosphoric acid addition salts can be prepared in the same manner except that about 1.5 molar equivalents of phosphoric acid are used.

Saline injectable compositions prepared as described above are prepared by dissolving the salt in sterile water and buffering the solution to a pH of from 3.5 to 7; the injectable solution may be prepared at a concentration of 1 mg / ml to 400 mg / ml based on the zwitterionic cefem derivative. Suitable buffers are, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, 1,1 (T) -lysine and (I) -arginine. The daily dose of the injectable preparation thus prepared for intramuscular or intravenous administration to an adult may range from about 750 mg to about 3000 mg; the daily dose can usually be given in several divided doses throughout the day.

Particularly in the case of sulfuric and diacetal addition salts, it is generally desirable to prepare the injectable preparation not only by adding sterile water to the salt, since these acid addition salts are not sufficiently soluble to form solutions which are generally desired for administration, in addition, such salts, when easily dissolved in water, form solutions having a very low pH (1.8 to 2.5) which may cause pain when injected. These drawbacks, as mentioned above, can be avoided by forming a solid physical mixture of said salts by addition of a base mentioned above as a suitable buffer; said base being used in an amount such that the resulting physical mixture, when diluted to a water injectable concentration (1-400 mg / ml of the zwitterionic compound), provides a pH of about 3.5 to about 7. To the prepared side for high performance liquid chromatography! its activity (based on the zwitterionic zephem derivative) may be, for example, 2 SO0 mg / ml.

The exact proportions of the components (zwitterionic cephem derivatives and base) in said physical mixtures may vary from batch to batch, since the purity of the salt employed may also vary from batch to batch. The exact volume ratios that may be employed may be determined in some cases by pre-titration at the desired pH.

The physical mixture of the zwitterionic zephem derivative and the base is in a solid state and is easily stored and transported as the salts used are sufficiently stable; the solid physical mixture can then be readily prepared for injection by the addition of water just prior to injection.

Said physical mixtures are prepared by mixing the salt and base, e.g.

196,602 liters; the mixing is carried out in a dry atmosphere and the resulting mixture is conveniently filled into an ampoule or other sealable container. All of these operations are performed under aseptic conditions.

Trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) arginine are suitable bases for the preparation of said compositions. In particular, L (+) - lysine and L (+) arginine are preferred for this purpose, since injectable solutions of the physical mixtures prepared with them are less likely to cause pain when injected than mixtures containing other bases. Preferably, the amount of L (+) - lysine used is such that the resulting mixture, when dissolved in water, provides a pH of between 3.5 and 6; water is preferably used in the solution in an amount such that the activity of the solution in the zwitterionic compound (as determined by high performance liquid chromatography) is 250 mg / ml.

Said salts, as well as a dry physical mixture of salt and base, can be stored well without cooling or insulated packaging and retain their high performance for extended periods of time.

In preparing these compositions, the starting material is generally the less stable zwitterionic zephem derivative. The preparation of this starting material is described in U.S. Patent No. 4,406,899. U.S. Pat. No. 1-3, Aburaki et al. example. The authors of this zwitterionic cephem derivative are 7 - [(Z) -2-methoxyimino-2- (2-amothothiazol-4-yl) acetamido] -3 - [(1-methyl-1-pyrrolidinium) methyl ] -3-cephem-4-carboxylate is mentioned in my name.

Practical embodiments of the process of the invention are illustrated by the following examples; it should be noted, however, that the scope of the invention is not limited to the content of these particular examples,

Example 1

Preparation of a sulfuric acid addition salt

1.5 g of the above zwitterionic zephem derivative are slowly added to 10 ml of 1 N sulfuric acid (1.59 molar equivalent); the addition is carried out at 20-26 ° C with rapid stirring. During this process, the zwitterionic zephem derivative is soluble in acetic acid. A sulfuric acid addition salt crystal was added to the solution to initiate crystallization and the mixture was stirred for 1/2 hour. The crystals were then collected by vacuum filtration, washed with 3 mL of 50:50 acetone-water, then with 2 x 5 mL of acetone and dried in vacuo at 40-50 ° C overnight. 1.3 g of crystalline sulfuric acid addition salt are obtained.

Analysis: The Ci9H ₂₄ N ₆ O _{2 S} · H ₂ SO ₄ O Calculated: C 39.44%, H 4.53%, N 14.52%;

S 16.62%, H ₂ O-;

Found: C 38.91%, Η 4.57%, N 14.64%,

S 16.71%, H ₂ O 1.42%.

Example 2

Preparation of a sulfuric acid addition salt

1.5 g of the zwitterionic zwitterion were dissolved in 5 ml of water; 5 ml of a 1 M sulfuric acid solution are slowly added with stirring. Crystallization was initiated by addition of a sulfuric acid addition salt crystal and the crystallization mixture was stirred for 1/2 hour. The crystals were then collected by vacuum filtration, washed with 3 mL of 50:50 acetone-water, then with 2 x 5 mL of acetone and dried in vacuo at 40-50 ° C overnight.

