DD254941A5 - PROCESS FOR PREPARING TEMPERATURE STABILIZED CRYSTALLINE SALTS OF 7- (DELTA- (2-AMINOTHIAZOL-4-YL) -2- (Z) METHOXYIMINOACETAMIDO) -3 - ((1-METHYL-1-PYRROLIDINIO) -METHYL) -3-CEPHEMINE 4-CARBOXYLATE (TWITTER) - Google Patents

Abstract

The invention relates to processes for the preparation of temperature-stable crystalline salts of 7- & a- (2-aminothiazol-4-yl) -a- (Z) -methoxy-iminoacetamido! -3- & (1-methyl-1-pyrrolidino) -methyl! 3-cephem-4-carboxylate (zwitterion) selected from the group consisting of sulfuric, di-nitric, mono-hydrochloric and di-hydrochloric acid addition salts and orthophosphoric acid addition salts. The crystalline sulfuric acid addition salt is prepared by mixing (a) at least 1 molar equivalent of sulfuric acid with (b) the zwitterionin in an amount such that it is present in the mixture at a concentration greater than 25 mg / ml, causing crystallization and the crystals separated, washed and dried. The crystalline monohydrochloride, dihydrochloride and orthophosphate salts are prepared by dissolving the zwitterion in the appropriate amount of the acid, causing crystallization by addition of acetone and isolating the crystals. Also provided are physical mixtures of these salts with certain bases present in proportions such that after being dehydrated with water to an injectable concentration, a p H of about 3.5 to about 7 is achieved.

Description

Field of application of the invention

The invention relates to a process for the preparation of novel, temperature-stable, semi-synthetic cephalosporin acid addition salts. The cephalosperin is 7- [a- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem- 4-carboxylate, which is present as zwitterion. These salts can be mixed with certain bases to give mixtures that can be injected with water after reconstitution.

Characteristic of the known technical solutions

Aburaki et al., US Pat. No. 4,408,899 discloses the zwitterionic form of 7- [α- (2-aminothiazol-4-yl) -Q; - (Z) -methoxyiminoacetamido] -3 - [(i-methyl-i There are also mentioned corresponding acid addition salts which are present in zwitterionic form in injectable agents. It is stated that the zwitterionic form has a broader spectrum of activity than ceftazidime and cefotaxime.

However, the cephalosporins described therein are stable for only a few hours in the form of injectables. The zwitterion is itself becomes unstable as a dry powder at room temperature and loses 30% or more of its activity at Iwöchiger storage at elevated temperature (for example 45 ⁰ C and above). Therefore, it is necessary to use and / or cool a specially insulated package. This preparation thus has disadvantages in terms of storage and packaging compared to ceftazidime and cefotaxime.

Although acid addition salts are mentioned in the above-referenced U.S. Patent, however, this patent does not teach how to prepare these salts, and which ones, if any, have a good stability in a dry powder form. Kessler et al., "Comparison of a New Cephalosporin, BMY 28142, with Other Broad-Spectrum / 3-Lactam Antibiotics", Antimicrobial Agents and Chemotherapy, Vol. 27, No. 2, pp. 207-216, February 1985, mention the sulfate salt, however not on how this salt can be obtained or that this salt is stable at room temperature and as a dry powder has a good stability even at elevated temperature.

Object of the invention

The crystalline acid addition salts of 7- [α- (2-aminothiazol-4-yl) -o: - (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-1-pyrrolidinylmethyl)-S-cephem] -carboxylate obtainable according to the invention have excellent stability at room temperature as dry powders and are more stable than the zwitterion at elevated temperature. \ "Dry powder \" refers to one whose moisture content is less than 5 wt%.

Explanation of the essence of the invention

The object of the invention is to provide a novel process for the preparation of new cephalosporin acid addition salts, which are stable in storage and can be advantageously used for medical purposes.

