CS276717B6 - Process for preparing heat stable crystalline addition salts - Google Patents

Description

(57)

A process for the preparation of thermally stable crystalline addition salts of 7- [o (1- (2-aminothiazol-4-yl) - N - (z) -methoxyiminoacetamido) -3- (1-methyl-1-pyrrolidinio) methyl] -3-cephem 4-carboxylate with acids selected from the group consisting of sulfate, dinitrate, monohydrochloride, dihydrochloride and orthophosphoric acid addition salts containing 1.5 to 2 moles of orthophosphoric acid, and solvates thereof, characterized in that the zwitterionic ion corresponding to the above mentioned the salts are treated with an appropriate amount of the appropriate acid, crystallization of the above salt is induced, and the resulting thermally stable crystalline acid addition salt is recovered The salts produced have excellent stability at elevated temperature and are suitable for preparing dry mixtures which after dilution with water to a suitable concentration. injections have a favorable pH.

The invention discloses thermally stable semisynthetic salts of cephalosporin, the preparation of which has not been previously described in the literature, a process for the preparation of these salts and mixtures containing said salts.

rs

Aburaki et al. U.S. Pat. No. 4,406,899 discloses 7- [beta] - (2-aminothiazol-4-yl) - [alpha] - (Z) -methoxyiminoacetamido] -3- (1-methyl-1-pyrrolidinio) methyl] -3cephem- 4-carboxylate in the form of zwitterion, mention the respective acid addition salts (which are present in injectable form in the form of zwitterion) and show that the zwitterion form has a broader spectrum of action than ceftazidime and cefotaxime.

The cephalosporins described by Aburaki et al. however, they are stable for only a few hours in the form of injectables, and in the form of zwitterion, the aforementioned substance is unstable at room temperature even as a dry powder which, when stored at a higher temperature (e.g. loses 30% or more of its activity within 1 week and therefore requires specially insulated packaging and / or cooling. With regard to packaging and storage, the above substance is disadvantageous compared to ceftazidime and cefotaxime.

Although Aburaki et al. mentions acid addition salts, does not disclose the aforementioned patent, nor how these salts are made, or whether any of these salts are stable in the form of a dry powder. Kessler et al., Comparison of New Cephalosporin, BMY 28142, with O-ther Broad-Spectrum Y-Lactam Antibiotics, Antimicrobial Agents and Chemotherapy, Vol. 27, No. 2, pp. 207-217 (February 1985) refer to sulfuric acid salts, but do not disclose the preparation of the salt or whether the salt is stable at room temperature and whether it has good thermal stability in the form of a dry powder. increased temperature.

It has now been found that certain crystalline addition salts of 7- [cC- (2-aminothiazol-4-yl)]

-cO- (z) -methoxyiminoacetamido-3- [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate with acids exhibit excellent stability at room temperature in the form of a dry powder and have, compared to the zwitterion, better stability at elevated temperature. By dry powder is meant a powder with a moisture content of less than 5% by weight.

These acid addition salts are crystalline salts of 7- [α- (2-aminothiazol-4-yl) -o (z - (Z) -methoxyiminoacetamido) -3- (1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate selected from the group consisting of sulfate, dinitrate, monohydrochloride, dihydrochloride and orthophosphoric acid addition salts (containing 1.5 to 2 moles of orthophosphoric acid per mole of salt, for example ranging from sesqui to di-orthophosphate) and solvates thereof. While sulphate, dinitrate, dihydrochloride and orthophosphoric acid addition salts are prepared in a clearly crystalline form (as evidenced by birefringence under a polarizing microscope) with precisely arranged molecules, the monohydrochloride is obtained only to a certain degree regularity in the arrangement of the molecule (as evident from a bad birefringence under a polarizing microscope) The term crystalline used includes not only brightly crystalline salts, but also poorly crystalline monohydrochloride.

<described acid addition salts, when converted to injectable aqueous preparations, form a solution of zwitterion in solution having the structure: • coirah ₂ n

IV \

0-CH-, coo

The wide range of applicability of this zwitterion, and thus the aqueous formulations prepared from the salts of the invention, to various organisms results from the data reported by Aburaki et al. in U.S. Patent No. 4,406,899.

The aqueous compositions prepared from the addition salts of the present invention by mere addition of sterile water form acidic solutions which, when administered intravenously to rabbits, cause unacceptable irritation and, when administered intramuscularly to rabbits, exhibit severe pain. Sulfate and dinitrate show only limited solubility, which is not sufficient for the preparation of typical injectables. However, it has been found that these disadvantages can be overcome by using the salts of the invention in the form of a physical mixture (i.e., a mixture of solids) and a pharmaceutically acceptable non-toxic organic or inorganic base in such a ratio that ml to 400 mg / ml, the resulting formulation has a pH in the range of about 3.5 to 7. Normally, the physical mixture is diluted with water to a zwitterionic concentration of 250 mg / ml. These concentrations are determined by high resolution liquid chromatography.

