LU86540A1 - CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS - Google Patents

Description

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CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS

The present invention relates to semi-synthetic temperature-resistant cephalosporin salts, the preparation of which has not been described in the literature, the preparation of these salts and mixtures containing these salts.

U.S. Patent No. 4,406,899 to Aburaki et al. describes 7- [a- (2-aminoth1azol-4-yl) -a- (Z) -methoxyiminoacëtamido> 3-r (l-methyl-l-pyrrolidinio) methyl] -3-cephem-4-carboxylate of dipolar ion (zwitterion) and mentions corresponding acid addition salts (which are present in the form of dipolar ion in injectable compositions) and indicates that the form of dipolar ion has an activity spectrum wider than ceftazidime and cefotaxime.

However, the cephalosporins mentioned above by Aburaki et al. are only stable for a few hours in the form of injectable compositions and even the form of dipolar ion in the form of dry powder is unstable at room temperature and loses 30% or more of its activity by storage at high temperatures (for example 45 ° C and above) even for a week and therefore requires specially insulated packaging and / or refrigeration and by comparison with ceftazidime and cefotaxime it is disadvantaged by its packaging and storage problems .

Although Aburaki et al. mention the acid addition salts, the patent does not explain how to prepare them nor does it indicate whether any of these salts has good stability in the form of dry powder. Kessler et al., "Comparison of a New Cephalosporin, BMY 28142, with Other Broad-Spectrum g-Lactam Antibiotics", Antimicrobial Agents and Chemotherapy, volume 27, no.2, pages 207-216, February 1985, mentions sulfate but does not indicate how to prepare it nor does it indicate whether this salt has good stability at room temperature and good stability at high temperature in the form of dry powder.

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It has now been found that certain crystalline acid addition salts of 7- [or (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [; (1-methyl-1-pyrrolidin1o ) methyl] -3-cephem-4-carboxylate in dry powder form exhibited excellent stability at room temperature and superior stability at elevated temperatures compared to the dipolar ion form. The term "as a dry powder" as used herein means a moisture content of less than 5% by weight.

These acid addition salts are the crystalline salts of 7-ra- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido> 3 - [(1-methyl-1-pyrrolidinio) -10 methyl > 3-cephem-4-carboxylate chosen from the group consisting of acid addition salts with sulfuric acid, diniträte, mono-hydrochloride and dihydrochloride and addition salts with orthophosphoric acid ( 1.5 to 2 moles of phosphoric acid per mole of salt, i.e. a range between sesqui-orthophosphates and di-orthophosphates) or their solvates. The term "crystalline" is used here to mean at least some characteristic arrangements of the molecules. While the sulphates, dinitrates, dihydrochlorides and orthophosphates obtained by the addition of acid are here prepared in a clearly crystalline form (this being demonstrated by birefringence 20 under a polarizing microscope) with a precise arrangement of the molecules, monohydrochloride n 'was prepared with a little regularity in the arrangement of its molecules (this being highlighted by a weak birefringence with the polarizing microscope) and not an arrangement which can be predicted in a precise way and it is thus "weakly" crystalline. The term "crystalline" is used herein to cover not only clearly crystalline salts but also monohydrochloride which appears "weakly" crystalline.

The acid addition salts according to the invention, when introduced into aqueous injectable compositions provide the dipole ion in solution. The dipolar ion has the structure: NO-CH3 COO® cH ^ 35 The usefulness of broad spectra with regard to various organisms of the dipolar ion form, and therefore of these aqueous compositions prepared from these salts , is indicated by data from Aburaki et al., US

4,406,899.

