SE469633B - PHYSICAL MIXTURES OF CEPHALOSPORINE SALTS, CRYSTALLINE SULPHATE SALTS, AND A PROCEDURE FOR THE PREPARATION OF THESE - Google Patents

Description

10 469 653 elevated temperature in dry powder form.

Summary of the invention It has been found that certain crystalline acid addition salts of 7-fi K- (2-aminothiazol-4-yl) -Q (Z) -methoxyiminoacetamido) -3- [T1-methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate in dry powder form has excellent stability at room temperature and has a superior stability at elevated temperature compared to zwitterionic forms. The term "dry powder form" as used herein lying context a moisture content of less than 5% by weight.

These acid addition salts are the crystalline salts of 7-fi K- (2-aminothiazol-4-yl) -ac (Z) -methoxyiminoacetamide] -3- [T1-methyl- ethyl 1-pyrrolidinio) -methyl 7-3-cephem-4-carboxylate which is of sulfuric acid, disalpetic acid, monochlorohydric acid and di- the hydrochloric acid addition salts and the orthophosphoric acid addition the salts (1.5-2 moles of orthophosphoric acid per mole of salt, for example a range from the sesqui- to diorthophosphoric acid salts) or solvate thereof. The term "crystalline" as used herein refers to context that the molecules show at least something characteristic arrangement. Although sulfuric acid, disalpeter- the acid, dichlorohydric and orthophosphoric acid addition salts prepared in clear crystalline form (as shown in birefringence under a polarizing microscope) with an exact arrangement of molecules, monochlorohydric acid has the addition salt is prepared only with some regularity as regards the arrangement of its molecules (as shown of its poor birefringence during polarizing micro- scoop) and not an exact predictable arrangement and is thus "low-grade" crystalline. The term "crystalline" thus includes in the present context not only those clearly the crystalline salts but also the “low-grade” crisis tallina monochlorohydric acid addition salt.

When the acid addition salts of the invention are prepared aqueous injectable preparations are obtained zwitterjo- 3 469 635 in solution. Zwitterjonen has the structure so p Ha / ës-Ä-É w fl å ° tfšg w; \ o-cn, cooê The broad-spectrum activity against various organisms in zwitter- ionic form and thus in aqueous. preparations prepared of the salts of the invention are shown by data in the perhaps patent 4,406,899.

Aqueous preparations prepared from acid addition the salts of the invention by simply adding puts sterile water, gives acidic solutions, which induce one unacceptable irritation in rabbits during intravenous administration and an unacceptably painful sensation during intranasal administration. nistma fi ng to rabbits. Sulfuric acid and disalpetic acid additives the salts exhibit reduced solubilities, which are sufficient for typical injectable preparations. We have set that these unfavorable properties can be eliminated by that the salts according to the invention are used in physical mixture (ie a mixture of solids) with a pharmaceutical non-toxic, non-toxic organic or inorganic base in such proportions that a pH of from about 3.5 to about 7 when diluted with water to a zwitterionic activity of from 1 mg / ml to 400 mg / ml, normally 250 mg / ml (determined by high performance liquid chromatography, in the following called HPLC).

A preferred salt of the invention is the crystalline the sulfuric acid addition salt. It is preferred because its low solubility in water (25 mg / ml) enables recovery in high yield of aqueous medium upon crystallization.

The crystalline sulfuric acid addition salt is easily prepared by a method comprising the steps involved that one (a) forms an aqueous mixture of (i) at least a molar equivalent of sulfuric acid and (ii) zwitterion in a 469 633 4 amount that it is present in the mixture in a concentrated exceeding 25 mg / ml, (b) producing crystallization of the sulfuric acid addition salt and (c) isolates the critical tallina sulfuric acid addition salt.

Brief description of the drawings Pig. 1 is a graphical representation of infrared absorption spectrum of crystalline 7- [R- (2-aminothiazol-4-yl) -0% (Z) - Methoxyiminoacetamide-3- [Y1-methyl-1-pyrrolidinio) methyl] -3- cephem-4-carboxylate sulphate salt, measured at KBr dilution thereof of.