1.3 g of crystalline sulfuric acid addition salt are obtained.

Example 3

Preparation of nitric acid acid addition salt

Dissolve 300 mg of the zwitterionic zwitterion in 0.5 ml of 2N nitric acid solution. Crystallization from the solution was initiated by rubbing the vessel wall with a glass stick, and 0.4 mL of 2-propanol was added and the mixture was cooled. Upon completion of crystallization, the resulting crystals were collected by filtration, washed with 0.4 mL of a 1: 1 mixture of 2-propanol and water, then with 2-propanol and finally with ether. 127 mg of the dinitrate salt are thus obtained.

Analysis: Calculated for C 19 H ₂₄ N ₆ O ₅ S ₂ · 2HNO ₃ : C 37.62%, H 4.32%, N 18.47%.

S, 10.54%:

found: C 36.92%, H 4.10%, N 18.08%,

S 10.67% (water content: 0.90%).

Example 4

Preparation of the monohydrochloride acid addition salt The zwitterionic cephem derivative is dissolved in 2.08 ml of 1N hydrochloric acid solution (1 molar equivalent) at 20-25 ° C. Under vigorous stirring, acetone (30 mL) was added over 15 minutes, when crystallization began. After stirring for 1 hour, the crystals formed were collected by vacuum filtration, washed with 10 ml of acetone and dried in vacuo at 50 ° C for 2 hours.

0.9 g of crystalline monohydrochloride salt are obtained.

Analysis: Calculated for C ₉ H ₂₄ N ₆ O ₅ S ₂ · HCl O: C 41.37%, H 4.75%, N 15,2%,

S 11.63%, Cl 12.86%;

found: C 39.32%, H 4.88%, N 13.95%,

S 11.28%, Cl 12.44%, H ₂ 04.5%.

196 602

Λ HjO-Tartaloine: C, 41.17; N, 14.61; S, 11.82; Cl, 13.03%.

Example 5

Preparation of the dihydrochloride acid addition salt and its conversion into the monohydrochloride salt

350 mg of the zwitterionic zwitterion were dissolved in 2 ml of 1 N hydrochloric acid. To the resulting solution was added acetone (10 mL) under vigorous stirring for 5 minutes while crystallization started. Stirring was continued for another 5 minutes. A further 10 ml of acetone was added and the mixture was stirred for a further 0.5 hours. The crystals were then collected by vacuum filtration, washed twice with 5 ml of acetone and dried in vacuo at 40-45 ° C for 24 hours.

300 mg of crystalline dihydrochloride acid addition salt are obtained.

Analysis: Calculated for Ci9H 4 N ₆ O _{2 S 2} O · 2HC1: C 41.38%, H 4.75%, N 15,2%,

S 11.62%, Cl 12.8%;

found: C 40.78%, II 4.98%, N 14.7%,

S 11.25%, H ₂ O 1.25%.

Adjusted for H ₂ O: C 41.4%, N 14.88%, S 11.39%, Cl 11.94%.

g of the dihydrochloride salt obtained above is suspended in 20 ml of dichloromethane in a sealable flask at 20-25 ° C, and 0.28 ml of triethylamine are added portionwise over 15 minutes. The slurry containing the crystals was stirred for 5 hours, then the separated monohydrochloride crystals were collected by vacuum filtration, washed twice with 5 ml of dichloromethane and dried in vacuo at 50 ° C for 2 hours. This gives 800 mg of the inonohydrochloride salt.

Example 6

Preparation of acid addition salt diorthophosphoric g zwitterion derivative (3.4 mL, 2.2 equiv) of 144 m | dissolved concentration foszforsavoldatban / ml at 15 C ^S. The resulting solution was filtered to clarify and 12 ml of acetone was added to the clarified solution over 10 minutes with vigorous stirring; during this time crystals precipitate out of solution. Stirring was continued for a further 10 minutes, then another 30 ml of acetone was added over 10 minutes and stirring was continued for another 15 minutes. The precipitated crystals were collected by vacuum filtration, washed with acetone (5 x 5 mL), ether (5 x 5 mL) and dried under high vacuum for 16 h. 1.1 g of crystalline diorthophosphoric acid addition salt are obtained.

Analysis: Calculated for C 19 H ₂₄ N ₅ O ₅ S ₂ · 2H ₃ PO ₄ : C 33.72%, H 4.47%, Ν 12.42%;

Found: C, 33.43; H, 4.65; N, 12.02;

H ₂ O 1.82%.

Corrected for H ₂ O content: C 34.0%; N, 12.2%.

