FR2585705A1 - CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS - Google Patents

Abstract

CRYSTALLINE ADDITION SALTS OF SULFURIC, DINITRIC, MONOCHLORHYDRATE, DICHLORHYDRATE AND DI- AND SESQUI-ORTHOPHOSPHATE OF 7-A- (AMINOTHIAZOL-4-YL) -A- (Z) -METHOXYIMYO-ACETAMID -1-PYRROLIDINIO) METHYL -3-CEPHEM-4-CARBOXYLATE ARE STABLE EVEN AT HIGH TEMPERATURES. THE CRYSTALLINE ADDED SALT OF SULFURIC ACID IS PREPARED BY FORMING A MIXTURE OF AT LEAST MOLAR SULFURIC ACID WITH A DIPOLAR ION IN QUANTITY AS PRESENT IN THE CONCENTRATION HIGHER THAN 25MGML, CRYSTALLIZATION IS CAUSED, CRYSTALS ARE SEPARATED, WASHED AND DRYED. MONOCHLORHYDRIQUE, DICHLORHYDRATE AND CRYSTALLINE ORTHOPHOSPHATE PREPARES BY DISSOLUTION OF THE DIPOLAR ION IN THE APPROPRIATE QUANTITY OF ACID, CRYSTALLIZATION BY ADDITION OF ACETONE IS OCCASIONED AND THE CRYSTALS ARE ISOLATED. PHYSICAL MIXTURES OF SALTS WITH CERTAIN BASES, IN APPROPRIATE PROPORTIONS, GIVE A pH BETWEEN APPROXIMATELY 3.5 AND APPROXIMATELY 7 WHICH, BY DILUTION WITH WATER, GIVE INJECTABLE COMPOSITIONS.

Description

CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS

  The present invention relates to semi-cephalosporin salts

  temperature resistant synthetics whose preparation 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 - ["- (2-aminothiazol-4-yl) -a- (Z) -methoxylminoacetamido] -3-r (1-

  methyl-1-pyrrolidinlo) methyl] -3-cephem-4-carboxylate in its ion form

  dipolar (zwitterion) and mentions corresponding acid addition salts

  dants (which are present as dipolar ions in compounds

  injections) and indicates that the dipolar ion form has a

  broader activity spectrum than ceftazidime and cefotaxime.

  However, the cephalosporins mentioned above by Aburaki and

  coll. are only stable for a few hours as a compound

  injections 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 more) even for a week and it therefore requires specially insulated packaging and / or refrigeration and by comparison with ceftazidtme and cefotaxime, it is disadvantaged by its problems

packaging and storage.

  Although Aburaki et al. mention the acid addition salts,

  the patent does not explain how to prepare them or indicate whether any

  that these salts have good stability in the form of dry powder.

  Kessler et al., "Comparison of a New Cephalosporin, BMY 28142, with Other Broad-Spectrum e-Lactam Antibiotics", Antimicrobial Agents and Chemotherapy, volume 27, n 2, pages 207-216, February 1985, mentions sulfate but n does not indicate how to prepare it nor does it indicate if this salt

  has good stability at room temperature and good stability

  high temperature in the form of dry powder.

  We have now found that certain crystalline addition salts

  7- [ú- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-

  methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate in dry powder form exhibited excellent stability at room temperature and greater stability at elevated temperatures compared to the dipolar ion form. The term "as dry powder" as used

  here means a moisture content of less than 5% by weight.

  These acid addition salts are the crystalline salts of 7 - ["- (2-

  aminothiazol-4-yl) - "- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1pyrrolidinlo) -

  methyl] -3-cephem-4-carboxylate selected from the group consisting of

  acid addition salts with sulfuric acid, dinitrate, mono-

  hydrochloride and dihydrochloride and addition salts with orthophosphoric acid (1.5 to 2 moles of phosphoric acid per mole of salt, i.e. an interval 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 sulfates, dinitrates, dihydrochlorides and orthophosphates obtained by the addition of acid are here prepared in a clearly crystalline form (this being demonstrated by birefringence under a polarizing microscope) with a precise arrangement of the molecules, the monohydrochloride does not has been prepared with a little regularity in the arrangement of its molecules (this being evidenced by a weak birefringence with a polarizing microscope) and not an arrangement which can be predicted with precision and it is thus "weakly" crystalline. The term