A preferred addition salt of the invention is crystalline sulfate, which is advantageous because its low solubility in water (25 mg / ml) allows it to be isolated from the aqueous medium by crystallization.

The crystalline salts of the invention (hereinafter the salts of the invention) have excellent stability at room temperature and lose less than 1% efficiency (as determined by high resolution liquid chromatography) after storage for one month at room temperature. These salts are also excellent stable at elevated temperature and, after storage for one month at 45 to 56 ° C, lose only less than 15% efficiency (as determined by high performance liquid chromatography).

A preferred salt of the present invention is a sulfuric acid addition salt which loses less than 10% activity after storage for one month at 45 to 56 ° C. Very important is the low solubility of this salt in water, which is about 25 mg / ml and allows crystallization of the salt from water with minimal losses.

The addition salt with two moles of nitric acid (dinitrate) also has a low solubility in water of about 60 mg / ml and, therefore, there is little loss when crystallized from water.

The monohydrochloride, dihydrochloride and sesqui- or di-orthophosphate have a solubility in water of greater than 20 mg / ml and are therefore preferably not crystallized from water but from organic solvents to obtain good yields.

It is an object of the present invention to provide a process for the preparation of thermally stable crystalline addition salts of 7- (2-aminothiazol-4-yl) -1 H- (Z) -methoxyiminoacetamido-3- [(1-methyl-1-pyrrolidinio) methyl] -3-cephem- 4-carboxylate with acids selected from the group consisting of sulfate, dinitrate, monohydrochloride, dihydrochloride and orthophosphoric acid addition salts containing 1.5 to 2 mole equivalents of orthophosphoric acid, and solvates thereof, characterized in that a zwitterionic ion corresponding to said salts is treated with an appropriate amount of the appropriate acid, crystallization of the aforementioned salt is induced and the resulting thermally stable crystalline acid addition salt is isolated.

Specifically, the sulfuric acid addition salt is prepared by (a) preparing an aqueous mixture of (i) at least 1 mol equivalent of sulfuric acid and (ii) a zwitterion in an amount such that it is present in the mixture at a concentration greater than 25 mg / ml (b) crystallizing and (c) isolating the crystalline sulfuric acid addition salt.

The double ion is preferably used in step (a) in an amount such that it is present in the mixture at a concentration of about 100 mg / ml to 200 mg / ml, and step (b) is preferably carried out in an aqueous solvent-free aqueous medium. Normally no more than 2 mol equivalents of sulfuric acid are used in step (a). Typically, in step (a), the zwitterion is used in an amount such that it is present in the mixture at a concentration of less than 500 mg / ml.

Step (a) is readily accomplished by adding a solid zwitterion to a solution of sulfuric acid (e.g. 1N sulfuric acid) with vigorous stirring to form a solution. Alternatively, step (a) may be accomplished by dissolving the solid zwitterion in water and slowly adding sulfuric acid with stirring to form a solution.

Step (b) is carried out by inducing crystallization, preferably by seeding, and then allowing the product to precipitate, preferably 15 minutes to 2 hours. It is preferred to carry out this crystallization step in an aqueous solvent-free aqueous medium, since in this case a purity of more than 98% is normally achieved. Although the presence of an organic solvent such as acetone promotes crystallization and increases yield by reducing the solubility of the resulting sulfuric acid addition salt in the crystallization medium, it can also promote precipitation of impurities, resulting in reduced product purity. When the zwitterion is used in step (a) in an amount such that it is present in the mixture at a concentration of less than 25 mg / ml, a solvent, preferably acetone, must be added to the crystallization medium to isolate the product in reasonable yield. If acetone is used, 0.5 to 10 volumes of acetone are expediently added to each volume of the aqueous crystallization medium.

Step (c) is effected by separating the crystals from the crystallization medium, preferably by vacuum filtration, followed by washing, for example with aqueous acetone 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). ) and then drying, for example by vacuum drying at 30 to 50 ° C for 4 to 20 hours.

