DD268395A5 - METHOD FOR PRODUCING A PHYSICAL MIXTURE FROM A CEPALOSPORIN SAEUREADDITION SALT AND AN ORGANIC OR INORGANIC BASE - Google Patents

Abstract

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

Description

Field of application of the invention

The invention relates to a process for the preparation of a physical mixture of at least one temperature-stable, semi-synthetic cephalosporin acid addition salts and of a pharmaceutically acceptable non-toxic organic or inorganic base. The cephalosporin jQ is 7- [α- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -? - [(1-methyl-1-pyrrolidinio) methyl] -3- Cephem-4-carboxylate, which is present as zwitterion.

The preparation of the salts used according to the invention is in the strain AP - & Q7D - / - ~ 2fr3 - ZS4-3γΊ

described. These salts can be mixed with certain bases to give mixtures that can be injected with water after reconstitution.

_"N Charakteris t ik of the known state of the art

In U.S. Patent 4,406,899 (Aburaki et al.), The zwitterionic form of 7- [α- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3- (1-methyl-1 -pyr, rolidinio) methyl] -3-cephem-4-carboxylate. There are also mentioned corresponding acid addition salts which are present in injectable agents in the zwitterionic form. 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 itself is unstable at room temperature as a dry powder and loses 30% or more of its activity when stored for one week at elevated temperature (e.g., 45 ° 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 Cefta. Idim 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 of them, if any, in dry powder form over a

! 0 have good stability. 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, February 1985, mention the sulfate salt, however, do not indicate how this salt can be obtained or that this salt is stable at room temperature and as a dry powder has good stability even at elevated temperature.

Object of the invention

The crystalline acid addition salts of 7- [a- (2-aminothiazol-4-yl) -a- (Z) methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4 used according to the invention As a dry powder, carboxylates have excellent stability at room temperature and are more stable at elevated temperature than the zwitterion. The term "dry powder" refers to one whose moisture content is less than 5% by weight. The physical mixtures obtainable with these salts according to the invention can be stored without difficulty and sold in solid form.

Explanation of the nature of the invention

The object of the invention is to provide a new method for Hergg position of mixtures of cephalosporin acid addition salts and organic or inorganic bases. These mixtures are storage stable and can be used advantageously for medical purposes.

The acid addition salts used according to the invention are

ptfe »* - W is S9"

after in the parent application AP. available method described. They are crystalline salts of

7- [α- (2-Aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate selected from the group consisting of sulfuric acid, di-nitric acid, mono-hydrochloric acid and di-hydrogen chloride addition salts and orthophosphorus addition salts (1/5 - 2 moles of orthophosphoric acid per mole of salt;

this corresponds for example to a range from the sesqui- to the di-orthophosphoric acid salts). The invention also includes the solvates of these salts. The term "crystalline" expresses that the molecules

at least partially arranged in a characteristic way 15

are. Whereas the sulfuric acid, di-nitric acid, di-hydrochloric acid and orthophosphoric acid addition salts prepared according to the invention have a clearly crystalline form (detected by birefringence under a polarizing microscope), the molecules being 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 a

_Λ interruption under the polarizing microscope) and thus

no precise arrangement, so they must be called "weak" crystalline. The term "crystalline" as used herein thus includes not only the distinctly crystalline salts but also the "weak" crystalline monohydrochloric 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:

M Λ

- C -CONH

COO '

The broad spectrum activity of this zwitterion, and thus the aqueous agents prepared from the salts described herein, against various organisms is evident from the data of U.S. Patent No. 4,406,899 (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 administered 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 zwitterionic activity of 1 mg / ml to 400 mg / ml, usually 250 mg / ml (determined by means of high performance liquid chromatography, HPLC) is achieved.

5 U / 39S

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 in a high yield upon crystallization from an aqueous medium.

The crystalline sulfuric acid addition salt is prepared by a process

(a) produces a mixture

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

(ii) from such an amount of zwitterion that

It's in the mix in one concentration

greater than 25 mg / ml is present,

, (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 efficacy (determined by HPLC) after 1 month of storage 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. It is very important that this salt has a low solubility in

Water, i. about 25 rag / 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 60 mg / ml. 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

(α) a mixture of

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

(ii) produces the zwitterion, which is used in a _ _c quantity such that in the micro

is present in a concentration greater than 25 mg / ml, and

(b) crystallized and

(c) isolating the crystalline sulfuric acid addition salt,

Preferably, the zwitterion is used in step (a) in an amount such that it is present in the mixture in

a concentration of 100 mg / ml to about 200 mg / ml 35

7 ZC / 3SS

is present. 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, 1N H 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 sludge up, preferably 15 min to 2 h. 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, it may also promote precipitation of impurities, 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 it is necessary to incorporate an organic solvent, preferably acetone, into the crystallization medium. to produce acceptable yields.