  "crystalline" is used here to embrace not only net salts-

  crystalline but also the monohydrochloride which appears "weakly" crystalline. The acid addition salts according to the invention, when they are introduced into aqueous injectable compositions, provide the dipolar ion in solution. The dipole ion has the structure::

C-- 'CORH

  O-CH, cooe CH3 The usefulness of broad spectra vis-à-vis various organisms of the dipolar ion form, and therefore of these aqueous compositions prepared from these salts, is indicated by the data of Aburaki et al. ., US

4,406,899.

  Aqueous compositions prepared from addition salts

  of acids according to the invention, simply by adding sterile water, provided

  acid solutions which cause unacceptable irritation when administered intravenously to rabbits and unacceptable painful sensations when administered intramuscularly to rabbits. Sulfate and dinitrate, which are acid addition salts, have

  reduced solubilities which are insufficient for compositions -

  typical injectables. We have now found that these questionable characteristics can be remedied by the use of these salts in physical mixture (i.e. in the form of a mixture of solids) with a base.

  non-toxic organic or mineral pharmaceutically acceptable in proportion

  such that they give a pH of about 3.5 to about 7 by dilution with water to a dipolar ion activity of i mg / ml to 400 mg / ml, normally 250 mg / ml (as determined by liquid chromatography at

  high performance, hereinafter referred to as HPLC).

  A salt that is now preferred is crystalline sulfate, the 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.

  The crystalline sulfate, or addition salt of sulfuric acid, can be easily prepared by a process which comprises the steps of: (a) forming an aqueous 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 the

  ambient temperature. These salts also exhibit excellent stability.

  lity at high temperatures and their loss of power (such as deter-

  mined by HPLC) is less than 15% k at storage for 1 month at 4556 C.

  The sulfuric acid addition salt is the salt which is preferred here.

  It has a power loss of less than 10% during storage for

  1 month at 45-56 C. What is very important is that he has low sclubi-

  lity in water, i.e. about 25 mg / ml, and that it crystallizes dcrc

  in water with minimal residual loss.

  Dinitrate, the acid addition salt according to the invention, also has a low solubility in water, that is to say about 60 mg / ml.

  and therefore it also provides a small residual loss when it

  tallization in water. Monohydrochloride, dihydrochloride and sesqui- or

  di-orthophosphate, other acid addition salts, have solubili-

  teas in water greater than 200 mg / ml and, as a result, they are made crystal-

  preferably read in organic solvents rather than water

in order to obtain 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 an aqueous 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 at a concentration greater than mg / ml; (b) initiation of crystallization; and

  (c) separation of the addition salt of sulfuric acid or crystal sulfate-

  linen. 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) in an aqueous medium free of organic solvent. Normally, we use

  in step (a) no more than 2 molar equivalents of sulfuric acid.

  Normally, the dipole ion is used in step (a) in such quantity

  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 H2SO4 1N) 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 m4se in slurry, preferably

  for 15 minutes to 2 hours. It is preferred that this crystallization step

  tion is carried out in an aqueous medium, free from organic solvent, and in this case, purities greater than 98% are normally obtained. Although the

  presence of organic solvent, for example acetone, promotes crystal-

  lization and increases the yield by lowering the solubility of the acid addition salt, the sulfate formed, in the crystallization medium, it can also promote the precipitation of impurities and lead to a

  decrease in purity. When using the dipole ion in the state

  pe (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, must

  be included in the crystallization medium to achieve a recovery

  reasonable. When we use acetone, we use it in a way

  suitable in an amount of 0.5 to 10 volumes / volume of crystallization medium

aqueous tion.

  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 acttone / water mixture, followed by washing with acetone alone or with 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 drying under vacuum at 30-50 C for 4 to 20 hours.