Fig. 2 is a graphical representation of the infrared absorption the spectrum of the crystalline sesquiphosphate salt of 7- [is (2-aminothiazol-4-yl) -X- (Z) -methoxy-iminoacetamide] -3- [K1-methyl- methyl 1-pyrrolidinio) -methyl7-3-cephem-4-carboxylate, measured at KBr dilution thereof.

Fig. 3 is a graphical representation of the infrared absorption the spectrum of the crystalline diphosphate salt of 7- [R- (2- aminothiazol-4-yl) -x- (Z) -methoxy-iminoacetamideq7-3- [T1-methyl- 1-pyrrolidinio) -methyl7-3-cephem-4-carboxylate, measured at KBr dilution thereof.

Detailed description of the invention The crystalline salts of the invention (which in it the following are simply referred to as ‘the salts finningen ") has excellent stability at room temperature and a loss of potency (when determined by HPLC) of less than 1% for storage for one month at room temperature. These sales ter also has excellent stability at elevated temperatures and has a loss of potency (when determined by HPLC) of less than 15% when stored for one month at 45-56 ° C.

The sulfuric acid addition salt is a preferred salt according to 469 633 the finding. It has a power loss of less than 10% at storage for one month at 45-56 ° C. What is very important is that it has low solubility in water, ie. about mg / ml, and therefore crystallizes out of water with a minimum possible residual loss.

The disalpetic acid addition salt of the invention also has low solubility in water, ie. about 60 mg / ml, and therefore gives there was also a residual loss on crystallization from water.

Monochlorohydric, dichlorohydric and sesqui- or diortho- the phosphoric acid addition salts have water solubilities exceeding 200 mg / ml and is therefore preferably crystallized from organic solvents instead of out of water to man shall achieve good yields.

The preparation of the salts according to the invention.

As stated above, the sulfuric acid addition salt is prepared according to the invention by means of a method which comprises one (a) forms an aqueous mixture of (i) at least one molar equivalent of sulfuric acid and (ii) zwitterion corresponding said salt in such an amount that it is present in a mixture at a concentration exceeding 25 mg / ml, (b) comes crystallization and (c) isolates the crystalline the sulfuric acid addition salt. Preferably zwitter- the ion in step (a) in such an amount that it is present in the mixture at a concentration of from about 100 mg / ml to about 200 mg / ml and step (b) is performed in an aqueous medium. dium, which is free of organic solvent. Normally an- no more than two molar equivalents of sulfuric acid were used in steps (a). Normally, the zwitterion in step (a) of one is used amount that it is present in the mixture in a concentrated less than 500 mg / ml.

Step (a) is easily performed either by attaching 469 653 e zwitterion to sulfuric acid solution (eg 1N HZSO4) with rapid stirring to form a solution. Alternatively step (a) can be performed by dissolving solid zwitter- ion in water and slowly add sulfuric acid during stirring to form a solution.

Step (b) is performed by inducing crystallization, preferably by the addition of seed crystals, and after preparing a slurry, preferably for a time of from 15 min to 2 hours. It is preferred that this crystallization steps are performed in aqueous medium, which is free of organic solvent, and in such cases, purities exceeding 98% are normally obtained. Although the presence of organic solvent, such as acetone, promotes crystallization and increases the yield by reducing the solubility of the sulfuric acid addition salt formed in the crystallization medium, it can also promote precipitation of contaminants, resulting in a reduced purity. When the zwitterion was used in step (a) in such an amount that it is present in the mixture in an amount of less than mg / ml, organic solvent, preferably acetone ton, is incorporated into the crystallization medium to shall achieve a reasonable exchange. When using acetone it is suitably used in amounts of 0.5-10 volumes per volume. glue aqueous crystallization medium.

Step (c) is performed by separating the crystals from the crystallization medium, preferably by vacuum filtration. ring, and then wash, for example, with acetone / water, followed by acetone alone or 0.1N sulfuric acid (e.g. 1/10 volumes) followed by acetone (for example 1/4 volumes), and then drying, for example by vacuum drying at 30 DEG-50 DEG C. for 4-20 hours.