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The aqueous compositions prepared from the acid addition salts according to the invention, simply by addition of sterile water, provide acid solutions which cause unacceptable irritation upon intravenous administration of rabbits and painful sensations. unacceptable when administered intramuscularly to rabbits. Sulfate and diniträte, which are acid addition salts, have reduced solubilities which are insufficient for typical injectable compositions. It has now been found that these questionable characteristics can be remedied by the use of these salts in a physical mixture (i.e. in the form of a mixture of solids) with a pharmaceutically non-toxic organic or inorganic base. acceptable in proportions such as to give a pH of about 3.5 to about 7 by dilution with water to a dipolar ion activity of 1 mg / ml to 400 mg / ml, normally 250 mg / ml (as determined by high performance liquid chromatography, hereinafter referred to as HPLC).

A salt which is now preferred is crystalline sulfate, an addition salt of sulfuric acid. It is preferred because its low solubility in water (25 mg / ml) allows high recovery in an aqueous medium during crystallization.

Crystalline sulfate, or addition salt of sulfuric acid, can be easily prepared by a process which comprises the steps of: (a) forming a mixture of (i) at least 1 molar equivalent of sulfuric acid; and (ii) a dipolar ion in an amount such that it is present in the mixture at a concentration greater than 25 mg / ml; (b) initiation of the crystallization of the sulfate or addition salt of sulfuric acid; and (c) separation of the crystalline sulfate or addition salt of sulfuric acid. The crystalline salts according to the present invention (hereinafter referred to simply as the present salts) exhibit excellent stability at ambient temperature and their loss of power (as determined by HPLC) is less than 1% on storage for 1 month at room temperature. These salts also exhibit excellent stability at high temperatures and their loss of power (as determined by HPLC) is less than 15 ° during storage for 1 month at 45-56 ° C.

The sulfuric acid addition salt is the salt which is preferred here. It has a power loss of less than 10¾ during storage for 1 month at 45-56 ° C. What is very important is that it has a low solubility in water, i.e. around 25 mg / ml, and that it therefore crystallizes / 4 in water with a minimum of loss residual.

The dini träte, acid addition salt according to the invention, also has a low solubility in water, that is to say about 60 mg / ml and it therefore also provides a low residual loss during of its crystallization in water. Monohydrochloride, dihydrochloride and sesqui- or di-orthophosphate, other acid addition salts, have solubilities in water greater than 200 mg / ml and, as a result, they are preferably crystallized from organic solvents rather than in water for good yields.

The preparation of the salts according to the present invention will now be described. As indicated above, the sulfate, sulfuric acid addition salt according to the present invention, is prepared by a process which comprises the steps of: (a) forming a mixture of (i) at least 1 molar equivalent of sulfuric acid; and (ii) a dipolar ion corresponding to this salt, in an amount such that it is present in the mixture S a concentration greater than 25 mg / ml; (b) initiation of crystallization; and (c) separation of the addition salt of sulfuric adde or linseed crystal sulfate.

The dipole ion is preferably used in step (a) in an amount such that it is present in the mixture at a concentration of between approximately 100 mg / ml and approximately 200 mg / ml and the step (b) 25 in an aqueous medium free of organic solvent. Normally, in step (a), no more than 2 molar equivalents of sulfuric acid are used. Normally, the dipole ion is used 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 easily carried out either by adding the solid dipole ion to the sulfuric acid solution (for example HgSO 4 IN) with rapid stirring to form a solution. Alternatively, step (a) can be carried out by dissolving the solid dipole ion in water and slowly adding sulfuric acid while stirring to form a solution.

Step (b) is carried out by initiating crystallization, preferably by seeding, and then put into a slurry, preferably for 15 minutes to 2 hours. It is preferred that this crystallization step is carried out in an aqueous medium, free of organic solvent, and in I ‘5

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in this case, purities greater than 98¾ are normally obtained. Although the presence of organic solvent, for example acetone, promotes crystallization and increases the yield by lowering the solubility of the acid addition salt, the sulfate formed, in the crystallization medium, it can also promote precipitation of impurities and lead to a decrease in purity. When the dipole ion is used in step (a) in an amount such that it is present in the mixture in an amount less than 25 mg / ml, an organic solvent, preferably acetone, should be included in the crystallization medium to arrive? reasonable recovery. When acetone is used, it is appropriately used in an amount of 0.5 to 10 volumes / volume of aqueous crystallization medium.

