KR930003121B1 - Process for preparing cephalosporin salts - Google Patents

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Description

Method for preparing cephalosporin salt

Figure 1 shows crystalline 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl as measured by dilution with KBr. Infrared absorption spectral graph of -1-pyrrolidinio) methyl] 3-cefe-4-carboxylate sulfate.

2 shows 7- [α- (2-aminothiazol-4-yl) -X- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1) as measured by dilution with KBr. Infrared absorption spectra of -pyrrolidinio) methyl] -3-cepm-4-carboxylate crystalline seskiphosphate are shown in graphs.

3 shows 7- [α- (2-aminothiazol-4-yl) -X- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1) as measured by dilution with KBr. Infrared absorption spectrum of crystalline diphosphate of -pyrrolidinio) methyl] -3-cepem-4-carboxylate is shown in graphs.

The present invention relates to semi-synthetic cephalosporin salts whose preparation methods are stable at temperatures not described in the literature, methods for preparing these salts, and mixtures containing these salts.

U.S. Patent Nos. 4, 406, 899 to Aburaki et al. Disclose 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamyl in the presence of zwitterions. FIG.]-3-[(1-methyl-1-pyrrolidinio) -methyl] -3-cepem-4-carboxylic acid and corresponding acid addition salts (present in the form of zwitterions in the injectable composition) The zwitterion has a broader spectral activity than ceftazidime and cytotaxime.

However, the aforementioned cephalosporins such as Aburaki are stable for injectable compositions only for several hours, and even in dry powder, the zwitterionic form is unstable at room temperature, and at elevated temperatures (eg 45 ° C. and above) for only one week. When stored, more than 30% of its activity is lost. Therefore, zwitterionic forms require specially blocked packaging and / or freezing and are disadvantageous over ceftazidime and cytotaxic in packaging and storage.

Aburaki et al. Refer to acid addition salts, but the patent does not mention how to prepare them or whether any of these salts have good stability when in dry powder form. Kessler et al. ("Comparison of a New Cephalosporin, BMY 28142, with Other Broad-Spectrum β-Lactam Antibiotics", Antimicrobial Agents and Chemotherapy, Vol. 27, No. 2, pp. 207-216, 1985. February edition) Although mentioned, the preparation method is not described as having room temperature safety and excellent temperature stability when the salt is in dry powder form.

7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) in dry powder form It has been found in the present invention that certain crystalline acid addition salts of) -methyl] -3-cepem-4-carboxylate have excellent room temperature stability and good temperature stability compared to zwitterionic forms. As used herein, the term "dry powder form" means containing less than 5% by weight of water.

These acid addition salts include sulfuric acid, di-nitric acid, mono-hydrochloric acid and di-hydrochloric acid addition salts and orthophosphoric acid addition salts (range of 1.5-2 moles of orthophosphoric acid per mole salt, for example Cesky-di-orthophosphate). 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrroli) selected from the group consisting of: Crystalline salt of dini) methyl] -3-cepem-4-carboxylate or solvates thereof. As used herein, the term "crystalline" is used to mean an arrangement of at least some characteristic molecules.

Sulfuric acid di-nitric acid, di-hydrochloric acid and orthophosphoric acid addition salts are used herein in the form of crystals with a precise arrangement of molecules (as evidenced by birefringence by a light microscope), whereas mono-hydrochloric acid addition salts have their molecular arrangements. It is only manufactured with some regularity (as evidenced by poor birefringence by a light microscope), and is not "predictably" because it is not a precisely predictable arrangement.

As used herein, the term "crystalline" includes not only obvious crystalline salts but also crystalline mono-hydrochloric acid addition salts which appear "poor".

Acid addition salts herein confer zwitterions in solution when in the form of aqueous injectable compositions. The zwitterion has the following structural formula:

The usefulness of a broad spectrum of zwitterionic forms for various organisms and the broad spectrum of aqueous compositions prepared from salts thereof is shown in the data of Aburaki et al. In U.S. Patent Nos. 4, 406, 899.

