FI84484B - FOERFARANDE FOER FRAMSTAELLNING AV TEMPERATURSTABILA, KRISTALLINA CEFALOSPORINSALT. - Google Patents

Description

! 84484

This invention relates to the preparation of temperature-stable semisynthetic cephalosporin salts. The preparation of salts has not been previously described in the literature.

Aburaki et al. describe in U.S. Patent No. 4,406,899 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] 10 - [- (1-methyl-1-pyrrolidino) - methyl] -3-cephem-4-carboxylate in the form of a zwitterion and mention the corresponding acid addition salts (which are in the form of a zwitterion in injectable preparations) and show that the zwitterionic form has a broader spectrum of activity than cefta-15 cidim and cefotaxime.

However, the above-mentioned Aburak et al. cephalosporins are stable for only a few hours in injectable preparations, and the zwitterionic form, even as a dry powder, is unstable at room temperature and loses 30% or more of its activity when stored at elevated temperatures (e.g. 45 ° C and above) for up to one week, and therefore they require special insulated packaging and / or refrigeration, and this is a disadvantage in packaging and storage compared to ceftazid-25 diim and cefotaxime.

Although Aburaki et al. mention acid addition salts, the patent does not disclose how they are prepared or which of these salts may be particularly stable in the form of a dry powder. Kessler et al. "Comparison 30 of a New Cephalosporin, BMY 28142, with Other Broad-Spectrum 8-Lactam Antibiotics" Antimicrobial Agents and Chemotherapy, Vol. 2, pp. 207-216, February 1985, mention the sulfate salt, but not how it is prepared, or that this salt would be particularly stable at 35 room temperature and elevated temperatures in the form of a dry powder.

2 84484

It has been found that certain 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido)] - 3 - [(1-methyl-1-pyrrolidinio) methyl] -3- the crystalline acid addition salts of cefem-4-carboxylate in the form of a dry powder have excellent stability at room temperature and good stability at elevated temperature compared to the zwitterionic form. The term "dry powder form" as used herein means that the moisture content is less than 5% by weight.

These acid addition salts are 7- [α- (2-aminothiazol-10-yl) -α- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem- Crystalline salts of 4-carboxylate, sulfur, di-nitrogen, monohydrochloride and dichlorohydrochloric acid addition salts and orthophosphoric acid addition salts (1.5-2 moles of orthophosphoric acid per mole of salt, e.g. .

For the process of the invention, thermally stable crystalline 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3 For the preparation of sulfur, di-nitrogen, mono-hydrochloric and dichlorohydrochloric acid addition salts and orthophosphoric acid addition salts of -20 cephem-4-carboxylate containing 1.5-2 molar equivalents of H3PO4, is characterized in that ( a) forming an aqueous mixture of the acid and the double ion corresponding to said salt, (b) causing the salt to crystallize, and (c) isolating the crystalline salt.

The term "crystalline" as used herein means at least some degree of organization of molecules. The sulfur, nitrous, dichlorohydrogen and orthophosphoric acid salts are prepared here in a clearly crystalline form (as evidenced by birefringence in a polarizing microscope) in which the molecules are precisely organized, whereas the monochloro-hydrochloric acid addition salt is prepared only in a form in which only if -35 I got a degree of organizedness (as evidenced by weak birefringence in a polarizing microscope), and 3 84484 are not in any precisely predictable order, being thus weakly crystalline. The term "crystalline" herein includes not only distinctly crystalline salts but also a weakly expressed crystalline hydrochloric acid addition salt.

When these acid addition salts are formed into aqueous injectable preparations, they form a zwitterion in solution. The zwitterion has a structure

10 S

N0-CH3 COD® CHj 15

The broad spectrum of the zwitterionic form, and thus of aqueous preparations prepared from the salts described above, against various organisms has been shown by Abu Rak et al. The data disclosed in U.S. Patent 4,406,899.

Aqueous preparations prepared from acid addition salts simply by the addition of sterile water form acidic solutions which cause unpleasant irritation when administered intravenously to rabbits and an unpleasant painful sensation when administered intramuscularly to rabbits. Sulfuric acid di-nitric acid addition salts have reduced solubility, which is insufficient for typical injectable preparations. These undesirable properties can be avoided by using the salts described herein as physical mixtures (i.e., mixtures of solids) with pharmaceutically acceptable non-toxic organic or inorganic bases in a ratio such that the pH is between 3.5 and 7 when diluted with water to a quadruple-35 concentration. is between 1 mg / ml and 400 mg / ml, usually 4,848,484,250 mg / ml (determined by high performance liquid chromatography, hereinafter HPLC).