The acid addition salts obtained by the process according to the invention are crystalline salts of 7- [α- (2-aminothiazole-4-)

yll-a-iZJ-methoxyiminoacetamido J-S-tlmethyl-i-pyrrolidinol methyne-S-cephem-1-carboxylate selected from the group consisting of sulfuric acid, di-nitric acid, mono-hydrochloric acid and di-hydrochloric acid addition salts, and Orthophosphorus addition salts (1.5-2 moles of orthophosphoric acid per mole of salt, this corresponds to, for example, a range of the sesqui- to the de-orthophosphoric acid salts), and according to the invention, the solvates of these salts are also included. The term "crystalline" indicates that the molecules are at least partially characteristically arranged, whereas the sulfuric acid, di-nitric acid, di-hydrochloric acid and orthophosphoric acid addition salts prepared according to the present invention have distinctly crystalline forms (as evidenced by birefringence under one) polarizing microscope), where the molecules are precisely aligned, the mono-hydrochloric acid addition salts prepared according to the invention have only a certain uniformity in the arrangement of their molecules (this is shown by only slight birefringence under the polarizing microscope) and thus no precisely defined arrangement. so they must be called "weak" crystalline. Thus, the term "crystalline" as used herein includes not only the distinctly crystalline salts but also the "weak" crystalline mono-hydrochloric acid addition salt. The acid addition salts described herein, when processed into aqueous injectables, release the zwitterion in the solution. This zwitterion has the following structure:

S.

C -CONH

COO

The broad spectrum effect of this zwitterion, and thus of the aqueous agents prepared from the salts described herein, against various organisms is evident from the data of US Pat. No. 4,408,899 (Aburaki et al.).

The aqueous agents obtained from the acid addition salts described herein, which are prepared by adding only sterile water, are acidic solutions which, when given intravenously to rabbits, cause unacceptable irritation. Upon intramuscular administration of these solutions to rabbits, an unacceptable pain response is noted. The solubilities of the sulfuric and disodium acid addition salts are lower and insufficient for typical injectables. It has now been found that these undesirable disadvantages can be overcome by using the salts described herein in the form of a physical mixture (a mixture of solids) with a pharmaceutically acceptable non-toxic organic or inorganic base in such proportions in that, after dilution with water, a pH of about 3.5 to about 7 and a zwitterion activity of from 1 mg / ml to 400 mg / ml, usually 250 mg / ml (determined by means of high performance liquid chromatography, HPLC) are achieved

An inventively preferred salt is the crystalline sulfuric acid addition salt. It is preferred because of its low solubility in water (25 mg / ml), so that this salt can be obtained on crystallization from an aqueous medium in high yield.

The crystalline sulfuric acid addition salt is prepared by a process wherein

(a) produces a mixture

(i) at least 1 molar equivalent of sulfuric acid and (ii) from such an amount of zwitterion that it is present in the mixture at a concentration greater than 25 mg / ml.

(b) crystallizing the sulfuric acid addition salt and

(c) isolating the crystalline sulfuric acid addition salt.

The crystalline salts described herein (hereinafter referred to as salts of the invention) are excellently stable at room temperature. Their loss of potency (determined by HPLC) after 1 month storage at room temperature is less than 1%. These salts are also excellently stable at elevated temperatures; their loss of potency (determined by HPLC) after storage for 1 month at 45-56 ° C is less than 15%.

The sulfuric acid addition salt is preferred. The efficacy loss of this salt is less than 10% after storage for 1 month at 45-56 ° C. Most importantly, this salt has a low solubility in water, i. about 25 mg / ml. The losses in crystallizing this salt from water are therefore very low.

Also, the di-nitric acid addition salt described herein has a low solubility in water, i. about 60mg / mI.

Thus, even with this salt, the losses in crystallizing from water are low.

The solubilities of the monochlorohydroyl, dichloride and sesqui- or diorthophosphoric acid addition salts are greater than 200 mg / ml. These salts are therefore not crystallized from water, but preferably from organic solvents to achieve good yield.