Aqueous compositions prepared from acid addition salts herein are acid solutions when simply added with sterile water and cause unacceptable irritation when administered intravenously to rabbits and cause unacceptable pain when administered intramuscularly to rabbits. Let's do it. Sulfuric acid and di-nitrate addition salts typically have reduced solubility that is insufficient for injectable compositions. These contradictory features herein refer to physical mixtures (ie, mixtures of solids) with pharmaceutically acceptable non-toxic organic or inorganic salts at a rate of diluting the salt of the invention with water to a pH of about 3.5 to about 7. It has been found that it can be overcome by using zwitterionic activity in the range of 1 mg / ml to 400 mg / ml, typically 250 mg / ml (measured by high performance liquid chromatography, hereinafter referred to as HPLC).

Preferred salts herein are crystalline sulfuric acid addition salts. This sulfuric acid addition salt is preferable in view of high recovery from an aqueous medium at the time of crystallization since its solubility in water is low at 25 mg / ml.

Crystalline sulfuric acid addition salts form an aqueous mixture of (a)) (i) at least one molar equivalent of sulfuric acid and (ii) an amount of zwitterion in an amount that can be present in the mixture at a concentration of at least 25 mg / ml, and (b) ) Is readily prepared by a process comprising the step of crystallizing sulfuric acid addition salts and (c) separating the crystalline sulfuric acid addition salts.

Crystalline salts (hereinafter simply referred to herein as salts) herein have excellent stability at room temperature and result in up to 1% loss of activity (measured by HPLC) when stored at room temperature for 1 month. These salts also have excellent stability at elevated temperatures and are less than 15% ineffective (determined by HPLC) when stored at 45-56 ° C. for 1 month.

Sulfuric acid addition salts are preferred salts herein. When stored at 45-56 ℃ for one month, less than 10% is lost. Very importantly, this sulfate addition salt exhibits low water solubility, ie about 25 mg / ml, thus minimizing residue loss and crystallizing in water.

Di-nitrate addition salts here also exhibit low water solubility, ie about 60 mg / ml, and therefore also have low residue losses when crystallized in water.

Mono-hydrochloric acid, di-hydrochloric acid and sesqui- or di-ortho phosphate addition salts exhibit water solubility of 200 mg / ml or more, and therefore, it is preferable to crystallize with an organic solvent rather than water to obtain a good yield.

Here again goes back to the preparation of the salts.

In the present specification, as pointed out above, the sulfate addition salt is a zwitterion corresponding to (a) (i) at least sunset equivalent sulfuric acid and (ii) in an amount of at least 25 mg / ml in a mixture thereof. To form an aqueous mixture of (b) crystallize and (c) separate the crystalline sulfuric acid addition salt. It is preferable to use thungionic in an amount such that (a) is present in the mixture at a concentration ranging from about 100 mg / ml to about 200 mg / ml, and step (b) is performed in an aqueous medium containing no organic solvent. It is desirable to. Normally, up to 2 molar equivalents of sulfuric acid are used in step (a). Normally, zwitterion is used in an amount such that (a) is present in the mixture at a concentration of less than 500 mg / ml.

Step (a) is easily carried out by adding solid zwitterion with rapid stirring to sulfuric acid solution (eg 1N, H ₂ SO ₄ ) to form a solution. Alternatively, step (a) may be performed by dissolving a solid zwitterion in water and adding a sulfuric acid with gentle stirring to form a solution.