Step (c) is carried out by separation of the crystals in the crystallization medium, preferably by vacuum filtration, and then by washing, for example with an acetone / water mixture, followed by washing. acetone alone or 3N 0.1N sulfuric acid (for example 1/10 by volume), followed by acetone (for example 1/4 by volume), and then by drying, for example by vacuum drying at 30 -50 ° C for 4 3 20 hours.

The method according to the invention for forming sulphate, addition salt of sulfuric acid, leads to the purification of the dipolar ion form because of the limited solubility of the sulphate compared with the dipolar ion form and it is possible to Use to purify the dipole without separating it in its solid form. If it is desired to obtain the substantially pure dipolar ion (free base) from the sulphate, acid addition salt formed, this can be done by dissolving the salt in water, addition of BafOH ^ .ß ^ O in an amount of 80 to 100¾ of theory, at a pH of not less than 6.5 to precipitate BaSO ^, filtration to remove BaSO ^ and recovery of the filtrate which contains dissolved dipole ion and use in solution or separation of dipole ion solid (free base) by lyophilization or addition of acetone to precipitate the amorphous dipole ion and then separation of the solid dipole ion by vacuum filtration, washing for example with acetone and drying under vacuum. Alternatively, the sulphate or addition salt of sulfuric acid is transformed into the free base using ion exchange resins, for example Dowex WGR (anion exchange resin in weak base form) and Dowex XU -40090.01 (strong acid cation exchange resin) and then lyophilization.

Coming now? the preparation of the crystalline dini träte, which is an acid addition salt according to the invention, is obtained by mixing 6 I 1 (1) with at least 2 molar equivalents of nitric acid and (ii) d dipolar ion corresponding to this salt so that it is present in the mixture 3 a concentration greater than 100 mg / ml, and then initiation of the crystallization by seeding or rubbing with a stirrer, dilution with propanol 2 and cooling. The crystalline diniträte, another acid addition salt, is recovered for example by filtration, washing successively for example with a mixture of propanol-2/1 ^ 0 (50¾ v / v), propanol-2 and ether, and then drying under vacuum at 50 ° C for 2 hours.

The monohydrochloride, acid addition salt according to the invention, is prepared by dissolving the dipolar ion in approximately 1 molar equivalent of hydrochloric acid and initiating crystallization by adding acetone with stirring and continuation of the stirring, which is followed by separation of the crystals, for example by vacuum filtration which is followed by washing with acetone and drying under vacuum. Alternatively, the monohydrochloride 3 is prepared from the dihydrochloride, by boiling the dihydrochloride in methylene chloride and addition of 1 molar equivalent of triethylamine, which is followed by boiling to form the monohydrochloride that separates, for example by vacuum filtration which is followed by washing with methylene chloride and drying under vacuum.

The crystalline dihydrochloride, which is an acid addition salt according to the invention, is prepared by dissolving the dipolar ion in at least 2 molar equivalents of hydrochloric acid and then initiating crystallization by adding acetone and then separation of the crystals, for example by vacuum filtration, washing with acetone and drying under vacuum.

Crystalline di-orthophosphate, which is an acid addition salt according to the invention, is prepared by dissolving the dipolar ion in at least 2 molar equivalents of phosphoric acid, initiating crystallization by adding acetone and separation of the crystals, for example by vacuum filtration, which is followed by washing first with acetone and then with ether, and then drying under vacuum. Crystalline sesqui-orthophosphate is formed by this same procedure except that about 1.5 molar equivalents of phosphoric acid are used.