The process according to the invention for the formation of acid the ion salt results in a purification of the zwitterionic form on due to the limited solubility of sulfuric acid addition 7,469,635 the salt compared to the zwitterionic form and can be used for purification of the zwitterion without isolation thereof as a solid material. If it is desired to obtain substantially pure zwitterion (free base) from the formed sulfuric acid addition salt This can be accomplished by dissolving the salt in water, add Ba (OH) 2.8H 2 O in an amount of 90-100% of the theoretical value at a pH below 6.5 for precipitation of BaSO4, filters to remove BaSO4 and extracts the filtrate, which contains the zwitterion dissolved therein, and use it as a solution or insulator solid zwitterion (free base) by lyophilization thereof or by addition of acetone to precipitate amorphous zwitterion, followed of isolation of solid zwitterion by vacuum filtration, washing, for example, with acetone and vacuum drying. Alter- natively, the sulfuric acid addition salt is converted to the free one the base using ion exchange resins, for example Dowex WGR (a weak base anion exchange resin) and Dowex XU-40090.01 (a strong acid cation exchange resin) with subsequent lyophilization sering.

Preparation of the crystalline disalpetic acid addition salt the invention is achieved by mixing (i) at least two molar equivalents of nitric acid and (ii) terion corresponding to said salt so that it is present in the mixture in a concentration exceeding 100 mg / ml and then crystallization induces by the addition of germ crystals or scraping with a glass rod, diluent with 2- propanol and cooler. The crystalline disalpetic acid addition The salt is recovered, for example, by filtration, washing in turn and order with, for example, 2-propanol-water (50% by volume), 2-propanol and ether and then vacuum drying at SOOC for 2 hours.

The monochlorohydric acid addition salt of the invention is prepared by dissolving the zwitterion in approximately one equivalent hydrochloric acid and causes crystallization by adding acetone while stirring and continuing to 469 633 8 stirring the mixture, followed by isolation of the crystals, for example by vacuum filtration, followed by washing with acetone and vacuum drying. Alternatively, monochlorohydrogen the acid addition salt from the dichlorohydric acid addition salt through suspending the dichlorohydric acid addition salt in the methylene chloride and add 1 molar equivalent of triethylamine, followed by slurry to form monochlorohydric acid addition salt which is isolated, for example by vacuum filtration, and then washed with methylene chloride and vacuum dried.

The crystalline dichlorohydric acid addition salt according to the finning is prepared by dissolving the zwitterion in at least two molar equivalents of hydrochloric acid, thereafter causes crystallization by the addition of acetone, iso- the crystals, for example by vacuum filtration, wash with acetone and vacuum dryer.

The crystalline diorthophosphoric acid addition salt according to the finning is prepared by dissolving the zwitterion in at least two molar equivalents of phosphoric acid, crystallization by the addition of acetone and isolates crystalline for example, by vacuum filtration, followed by washing first with acetone and then with ether and finally vacuum drying. The crystalline sesqui-orthophosphoric acid additive the salt is formed by the same procedure with the exception of using approximately 1.5 molar equivalents of phosphorus acid.

The salts of the invention are formulated into injectables. rescues by dilution with sterile water and buffering to a pH of 3.5-7 to obtain an injectable con- concentration of 1 mg / ml up to 400 mg / ml of zwitterion.

Suitable buffering agents include, for example, trisodium ortho- phosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) - arginine. For intramuscular or intra- Venous administration to an adult is a total dose of from about 750 to about 3000 mg per day in æKæLïæ 9,469,633 normally sufficient.

The salts according to the invention are not advantageously prepared injectable preparations by simply adding sterile water, since sulfuric acid and disalpeter the acid addition salts are not sufficiently soluble to form preparations of normal concentration for administration and since the salts of the invention at dissolution gives very low pH values (1.8-2.5), which give hoof to painful sensations when injected. As requested given above, it has been found according to the invention that these disadvantages can be eliminated by preparing the salts according to the invention to a physical, i.e. solid mixture pharmaceutically acceptable, normally solid, non-toxic organic or inorganic bases in such proportions that: a pH range of from about 3.5 to about is obtained 7, preferably from about 4 to about 6, upon dilution of the mixture with water to injectable concentration of 1 mg / ml up to 400 mg / ml of zwitterion, for example one zwitterionic activity of 250 mg / ml when determined by HPLC analysis.