  The method according to the invention for the formation of 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 ion 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 Ba (OH) 2.8H20 in amount of 80 to 100% of theory, at a pH not less than 6.5 to precipitate BaSO4, filtration to remove BaSO4

  and recovering the filtrate which contains the dissolved dipolar ion and used

  tion in solution or separation of the solid dipolar ion (free base) by its lyophilization or addition of acetone to precipitate the amorphous dipolar ion and then separation of the solid dipolar ion by vacuum filtration, washing for example with acetone and vacuum drying. 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 the form of weak base) and Dowex XU-40090. . 01 (resin

  exchange of strong acid cations) and then lyophilization.

  Now coming to the preparation of crystalline dinitrate, which is an acid addition salt according to the invention, it is obtained by mixing (1) at least 2 molar equivalents of nitric acid and (ii) dipole ion corresponding to this salt so that it is present in the

  mixture at a concentration higher than 100 mg / ml, and then triggers

  ment of crystallization by seeding or rubbing with a stirrer

  tor, dilution with propanol-2 and cooling. Dinitrate cris-

  tall oil, another acid addition salt, is recovered for example by

  tion, washing successively for example with a propanol-2 / H2O mixture (50% 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 dipole ion in approximately 1 equivalent

  slow molar of hydrochloric acid and initiation of crystallization by addition of acetone with stirring and continued stirring, which is followed by the separation of the crystals, for example by vacuum filtration which is followed by '' Acetone washing and vacuum drying. Alternatively, the monohydrochloride 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 the '' are separated, for example by vacuum filtration which is followed by washing with

  methylene chloride and vacuum drying.

  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 addition of 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, triggering crystallization by addition of acetone and separating the crystals, for example by vacuum filtration, which is followed by washing first with acetone and then with ether, and then drying under vacuum. The crystalline sesqul-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

  dipolar. Suitable buffering agents include, for example, ortho-

  trisodium phosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) lysine and L (+) arginine. For intramuscular or intravenous administration to an adult human, a total dose of about 750 to about 3000 mg / d in divided doses is normally sufficient. It is undesirable 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 when injected. As indicated

  above, we have now found that we can remedy these

  come by passing these salts into a physical mixture, that is to say solid, with non-toxic organic or inorganic bases normally solid pharmaceutically acceptable in proportions such that they give a pH of between approximately 3.5 and approximately 7, preferably between

  about 4 and about 6, by diluting the mixture with water to a concentration

  1 mg / l injection up to 400 mg / l in dipolar ion, for example having a dipolar ion activity of 250 mg / ml such 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 preti-

  trage a sample to obtain a selected pH found in

the interval 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, for example. the nurse or the

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 is then preferably introduced into a flask or

  another container, all under 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. The L (+)

  lysine and L (+) arginine are the preferred ones since mixtures

  ges which contain them are reconstituted to provide injectable compositions which, upon injection, cause less suffering to animals than the compositions originating from a mixture containing other bases. L (+) lysine is very preferably used in a 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 packaging

  isolated and they retain 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 to 3 of Aburaki et al., patent of the United States of America

  rique 4,406,899. The dipole ion is indicated in Aburaki et al. under the

  name of 7-ra- (2-aminothiazol-4-yl) - "- (Z) -methoxyiminoacetamido] -3 - [(1-

  methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate.

  The following figures are given for explanatory and clarification purposes.

  cation: - Figure 1 - Figure 2 - Figure 3 The invention is a graphical representation of the absorption spectrum

  infrared crystalline sulfate of 7-úa- (2-amino-

  thiazol-4-yl) -a- (Z) -methoxyiminoacetamido3-3 - [(1-methyl-

  1-pyrrolidinio) methyl] -3-cephem-4-carboxylate measured on a dilution of this in KBr; is a graphical representation of the absorption spectrum

  infrared of crystalline sesquiphosphate of 7- [a- (2-

  aminothiazol-4-yl) - "- (Z) -methoxyiminoacetamido] -3 - [(1-

  methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate measured on a dilution of this in KBr; is a graphical representation of the absorption spectrum

  infrared crystalline diphosphate of 7-ra- (2-amino-

  thiazol-4-yl) -a- (Z) -methoxylminoacetamidoJ-3 - [(1-methyl-

  1-pyrrolidinio) methyl1] -3-cephem-4-carboxylate measured on

  a dilution of it in the KBr.

  is illustrated by the following working examples.