The salts according to the invention are put into injectable compositions by dilution with sterile water and buffering at a pH of 3.5 to 7 to form an injectable concentration of 1 mg / ml up to 400 mg / ml of ion f 7 dipole. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) lysine and L (+) arginine. For intramuscular or intravenous administration to an adult human, a total dose of from about 750 to about 3000 mg / d in divided doses is normally sufficient.

It is not desirable that the salts according to the present invention be made into injectable compositions simply by addition of sterile water, because the sulfate and dinitrate, which are acid addition salts, are not sufficiently soluble to form compositions of normal concentration for administration and because these salts, when dissolved, give compositions of very low pH (1.8 to 2.5) which give painful sensations during injection . As indicated above, we have now found that these disadvantages can be remedied by passing these salts into a physical mixture, that is to say solid, with organic or inorganic bases. non-toxic, normally solid, pharmaceutically acceptable in proportions such that they give a pH of between approximately 3.5 and approximately 7, preferably between approximately 4 and approximately 6, by diluting the mixture with water to an injectable concentration. from 1 mg / 1 up to 400 mg / 1 in dipolar ion, for example having a dipolar ion activity of 250 mg / ml as determined by an HPLC test.

The exact proportions of ingredients in the physical mixture vary from batch to batch of salt, since the purity of salt varies from batch to batch. The proportions of ingredients in a particular batch are determined by pre-titration of a sample to obtain a selected pH within the range mentioned above.

The physical mixture can easily be stored and shipped in solid form, thus taking advantage of the advantage of the stability of the salts according to the invention and it easily transforms into an injectable composition simply by adding water, which is done by example the nurse or doctor just before use.

: The physical mixture is prepared by mixing the salts and the base into a uniform mixture, for example using a conventional mixer in a dry atmosphere, and then preferably introduced into a flask or other container, all in aseptic conditions.

The bases which are 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 are the preferred ones since mixtures containing them are reconstituted to provide injectable compositions which, when injected, cause animals less pain than the compositions. from mixture containing other bases. L (+) lysine is very preferably used in proportion such that it gives a pH of 3.5 to 6 by diluting the mixture with water and provides a composition whose activity of the dipolar ion is 250 mg / ml (as determined by HPLC test).

The salts according to the invention and the substantially dry physical mixtures which contain them can be stored without refrigeration or insulated packaging and they retain a high power.

In several of the preparations according to the invention, the unstable dipolar ion is used as raw material. Its preparation is described in Examples 1 3 3 of Aburaki et al., US Patent 4,406,899. The dipolar ion is indicated in Aburaki et al. as 7-ra- (2-am1nothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl? -3-cephem-4-carboxylate.

The following figures are given for explanatory and clarification purposes: FIG. 1 is a graphic representation of the infrared absorption spectrum of crystalline sulfate of 7- [a- (2-amino-thiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3-C (1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate measured on a dilution thereof in KBr; - Figure 2 is a graphical representation of the infrared absorption spectrum of crystalline sesqulphosphate of 7- [a- (2-am1noth1azol-4-yl) -a- (Z) -methoxyiminoacëtam1do] -3-C (l-methyl- l-pyrrolid1n1o) methyl] -3-cephem-4-carboxylate 30 measured on a dilution thereof in KBr; - Figure 3 is a graphical representation of the infrared absorption spectrum of crystalline diphosphate of 7-ra- (2-amino-thiazol-4-yl) -a- (Z) -methoxyiminoacétamidoI> -3 - [(l-methyl -l-pyrrolidinio) methyl] -3-cephem-4-carboxylate measured on a dilution thereof in KBr.

The invention is illustrated by the following working examples.

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EXAMPLE I

Preparation of sulfuric acid addition salt

1.5 g of dipolar ion are added slowly S 10 ml of i ^ SO ^ IN (1.59 molar equivalents) stirred quickly at 20-26 ° C. A solution is obtained. The crystallization is then induced by seeding with crystalline sulfate and the crystalline mass is passed into a slurry for 0.5 hour. The crystals are then separated by vacuum filtration, washed with 3 ml of an acetone / water mixture at 50 ° by volume and with 2 portions of 5 ml of acetone, and dried under vacuum at 40-50 ° C for the duration 10 of a night.