The preferred salt here is a crystalline sulfuric acid addition salt. It is preferable because, due to its low water solubility (25 mg / ml), it is obtained in high yield by crystallization from an aqueous medium.

The crystalline sulfuric acid addition salt is readily prepared by a process comprising the steps of (a) forming an aqueous mixture of (i) at least one molar-10 equivalent sulfuric acid and (ii) a zwitterion in an amount greater than 25 mg / ml, (b) crystallization of the sulfuric acid addition salt. and (c) isolating the crystalline sulfuric acid addition salt.

Figure 1 is a graphical representation of crystalline 7- [α- (2-15 aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinide); inio) me ty 1 i] - 3 - ke f em - 4 - kar bok sy 1 aa tin sulfate salt infrared absorption spectrum measured from its KBr dilution.

Figure 2 is a graphical representation of crystalline 7- (α- (2-20 aminothiazol-4-yl) -x- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3 Infrared absorption secretor of the sesquiphosphate salt of cephem-4-carboxylate as measured by its KBr dilution.

Figure 3 is a graphical representation of crystalline 7- [α- (2-25 aminothiazol-4-yl) -x- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3 Infrared absorption spectrum of the diphosphate salt of cephem-4-carboxylate measured from its KBr dilution.

These crystalline salts (hereinafter hereinafter simply referred to as salts) have excellent stability at room temperature and a loss of potency (as determined by HPLC) of less than 1% when stored for one month at room temperature. These salts also have excellent stability at elevated temperatures and have a loss of potency (as determined by HPLC: 1-8 84484) of less than 15% when stored for one month at 45-56 ° C.

The sulfuric acid addition salt is the most preferred salt here. Its loss of potency is less than 10% when stored for 5 months at 45-56 ° C. And most importantly, it has a low solubility in water, i.e. about 25 mg / ml, and as a result it can be crystallized from water with minimal residual losses.

The D1-nitric acid addition salt also has a low Liu-10 content in water, i.e. about 60 mg / ml, and therefore also has a low residual loss on crystallization from water.

The solubilities of the monohydrochloride, dichlorohydrogen and sesqui or diorthophosphate acid addition salts are greater than 200 mg / ml, which is why they are more preferably crystallized from organic solvents than water in order to obtain good yields.

We now turn to the preparation of the salts described herein.

As indicated above, the sulfuric acid addition salt is prepared by a process comprising the steps of (a) forming an aqueous mixture of (i) at least one molar equivalent of sulfuric acid and (ii) a zwitterion corresponding to said salt in an amount greater than 25 mg / ml, ( b) inducing crystallization; and (c) isolating the crystalline sulfuric acid addition salt.

The zwitterion is preferably used in step (a) in an amount such that its concentration in the mixture is between about 100 mg / ml and 200 mg / ml, and step (b) is preferably carried out in an aqueous medium without an organic solvent. Usually, no more than 2 molar equivalents of sulfuric acid are used in step (a). Usually, the zwitterion is present in step (a) in an amount such that its concentration in the mixture is less than 500 mg / ml.

6 84484

Step (a) is readily performed by either adding a solid zwitterion to a sulfuric acid solution (e.g., 1 N H 2 SO 4) while stirring vigorously to form a solution. Alternatively, step (a) can be performed by dissolving the solid zwitterion in water and slowly adding sulfuric acid while stirring to form a solution.

Step (b) is performed by inducing crystallization, preferably by seeding, and then forming a slur-10, preferably in 15 minutes to 2 hours. It is preferred that this crystallization step be performed in an aqueous medium without an organic solvent, and in this way a purity of more than 98% is usually obtained. Although an organic solvent such as acetone favors crystalline sea buckthorn and increases the yield by lowering the solubility of the sulfuric acid addition salt formed in the crystallization medium, it also favors the crystallization of impurities and thus leads to a decrease in purity. When the zwitterion in step (a) is used in the mixture in an amount of less than 25 mg / ml, an organic solvent, preferably acetone, must be used in the crystallization medium to obtain a reasonable yield. When acetone is used, it is used in an amount of 0.5 to 10 volume units per unit volume of the aqueous crystallization medium.

Step (c) is carried out by separating the crystals from the crystallization medium, preferably by filtration in vacuo, then washing with e.g. acetone / water and then with acetone alone or first with 0.1 N sulfuric acid (e.g. 1/10 volume) and then with acetone (e.g. 1 / 4 volume), and then with a how-30 dowel, e.g. under vacuum at 30-50 ° C for 4-20 hours.