As already stated above, the sulfuric acid addition salt is prepared by a process in which

(a) a mixture of

(i) at least 1 molar equivalent of sulfuric acid and

(ii) preparing the zwitterion which is used in an amount such that it is present in the mixture in a concentration greater than 25 mg / ml, and

(b) crystallized and

(c) isolating the crystalline sulfuric acid addition salt.

Preferably, the zwitterion in step (a) is employed in an amount such that it is present in the mixture at a concentration of from 100 mg / ml to about 200 mg / ml. The step (b) is preferably carried out in an aqueous medium containing no organic solvent. Usually, no more than 2 molar equivalents of sulfuric acid are used in step (a). The zwitterion is normally employed in step (a) in an amount such that it is present in the mixture at a concentration of less than 500 mg / ml.

Step (a) is carried out by either adding the solid zwitterion to a sulfuric acid solution (eg, 1NH ₂ SO ₄ ) with vigorous stirring to form a solution. Alternatively, step (a) may be carried out by dissolving the solid zwitterion in water and slowly adding sulfuric acid with stirring to give a solution.

Step (b) is carried out by inducing crystallization, for example by seeding. Then you slumber up, preferably 15min to 2h. This crystallization step is preferably carried out in an aqueous medium which has no organic solvent. In this case, the purity achieved is usually higher than 98%. Although the presence of an organic solvent such as acetone promotes crystallization and increases the yield by lowering the solubility of the resulting sulfuric acid addition salt in the crystallization medium, precipitation of impurities may also be promoted thereby resulting in reduced purity. If the zwitterion is used in step (a) in such an amount that it is present in the mixture in an amount of less than 25 mg / ml, then an organic solvent, preferably acetone, must be incorporated into the crystallization medium to be acceptable To achieve yields. If acetone is used, it is used in amounts of about 0.5-10 parts by volume / volume of aqueous crystallization medium.

Step (c) is carried out by separating the crystals from the crystallization medium, preferably by vacuum filtration. The crystals are then washed, for example with acetone / water and then with acetone alone or with 0.1N sulfuric acid (eg 1/10 volume) and then with acetone (eg 1/4 volume). Then it is dried, for example by drying in vacuo at 30-50 ⁰ C for a period of 4-2Oh.

The process described herein for the preparation of the sulfuric acid addition salt leads to a purification of the zwitterionic form due to the limited solubility of the sulfuric acid addition salt as compared with the zwitterionic form. This method can thus be used to purify the zwitterion without isolating it as a solid. If a substantially pure zwitterion (free base) to be obtained from the sulfuric acid addition salt formed, this can be achieved by dissolving the salt in water, Ba (OH) ₂ · 8H ₂ O in an amount of 90-100% of Add theory at pH less than 6.5 to precipitate BaSO ₄ , filter off the BaSO ₄ and recover the filtrate by dissolving the zwitterion and using it as a solution or solid zwitterion (free base) therefrom by lyophilization isolated. It is also possible to add acetone to precipitate the amorphous zwitterion. Subsequently, the zwitterion is isolated as a solid by means of vacuum filtration, washing z. B. with acetone and dried in vacuo. Alternatively, the sulfuric acid addition salt may be converted to the free base using ion exchange resins such as Dowex WGR (a weakly basic anion exchange resin) and Dowex XU-40090.01 (a strong acid cation exchange resin) followed by lyophilization.

The crystalline di-nitric acid addition salt is prepared by reacting (i) at least 2 molar equivalents of nitric acid with (ii) the zwitterion

which is present in the mixture in a concentration greater than 100 mg / ml, and then induces crystallization by seeding or rubbing with a glass rod, diluted with 2-propanol and cooled. The crystalline disalpeter addition salt is obtained, for example, by filtration, washing sequentially with, for example, 2-propanol-H ₂ O (50% v / v), 2-propanol and drying in vacuo over a period of 2 hours at 50 ° C.