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

On analysis, it is found that the product obtained has the formula: C19H24N6 ° 5S2 * H2S04 15 and the following values are obtained: CX HX NX SX H20% - calculated ...... 39.44 4.53 14, 52 16.62 none - found ....... 38.91 4.57 14.64 16.71 1.42

EXAMPLE II

20 Preparation of the addition salt of sulfuric acid

1.5 g of the dipole ion are dissolved in 5 ml of water. 5 ml of 1M HgSO 4 is slowly added to this solution while stirring. The crystallization is then induced by seeding with a crystalline acid addition salt and the crystalline mass is passed into a slurry for 0.5 hour. The crystals are then separated by vacuum filtration, washed with 3 ml of an acetone / water mixture at 50% by volume and with 2 portions of 5 ml of acetone and dried under vacuum at 40-50 ° C during the duration of one night.

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

EXAMPLE III

Preparation of the acid addition salt (HN03) 2

300 mg of dipolar ion are dissolved in 2N nitric acid (0.5 ml). The solution is rubbed with a glass shaker, diluted with 2-propanol (0.4 ml) and cooled. The title crystalline compound is collected and washed successively with 0.4 ml of a propanol-2 / H2O mixture (1/1), propanol-2 and then ether to give 127 mg of nitrate .

On analysis, it is found that the product obtained has the formula: C19H24N6 ° 5S2.2HN03 10 and the following values are obtained:

CX H% NX SX

- calculated ...... 37.62 4.32 18.47 10.57 - found ....... 36.92 4.10 18.08 10.67 5 (HgO content: 0.90 %).

EXAMPLE IV

Preparation of monohydrochloride

1 g of dipolar ion is dissolved in 2.08 m of IN HCl (1 molar equivalent) at 20-25 ° C. Thirty ml of acetone are added while stirring rapidly for a period of 15 minutes, whereby crystals are formed. Agitation is continued for 1 hour. The crystals are separated by vacuum filtration, washed with 10 ml of acetone and dried in vacuo at 50 ° C for 2 hours.

The typical yield is 0.9 g of crystalline monohydrochloride.

15 Upon analysis, it can be seen that the product obtained has the formula: C19H24N6 ° 5S2 * HC1 and the following values are obtained: CX HX NX SX C1X H20% - calculated ...... 41.37 4.75 15 , 2 11.63 12.86 20 - found ....... 39.32 4.88 13.95 11.28 12.44 4.5

(correction for H20: CX = 41.17; NX = 14.61; SX = 11.82; Cl% = 13.03). EXAMPLE V

Preparation of the dihydrochloride and preparation of the monochloride hydrate, starting therefrom 350 mg of dipolar ion are dissolved in 2 ml of IN HCl. We add

10 ml of acetone 8 the resulting solution while stirring rapidly and during an interval of 5 minutes, whereby crystals are formed. Agitation is continued for another 5 minutes. An additional 10 ml of acetone is then added and stirring is continued for 0.5 hour. The crystals are removed by vacuum filtration, washed with 2 portions of 5 ml of acetone and dried under vacuum at 40-45 ° C

s for 24 hours.

The typical yield is 300 mg of crystalline dihydrochloride.

On analysis, it is found that the product obtained has the formula: 35 C19H24N6 ° 5S2 * 2HC1 and the following values are obtained:

CX HX NX SX C1X H20X

- calculated ...... 41.38 4.75 15.2 11.62 12.8 - found ....... 40.78 4.98 14.7 11.25 1.25 11

1 g of dihydrochloride prepared as indicated above is boiled in 20 ml of methylene chloride at 20-25 ° C in a sealed flask and 0.28 ml of triethylamine is added over an interval of 15 minutes. The crystalline mass is then passed into a slurry for 55 hours. The resulting monohydrochloride crystals are then isolated by vacuum filtration, washed with two 5 ml portions of methylene chloride and dried under vacuum at 50 ° C for 2 hours. The typical yield is 800 mg.