The process described above for the preparation of the sulfuric acid addition salt results in the purification of the zwitterion, due to the limited solubility of the sulfuric acid addition salt compared to the zwitterion, and can be used to purify the zwitterion without isolating it as a solid. If it is desired to obtain substantially pure 7 84484 zwitterions (free base) from the formed sulfuric acid addition salt, this can be done by dissolving the salt in water, adding Ba (OH) 2.8H2O 90-100% of theory at pH below 6.5 to precipitate BaSO4. , filter-5 rows to remove BaSO 4 and recovering the filtrate in which the zwitterion is dissolved and using it or isolating the solid zwitterion (free base) by lyophilization or adding acetone to precipitate an amorphous zwitterion, followed by recovery of the solid zwitterion by vacuum filtration, washing e.g. with acetone, and dried in vacuo. Alternatively, the sulfuric acid addition salt is converted to the free base using an ion exchange resin, e.g., Dowex WGR (weak basic anion exchange resin) and Dowex XU-40090.01 (strong acidic cation-15 exchange resin) followed by lyophilization.

We now turn to the preparation of the crystalline di-nitric acid addition salt, which is obtained by mixing (i) at least two molar equivalents of nitric acid and (ii) zwitterions to a concentration of more than 100 mg / ml, 20 and then inducing crystallization by seeding or rubbing with a glass rod, diluting with 2-propanol and cooling. The crystalline di-nitric acid addition salt is recovered, e.g. by filtration, washed alternately with e.g. 2-propanol-water (50% v / v), 2-propanol and ether, and then dried in vacuo at 50 ° C for 2 hours.

The monohydrochloric acid addition salt is prepared by dissolving the zwitterion in about one molar equivalent of hydrochloric acid and causing crystallization by adding acetone while stirring and continuing to stir, after which the crystals are isolated, e.g. by filtration in vacuo, washed with acetone and dried in vacuo. Alternatively, the monochlorohydric acid salt is formed from the dichlorohydric acid salt by forming a slurry of the dichlorohydrogen-35 acid salt into methylene chloride and adding 1 molar equivalent of triethylamine followed by formation of the slurry β 84484. in vacuo.

The crystalline dichlorohydric acid salt is prepared by dissolving the zwitterion in at least two molar equivalents of hydrochloric acid, then crystallizing by adding acetone, then isolating the crystals, e.g., by filtration in vacuo, washing with acetone and drying in vacuo.

The crystalline di-orthophosphoric acid addition salt is prepared by dissolving the zwitterion in at least 2 molar equivalents of phosphoric acid, causing crystallization by adding acetone, and isolating the crystals, e.g., by filtration under vacuum, then washing with acetone and then ether and then drying in vacuo. The crystalline sesqui-orthophosphoric acid addition salt is formed by the same method except that about 1.5 molar equivalents of phosphoric acid are used.

Injectable preparations are prepared from the salts described herein by diluting with sterile water and buffering to pH 3.5-7 to an injectable concentration of zwitterion of 1 mg / ml to 400 mg / ml. Suitable buffering agents are, for example, trisodium ortho-25 phosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) - arginine. When administered intramuscularly or intravenously to an adult human, a total dose of about 750-3000 mg per day in divided doses is usually sufficient.

30 Salts and substantially dry physical mixtures containing them can be stored without refrigeration or insulating packaging, and still retain high performance.

In several preparations, 35 volatile zwitterions have been used as starting materials. The preparation of this is described in Examples 1-3 by Aburak et al. U.S. Patent 4,406,899.

9 84484

Aburakin et al. in the patent the zwitterion is 7 - [(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido-3 - [(1-methyl-1-pyrrolidinium) methyl] -3-cephem -4-carboxylate.

The invention is illustrated by the following signs of your work.

Example I

Preparation of the sulfuric acid addition salt 1.5 g of zwitterion are slowly added to 10 ml of vigorously stirred 1 N H 2 SO 4 (1.59 molar equivalents) at 20-26 ° C. A solution is obtained. Crystallization is accomplished by seeding with a crystalline sulfuric acid addition salt, and the crystalline mass is stirred for 0.5 hours. The crystals are then separated by filtration in vacuo, washed with 3 ml of 50% acetone / water (v / v) and two 5 ml portions of acetone, and dried in vacuo at 40-50 ° C overnight.