Step (b) is preferably carried out by inducing crystallization by seeding followed by slurrying for preferably 15 minutes to 2 hours. This crystallization step is preferably carried out in an aqueous medium containing no organic solvent, in which case a purity of 98% or more is normally obtained. The presence of an organic solvent such as acetone lowers the solubility of the formed sulfuric acid addition salt in the crystallization medium, thereby facilitating crystallization and increasing yield, while also facilitating precipitation of impurities that reduce purity. When zwitterions are used in an amount such that (a) is present in the mixture in an amount of less than 25 mg / ml, the organic solvent, preferably acetone, must be contained in the crystallization medium to allow proper recovery of the zwitterions. When acetone is used, it is suitably used in an amount of 0.5 to 10 volumes per volume of aqueous crystallization medium.

step (c) separates the crystals from the crystallization medium, preferably by vacuum filtration and, for example, with acetone / water, and then with acetone alone or with 0.1 N sulfuric acid (e.g. 1/10 volume) followed by acetone (E.g. 1/4 volume) followed by drying, for example vacuum drying at 30-50 ° C. for 4-20 hours.

In the method of forming the sulfate addition salt of the present invention, since the solubility of the sulfate addition salt is limited compared to the zwitterion form, the purification of the zwitterion form occurs, and this method can be used to purify the zwitterions without separating them into a solid form. If it is necessary to obtain an almost pure zwitterion (free base) from the sulfate addition salt formed, this method dissolves the salt in water and Ba (OH) ₂ .8H ₂ O in an amount of 90-100% of theory. Was added to precipitate BaSO ₄ at a pH of less than 6.5, filtered to remove BaSO ₄ and recovered filtrate containing zwitterions dissolved in it, used as a solution or lyophilized to give a solid zwitterion (glass- Base) or by adding acetone to precipitate the amorphous zwitterion, followed by vacuum filtration to separate the solid zwitterion, for example by washing with acetone and vacuum drying. Or sulfuric acid addition salts are converted into free bases using ion exchange resins such as Dowex WGR (weakly basic anion exchange resin) and Dow XX-40090.01 (cation exchange resin of strong acid) and then lyophilized. .

Recalling the preparation of crystalline di-nitrate addition salts, diacid addition salts are prepared by mixing (i) at least 2 molar equivalents of nitric acid and (ii) a zwitterion corresponding to the salt such that they are present in the mixture at a concentration of at least 100 mg / ml. It is then seeded or stirred with a glass rod to induce crystallization, obtained by dilution with 2-propanol and cooling. Crystalline 2-nitrate addition salt is, for example, filtered and washed continuously with, for example, 2-propanol-H ₂ O (50% volume / volume), 2-propanol and ether, followed by 2 at 50 ° C. Recover by vacuum drying for a time.

The mono-hydrochloric acid addition salt of the present invention dissolves zwitterion in about 1 molar equivalent of hydrochloric acid, adds acetone with stirring and continues stirring to cause crystallization, and then, for example, to separate the crystals by vacuum filtration, and then Prepared by washing with acetone and vacuum drying. Alternatively, mono-hydrochloric acid addition salts may be used to slurry di-hydrochloric acid addition salts in methylene chloride and

Molar equivalents of triethylamine are added followed by slurrying to form mono-hydrochloric acid addition salts, which are separated by, for example, vacuum filtration, which are then washed with methylene chloride and dried in vacuo to di-hydrochloric acid addition salts. From.

In the crystalline di-hydrochloric acid addition salt of the present invention, after dissolving zwitterion in at least 2 molar equivalents of hydrochloric acid, crystallization occurs by adding acetone, the crystals are separated by a method such as vacuum filtration, washed with acetone and vacuum dried. Manufacture.

The crystalline di-orthophosphate addition salt of the present invention dissolves zwitterions in at least 2 molar equivalents of phosphoric acid, adds acetone to cause crystallization, and separates the crystals by vacuum filtration, followed by washing with acetone first. It is then prepared by washing with ether and then vacuum drying. The crystalline seski-orthophosphate addition salt is formed by this same procedure except using about 1.5 molar equivalents of phosphoric acid.