8 $ 9 $

len. 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 0.1 N sulfuric acid (for example 1/10 volume) and then with acetone (for example 1/4 volume).

Then it is dried, for example by drying in vacuo

4-2Oh.

Vacuum at 30 - 50 ⁰ C during a period of

The process for the preparation of the sulfuric acid addition salt described here, due to the limited solubility of the sulfuric acid addition salt, leads to a purification of the zwitterionic form 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) is to be obtained from the sulfuric acid adipate formed, this can be achieved by dissolving the salt in water, Ba (OH) ₂ .8H ₂ O in an amount of 90-100% Theory at a pH of less than 6.5 for the precipitation of BaSO 2, admits the BaSO. filtered off and the filtrate is recovered by dissolving the zwitterion and using it as a solution or isolating the solid zwitterion (free base) therefrom by lyophilization. It is also possible to add acetone to precipitate the amorphous zwitterion. Subsequently, the zwitterion is isolated as a solid by means of Vakuumfiltratio .. washed, for example, with acetone and trccknet in vacuo. Alternatively, the sulfuric acid addition salt in oie

free base by using ion exchangers, for example, 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 Mcläquivalente nitric acid with

(ii) the zwitterion

when present in the mixture at a concentration greater than 100 mg / ml and then inducing crystallization by seeding or rubbing with a glass rod, diluting with 2-propanol and cooling. The crystalline disodium acid addition salt is obtained, for example, by filtration, washing successively 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 may be obtained from the di-hydrochloric acid addition salt by slurrying the di-hydrochloric acid addition salt in methylene chloride and adding 1 mole of equivalent of triethylamine. It is then slurried to form the mono-hydrochloric acid addition salt which is isolated, for example by vacuum filtration.

filtration. It is then washed with methylene chloride and dried in vacuo.

The crystalline di-chloro-hydrogen acid addition salt is prepared by dissolving the zwitterion in at least 2 molar equivalents of hydrochloric acid, by addition of acetone causes crystallization, the crystals formed, for example, by vacuum filtration, washed with acetone and dried in vacuo.

The crystalline di-orthophosphoric acid additon salt is prepared by dissolving the zwitterion in at least 2 molar equivalents of phosphoric acid, crystallizing by 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, having 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 may be, for example, trisodium orthophosphate, sodium bicarbonone, sodium citrate, N-methylglucamine,

Pj 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.

_n ZC / 335

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 which cause a shingling reaction 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. The physical mixture can also be converted without difficulty into an injectable agent by

₁₂ ZUS 3 p

only water is added. This can be done by a nurse or a doctor shortly before use.

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

Among the bases that can be used in the mixture include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine,

IZ L (+) - lysine and L (+) - arginine. L (+) - lysine and L (+) - arginine are preferred because the mixtures containing these compounds can be reconstituted into injectable agents which, when injected into the animals, elicit a lower pain response than those derived from the mixtures. which contain the other bases. The L (+) - lysine is preferably employed in an amount such that after dilution of the mixture with water to an agent having a zwitterion activity of 250 mg / ml (determined by HPLC) a pH of 3.5-6 is reached becomes.

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 starting compound.

₁₃ Ζ & Ϊ335

a training. The preparation of this zwitterion is described in Examples 1 to 3 of US Pat. No. 4,406 (Aburaki et al.). The zwitterion is designated as follows: 7- ((Z) ^ -methoxyimino) - (2-aminothiazol-4-yl) -acetamido] -3 - [(1-methyl-1-pyrrolidinium) -methyl] -3- cephem-4-carboxylate.

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

Execution example

example 1

Preparation of sulfuric acid addition salt

Dissolve 1.5 g of zwitterion slowly into 10 ml of rapidly stirred IN H ₃ SO ₄ (1.59 molar equivalents) at ? 0 - 26 ° 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 with two 5 ml portions of acetone. Then it is dried in vacuo. 40 - 50 C over

night

 25

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

Elemental analysis for C _in H _{/ l} N, .O, .S., 'H_SO .:

19 24 65224

CH NS H ^ f

Calc .: 39.44 4.53 14.52 16.62 β

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 1M H ₂ SO are added. slowly with stirring to this solution. 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, 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 ° C.