A typical yield is 1.3 g of sulfuric acid addition salt. Analysis: Calculated for C 19 H 24 N 6 O 5 S2.H 2 SO 4:% C, 39.44; % H, 4.53; % N, 14.52; % S, 16.62; % H 2 O, none. Found:% C, 38.91; % H, 4.57; % N, 14.64; % S, 16.71; % H 2 O, 1.42.

20 Example II

Preparation of the sulfuric acid addition salt 1.5 g of zwitterion are dissolved in 5 ml of water. To this solution is slowly added 5 ml of 1M H 2 SO 4 with stirring. Crystallization is then effected by seeding with a crystalline acid addition salt, and the crystalline mass is stirred as a slurry for 0.5 hours. The crystals are then separated by filtration in vacuo, washed with 3 ml of 50% acetone / water (v / v) and two 5 ml portions of acetone, and dried in vacuo at 40-50 ° C overnight.

A typical yield is 1.3 g of sulfuric acid addition salt.

Example III

Preparation of the (HNO 3) 2-acid addition salt 300 mg of the zwitterion are dissolved in 2N nitric acid 35 (0.5 ml). The solution is triturated with a glass rod, diluted with 2-propanol (0.4 mL) and cooled. The crystalline title compound is collected and washed first with 0.4 ml of 2-propanol / water (1: 1), then with 2-propanol and finally with ether to give 127 mg of the dinitrate salt. Analysis: Calculated for C 19 H 24 N 6 O 5 S 2 .2HNO 3% C, 37.62; % H, δ 4.32; % N, 18.47; % S, 10.57. Found:% C, 36.92; % H, 4.10; % N, 18.08; % S, 10.67; (H 2 O content 0.90%).

Example IV

Preparation of the hydrochloric acid addition salt 1 g of the zwitterion was dissolved in 2.08 ml of 1N HCl 10 (1 molar equivalent) at 20-25 ° C. 30 ml of acetone were added with vigorous stirring over 15 minutes to form crystals. Stirring was continued for 1 hour. The crystals were isolated by filtration in vacuo, washed with 10 ml of acetone and dried in vacuo at 50 ° C for 2 hours.

A typical yield is 0.9 g of crystalline monohydrochloride salt.

Analysis: Calculated for C 19 H 24 N 6 O 5 S2.HCl 1% C, 41.37; % H, 4.75; % N, 15.2; % S, 11.63; % C1, 12.86. Found:% C, 39.32; % H, 4.88; % N, 13.95; % S, 11.28; % C1, 12.44; % H 2 O, 4.5.

(Correction for H 2 O:% C, 41.17;% N, 14.61;% S, 11.82;% Cl, 13.03).

Example V

Preparation of dichlorohydric acid addition salt and preparation of mono-hydrochloric acid addition salt thereof 25 350 mg of zwitterion were dissolved in 2 ml of 1 N

HCl. To the resulting solution was added 10 ml of acetone while stirring vigorously for 5 minutes to form crystals. Stirring was continued for another 5 minutes. An additional 10 mL of acetone was then added and stirring was continued for 0.5 h. The crystals were removed by filtration in vacuo, washed with two 5 ml portions of acetone and dried in vacuo at 40-45 ° C for 24 hours.

A typical yield is 300 mg of crystalline dichlorohydric acid addition salt.

Analysis calculated for C 19 H 24 N 6 O 5 S 2 .2HCl:% C, 41.38; % H, 4.75; % N, 15.2; % S, 11.62; % C1, 12.8. Found:% C, 40.78; 11 84484% H, 4.98; % N, 14.7; % S, 11.25; % H 2 O, 1.25. (Correction for H 2 O:% C, 41.1;% N, 14.88;% S, 11.39;% Cl, 11.94).

From 1 g of the dihydrochloride salt prepared above, a slurry was prepared in 20 ml of methylene chloride at 20-5 at 25 ° C in a sealed flask, and 0.28 ml of triethylamine was added over 15 minutes. The crystalline mass was then stirred for 5 hours. The resulting monohydrochloride crystals were isolated by filtration in vacuo, washed with two 5 ml portions of methylene chloride and dried in vacuo at 50 ° C for 2 hours. A typical yield is 800 mg.