Salts of the present invention are made into injectable compositions by diluting with sterile water and buffering to a pH of 3.5-7 to form an injectable concentration of zwitterions of 1 mg / ml up to 400 mg / ml. Suitable buffers include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) lysine and L (+) arginine. In the case of intramuscular or intravenous administration to adult men, it is usually sufficient to divide the total dose, about 750 to 3,000 mg, per day.

In the present invention, salts are not preferably formed into injectable compositions by simply adding sterile water, since sulfuric acid and di-nitrate addition salts are not soluble enough to form compositions at normal dosage concentrations. This is because it results in a very low pH composition (1.8-2.5). As noted above, these drawbacks have been found in the present invention to overcome these shortcomings by making the salts physically ie a mixture of solid, non-toxic organic or inorganic bases, with pharmaceutically acceptable solids. Wherein the organic or inorganic bases are diluted by diluting the mixture to an injectable concentration of zwitterion (e.g. zwitterionic activity of 250 mg / ml) of 1 mg / ml to 400 mg / ml or less as determined by HPLC using water. A pH range of about 3.5 to about 7 is preferably used at a rate such that it is in a pH range of about 4 to about 6.

The exact proportion of the components in the physical mixture varies from lot to lot of the salt because the purity of the salt varies from lot to lot. In order to obtain the selected pH within the aforementioned ranges, pre-titration of the sample is carried out to set the proportions of the components for the particular lot.

Physical mixtures have the advantage of being easily stored and transported in solid form to stabilize the salts of the present invention and are readily converted into simple injectable compositions by the addition of water by a nurse or physician immediately before use.

The physical warfare mixture is preferably prepared by mixing salts and bases in the form of a homogeneous mixture in a dry atmosphere using a standard mixer, and then filling a small bottle or other container under complete aseptic conditions.

Bases used in this mixture include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) lysine and L (+) arginine. L (+) lysine and L (+) arginine are preferred because the mixtures containing them are formulated to be injectable compositions that are less painful to animals than compositions derived from mixtures containing other bases upon injection. to be. It is highly desirable to use a ratio of dilution of the mixture with water to a pH of 3.5-6 to give a composition with zwitterionic activity (measured by HPLC analysis) of 250 mg / ml L (+) lysine.

The salts of the present invention and the almost dried physical mixtures containing the salts can be stored without freezing or heat dissipation packaging and still maintain high efficacy.

In some preparations of the invention unstable zwitterions are used as starting materials. Its manufacturing method is described in Example 1-3 of US Patent No. 4,406, 899 of Aburaki et al. Zwitterions are described in the patents of Aburaki et al. 7-[-(Z) -2-methoxyimino-2- (2-aminothiazol-4yl)] acetamido-3-[(1-methyl-1- It is called pyrrolidinium) methyl] -3-cepem-4-carboxylic acid salt.

The invention is illustrated in the following examples.

Example I

Preparation of sulfuric acid addition salt

1.5 g of zwitterion is slowly added to 10 ml of rapidly stirred 1N H ₂ SO ₄ (1.59 molar equivalents) at 20-26 ° C. to obtain a solution. Seeding with crystalline sulfuric acid addition salts induces crystallization and slurries the crystalline mass for 0.5 hour. The crystals are then separated by vacuum filtration, washed with 3 ml of 50% acetone / water (volume / volume), washed twice with 5 ml of acetone and vacuum dried at 40-50 ° C. overnight.

Representative yield is 1.3 g of sulfuric acid addition salt.

Elemental Analysis for _{C 19 H 24 N 6 O 5} S 2 · H 2 SO 4

Calculated Value: C; 39.44, H; 4.53, N; 14.52, S; 16.62%, no H ₂ O.

Found: C; 38.91, H; 4.57, N; 14.64, S; 16.71, H ₂ O 1.42%.