The exact proportions of constituents in the physical The mixture may vary from batch to batch of the salt since the purity of the salt varies from batch to batch. Pro- the portions of ingredients are determined for a particular by titrating a sample to obtain a selected pH within the above range.

The physical mixture is stored and transported easily in solid form, taking advantage of the stability of the salts of the invention, and is readily prepared into a injectable preparation simply by adding water, which is performed by a nurse or doctor, just before use.

The physical mixture is prepared by mixing 469 633 10 the salt and base in a homogeneous mixture, for example under use of a standard mixer in a dry atmosphere, and preferably then filled into an ampoule or other device. holder, constantly under aseptic conditions.

The bases for use in the mixture include, for example trisodium orthophosphate, sodium bicarbonate, sodium citrate, N- methylglucamine, L (+) - lysine and L (+) - arginine. L (+) - lysine and L (+) - arginine is preferred because mixtures containing des- said at reconstitution gives injectable preparations, as at injection gives less pain in animals than preparations derived from from mixtures containing other bases. It is highly preferred to use L (+) - lysine in such an amount that a pH of 3.5-6 is obtained when diluting the mixture. water to provide a preparation with a .zwitter ionic activity of 250 mg / ml (when determined with HPLC analysis).

The salts according to the invention and mainly dry physics mixtures containing these can be stored without refrigeration cabinet storage or insulating packaging and still 1 maintain high potency.

In several of the examples below, the unstable zwitter- ion as a starting material. The preparation of this shown in Embodiments 1-3 of U.S. Pat. 4 406 899. Zwitterjonen is designated according to the said patent patent as 7- [1Z) -2-methoxyimino-2- (2-aminothia- zol-4-yl) acetamido-3- [11-methyl-1-pyrrolidinium) methyl] -3- cephem-4-carboxylate.

The invention is illustrated by the following embodiments. pel. 11 469 655 Example I Preparation of the sulfuric acid addition salt 1.5 g of zwitterion is slowly added to 10 ml vigorously stirred 1N H 2 SO 4 (1.59 molar equivalents) at 20-26 ° C. One solution is obtained. Crystallization is then induced by adding the solution with crystalline seed crystals pine sulfuric acid addition salt and the crystalline mass slurried for 0.5 hours. The crystals are then separated after by vacuum filtration, washed with 3 ml of 50% (volume%) acetone / water and with 2 x 5 ml acetone and vacuum dried at 40-5000 overnight.

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

Analysis: Calculated for C 19 H 24 N 6 O 5 S 2 .H 2 SO 4:% C, 39.44; % H, 4.53; % N, 14.52; % S, 16.62; % H2O, none.

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

Exemgel II Preparation of the sulfuric acid addition salt 1.5 g of zwitterion are dissolved in 5 ml of water and 5 ml of 1M sulfur acid is slowly added to this solution with stirring.

Crystallization is then induced by continuing the solution with seed crystals of crystalline acid addition salt and the crystalline mass is slurried for 0.5 hours.

The crystals are then separated by vacuum filtration. wash with 3 ml of 50% v / v acetone / water and with 2 x 5 ml acetone and vacuum dried at 40-50 ° C overnight.

A typical yield is 1.3 g of sulfuric acid addition salt. 469 653 12 Example III Preparation of the disalpetic acid addition salt 300 mg of zwitterion are dissolved in 0.5 ml of 2N nitric acid.

The solution is scraped with a glass rod, diluted with 0.4 ml 2- propanol and cooled. The crystalline indicated in the title the compound is then recovered and washed in turn 0.4 ml of a 1: 1 mixture of 2-propanol and aqueous 2-propanol and ether to give 127 mg of di- the nitrate salt.

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, 10.57.