Example VI

Preparation of the di-orthophosphoric acid addition salt 1 g of zwitterion was dissolved in 3.4 ml of H 3 PO 4, 144 mg / ml (2.2 molar equivalents) at 15 ° C. The resulting solution 15 was suitably filtered to clarify it. To the clarified solution was added 12 ml of acetone over 10 minutes with vigorous stirring to form crystals. Stirring was continued for 10 minutes. 30 ml of acetone were then added over 10 minutes and stirring was continued for a further 15 minutes. The crystals were collected by filtration in vacuo, washed with two 5 ml portions of acetone and two 5 ml portions of ether and dried under high vacuum for 16 hours.

A typical yield in this type of preparation is 1.1 g of crystalline di-orthophosphoric acid addition salt. Analysis: Calculated for C 19 H 24 N 6 O 5 S 6.2H 3 PO 4:% 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 sesqui orthophosphoric acid addition salt is prepared as described above, except that 1.5 molar equivalents of H 3 PO 4 are used instead of 2.2 molar equivalents.

Example VII

Stability at elevated temperatures

Stability at elevated temperatures was determined by storing preparations in dry containers at said temperatures for the periods indicated, and power losses were determined by HPLC. The increase in power is indicated by a plus sign in front of the number. A loss of power of less than 10% in 2-4 weeks at 45-56 ° C usually means a loss of power of less than 10% in 2-3 years at room temperature.

loss percentage

_4 5 ° C_ 5 6 ° C 10 0 ° C

10 (Weeks) (Weeks) (Days)

Form 1 2 4 6 1 2 4 j

Zwitterion 37 51 71 ,, 57 "- 100 H2SO4 Salt 2f4 t0 45 3 +5 1,4 5 to +6 +3 0 to +6 0-10 15 <HN03) 2 SuQla β, Β 3, 4 0, 68 1 0.3 3.7 2.4 HCl Salt 4'8 2f3 670 6.4 -.

(HCl) 2 Salt 0 to 7; 4 to 0 to 7.2 12.4 (H3PO4.2 Salt 0 3.0 1.0 to 27 5.0 20___

Figure 1 is an infrared absorption spectrum of a crystalline sulfate salt prepared in Example I or II and pelleted in crystalline form with potassium bromide.

7- [a- (2-aminothiazol-4-yl) -a- (Z) -methoxy-sucked-noasetamido] -3 - [(l-methyl-l-pyrrolidinio) -methyl] -3-kb-fem The powder X-ray diffraction values of the crystalline sulfate salt of 4-carboxylate prepared in Examples I and II were determined on a Rigaku Powder Diffractometer using a copper cathode X-ray tube, a Nikke filter and a sample on a glass plate. The sweep sync rate was 2 degrees per minute from 5 degrees to 40 degrees, and a plot was mechanically printed on the plotter, showing the angles and maximum diffraction. Of these, the distances (d) and relative intensities (1/1 °) were calculated for the 84484 chain. They are tabulated below.

d distance (° A) 1/1 ° (%) 5 9.20 100 6, BO 50 28 5.09 22 10 * f50 38 4.41 44 63 3r7B 3g 3.64 44 15 3'39 25 3 r33 31 3fl5 47

20 Example IX

Preparation of sesquiphosphate salt

The zwitterion, 0.70 g, was dissolved with vigorous stirring in 2/2 to 2.4 ml of 85% phosphoric acid (2.1-2.2 molar equivalents) diluted 1:10 (v / 25 vol) with water. . The solution was clarified by filtration through a 0.22-0.45 micron porous membrane filter. To the filtrate was added 5-7 volumes (15-20 ml) of methanol with vigorous stirring for 30-60 minutes. During this procedure, crystals formed, and rapid stirring was continued for 1.5-2 hours. The crystalline product was recovered by filtration in vacuo. The product was washed on the filter first 6-8 ml 11a methanol: acetone (volume ratio 1: 1) while maintaining ensure that it remained tightly packed filter cake and then with acetone. The product was dried in vacuo at 50 ° C for 2 hours; typical yield - 84484 to 0.7.0.75 g.

Interpretation of the infrared spectrum (See Figure 2) (IR, KBr pellet) 5 -1

Peak location (cm) Functional group

2800-3400 NH, carboxyl-OH

1780 β-lactam C = 0 1680 Carboxyl C = 0

10 1660 Amidi OO

1630 ON, OC

1550 Amidi OH

980.1040 PO = 4 15 Behavior on heating

An exotherm was observed at 171.8 ° C on a differential scanning calorimeter curve.