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

 15

Example 3

Preparation of the (HNO ₃ ) ₂ acid addition salt

300 mg of the zwitterion are dissolved in 2N nitric acid (0.5 ml). The solution is rubbed with a glass rod, diluted with 0.4 m3. 2 propanol and cool. 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 ₁₀ H ₂₄ NgO ₅ S ₂ · 2ΗΝΟ ~:

Ber. : O, 90%) 37 C 4 H 1 8th N 30 Gef .: 36 , 62 4 , 32 1 8th , 47 (H ₂ 0 content , 92 10 , 08

10.67

15 UiS 9 5

Example 4

Preparation of monohydrochloride acid addition salt

1 g of the zwitterion is dissolved in 2.08 ml of 1N HCl (1 mol equivalent) at 20-25 ° C. While vigorously stirring, 15 ml of acetone are added over a period of 15 minutes to form crystals. Stir another hour. The crystals are isolated by vacuum filtration ι washed with 10 ml of acetone and dried in vacuo for 2 h at 50 ⁰ C.

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

Elemental analysis for

C 37 4 H 1 N 2 1 S , 63 1 Cl 86 H 2 ° % Ber. : 41 32 4 75 1 5, 95 1 1 , 28 1 2, 44 , 5% Found .: 39, 17 , 88 1 3, 61 1 1 , 82 1 2, 03 4 (Corrected for H ₃ Or 41 4, 1 3, %) 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 to the resulting solution with vigorous stirring over a period of 5 minutes to form crystals. The mixture is stirred for a further 5 min, then added to another 10 ml of acetone and 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 at 40-45 ° C.

1 S 1 Cl 8th H 2 ° 1 1 , 62 2, Λ " 1 25 1 25

₁₆

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

Elemental analysis for C ₁₉ H ₃₄ NO ₅ S ₂

^fi CHN

Ber .: 41.38 4.75 15.2

Gef .: 40.78 4.98 14.7

(Corrected for H ₂ O: 41.1 14.88 11.39 11.94%)

1 g of the dihydrochloride salt thus prepared is suspended in 20 ml of methylene chloride at 20-25 ° C. in a sealed flask and 0.28 ml of triethylamine are added over a period of 15 minutes. The crystalline mass is then slurried for 5 h. The monohydrochloride crystals obtained are then isolated by vacuum filtration, washed twice

with 5 ml of methylene chloride and dried for 2 h in a vacuum 20

at 50 ^° C. A typical yield is 800 mg.

Example 4

Preparation of the di-orthophosphoric acid addition salt

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. The solution is suitably filtered 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

35 ether and dried. 16 h in a high vacuum.

ZCfJJ5

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

Elemental analysis for C ₁₉ H ₂₄ N ₆ O ₅ S ₂ H ₃ PO ₄ :

Ber. : Gef .:

(Corrected for H-O: 10

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.

C 4 H 1 2 N %) 1 ^H 2 ° % 33 72 4 , 47 1 2 , 42 % 33 , 43 65 1 2 , 02 , 82 34 , 0 2

Example 7

Stability tests at elevated temperatures

The elevated temperature stability studies were performed by storing the preparations in dry containers at the temperatures listed below for the tent spaces 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. An efficacy loss of less than 10% over a period of 2-4 weeks at 45-5 ° C normally indicates that the efficacy loss is less than 10% for a 2 to 3 year storage at room temperature.

Percentage loss

substance 4 5 ° C (Weeks) 4 71 --5 C 4 56 ° C (Weeks) 4 +6 100 ° C (days) 1 1 2 , 68 3 1 2 100 0-10 Zwitterion H ₂ SO ₄ -SaIz 37 2.4 - + 5 51 3 0 , 0 10 4 57 5 - +6 + 3 0 - - (HNO ₃ ) ₂ salt 8.8 3.4 6 , 4 6 3.7 2.4 - 2 - HCl SAIZ 4.8 2.3 7 , 0 - 6.4 - 7, 12.4 (HCl) ₂ salt 0 - 1 0 - (H ₃ PO ₄ ) ₂ salt 0 3.0 2.7 5.0

1 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 10

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. _{c were} obtained

Trisodium orthophosphate (pH of 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.

Substituting the other salts described herein in the physical mixtures with the r.aten described above, then you get similar results. The solubility is similarly good and the pain occurring after the intramuscular injection is within tolerable limits

 35

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

FIG. 2 shows the infrared absorption spectrum of the crystalline sesquiphosphate salt of 7- [α- (2-aminothiazol) -4-yl) -3- (Z) -methoxyiminoacetamido] -3- [(1-methyl-1-pyrrolidinio)] methyl] -3-cephem-4-carboxy-lat (KBr-compact).