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 zwitterion is dissolved in 2.08 ml of 1N hydrochloric acid (1 molar) equivalent) at 20-25 ° C. 30 ml of acetone are added below vigorous stirring for a period of 15 minutes, during which plates are formed. Stirring is continued for 1 hour. Crisis- the plates are isolated by vacuum filtration, washed with 10 ml acetone and vacuum dried at 50 ° C for 2 hours.

A typical yield is 0.9 g of crystalline monochlorohydric acid. salt.

Analysis: Calculated for C 19 H 24 N 6 O 5 S 2 .HCl:% C, 41.37; % H, 4.75; % N, 15.2; % S, 11.63; % Cl, 12.86.

% C, 39.32; % H, 4.88; % N, 13.95; % S, 11.28; % Cl, 12.44; % H 2 O, 4.5.

Found: U 469 653 % C, 41.17; % N, 14.61; % S, 11.82; % Cl, 13.03) (Corrected for H20: Example V Preparation of the dichlorohydric acid addition salt and preparation position of the monochlorohydric acid addition salt therefrom 350 mg of zwitterion are dissolved in 2 ml of 1N hydrochloric acid. 10 ml ace- tons is added to the resulting solution under vigorous stirring. and for a period of 5 minutes, crystals forming das. Stirring is continued for another 5 minutes. Therefore add an additional 10 ml of acetone and stir travel for 0.5 hours. The crystal is removed by vacuum filtration, washed with 2 x 5 ml of acetone and vacuum dried at 40-4s ° 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; % Cl, 12.8.

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

% C, 41.1; % N, 14.88; % S, 11.39; % Cl, 11.94).

Found: (Corrected for H20: 1 g of dichlorohydric acid salt, which has been prepared as above, slurried in 20 ml of methylene chloride at 20-25 ° C in a closed flask and 0.28 ml of triethylamine are added over a period of space of 15 min. The crystalline mass is thus suspended. for 5 hours. The obtained monohydrochloride crystals are then isolated by vacuum filtration, washed with 469 633 '14 2 x 5 ml of methylene chloride and vacuum dried at 50 ° C below 2 hours. A typical yield is 800 mg.

Example VI Preparation of the diorthophosphoric acid addition salt 1 g of zwitterion is dissolved in 3.4 ml of 144 mg / ml phosphoric acid (2.2 molar equivalents) at 15 ° C. The solution obtained one is then suitably filtered to clarify it. 12 ml acetone is added to the clarified solution under vigorous stirring and for a period of 10 minutes, crystals formed. Stirring is continued for 10 minutes. Then add add 30 ml of acetone over a 10-minute period and stir the ring is continued for another 15 minutes. The crystals recovered by vacuum filtration, washed with 2 x 5 ml acetone and 2 x 5 ml of ether and dried in a high vacuum for 16 hours.

A typical yield for this type of preparation was 1.1 crystalline diorthophosphoric acid addition salt.

Analysis: Calculated for C 19 H 24 N 6 O 5 S 2.2.2H 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, 12.2L The sesqui-orthophosphoric acid addition salt is formed as above except that 1.5 molar equivalents of phosphoric acid was used instead of 2.2 molar equivalents.

Example VII Stabilities at elevated temperatures The elevations at elevated temperature were determined by the preparations were stored in dry containers at and for periods of time specified in the table below and 469 635 potency losses or increases were determined by HPLC.

A percentage increase in power is indicated by a plus sign for the number. A power loss of less than 10% during 2-4 weeks at 45-56 ° C is usually an indication of less than % loss of potency for 2-3 years at room temperature.