EXAMPLE I

  Preparation of the sulfuric acid addition salt 1.5 g of dipolar ion are added slowly to 10 ml of 1N H 2 SO 4 (1.59 molar equivalents), stirred rapidly 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

  5 ml of acetone, and vacuum dried at 40-50 C for the duration

of a night.

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

  risk. Upon analysis, it can be seen that the product obtained has the formula:

C19H24N605S2. H2S04

  and we get the following values:

C% H% N% S% H20%

  - calculated ...... 39.44 4.53 14.52 16.62 none - found ....... 38.91 4.57 14.64 16.71 1.42

EXAMPLE II

  Preparation of the sulfuric acid addition salt 1.5 g of the dipole ion are dissolved in 5 ml of water. 5 ml of 1M H2SO4 is slowly added to this solution while stirring. We induce

  then crystallization by sowing with a crystalline salt of ad-

  addition of acid 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

  S ml of acetone and dried under vacuum at 40-50 C for the night.

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

risk.

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 heading crystalline compound is collected and washed successively with 0.4 ml of a propanol-2 / H2O mixture (1/1),

  propanol-2 and then ether, which gives 127 mg of dinitrate.

  Upon analysis, it can be seen that the product obtained has the formula:

C19H24N605S2-2HNO3

  and we obtain the following values: C% - calculated ...... 37.62 4.32 18.47 10.57 - found ....... 36.92 4.10 18.08 10.67 (H2O content: 0.90%).

EXAMPLE IV

  Preparation of the monohydrochloride 1 g of dipolar ion is dissolved in 2.08 m of IN HCl (1 equivalent

  molar) at 20-25 C. 30 ml of acetone are added while stirring rapidly.

  for a period of 15 minutes, which is what forms crystals. Agitation is continued for 1 hour. The crystals are separated by vacuum filtration, washed with 10 ml of acetone and dried

under vacuum at 50 C for 2 hours.

  The typical yield is 0.9 g of crystalline monohydrochloride.

  On analysis, it is found that the product obtained has the formula: C19H24N605S2.HCl and the following values are obtained: C% H% N% S% Cl% H20% - calculated ...... 41.37 4, 75 15.2 11.63 12.86 - found ....... 39, 32 4.88 13.95 11.28 12.44 4.5

  (correction for H2O: C% = 41.17; N% = 14.61; S% = 11.82; Cl% = 13.03).

EXAMPLE V

  Preparation of the dihydrochloride and preparation of the monohydrochloride, starting from it 350 mg of dipolar ion are dissolved in 2 ml of 1N HCl. Add a ml of acetone to the resulting solution while stirring quickly and

  during an interval of 5 minutes, thanks to which 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

for 24 hours.

  The typical yield is 300 mg of crystalline dihydrochloride.

  On analysis, it is found that the product obtained has the formula: C19H24N605S2. 2HCl and we obtain the following values: C% H% N% S% Cl% H20% - calculated ...... 41.38 4.75 15.2 11.62 12.8 - found ..... .. 40.78 4.98 14.7 11.25 1.25

  (correction for H2O: C% = 41.1; NZ = 14.88; S% = 11.39; Cl% - 11.94).

  H% N% S% 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 during an interval of minutes. The crystalline mass is then passed into a slurry for 5 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

  Preparation of di-orthophosphate 1 g of dipolar ion is dissolved in 3.4 ml of H3PO4 at 144 mg / ml

  (2.2 molar equivalents) at 15 C. The resulting solution is suitable

  filtered to clarify it. 12 ml of acetone are added to the solution.

  clarified while stirring rapidly for a period of 10 minutes

  your, what makes crystals. Agitation is continued for 10 minutes. 30 ml of acetone are then added for a period of 10 minutes and the stirring is continued for a further 15 minutes. The crystals are collected by vacuum filtration, washed with 2 portions of 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.

  Upon analysis, it can be seen that the product obtained has the formula:

C19H24N605S2. 2H3P04

  and we get the following values:

C% H% N% H20%

  - calculated ...... 33.72 4.47 12.41 - found ....... 33.43 4.65 12.02 1.82

  (corrected for H2O: C% = 34.0; N% = 12.2).