The infrared absorption spectrum (in potassium bromide) of the diorthophosphate salt is illustrated in Figure 3.

The sesquioorthophosphoric acid addition salt was also prepared as described above, except that this time only 1.5 molar equivalents of phosphoric acid were used instead of 2.2 molar equivalents (see Example 9).

Example 7

Stability of salts at higher temperatures

To determine the stability at elevated temperatures, the substances were determined to exhibit reduced or increased potency in dry vessels at the temperatures indicated in the table below and for the same period of time, followed by high pressure liquid chromatography. The find! the percentages are given in% in the table, where growth is denoted by a sign before the numerical value; unlabeled values represent loss of effect.

If the test substance shows a decrease in efficacy of less than 10% over a period of 2-4 weeks at 45-56 ° C, this indicates that only a decrease in efficacy of less than 10% at room temperature is expected over a period of 2-3 years.

Example 8

Examination of physical mixtures

To study the properties of the physical mixtures of salts and bases prepared as described above, the crystalline sulfuric acid addition salt was prepared with a) trisodium orthophosphate, b) sodium bicarbonate, c) L (+) lysine, and d) L (+) - arginine. is mixed as described above. The bases are added in such proportions to the acid addition salt that the solutions obtained by dilution with water have an activity of the zwitterionic cephem derivative determined by high pressure liquid chromatography at the following pH values:

with trisodium orthophosphate 6.0 sodium bridge with roge n-carbonate 6.0,

L (+) - lysine 6.0,

L (+) - arginine 6.0.

Sterile water corresponding to said 250 mg / ml zwitterionic activity was added to the physical mixture to prepare injectable solutions. No solubility problems were encountered. Injections (100 mg / kg) were administered intramuscularly to rabbits; pain sensation was only within acceptable limits. The slightest sense of pain is. injections with arginine.

Good solubility and acceptable pain-611

196 602

Loss%

Material

56 ° C 100 ° C ° C (week) (week) (day)

1 2 4 6 1 2 4 1 A twin-figure 37 51 71 57 _ _ 100 H ₂ SO ₄ salt 2.4 to +5 3 +5 1.4 5- + 6 +3 0- + 6 0-10 (HNO ₃ ) 2 salts 8.8 3.4 0.68 10.3 3.7 2.4 - - HClsó 4.8 2.3 6.0 6.4 6.4 - - - (HCl) ₂ salts 0 - 7.4 0 - 7.2 12.4 (H ₃ PO ₄ ) ₂ salts 0 3.0 1.0 2.7 5.0 - - we have achieved similar results by dilution. The resulting ol from other salts prepared as described above. 20 dates 0.22-0.45 micron pore size membrane

even when administered by intramuscular injection.

The infrared adsorption spectrum of the crystalline sulfate addition salt prepared according to Example 1 or 2 (as measured in a potassium bromide tablet) is shown in Figure I.

7 - [? - (2-Aminothiazol-4-yl) -? - N -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -3- _? crystalline cephem-4-carboxylate sulfate salt - ^r LYET TSI ³³ prepared according to Example 1 or 2 - X-ray powder diffraction pattern determined by Rigaku diffractometer, copper X-ray tube, a nickel filter, and the glass plate powder using a sample pattern The scan rate was 2 ° per minute within the range of 5 ° to ³⁵ ° to 40 °; the diagram was mechanically plotted to illustrate the maximum diffraction angles. Based on this, the d-spacing and the relative intensities of 1/1 were calculated.

The values obtained are shown in the table below;

clarification. To the clarified solution, 5-7 volumes (15-20 ml) of methanol are added with vigorous stirring for 30-60 minutes. The mixture of crystals formed below was stirred vigorously for 1.5-2 hours and the crystalline product was collected by vacuum filtration. The product was washed on the filter with 6-8 ml of a 1: 1 mixture of methanol / acetone, taking care to keep the filter cake tightly packed, which was then washed with acetone. The product thus obtained is dried under vacuum at 50 ° C for 2 hours; 0.7-0.75 g of sesquiphosphate acid addition salt is obtained.

The infrared absorption spectrum of the resulting product is shown in Figure 2; the vertical axis shows 27 to 77% transmittance.

IR spectra prepared with potassium bromide tablets;

d-spacing (λ.) 9.20 100 6.80 50 5.50 28 5.09 22 4.50 38 4.41 44 4.19 63 3.78 38 3.64 44 3.39 25 3.31 31 3.15 47

Peak Position (cm ~ ^l ) Functional group

2800-3400 NH, _NH3 \ carboxyl; 1780 beta-lactam C = O 1680 carboxyl C = O 1660 amide C = O 1630 C = C = NC 1550 amide-OH 980.1040 PO ₄ ⁼

Behavior during heating

The substance exhibits exotherm at 171.8 ° C when tested with a differential scanning calorimeter.