EXAMPLE VI

10 Preparation of di-orthophosphate

1 g of dipolar ion is dissolved in 3.4 ml of HgPO 4 S 144 mg / ml (2.2 molar equivalents) S 15 ° C. The resulting solution is properly filtered to clarify it. 12 ml of acetone are added to the clarified solution while stirring rapidly for a period of 10 minutes, whereby crystals are formed. Agitation is continued for 10 minutes. 30 ml of acetone are then added over a period of 10 minutes and stirring is continued for a further 15 minutes. The crystals are collected by vacuum filtration, washed with 2 portions of 5 ml of acetone and 2 portions of 5 ml of ether, and dried under high vacuum for 16 hours.

The typical yield of this type of preparation is 1.1 g of crystalline di-orthophosphate.

On analysis, it is found that the product obtained has the formula: C19H24N6 ° 5S2 * 2H3P04 25 and the following values are obtained: C% Hï N% Hz0% - calculated ...... 33.72 4.47 12 , 41 - found ....... 33.43 4.65 12.02 1.82 (corrected for HpO: C% = 34.0; NX = 12.2).

The sesqui-orthophosphate is formed as above, except that 1.5 molar equivalents of H 2 PO 4 are used instead of 2.2 molar equivalents.

EXAMPLE VII

Stabilities at elevated temperatures Stabilities at elevated temperatures are determined by storing the preparations in dry packages at temperatures and for periods of time as indicated below, and determining losses or gains in potency by HPLC. A power gain in% is 12

Indicated as a "plus" sign at the beginning of a figure. A loss of power less than 3 10¾ over a period of 2 to 4 weeks at 45-56 ° C is usually indicative of a loss of power less than 10% during a period of 2 3 3 years at room temperature.

5 --- LOSS IN%

45 ° C 56 ° C 100 ° C

(weeks) (weeks) (days)

Form 1246 1 24 1

Dipolar ion 37 51 71 57 - 100 15 Salt of H ^ SO ^ 2.4 to +5 3 +5 1.4 5 to +6 +3 O to +6 0-10

Salt of (HNO ^ 8.8 3.4 0.68 10.3 3.7 2.4

HCl salt 4.8 2.3 6.0 6.4 6.4 20 ----

Salt of (HC1) 2 0 7.4 0 - 7.2 12.4

Salt of (H ^) ,, 0 3.0 1.0 - 2.7 5.0

EXAMPLE VIII

Test of physical mixtures

The physical mixtures consist of crystalline sulfate, with (a) sodium orthophosphate, (b) sodium bicarbonate, (c) L (+) lysine and (d) L (+) arginine. The bases are added in proportions 30 such that they provide, by diluting the mixture with water 3, a dipolar ion activity of 250 mg / ml (determined by HPLC test) in the following manner: the trisodium orthophosphate of pH (providing a pH of 6.0); sodium bicarbonate (providing a pH of 6.0), L (+) lysine (providing a pH of 6.0); L (+) arginine (providing a pH of 6.0). The injectable compositions are prepared by reconstitution with sterile water 3 of a dipolar ion activity of 250 mg / ml, as determined by HPLC test. There are no solubility problems. Injections (100 mg / kg) are made intramuscularly into rabbits, the pain now remaining at acceptable levels. The least pain is that which is obtained with the composition containing arginine.

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

FIG. 1 represents the infrared absorption spectrum of the crystalline sulfate prepared as described in Example I or Example II, placed in pellets in its crystalline form in the presence of potassium bromide.