  The sesqui-orthophosphate is formed as above except that 1.5 molar equivalents of H3PO4 are used instead of 2.2 molar equivalents.

EXAMPLE VII

  Stability at elevated temperatures Stability at elevated temperatures is determined by storing the preparations in dry packages at temperatures and for time periods as shown below, and determining power loss or gain by HPLC . A power gain in% is indicated in the form of a "plus" sign at the beginning of a figure. A lower power 9 10% for a period of 2 to 4 weeks a is usually indicative of a lower power loss

  for a period of 2 to 3 years at room temperature.

loss of -56 C at 10%

EXAMPLE VIII

  Test of physical mixtures The physical mixtures consist of crystalline sulfate, with (a) trisodium orthophosphate, (b) sodium bicarbonate, (c) L (+) lysine and (d) L (+) arginine. The bases are added in proportions such that they dilute the mixture with water to 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 to a dipolar ion activity of 250 mg / ml, as determined by test in

  HPLC. There are no solubility problems. Injections (100 mg / kg) are performed intramuscularly on rabbits, the pain

LOSS IN%

  C 56oC 100oC (weeks) (weeks) (days) Form 1 2 4 6 1 2 4 1 Dipolar ion 37 51 71 - 57 - 100 Sel-deR 2SO, 2.4 to +5 3 +5 1.4 5 A + 6 +3 0 to +6 0-10

  Salt (! W03) 2 8.8 3.4 0.68 10.3 3.7 2.4 -

BC1 salt 4.8 2.3 6.0 6.4 6.4 - -

  (BCl) salt 20 - 7.4 - 0 - 7.2 12.4

  Salt of (H3P04) 2 0 3.0 1.0 - 2.7 5.0 - -

  3 42 now at acceptable thresholds. The slightest pain is that which one

  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, set up

  lozenges in its crystalline form in the presence of potassium bromide.

  The powder X-ray diffraction pattern of crystalline sulfate

  7-r "- (2-aminothiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-

  1-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 and copper target, a nickel filter and the sample being contained between two glass plates. The speed of

  scanning is 2 per minute over the 5 to 40 C interval, and

  mechanically stores the graph to indicate the maximum diffraction angles. From this, we calculate the spacings (D) and the intensities

  relative (I / Io). They are listed below.

o Spacing d (A) I / Io (X)

9.20 100

6.80 50

, 50 28

, 09 22

4.50 38

4.41 44

4.19 63

3.78 38

3.64 44

3.39 25

3.31 31

3.15 47

EXAMPLE IX

  Preparation of sesquiphosphate The dipolar ion, 0.70 g, is dissolved, while stirring rapidly in 2.2 A 2.4 ml of 85% phosphoric acid (2.1 A 2, 2 molar equivalents) which have diluted 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.

  5 to 7 parts by volume (15 to 20 ml) of methanol are added to the

  filtrate while stirring rapidly for a period of 30 to 60 minutes.

  During this operation, crystals are formed and a

  rapid agitation for 1.5 to 2 hours.

  The crystalline product is recovered by vacuum filtration, the product is washed on filter first with 6) 8 ml of a 1/1 mixture (v / v)

* methanol / acetone taking care to keep the filter cake narrow

  tightly and then with acetone.

  The product is dried under vacuum at 50 ° C. for 2 hours, the yield

typical is 0.7 to 0.75 g.

  Interpretation of infrared (see figure 2)

(IR, KBr tablet).

  Position of the peaks (cm- 1) functional group

2800-3400NH +

  02800-3400 N NH, NH3 +, carboxyl OH 1780 e-lactam C = O 1680 carboxyl C = O 1660 amide C = O

1630 C = N, C = C

1550 amide OH

980, 1040 P04

  Heating behavior: An exotherm appears at 171.8 C in the differential scan 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: d 11.04 9.2 7.89 7.02 6.7, 5 4.64 4.456 4.3 I / Io 3.88 3.75 3.56 3.31 3.05 NMR interpretation: (1H 90 MHz NMR, solution in D20) a CO.

the COZ.