Example II

Preparation of sulfuric acid addition salt

Dissolve 1.5 g of zwitterion in 5 ml of water. 5 ml of 1M H ₂ SO ₄ is slowly added to the solution with stirring. It is then seeded with crystalline acid addition salt to induce crystallization and slurry the crystalline mass for 0.5 hour. The crystals are then separated by vacuum filtration, washed with 3 ml of 50% acetone / water (volume / volume) and twice with 5 ml of acetone and vacuum dried overnight at 40-50 ° C.

Representative yield is 1.3 g of sulfuric acid addition salt.

Example III

Preparation of (HNO ₃ ) ₂ acid addition salts

300 mg of zwitterion is dissolved in 2N nitric acid (0.5 ml). Stir the solution with a glass rod, dilute with 2-propanol (0.4 ml) and cool. The crystalline title compound was collected and washed successively with 0.4 ml of 2-propanol-H ₂ O (1: 1), 2-propanol and ether, yielding 127 mg of di-nitrate.

Elemental Analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ · 2HNO ₃

Calculated Value: C; 37.62, H; 4.32, N; 18.47, S; 10.57%

Found: C; 36.92, H; 4.10, N; 18.08, S; 10.67% (90% H ₂ O content).

Example IV

Preparation of monohydrochloric acid addition salt

Dissolve 1 g of zwitterion in 2.08 ml of 1N HCl (1 molar equivalent) at 20-25 ° C.

300 ml of acetone are added over 15 minutes with rapid stirring to form crystals. Continue stirring for 1 hour. The crystals are separated by vacuum filtration, washed with 10 ml of acetone and vacuum dried at 50 ° C. for 2 hours.

Representative yield is 0.9 g of crystalline mono-hydrochloride.

Elemental Analysis for _{C 19 H 24 N 6 O 6} S 2 · HCl

Calculated Value: 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 O 4.5%.

(Corrected for water: C; 41.7, N; 14.61, S; 11.82, Cl; 13.03%)

Example V

Preparation of di-hydrochloride addition salts and preparation of mono-hydrochloride addition salts therefrom

350 ml of zwitterion are dissolved in 2 ml of 1N-HCl. 10 ml of acetone are added to the resulting solution over 5 minutes with rapid stirring to form crystals. Stirring is continued for another 5 minutes. Then 10 ml of acetone is further added and stirring is performed for 0.5 hours. The crystals are removed by vacuum filtration, washed twice with 5 ml of acetone and vacuum dried at 40-45 ° C. for 24 hours.

Representative yield is 300 mg of crystalline di-hydrochloric acid addition salt.

Elemental Analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ · 2HCl

Calculated Value: C; 41.38, H; 4.75, N; 15.2, S; 11.62%, Cl; 12.8%.

Found: C; 40.78, H; 4.98, N; 14.7, S; 11.25, H ₂ O; 1.25%

(Corrected for H ₂ O: C; 41.1, N; 14.88, S; 11.39, Cl; 11.94%)

1 g of dihydrochloride prepared as described above is slurried in 20 ml of methylene chloride at 2-25 ° C. in a closed flask and 0.28 ml of triethylamine is added over 15 minutes. The crystalline mass is then slurried for 5 hours. The resulting mono-hydrochloride crystals are then separated by vacuum filtration, washed twice with 5 ml of methylene chloride and vacuum dried at 50 ° C. for 2 hours. Representative yield is 800 mg.

Example VI

Preparation of Di-orthophosphate Additives

1 g of zwitterion is dissolved in 3.4 ml of 144 mg / ml H ₃ Po ₄ (2.2 molar equivalents) at 15 ° C. Filter appropriately to purify the resulting solution. To this clarified solution, 12 ml of acetone are added over 10 minutes with rapid stirring to form crystals. Stirring is continued for 10 minutes. Thereafter, 30 ml of acetone is added over 10 minutes and stirring is continued for another 15 minutes. The crystals were collected by vacuum filtration, washed twice with 5 ml of acetone and twice with 5 ml of ether, and dried under high vacuum for 16 hours.

For this preparation, a typical yield is 1.1 g of crystalline di-orthophosphate addition salt.