The powder X-ray diffraction pattern of crystalline sulfate 10 of 7-ra- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(l-methyl-l-pyrrolidinio) methyl ] -3-cephem-4-carboxylate prepared as described in example I or II, is determined with a Rigaku powder diffractometer using an X-ray tube? copper target, a nickel filter and the sample being contained between two glass plates. The scanning speed is 2 ° per minute over the range of 5 to 40 ° C, and the graph is recorded mechanically to indicate the maximum diffraction angles. From this, we calculate the spacings (D) and the relative intensities (I / IJ. They are listed below.

Spacing d (A) I / IQ (¾) 20 9.20 TÖÖ 6.80 50 5.50 28 5.09 22 4.50 38 25 4.41 44 4.19 63 3.78 38 3.64 44 3.39 25 30 3.31 31 3.15 47

EXAMPLE IX

Sesquiphosphate preparation

The dipole ion, 0.70 g, is dissolved, while stirring rapidly in 2.2? 2.4 ml of 85% phosphoric acid (2.1 to 2.2 molar equivalents) which was diluted S 1/10 (v / v) with water. The solution is clarified by filtration on a filter membrane with a pore size of 0.22 to 0.45 microns.

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We add 5? 7 parts by volume (15 to 20 ml) of methanol in the filtrate while stirring rapidly for a period of 30 to 60 minutes. During this operation, crystals are formed and rapid stirring is continued for 1.5 to 2 hours.

5 The crystalline product is recovered by vacuum filtration, the product is washed on filter first with 6? 8 ml of a 1/1 (v / v) methanol / acetone mixture, taking care to keep the filter cake tightly and then with acetone.

The product is dried under vacuum 850 ° C for 2 hours, the typical yield is 0.75 0.75 g.

Interpretation of infrared (see Figure 2) (IR, KBr patch).

Position of the peaks (cm ~ ^) functional group

2800-3400 NH, NH3 +, carboxyl 0H

15 1780 ß-lactam OO

1680 carboxyl C = 0 1660 amide C = 0

1630 ON, OC

1550 amide OH

20 980, 1040 P04 ““

Heating behavior:

An exotherm appears at 171.8 ° C in the differential scanning of the calorimeter plot.

X-ray diffraction pattern

The X-ray powder diffraction pattern of the preceding sesquiphosphate is measured with a Rigaku powder diffractometer, in the same manner as described above with regard to sulfate, with the following results:

30 11.04 "5T

9.2 16 7.89 24 7.02 42 6.7 32 35 5.5 26 4.64 100 4.456 53 4.3 58 15 3.88 26 3.75 89 3.56 21 3.31 26 5 3.05 16

Interpretation of NMR: (¾ 90 MHz NMR, solution in DgO) j ”- '/ OCH, λ / S” ï / -n ^ vvh' 1 · COj 15 Chemical drift (ppm tt / TSP) Full Description Indication 2, 0-2.4 multiplet 4 14CH2, 14'CH2 3.04 singlet 3 120Η ^ 3.3-3.6 multiplet 5 2CH, 13CH2, 13'CH2

20 3.94 doublet 1 2CH

4.12 singlet 3,200Η ^

4.12 doublet 1 11CH

4.8 doublet 1 11CH

5.42 doublet 1 6CH

25 5.88 doublet 1 7CH

7.21 singlet 1 18CH

Stability

Time-temperature% of loss 1 day - 100 ° C 10.9 30 3 days - 70 ° C 0 7 days - 70 ° C 1.9 1 week - 56 ° C 1.0 2 weeks - 56 ° C 1.4 4 weeks - 56 ° C 0 35 1 week - 45 ° C 0 2 weeks - 45 ° C 1.4 4 weeks - 45 ° C 0.7 8 weeks - 45 ° C 1.6 1 month - 37 ° C 2, 5 # 16

Elementary analysis (¾ by weight) found dry basis theory (sesquiphosphate) C ...... 35.44 36.3 36.4 H ...... 4.66 4.41 4.7 5 N .. .... 12.88 13.2 13.4

HgO ---- 2.29 * - monohydrate = 2.8% H3PO4 .. 23.06 23.6 23.6 Karl Fischer method.