The mono-hydrochloric acid addition salt is prepared by dissolving the zwitterion in about 1 molar equivalent of hydrochloric acid and crystallizing by adding acetone with stirring and stirring. The crystals formed are then isolated, for example by means of vacuum filtration. Then it is washed with acetone and dried in vacuo. Alternatively, the mono-hydrochloric acid addition salt can be obtained from the di-hydrochloric acid addition salt by slurrying the di-hydrochloric acid addition salt in methylene chloride and adding 1 molar equivalent of triethylamine. It is then slurried to form the mono-hydrochloric acid addition salt which is isolated, for example by vacuum filtration. It is then washed with methylene chloride and dried in vacuo. The crystalline di-hydrochloric acid addition salt is prepared by dissolving the zwitterion in at least 2 molar equivalents of hydrochloric acid, crystallizing by addition of acetone, isolating the crystals formed, for example by vacuum filtration, 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, crystallizing by the addition of acetone, isolating the crystals formed, for example by vacuum filtration, then washing first with acetone and then with ether and then dried in vacuo. The crystalline sesqui-orthophosphoric acid addition salt is obtained by the same procedure but using 1.5 molar equivalents of phosphoric acid.

Injectable agents are prepared from the salts described herein which have an injectable concentration of 1 mg / ml to 400 mg / ml of the zwitterion by diluting and buffering with sterile water (pH 3.5-7). , Suitable buffers include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucanamine, L (+) - lysine and L (+) arginine. For intramuscular or intravenous administration to an adult patient, a total dosage of about 750 to about 3,000 mg / day, divided into several doses, is usually sufficient. It is not appropriate to prepare injectables from the salts described herein by merely adding sterile water since the sulfuric acid and di-nitric acid addition salts are not sufficiently soluble to give agents of sufficient concentration for administration and as described herein Salts, when dissolved, result in very low pH (1.8-2.5) agents that cause a pain response after injection. As stated above, it has been found according to the invention that these disadvantages can be overcome by using a physical mixture (ie mixture of solids) of pharmaceutically acceptable, normally solid non-toxic organic or inorganic bases in such proportions from the salts described herein prepares that after dilution of the mixture with water to an injectable concentration of 1 mg / ml up to 400 mg / ml of zwitterion, eg a zwitterion activity of 250 mg / ml (determined by HPLC) has a pH of from about 3.5 to about 7, preferably from about 4 to about 6 achieved.

The exact proportions of the ingredients in the physical mixture vary from batch to batch of salt as the purity of the salt varies from batch to batch. The proportions of ingredients are determined for a particular batch by pre-titrating and comparing with a sample to obtain a desired pH within the above range. The physical mixture can be stored without difficulty and distributed in solid form, taking advantage of the stability of the salts. In addition, the physical mixture can be readily converted to an injectable by merely adding water. This can be done by a nurse or a doctor just before the application

-5- Ζ54 94Ί

The physical mixture is prepared by making the salt and base into a uniform mixture using, for example, a standard mixer in a dry atmosphere. Then you fill in vials or other containers. All these actions must be done under aseptic conditions.

The bases that can be used 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 the mixtures containing these compounds can be reconstituted into injectable agents which, when injected into animals, produce less pain response than those derived from the mixtures containing the other bases. Lysine is preferably used in such a proportion that after dilution of the mixture with water to an agent having a zwitterionenkativität of 250 mg / ml (determined by HPLC), a pH of 3.5-6 is achieved.

The salts obtainable according to the invention and the dry physical mixtures containing these salts can be stored without cooling and without the use of an insulating packaging and still retain their high effectiveness.