Example 9

Preparation of the sesquiphosphate acid addition salt

0.70 g of the zwitterionic zwitterion is dissolved under vigorous stirring in 2.2-2.4 ml of 85% phosphoric acid (2.1-2.2 molar equivalent) in 1:10 v / v water

X-ray diffraction pattern

Sesquiphosphate prepared above acid addition salt diffractometer Rigaku powder X-ray diffraction pattern measured as described above shows the following ^three értéθ Keken:

-713 d 1 / Γ

11.04 32 9.2 16 7.89 24 7.02 42 6.7 32 5.5 26 4.64 100 4.456 53 4.3 58 3.88 26 3.75 89 3.56 21 3.31 26 3.05 16

Nuclear Magnetic Resonance Spectrum (* H 90 MHz NMR in deuterium oxide solution)

Chemical shift (ppm δ vs. TSP)

2.0-2.4 m 4 I4CH ₂ , 14'CH ₂ 3.04 s 3 12CH ₃ 3.3-3.6 m 5 2CH, 13CH ₂ , 13'CH ₂ 3.94 doublet 1 2CH 4.12 s 3 2OCH ₃ 4.12 doublet 1 11CH 4.8 doublet 1 11CH 5.42 doublet 1 6CH 5.88 doublet 1 7 CH 7.21 s I 18CH

Stability

Time Temperature Loss% One day 100 ° C 10.9 3 days 70 ° C 0 7 days 70 ° C 1.9 1 week 56 ° C 1.0 2 weeks 56 ° C 1.4 4 weeks 56 ° C 0 1 week 45 ° C 0 2 weeks 45 ° C 1.4 4 weeks 45 ° C 0.7 8 weeks 45 ° C 1.6 1 month 37 ° C 2.5

Analysis data (in bulk)

Found Dry Calculated value calculated for substance (sesquiphosphate)

C 35.44 36.3 36.4 H 4.66 4.41 4.7 N 12.88 13.2 13.4 H ₂ O 2.29 - monohydrate = = 2.8% H ₂ O h _{3 after 4} 23.06 23.6 23.6

Note: The content of Λ il ₂ O was measured by Kari Fisclier's method. .

Claims (9)

Claims J. Procedure for the preparation of 7- [alpha] - (2-anionothiazol-4-yl) - N, N -ethoxyiminoacetamido-3 - [(1-mephyl-1-pyrrolidino) methyl] -3-cephem-4 temperature stable crystalline acid addition salts of crystalline sulfate, dinitrate, monohydrochloride and dihydrochloride containing 1.5-2 molar equivalents of orthophosphoric acid, characterized in that the zwitterionic is 7- (a- (2-aminothiazol-4-) il) -α-N-methoxyiminoacetamido] -3- (1-methyl-1-pyrrolidino) methyl] -3-cephem-4-carboxylate in an aqueous medium with at least one molar equivalent of the aforementioned acids forming; the salt formed is crystallized, whereby if said zwitterionic cephem derivative is present in an aqueous crystallization medium at a concentration of less than 25 mg / ml, the crystallization is carried out in water. adding a miscible organic solvent; and isolating the precipitated crystalline acid addition salt. Process according to claim 1, characterized in that the acid addition salt is crystallized in an aqueous solvent-free aqueous medium. 3. The process of claim 2, wherein the zwitterionic cefem derivative is used in the salt-forming step in an amount such that it is present in the crystallization mixture in a concentration of less than 500 mg / ml. The process according to claim 1, wherein the zwitterionic cefem derivative is used in the salt-forming step in an amount such that its concentration in the crystallization mixture is greater than 25 mg / ml. The process according to claim 2, wherein the zwitterionic cefem derivative is used in the salt-forming step in an amount such that its concentration in the crystallization mixture is between 100 mg / ml and 200 mg / ml. Process for the preparation of 7- [α- (2-aminothiazol4-yl) - N - methoxyiminoacetamido-3 - [(1-methyl-1-pyrrolidino) methyl] -3-cephem-4-carboxylate A process for preparing solid injectable aqueous solutions containing the acid addition salts according to claim 1, characterized in that the crystalline acid addition salt prepared according to claim 1 is a base, namely trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, Addition of L (+) - lysine or L (+) arginine to form a dry physical mixture at pH 3.5-7. 7. The process according to claim 6, wherein the crystalline acid addition salt obtained is dissolved in a water-injectable concentration to form a dry physical mixture having a pH of 4 to 6. -815 The process according to claim 6 or 7, wherein L (+) - lysine is used as the base for the formation of the physical mixture of the crystalline salt and the base. 9. The process according to claim 6 or 7, wherein L (+) - arginine is used as the base for the formation of the physical mixture of the crystalline salt and the base.