Elemental Analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ · 2H ₃ PO ₄

Calculated Value: C; 33.72, H; 4.47, N; 12.42%.

Found: C; 33.43, H; 4.65, N; 12.02, H ₂ O; 1.82%.

(Corrected for H ₂ O: C; 34.0, N; 12.2%)

The seski-orthophosphate addition salt is formed as described above except that 1.5 molar equivalents of H ₃ PO ₄ is used instead of 2.2 molar equivalents.

EXAMPLE VII

Stability at elevated temperatures

Temperature stability is measured by keeping the formulation in a dry container for temperature and time as indicated below, and potency loss or gain is measured by HPLC. The% gain is indicated by a + sign before the number. A loss of less than 10% at 45-56 ° C. over 2-4 weeks usually corresponds to a loss of less than 10% over 2-3 years at room temperature.

EXAMPLE VII

[Test of physical mixture]

The physical mixture consists of (a) trisodium orthophosphate, (b) sodium bicarbonate (c) L (+) lysine, and (d) L (+) arginine and crystalline sulfate. The following base is added at a rate which gives the following pH when the mixture is diluted with water to give a 250 mg / ml zwitterionic activity (measured by HPLC analysis): trisodium orthophosphate (pH 6.0) ; Sodium bicarbonate (pH 6.0); L (+) lysine (pH 6.0); L (+) arginine (pH 6.0). Injectable compositions are made by adding sterile water to exhibit 250 mg / ml zwitterionic activity as determined by HPLC analysis. There was no problem with solubility. Inject intramuscularly (100 mg / kg) to afflicted rabbits within acceptable limits. The least painful was when injecting an arginine-containing composition.

Similar results of good solubility and acceptable pain when injected intramuscularly are obtained when other salts of the invention are used in a physical mixture containing these bases.

1 is an infrared absorption spectrum of crystalline sulfate prepared as described in Examples I or II pelletized into crystalline form containing potassium bromide.

7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyimino-acetamido] -3-[(1-methyl prepared as described in Examples I or II) The X-ray powder diffraction pattern of the crystalline sulfate of -1-pyrrolidinio) -methyl] -3-cefe-4-carboxylic acid is a Rigaku Powder Diffractometer with a copper target X-ray tube, Nickel Measure with a sample in the filter and glass dish. The scan rate was 2 ° / min in the range of 5 ° to 40 ° C, and the chart was mechanically recorded to indicate the maximum diffraction angle. From this, (d) the space and relative strength (I / I °) are calculated. These are listed below.

EXAMPLE VII

Preparation of Cesky Phosphate

0.70 g of zwitterions are dissolved in 2.2-2.4 ml of 85% phosphoric acid (2.1-2.2 molar equivalents) with rapid stirring and diluted to 1:10 (volume / volume) with water. The solution is clarified by filtration through a 0.22-0.45 micron pore size membrane filter. 5-7 volume parts (15-20 ml) of methanol are added to the filtrate with rapid stirring for 30 to 60 minutes. Crystals form during this operation and rapid stirring is continued for 1.5 to 2 hours. The crystalline product is recovered by vacuum filtration. The product is first washed carefully using a 1: 1 (volume / volume) of methanol (6-8 ml of acetone) in a filter to maintain a tightly packed filter cake and then washed with acetone. The product was dried under vacuum at 50 ° C. for 2 hours; Typical yields of 0.7 to 0.75 g are produced.

Infrared analysis (see figure 2)

(IR, KBr pellets)

Form for heat

Exothermic at 171.8 ° C. by differential scanning sequence analysis.