In various of the preparations described here, the unstable zwitterion is used as the starting compound. The preparation of this zwitterion is described in Examples 1 to 3 of US Patent 4406899 (Aburaki et al.). The zwitterion is designated as follows: 7 - [(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3 - [(1-methyl-pyrrolidinium) -methyl] -3- cephem-4-carboxylate.

The invention will be explained in more detail below with reference to the examples.

example 1

Preparation of sulfuric acid addition salt

1.5 g of zwitterion are added slowly to 10 ml of rapidly stirred 1 NH ₂ SO ₄ (1.59 molar equivalents) at 20-26 ⁰ C. A solution is obtained. Crystallization is induced by inoculation with crystalline sulfuric acid addition salt and the crystalline mass is slurried for 0.5 h. The crystals are then separated by vacuum filtration, washed with 3 ml of 50% acetone / water (v / v) and two 5 ml portions of acetone. It is then dried in vacuo at 40-50 ⁰ C overnight.

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

Elemental analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ .H ₂ SO ₄ :

CHNSH ₂ O

calculated: 39.44 4.53 14.52 16.62 -%

Filled: 38.91 4.57 14.64 16.71 1.42%

Example 2

Preparation of sulfuric acid addition salt

Dissolve 1.5 g of zwitterion in 5 ml of water. 5 ml of 1 MH ₂ SO _{4 are} slowly added to this solution while stirring. The crystallization is induced by pickling with crystalline acid addition salt and the crystalline mass is slurried for 0.5 h. The crystals are separated by vacuum filtration from, washed with 3 ml of 50% acetone / water (v / v) and twice with 5 ml of acetone and dried in vacuo overnight at 40-50 ⁰ C.

The sulfuric acid addition salt is usually obtained in a yield of 1.3 g.

Example 3

Preparation of the (HNO ₃ ) ₂ acid addition salt

300mg of zwitterion is dissolved in 2N nitric acid (0.5ml). The solution is rubbed with a glass rod, diluted with 0.4 ml of 2-propanol and cooled. The crystalline title compound is collected and washed successively with 0.4 ml of 2-propanol / H ₂ O (1: 1), 2-propanol and then with ether to give 127 mg of the dinitrate salt.

Elemental analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ 2HNO ₃ :

CHASE

Re: 37.62 4.32 18.47 10.57%

Gef .: 36.92 4.10 18.08 10.67

(H ₂ O content 0.90%)

Example 4

Preparation of monohydrochloride acid addition salt

1 g of zwitterion is dissolved in 2,08ml 1 N HCl (1 molar equivalent) at 20-25 ⁰ C. is added, with vigorous stirring during a period of 15 min 30 ml of acetone, whereby crystals form. Stir another hour. Isolating the crystals by VakuumfiltratioTi, washed with 10 ml acetone and dried in vacuum for 2 h at 50 ⁰ C.

A typical yield of the crystalline monohydrochloride salt is 0.9 g.

Elemental analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ .HCl:

H ₂ O

4.5 for H ₂ O: 41.17 14.61 11.82 13.03%)

Example 5

Preparation of the dihydrochloride acid addition salt and preparation of the monohydrochloride acid addition salt from the first salt

Dissolve 350 mg of zwitterion in 2 ml of 1N HCl. 10 ml of acetone are added with vigorous stirring over a period of 5 minutes

C H N S Cl Calc .: 41.37 4.75 15.2 11.63 12.86 Found .: 39.32 4.88 13.95 11.28 12.44 (Corrected for H ₂ O: 41.17 14.61 11.82 13.03

C H N S Cl Calc .: 41.38 4.75 15.2 11.62 12.8 Found .: 40.78 4.98 14.7 11.25 (Corrected for H ₂ O: 41.1 14,88 11.39 11.9

the resulting solution, wherein crystals form. The mixture is stirred for a further 5 minutes, then another 10 ml of acetone are added and the mixture is stirred for a further 0.5 h. The crystals are removed by vacuum filtration, washed twice with 5 ml of acetone and dried for 24 h in vacuo

40-45 ⁰ C.