The X-ray diffraction curve

The X-ray powder diffraction pattern of the sesquiphosphate salt described above was measured with a Rigaku Powder Diffractometer in the same manner as described above for the sulphate salt, and the following results were obtained.

d I / I * 11.04 - 32 9.2 - 16 7.89 - 24 7.02 - 42 617 - 32 5.5 - 26 4.64 - 300 4.456 - 53 4 r 3 - 58 3.88 - 26 3 .75 - 89 3.56 - 21 3.31 26 3.05 - 16 i5 84484 NMR Interpretation (1H 90 MHz NMR, DO solution) ch3 .NHi-X J 1 Lu ^ A ^ lsJ "S ^ U. O '- ·« ; *3 * 1 »COj *

Chemical shift (ppm vs. TSP) Description Integral 2.0-2.4 Multiplet 4 14CH14'CH ^ 3.04 Singlet 3 12CH3 3.3-3.6 Multiplet 5 2CH, ISCH ^, l ^ 'C ^

3.94 Dublin 1 2CH

4.12 Singlets 3 20CH.J

4.12 Dublin 1 11CH

4.8 Dublin 1 11CH

5.42 Dublin 1 6 CH

5.88 Dublin 1 7CH

7.21 Singlet 1 18CH

stability

Time- Temperature% Loss 1 day; 100 ° C to 10.9 for 3 days; 7 ° C - 0 7 days; 70 ° C - 1.9 for 1 week; 56 ° C to 1.0 for 2 weeks; 56 ° C to 1.4 for 4 weeks; 56 ° C - 0 for 1 week; 45 ° C - 0 for 2 weeks; 45 ° C to 1.4 for 4 weeks; 45 ° C to 0.7 for 8 weeks; 45 ° C - 1.6 for 1 month; 37 ° C - 2.5 ie 84484

Alkuaineanalyysi_ (wt%)

Obtained in Theory (Sesiphosphate) 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% 1 ^ 0 H3PO4 23.06 23.6 23.6 * Karl Fischer method

Claims (8)

A process for the preparation of temperature-stable, crystalline sulfur, di-nitrogen, mono-hydrochloric and di-hydrochloric acid addition salts of 7- [α- (2-aminothiazol-4-yl) -α- (Z) methoxy-iminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate, and orthophosphoric acid addition salts containing 1.5-2 molar equivalents of H3PO4, characterized in that the process comprises (A) forming the aqueous mixture of the acid with a zwitterion corresponding to the site, (b) crystallizing the salt, and (c) isolating the crystalline salt. 15 2. A process according to claim 1 for preparing the sulfuric acid addition salt as defined in claim 1, characterized in that it comprises the following steps: (a) forming an aqueous mixture of (i) at least 1 molar equivalent of sulfuric acid and (ii) a (b) causing the sulfuric acid addition salt to crystallize, provided that where the zwitterion content of the mixture is below 25 mg / ml, crystallization is carried out in the presence of an organic solvent, and (c) isolation of the crystalline salt. sulfuric acid addition salt. Process according to claim 2, characterized in that step (b) is carried out in an aqueous medium which does not contain an organic solvent. 30 4. A process according to claim 3, characterized in that the zwitterion in step (a) is used in such an amount that its content in the mixture is below 500 mg / ml. 5. A process according to claim 2, characterized in that the amount of the zwitterion in step (a) is such that its content in the mixture is above 25 mg / ml. 6. A process according to claim 3, characterized in that the zwitterion in step (a) is used in such an amount that its content in the mixture varies between about 100 mg / ml and 200 mg / ml. Process according to Claim 1, characterized in that a crystalline sulfate salt of 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxy-iminoacetamido] is prepared. [(1-methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate having the following X-ray diffraction values in powder form: dilution (A) 1/1 ° (%) 9.20 100 6.86 50 5.50 28 5.09 22 4.50 38 4.41 44 20 4.19 63 3.78 38 3.64 44 3.39 25 3.31 31 25 3.15 47 Process according to Claim 1, characterized in that a crystalline 7- [α- (2-aminothiazol-4-yl) -a- (Z) -methoxy-iminoacetamido] -30- - ((1- methyl 1-pyrrolidinio) methyl] -3-cephem-4-carboxylate phosphate, which has the following X-ray diffraction values in powder form: 22 8 4 484 d 1/1 ° 11.04 - 32 9.2 - 16 7.89 - 24 5 7.02 - 42 6.7 - 32 5.5 - 26 4.64 - 100 4.456 - 53 10 4.3 - 58 3.88 - 26 3.75 - 89 3.56 - 21 3.31 - 26 15 3.05 - 16