X-ray diffraction pattern

The X-ray powder diffraction pattern of the above-mentioned sesquiphosphate was measured by Rikaku powder diffraction meta in the same manner as described above for the sulfate, and the following results were obtained. :

NMR analysis

( ¹ H 90 MHz NMR, D ₂ O solution)

Stability

Elemental Analysis (wt%)

* Karl Fischer Method

Claims (13)

(a) at least one molar equivalent of sulfuric acid and (ii) 7-[[alpha]-(2-aminothiazol-4-yl)-[alpha]-(Z) -methoxyiminoacetamido] -3- [ Forming an aqueous mixture of zwitterions corresponding to (1-methyl-1-pyrrolidinio) -methyl] -3-cepem-4-carboxylate, (b) crystallizing sulfuric acid addition salts (but not When ions are present in the mixture at a concentration of less than 25 mg / ml, the crystallization must be carried out in the presence of an organic solvent), (c) to separate crystalline sulfuric acid addition salts, which are stable at temperatures. α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3- Cefem-4-carboxylate prepares sulfate addition salts. The process of claim 1, wherein step (b) is carried out in an organic solvent-free aqueous medium. The process of claim 2 wherein the zwitterion is used in an amount such that the zwitterion is present at a concentration of less than 500 mg / ml in the mixture in step (a). The method of claim 1, wherein the amount of zwitterion used in step (a) is such that it can be present in the mixture at a concentration of at least 25 mg / ml. The method of claim 2 wherein the zwitterion is used in an amount such that the zwitterion can be present in the mixture at a concentration ranging from about 100 mg / ml to about 200 mg / ml in step (a). 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacet such that (i) at least 2 molar equivalents of nitric acid and (ii) are present in the mixture at a concentration of at least 100 mg / ml. After forming an aqueous mixture of zwitterions corresponding to amido] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3-cepem-4-carboxylate, induce crystallization, It is characterized by the recovery of crystalline di-nitrate addition salt, which is stable to temperature. Crystalline 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido ] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3-cepem-4-carboxylate to prepare a di-nitrate addition salt. 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] The zwitterion corresponding to the 3-cefe-4-carboxylic acid salt is dissolved in about 1 molar equivalent of hydrochloric acid, and acetone is added while stirring, followed by continued stirring to crystallize, followed by separation of the crystals, thereby crystallizing the temperature. Sex 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl ] Method for preparing mono-hydrochloric acid addition salt of cefe-4-carboxylate. 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] Di-hydrochloric acid addition salt of -3-cepem-4-carboxylate is slurried in methylene chloride, 1 molar equivalent of triethylamine is added followed by slurry to form mono-hydrochloric acid addition salt, which is separated. Characterized in that, from the di-hydrochloric acid addition salt, stable to temperature 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3 A process for preparing mono-hydrochloric acid addition salt of-[(1-methyl-1-pyrrolidinio) -methyl] -3-cepem-4-carboxylate. 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] The zwitterion corresponding to -3-cefe-4-carboxylate is dissolved in at least 2 molar equivalents of hydrochloric acid, followed by crystallization by addition of acetone, followed by crystallization. α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3- Process for preparing di-hydrochloric acid addition salt of cefem-4-carboxylate. 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] The zwitterion corresponding to -3-cefe-4-carboxylate is dissolved in at least 2 molar equivalents of phosphoric acid, followed by crystallization by addition of acetone and separation of crystals. -(2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3-cepem Process for preparing di-orthophosphoric acid addition salt of 4-carboxylate. 11. A crystalline 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyimide that is stable at temperature, characterized in that about 1.5 molar equivalents of phosphoric acid are used. Noacetamido] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3-cefe-4-carboxylate for preparing sesquiorthophosphate addition salts or hydrates thereof. The crystalline 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido according to claim 2, which is stable at a temperature having the following X-ray powder diffraction pattern. ] -3-[(1-methyl-1-pyrrolidinio) -methyl] -3-cepem-4-carboxylate sulfate

12. The crystalline 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyimide which is stable at a temperature having the following X-ray powder diffraction pattern Method for preparing Noacetamido] -3-[(1-methylpyrrolidinio) -methyl] -3-cefe-4-carboxylate phosphate:

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