PERCENTAGE LOSS 45 ° C 56 ° C 100 ° C (weeks) (weeks) (days) Form 1 2 4 6 1 2 4 1 Zwitterjon 37 51 71 - 57 - - 100 HZSO4 salt 2.4 to +5 3 +5 1.4 5 to +6 +3 0 to +6 0-10 (HO3) 2-salt 8.8 3.4 0.68 10.3 3.7 2.4 - - Hcl-salt 4.8 2.3 6.0 6.4 6.4 - - - (HCl) 2-salt 0 - 7.4 - 0 - 7.2 12.4 (H3PO4) 2-salt 0 3.0 1.0 - 2.7 5.0 - - Example VIII Testing of physical mixtures Physical mixtures were prepared from crystalline sulfur acid salt with (a) trisodium orthophosphate, (c) L (+) - lysine and (d) L (+) - arginine. The bases were added nat, (b) sodium bicarbonate in such proportions that the pH values given below were obtained when diluting the mixture with water to a zwitterionic 250 mg / ml activity (determined by HPLC analysis): trinat- 469 633 16 rium orthophosphate - pH 6.0; sodium bicarbonate - pH 6.0; L (+) - lysine - pH 6.0; L (+) - arginine - pH 6.0. Injectable preparations were prepared by reconstitution of sterile water to a zwitterionic activity of 250 mg / ml, determined by HPLC analysis. It was available no solubility problems. Injections (100 mg / kg) was administered intramuscularly to rabbits with pain within acceptable ra thresholds. The least painful preparation was the gin-containing preparation.

Similar results with good solubility and acceptable pain by intramuscular injection is obtained using the the other salts according to the invention in physical mixture with the above bases.

Fig. 1 shows the infrared absorption spectrum of the crystalline the sulphate salt prepared according to Examples 1 or 2, letised in crystalline form with potassium bromide.

The X-ray powder diffraction pattern of the crystalline sulfate the salt of 7- [yk (2-aminothiazol-4-yl) -then (z) -methoxyiminoacet- amidg7-3- [X1-methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxy- prepared as described in Example 1 or 2, determined with a Rigaku powder diffractometer using a copper X-ray tube, a nickel filter and the sample contained in a glass bowl. The sweep speed was 20 / min within the interval 5-400 and in a diagram the maximums were automatically obtained the diffraction angles. Based on these, the d- stocks and the relative intensities I / IQ. These values listed below. 17 469 653 O d-distance (A) EÅEO (%) ' 9.20 100 6.80 50 , 50 28 , 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 Example IX Preparation of the sesquiphosphate salt 0.70 g of zwitterion is dissolved with vigorous stirring in 2,2- 2.4 ml of 85% phosphoric acid (2.1-2.2 molar equivalents) ter), which has been diluted in a volume ratio of 1:10 with water.

The solution is clarified by filtration through a membrane filter with the pore size 0.22-0.45 microns. 5-7 volume parts (15-20 ml) methanol is added to the filtrate with vigorous stirring for a period of 30-60 min. Crystals form below this operation and the vigorous stirring is continued the 1.5-2 hours. The crystalline product is recovered by vacuum filtration. The product is washed on the filter first 6-8 ml of a mixture of methanol and acetone in volume country 1: 1, ensuring that a dense packed filter cake, and then with acetone. The product is dry in vacuum at 5000 for 2 hours; typical yield 0.7- 0.75 g. 469 635 18 Infrared spectrum (see Fig. 2) (IR, KBr tablet) 1 Top position (cm-) Functional grugg zsoø-3400 NH, NH3 +, carboxyl-one 1780 β-lactam C = 0 1680 carboxyl-C = O 166Û amid ~ C = O 1630 c = N, c = c 155Û âmid-OH 980,1040 P04- Behavior when heating An exotherm is shown at 171.8 ° C when measured in differential sweep calorimeter.

X-ray diffraction pattern The X-ray powder diffraction pattern of the oven specified sesqui- phosphate salt was measured with a Rigaku powder diffractometer on the same as described above for sulphate salts the following results were obtained.