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

Elemental analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ .2HCl:

H ₂ O

1.25%

Slurry 1 g of the dihydrochloride salt thus prepared in 20 ml of methylene chloride at 20-25 ⁰ C in a sealed flask and outputs of triethylamine over a period of 15 minutes 0.28 ml. The crystalline mass is slurried for 5 h. The resulting monohydrochloride crystals are then isolated by vacuum filtration, washed twice with 5rnl methylene chloride and dried for 2 h in vacuo at 50 ° C. A typical yield is 800 mg.

Example 4

Preparation of the di-orthophosphoric acid addition salt

1g zwitterion is dissolved in 3.4 mL of 144mg / ml H ₃ PO ₄ (2.2 molar equivalents) at 15 ⁰ C. The solution is filtered in a suitable manner in order to clarify it. With vigorous stirring and over a period of 10 minutes, 12 ml of acetone are added to the clarified solution to form crystals. The mixture is stirred for a further 10 minutes, then 30 ml of acetone are added over a period of 10 minutes and the mixture is stirred for a further 15 minutes. The crystals are collected by vacuum filtration, washed twice with 5 ml of acetone and twice

with 5 ml of ether and dried for 16 h in a high vacuum.

A typical yield of crystalline diorthophosphoric acid addition salt in this type of preparation is 1.1g.

Elemental analysis for CigH ₂₄ N ₆ O ₅ S ₂ 2H ₃ PO ₄ :

H ₂ O

1.82%

The sesqui-orthophosphoric acid addition salt is obtained as described above, but using 1.5 molar equivalents of H ₃ PO ₄ instead of 2.2 molar equivalents.

Example 7

Stability tests at elevated temperatures

The stability studies at elevated temperature were carried out by storing the preparations in dry containers at the temperatures listed below for the periods also listed below. The efficacy increases or losses were determined by HPLC. An increase in effectiveness is indicated by a plus sign in front of the number. A potency loss of less than 10% during a period of 2 to 4 weeks at 45-56 ⁰ C normally indicates that the efficiency loss at a 2 to 3 years of storage at room temperature is less than 10%

is.

C H N Calc .: 33.72 4.47 12.42 Found .: 33.43 4.65 12.02 (Corrected for H ₂ O: 34.0 12.2%)

Percentage loss

substance 45 ⁰ C (weeks) 2 4 6 56 ⁰ C (weeks) 2 4 100 ⁰ C 51 71 - - - (Days) 1 3 + 5 1.4 1 +3 0- + 6 1 zwitterion 37 3.4 0.68 10.3 57 2.4 - 100 H ₂ SO ₄ salt 2,4- + 5 2.3 6.0 6.4 5- + 6 - - 0-10 (HNO ₃ I ₂ salt 8.8 - 7.4 - 3.7 - 7.2 - HCI SAIZ 4.8 3.0 1.0 - 6.4 5.0 - - (HCl) ₂ salt 0 0 12.4 (H ₃ PO ₄ J ₂ salt 0 2.7 -

Example 8

Investigations of physical mixtures

There were physical mixtures of the crystalline sulfuric acid salt with

(a) trisodium orthophosphate,

(b) sodium bicarbonate,

(c) L (+) - lysine and

(d) L (+) Arginine

manufactured. The bases were added in such amounts that after diluting the mixture with water to a zwitterion activity of 250 mg / ml (determined by HPLC assay), the following pH values were obtained: trisodium orthophosphate (pH 6.0); Sodium bicarbonate (pH 6.0); L (+) - lysine (pH of 6.0); (+ (- arginine (pH of 6.0).

By reconstitution with sterile water to a zwitterion activity of 250 mg / ml (determined by HPLC assay), injectables were prepared. There are no solubility problems. Rabbits were given injections (100 mg / kg) intramuscularly, with pain responses being limited. The least pain reaction occurred in the arginine-containing agent.