10 15 20 25 30 35

Claims (12)

1. Crystalline salts stable at the temperature of 7- [a- (2-amino-thiazol-4-yl) -a- (Z) -methoxyiminoacêtamido] -3 - [(1-methyl-1-pyrrolidinio) -methyl> 3-cephem-4-carboxylate selected from the group consisting of the 5 addition salts of sulfuric acid, dinitrate, monohydrochloride and dihydrochloride and the addition salts of orthophosphoric acids containing 1.5 8 2 molar equivalents of H ^ PO ^ or their solvates. 2. Crystalline salts according to claim 1, selected from the group consisting of sulfate, monohydrochloride, dihydrochloride and orthophosphate, acid addition salts, or their solvates. 3. physical mixture of the salt according to claim 1, with a non-toxic organic or inorganic base pharmaceutically acceptable in proportions such that they give a pH of approximately 3.5 3 approximately 7 by diluting the mixture with water to a concentration injectable. 4. A physical mixture according to claim 3, in which the salt and the base are present in proportions such that they give a pH of approximately 4 8 approximately 6 by diluting the mixture with water in injectable concentration. 5. Physical mixture according to claim 4, in which the base is L (+) lysine. 6. Physical mixture according to claim 4, in which the base is L (+) arginine. 7. A process for the preparation of the sulfuric acid addition salt, comprising the steps of: (a) forming an aqueous mixture of: (i) at least 1 molar equivalent of sulfuric acid; and (1i) a dipolar ion corresponding to these salts; (b) initiation of crystallization of the sulfuric acid addition salt provided that when the dipole ion is present in the mixture at a concentration below 325 mg / ml, crystallization is carried out in the presence of an organic solvent ; and (c) separation of the crystalline sulfate or addition salt of sulfuric acid. 8. The method of claim 7, wherein step (b) is carried out in an aqueous medium free of organic solvent. 9. The method of claim 8, wherein the dipole ion is used in step (a) in an amount such that it is present in the mixture at a concentration below 3,500 mg / ml. 18 10. The method of claim 7, wherein the amount of dipolar ion used in step (a) is such that it is present in the mixture at a concentration greater than 25 mg / ml. 11. Method according to claim 8, in which the dipole ion 5 is used in step (a) in an amount such that it is present in the mixture? a concentration of between 100 mg / ml 5 approximately 200 mg / ml. 12. Crystalline sulphate or sulfuric acid addition salt according to claim 1. 13. Crystalline sulfate of 7-Ca- (2-aminothiazol-4-yl) -a- (Z) -methoxy-10 iminoacetamido3-3-l [(l-methyl-1-pyrrolidinio) methyl3-3-cëphem-4 -carboxylate, showing the following X-ray powder diffraction pattern: Spacing d (A) I / IQ (¾) 9.20 ““ ÏSÔ 6.86 50 15 5.50 28 5.09 22 4.50 38 4 , 41 44 4.19 63 20 3.78 38 3.64 44 3.39 '25 3.31 31 3.15 47 25 14.- Crystalline orthophosphate according to claim 1 and its hydrates. 15.- Crystalline phosphate of 7- [a- (2-aminothiazol-4-yl) -a- (Z) -methoxy-imi noacetamidol-3-C (1-methyl -1-pyrrol i di nio) methylü-3 -céphem-4-carboxylate, showing the following X-ray powder diffraction pattern: Ü! / Ιο 30 11.04 “3F 9.2 16 7.89 24 7.02 42 6.7 32 35 5.5 26 4.64 100 4.456 53 4.3 58 Λ ^ 19 * 3.88 26 3.75 89 3.56 21 3.31 26 5 3.05 16 10 15 25 30 35