Chemical drift (ppm * / TSP)

2.0-2.4

3.04

3.3-3.6

3.94

4.12 4.12 4.8, 42

5.88

7.21 Stability

Description

  multiplet singlet multiplet doublet singlet doublet doublet doublet doublet doublet singlet Full Indication

14CH2, 14'CH2

12CH3

2CH, 13CH2, 13'CH2

  2CH CH3 11CH 11CH 6CH 7CH 18CH Time-temperature 1 day - 100 C 3 days 70 C 7 days - 70 C 1 week - 56 C 2 weeks - 56 C 4 weeks - 56 C i week - 45 C 2 weeks - 45 C 4 weeks - 45 C 8 weeks - 45 C 1 month - 37 C% loss, 9 1.9 1.0 1.4 o 1.4 0.7 1.6 2.5 Elemental analysis (% by weight) found basic dried

C ...... 35.44 36.3

H ...... 4.66 4.41

N ...... 12.88 13.2

H20 .... 2.29

22,

* H3P04 .. 23.06 23.6

Karl Fischer method.

  theory (sesquiphosphate) 36.4 4.7 13.4 monohydrate = 2.8% H2O 23.6

Claims (5)

  1.- Crystalline salts stable at the temperature of 7 - ["- (2-amino-   thiazol-4-yl) -a- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) -   methyl] -3-cephem-4-carboxylate selected from the group consisting of addition salts of sulfuric acid, dinitrate, monohydrochloride and dihydrochloride and addition salts of orthophosphoric acids   containing 1.5 to 2 molar equivalents of H3PO4 or their solvates.   2.- crystalline salts according to claim 1, chosen from the group   consisting of sulfate, monohydrochloride, dihydrochloride and ortho-   phosphate, acid addition salts, or their solvates.   3.- physical mixture of salt according to claim 1, with a base   non-toxic organic or mineral pharmaceutically acceptable in proportion   such that they give a pH of about 3.5 to about 7 per dilution   mixing with water to an injectable concentration.   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 approx.   ron 4 to about 6 by diluting the mixture with concentrated water injectable.   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 preparing 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 (ii) a dipolar ion corresponding to these salts;   (b) initiation of the crystallization of the acid addition salt   furic provided that when the dipole ion is present in the mixture at a concentration of less than 25 mg / ml, crystallization is carried out in the presence of an organic solvent; and   (c) separation of crystalline sulfate or addition salt of sulfuric acid   than. 8.- Method according to claim 7, wherein one puts step (b)   used in an aqueous medium free of organic solvent.   9.- method according to 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 of less than 500 mg / ml.   10.- Method according to claim 7, wherein the amount of dipole ion used in step (a) is such that it is present in the   mixture at a concentration greater than 25 mg / ml.   11. A method according to claim 8, in which the dipole ion is used in step (a) in an amount such that it is present in the   mixture P a concentration of between 100 mg / ml to approximately 200 mg / ml.   12.- Crystalline sulfate or addition salt of sulfuric acid depending on the claim 1.   13.- Crystalline sulfate of 7-E "- (2-aminothiazol-4-yl) -a- (Z) -methoxy-   iminoacetamidoJ-3 - [(1-methyl-1-pyrrolidinio) methyl J-3-cephem-4carboxylate, showing the following X-ray powder diffraction pattern: Spacing d (A) I / Io (X) 9.20 100 6.86 50 5.50 28 , 09 22 4.50 38 4.41 44 4.19 63 3.78 38 3.64 44 3.39 25 3.31 31 3.15 47   14.- Crystalline orthophosphate according to claim 1 and its hydrates.   15.- Crystalline phosphate of 7-ra- (2-aminothiazol-4-yl) -a- (Z) -methoxy-   iminoacetamidoJ-3 - [(1-methyl-1-pyrrolidinio) methyll-3-cephem-4carboxylate, with the following X-ray powder diffraction pattern: d I / Io 11.04 9.2 16 7.89 24 7.02 42 6.7 32 5.5 26 4.64 100 4.456 53 4.3 58 3.88 26 3.75 89 3.56 21 3.31 26 5.3.05 16