Using the other salts described herein in the physical mixtures with the bases described above gives similar results. The solubility is similarly good and the pain occurring after the intramuscular injection is within tolerable limits.

Figure 1 shows the infrared absorption spectrum of the crystalline 7- [α- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3- [d -methyl-i-pyrrolidinol-methyl] -s-cephem ^ -carboxylate sulfate salt (prepared according to Examples 1 or 2). The spectrum was recorded with a KBr pellet.

Figure 2 shows the infrared absorption spectrum of the crystalline sesquiphosphate salt of 7- [α- (2-aminothiazoil-4-yl) -3- (Z) -methoxyiminoacetamidol-S-Id-methyl-i-pyrrolidinol-methyl-1-cephem ^ -carboxylate (KBr-compact).

Figure 3 shows the infrared absorption spectrum of the crystalline diphosphate salt of 7- [α- (2-aminothiazol-4-yl) -3- (Z) -methoxyiminoacetamidol-S-IO-methyl-i-pyrrolidinol-methyl-1-cephem ^ -carboxylate (KBr-compact).

The X-ray powder diffraction pattern of the crystalline sulfate salt of 7- [α- (2-aminothiazol-4-yl) -a; (Z) -methoxyiminoacetamidol-S-t-methyl-i-pyrrolidinol-methyl-S-cephem] -carboxylate (prepared according to Examples or 2) was taken with a Rigaku powder diffractometer using a copper X-ray tube and a nickel filter with the sample in a glass dish. The scan speed was 27 minutes over a range of 5-40 °. To determine the angles of maximum diffraction, a diagram was recorded mechanically. From this the distances (d) and the relative intensities (1 / I ₀ ) were calculated. These data are listed below.

d distance (A) l / l _o (%)

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

Example 9

Preparation of sesquiphosphate salt Dissolve 0.70 g of zwitterion with vigorous stirring in 2.2-2.4 ml of 85% phosphoric acid (2.8-2.2 molar equivalents) diluted 1: 1 (v / v) with water. To clarify the solution, it is filtered through a membrane filter with a pore size of Θ, 22-0.45μηι. To the filtrate is added 5-7 parts by volume (15-20 ml) of methanol with vigorous stirring over a period of 30 to 60 minutes. This forms crystals. Stirring is continued for a further 1.5-2 h. The crystalline product is collected by vacuum filtration, washed first with 6-8 ml of methanol / acetone (1: 1 v / v) on the filter, taking care to keep the filter cake tight, then acetone and drying the product 2 h at 50 ° C in vacuo; typical yield: 0.7-0.75g. Interpretation of the infrared spectrum (see Fig.2) (IR, KBr-compact)

Position of the peak (cm " ¹ ) Functional group

2,800-3400 NH, NH ₃ ⁺ , carboxyl OH

1780/3 lactam C = O

1 680 carboxyl C = O

1660 amide C = O

1630 C = N, C = C

1550 amide OH

980,1040 PO ₄ =

Behavior on heating:

Examination in the differential calorimeter reveals an exotherm at 171.8 ° C.

X-ray diffraction pattern:

The X-ray powder diffraction pattern of the above-described sesquiphosphate salt was determined in the same manner with a Rigaku powder diffractometer as described above for the sulfate salt. The result is shown below:

d l / L

11.4 - 32 9.2 - 16 7,89 - 24 7.02 - 42 R7 - 3?

l / U

4.64

4,456

4.3

3.88

3.75

3.56

3.31

3.05

100 53 58 26 89 21 26 16

Interpretation of the ¹ H NMR spectrum (90MHz, D ₂ O solution) of:

13

10 CO,

Chemical shift Stability: Time description integral assignment (ppm in δ vs. TSP) 2.0-2.4 1 day Multiple " 4 14 CH ₂ , 14'CH ₂ 3.04 3 days singlet 3 12CH ₃ 3.3-3.6 7 days Multiple " 5 2CH, 13CH ₂ , 13'CH ₂ 3.94 1 week doublet 1 2CH 4.12 2 weeks singlet 3 20CH ₃ 4.12 4 weeks doublet 1 11CH 4.8 1 week doublet 1 11CH 5.42 2 weeks doublet 1 6CH 5.88 4 weeks doublet 1 7CH 7.21 8 weeks singlet 1 18CH 1 month Elemental analysis (wt%): temperature percentage loss 100 ° C 10.9 C 70 "C 0 H 70 ⁰ C 1.9 N 56 ⁰ C 1.0 H ₂ O 56 ⁰ C 1.4 H ₃ PO ₄ 56 ⁰ C 0 45 ⁰ C 0 45 ⁰ C 1.4 45 ° C 0.7 45 ° C 1.6 37 ° C 2.5 Found AufTrocken- theory Base (Sesquiphosphate) 35.44 36.3 36.4 4.66 4.41 4.7 12.88 13.2 13.4 2.29 * - Monohydrate = 2.8% H ₂ O 23.06 23.6 23.6

determined by Karl Fischer

Claims (9)

1. A process for the preparation of temperature-stable crystalline salts of 7- [α- (2-aminothiazol-4-yl) -a- (Z) -methoxyrninoacetamido] -3 - [(1-methyl-1-pyrrolidino) -methyl] -3 -cephem-4-carboxylate (zwitterion) selected from the group consisting of the sulfuric acid, di-nitric acid, mono-hydrochloric acid and di-hydrochloric acid addition salts and orthophosphoric acid addition salts with 1.5-2 molar equivalents of H ₃ PO ₄ , or the solvate thereof, characterized in that one (A) produces an aqueous mixture, the (i) at least 1 molar equivalent of sulfuric or hydrochloric acid; or (ii) at least 2 molar equivalents of nitric or hydrochloric acid or (iii) 1.5-2 molar equivalents of phosphoric acid and
(iv) contains the zwitterion, (B) crystallizing the acid addition salt, wherein the crystallization is optionally carried out in the presence of an organic solvent, and (c) isolating the crystalline acid addition salt. 2. The method of item 1 for the preparation of the crystalline sulfuric acid addition salt, characterized in that (a) preparing an aqueous mixture of at least 1 molar equivalent of sulfuric acid and the zwitterion, (B) crystallizing the sulfuric acid addition salt, wherein, if the zwitterion is present in the mixture in 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. 3. The method according to item 2, characterized in that one carries out the step (b) in an aqueous medium containing no organic solvent. 4. The method according to item 3, characterized in that one uses the zwitterion in the step (a) in such an amount that it is present in the mixture in a concentration of less than 500 mg / ml. 5. The method according to item 2, characterized in that one uses the zwitterion in the step (a) in such an amount that it is present in the mixture in a concentration greater than 25 mg / ml. 6. The method according to item 3, characterized in that one uses the zwitterion in step (a) in an amount such that it is present in the mixture in a concentration of about 100 mg / ml to about 200 mg / ml. 7. The method according to any one of the preceding points, characterized in that one crystalline 7- [a- (2-aminothiazol-4-yl) a (Z) -methoxyiminoacetamidol] -3 - [(1-methyl-1-pyrrolidinio ) -methyl] -3-cephem-4-carboxylate sulfate salt obtained with the following X-ray diffraction powder diagram: 8. The method according to item 1, characterized in that one prepares the crystalline Otthophosphorsäure addition salt and hydrates thereof. 9. The method according to item!, Characterized in that crystalline 7- [a- (2-aminothiazol-4-yl) -a (Zl-methoxyiminoacetamidoj-S-td-methylpyrrolidinioJ-methyll-S-cephem- ^ carboxylat- Phosphate obtained with the following X-ray diffraction powder diagram: For this 3 pages drawings