Figure 3 shows the infrared absorption spectrum of the crystalline diphosphate salt of 7- [α- (2-aminothiazol-4-yl) -3- (Z) -methoxyiminoacetamido] -3-1 (1-methyl-1-pyrrolidinio) methyl ] -3-cephem-4-carboxylate (KBr pellet).

The X-ray powder diffraction pattern of the crystalline sulfate salt of 7- (α- (2-aminothiazol-4-yl) -a- (Z) methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem 4-Carboxylate (prepared according to Examples 1 or 2) was taken up 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 2 rpm over a range of 5 - 40. To obtain the maximum diffraction angles, a diagram was mechanically recorded and the distances (d) and relative intensities (I / I) were calculated, which are listed below.

ίο

d distance (A) I / I _o (I) 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

20

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 having a pore size of 0.22-0.45 μm. To the filtrate, 5-7 parts by volume (15-20 ml) of methanol are added with vigorous stirring over a period of 30-60 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 intact and then acetone and drying Product 2] Yield: o, 7 - o, 75 g.

the product is dried at 50 ° C for 2 h in vacuo; tycrsche

Ζίί395

Interpretation of the Infrared Spectrum (see Fig. 2) (IR, KBr compact)

ivjc d? g pe a ks (cm)

2800 - 3400 1780 1680 1660 1630 1550 980, 1040

Functional group

NH, NH ₃ *, carboxyl OH 3-lactam C = O carboxyl C = O amide C = OC = N, C = C amide OH

Behavior on heating:

In the case of the differential calorimeter, an exotherm is found at 171.8 ° C.

X-ray diffraction diagram:

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:

I / I

11.04 - 32 9.2 - 16 7.89 - 24 7.02 - 42 6.7 - 32 5.5 - 26 4.64 - 100 i, 456 - 53 4.3 - 58 3.88 - 26 3.75 - 89 3.56 - 21 3.31 - 26 3.05 - 16

Interpretation of the H- * NMR spectrum (90 MHz, DjO solution) of:

Chemical shift (ppm in 6 over TSP) Opposing description Inte gral assignment 2,0 - 2, 4 multiplet 4 14CH ₂ , 14 ¹ CH ₂ 3.04 singlet 3 12CH ₃ 3,3 - 3, 6 Multjplett 5 2CH, 13CH ₉ , 13'CH- 3.94 4.12 Doublet singlet 1 3 " 2CH 20CH ₃ 4.12 doublet 1 11CH 4.8 doublet 1 11CH 5.42 doublet 1 6CH 5.88 doublet 1 7CH 7.21 singlet 1 18CH

1 Stability: temperature percentage loss Time 100 ⁰ C 10.9 5 1 day 70 ⁰ C 0 3 days 70 ⁰ C 1.9 7 days 56 ° C 1/0 1 week 56 ° C 1.4 2 weeks 56 ° C 0 Λ 4 weeks 45 ° C 0 KJ 1 week 4 5 ° C 1.4 2 weeks 4 5 ° C 0.7 4 weeks 4 5 ° C 1.6 8 weeks 37 ° C 2.5 5 1 month

Elemental analysis (wt%):

Found On dry theory Base (Sesquiphosphate) C 35.44 36.3 36.4 H 4.66 4.41 4.7 N 12.88 13.2 13.4 H ₂ O 2.29 * - Monohydrate = 2.8 H ₃ PO ₄ 23.06 23.6 23.6

♦ determined by Karl Fischer

Claims (4)

M / 28 290 claims 1. A process for preparing a physical jQ mixture of at least one temperature-stable crystalline salt of 7- [α- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate (Zwitterion), selected from the group consisting of the sulfuric acid, ι-di-nitric acid, mono-hydrochloric acid and di-hydrochloric acid addition salts and orthophosphoric acid addition salts with 1.5-2 molar equivalents Η-, ΡΟ. , or the solvate of it and from a pharmaceutically acceptable non-toxic organic or inorganic base, characterized in that one nc mixes said ingredients in proportions such that after diluting the mixture with water to an injectable concentration, a pH of from about 3.5 to about 7 is achieved. "Q 2. The method according to item 1, characterized in that mixing the Bestanöteile in such proportions that after dilution of the mixture with water to a injectable concentration, a pH of about 4 to 6 receives. 3. The method according to item 1 or 2, characterized in that c is used as base L (+) - lysine. 4. Method according to item 1 or 2, characterized in that one uses as Ba ^ e L (+) - arginine. HitfZu J Jft '/ ei «. UitUh Uixf