Q I / I ° 11.04 - 32 9.2 - 16 7.89 - 24 7.02 - 42 6.7 - 32 , 5 - 26 4.64 - 100 4,456 - 53 4.3 - 58 3.88 - 26 3.75 - se 3.56 - 21 3.31 - 26 3 05 - 16 fi n 19 469 655 NMR spectrum (1H 90 MHz NMR, D 2 O solution) Chemical displacement Attributed (ppm 6 vs. TSP) Description Integral grouping 2.0-2.4 Multiplet 4 14CH2, 14'CH2 3.04 Singlett 3 12CH3 3.3-3.6 Multiplet 5 ZCH, 13CH2, 13'CH2 3.94 Duplicate 1 1 2CH 4.12 Singlet 3 ZOCH3 4.12 Duplicate 1 11CH 4.8 Duplicate 1 11CH , 42 Duplicate 1 6CH , 88 Duplicate 1 7CH 7.21 Singlet 1 18CH 469 635 Stability Time; temgeratur day; days; days; week; weeks; weeks; week; weeks; weeks; weeks; month; - * @ ol> l \) ~ ^ sI> I \ J - \\ lLO- \ O 133% 7 ° C ssgc ÉÉ ° É 4s ° c 4s ° c 4s ° c 45gc 37 c % loss s \ D IN ua- »o-» c> c> »- A-; c> o _ å Q ä Ü fi Q I u1owu »>.> <: \ o Elemental analysis (fold fi-%) Found On Dry Base Theoretical (sesquiphosphate) , 44 36.3 36.4 4.66 4.41 4.7 12.88 13.2 13.4 2.29 * - monohydrate = 2.8% HEO 23.06 23.6 23.6 * The Karl Fischer method

Claims (11)

10 15 20 25 30 21 469 633 Patent claims Physical mixture of a sulfuric acid, disalpetic acid, monochloroacetic acid and dichlorohydric acid or orthophosphoric acid addition salt containing 1.5-2 molar equivalents of phosphoric acid of the compound 7- [oz- (2-arninothiazol-4-yl) -oc- (Z) -methoxyimino-acetaneddo] -3 - [(1-methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate having a pharmaceutically acceptable, non-toxic organic or inorganic base in such proportions as to obtain a pH of from about 3.5 to about 7 when diluting the mixture with water to injectable concentration. Physical mixture according to claim 1, characterized in that the salt and the base are present in such proportions that a pH of from about 4 to about 6 is obtained upon dilution of the mixture with water to injectable concentration. Physical mixture according to Claim 2, characterized in that the base is L (+) - lysine. Physical mixture according to Claim 2, characterized in that the base is L (+) - arginine. Crystalline 7- [oL- (2-aminothiazol-4-yl) -oc- (Z) -methoxyiminoacetanido] -3 - [(1-methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate -sulfate salt with the following X-ray powder diffraction pattern: d-distance (Å) I / IQ §% 2 9.00 100 6.86 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 10 '15 20 25 30 469 653 22 Crystalline methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate phosphate with the following X-ray 7- [oz- (2-aminothiazol-4-yl-oz- (Z) -methoxy] aminoacetamido] -3 - [(1-powder diffraction pattern: d-distance (Å) I / P (76) 11.64 62 9.2 16 7.69 24 7.62 42 6.7 62 5.5 26 4.64 _ 1oo 4.456 56 4.6 56 6.66 26 6.75 69 6.56 21 6.61 26 6.05 16 Process for preparing the sulfuric acid addition salt included in the mixture according to claim 1, characterized in that (a) an aqueous mixture of (i) at least one molar equivalent of sulfuric acid and (ii) zwitterion corresponding to said salt is formed; (b) crystallizing the sulfuric acid addition salt with the proviso that, when the zwitterion is present in the mixture at a concentration of less than 25 mg / ml, the crystallization is carried out in the presence of an organic solvent; and (c) isolating the crystalline sulfuric acid addition salt. Process according to Claim 7, characterized in that step (b) is carried out in an aqueous medium which is free from organic solvent. Process according to Claim 8, characterized in that the zwitterion is used in step (a) in such an amount that it is present in the mixture in a concentration of less than 500 mg / ml. Process according to Claim 7, characterized in that the amount of the zwitterion used in step (a) is such that it is present in the mixture in a concentration exceeding 25 mg / ml. ll. Process according to claim 8, characterized in that the zwitterion is used in step (a) in such an amount that it is present in the mixture in a concentration from about 100 mg / ml to about 200 mg / ml.