The described process for the preparation of the sulfuric acid addition salt results in the purification of the zwitterion due to the lower solubility of the sulfuric acid addition salt as compared to the solubility of the zwitterion and can also be used to purify the zwitterion without isolating it in solid form. If practically pure zwitterion (free base) is to be obtained from the sulfuric acid addition salt prepared, this can be accomplished by dissolving the salt in water, at a pH of less than 6.5 barium hydroxide octahydrate is added in an amount of 90 to 100% of theory, the precipitated barium sulphate is separated and the filtrate containing the dissolved zwitterion is either used as a solution or a solid zwitterion (free base) is isolated from it by lyophilization or by adding acetone to precipitate amorphous zwitterion by isolating this solid zwitterion by vacuum filtration by washing with acetone and drying under vacuum. Alternatively, the sulfuric acid addition salt is converted to the free base using an ion exchanger such as Dowex KGR (weakly basic anion exchange resin) or Dowex XU-40090.01 (strongly acidic cation exchange resin) followed by lyophilization.

The crystalline dinitrate of the invention is prepared by mixing (i) at least two mol equivalents of nitric acid and (ii) an appropriate zwitterion in an amount such that it is present in the mixture at a concentration greater than 100 mg / ml by seeding or scratching the vessel walls. Crystallize with a glass rod, dilute the mixture with 2-propanol and cool. The crystalline dinitrate is isolated, for example, by filtration, washed successively with, for example, 50% (v / v) aqueous 2-propanol, 2-propanol alone and ether, and dried under vacuum at 50 ° C for 2 hours.

The monohydrochloride is prepared by dissolving the zwitterion in about 1 mole equivalent of hydrochloric acid by adding acetone. Crystallization is induced with stirring, stirring is continued, and the precipitated crystals are isolated, for example by vacuum filtration followed by acetone washing and vacuum drying. ,

Crystalline dihydrochloride is prepared by dissolving the zwitterion in at least two equivalents of hydrochloric acid, inducing crystallization by adding acetone, and isolating the crystals, for example by vacuum filtration, washing with acetone, and drying in vacuo.

The crystalline di-orthophosphate according to the invention is prepared by dissolving the zwitterion in at least two mole equivalents of phosphoric acid, inducing crystallization by adding acetone and isolating the crystals, for example by vacuum filtration, washing first with acetone and then ether, followed by drying under vacuum. Crystalline sesquiorthophosphate is prepared in the same manner except that about 1.5 mol equivalents of phosphoric acid are used.

The salts of the invention are formulated into injectables by dilution with sterile water and buffering to pH 3.5 to 7. The zwitterion concentration in the injectable formulation ranges from 1 mg / ml to 400 mg / ml. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine, and L (+) - arginine. Intramuscular or intravenous administration to adult patients in human medicine normally requires a total daily dose of about 750 to 3000 mg, which is administered in several divided doses.

It is not desirable to process the salts of the invention into injectable formulations by the addition of sterile water only, since the sulfate and dinitrate are not sufficiently soluble and thus do not provide a normal concentration formulation suitable for administration, and since these salts form a very low pH. , 8 to 2.5) which are painful for injection. As mentioned above, this deficiency can be overcome by preparing a physical (i.e. solid) mixture of these salts with a pharmaceutically acceptable, normally solid, non-toxic alkaline organic or inorganic nature, in such a proportion that after diluting the mixture with water to a zwitterionic concentration of from 1 mg / ml to 400 mg / ml, for example 250 mg / ml, as determined by high-resolution liquid chromatography, the resulting injectable preparation has a pH in the range of about

3.5 to 7, preferably from about 4 to 6.

The exact proportions of the ingredients in this physical composition vary from batch to batch because the purity of the salt varies from batch to batch. The necessary proportions of the individual components are determined for a given batch by pre-titrating the sample so that the resulting preparation has a pH within the above range.

The physical composition described above is easy to store and transport in solid form, utilizing the advantageous stability of the salts of the invention, and is easily converted into an injectable formulation by simply adding water just prior to use by the nursing staff or physician.

The physical mixture is prepared by mixing the salt and the base into a homogeneous mixture using, for example, a standard mixer in a dry atmosphere, and then preferably being filled into ampoules or other containers, all operating under aseptic conditions.

As mentioned above, the bases useful for preparing the physical compositions of the invention include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine, and L (+) - arginine. Of these bases, L (+) - lysine and L (+) - arginine are preferred because the compositions containing these bases form, upon reconstitution, injectable compositions which are less painful when injected than compositions prepared from compositions containing other bases. Very preferably, L (+) - lysine is used in such a ratio that diluting the resulting mixture with water gives a zwitterionic concentration of 250 mg / ml (as determined by high resolution liquid chromatography) having a pH in the range of 3.5 to 6.

The salts of the invention and practically dry physical compositions containing them can be stored without cooling and without the need for insulated packaging without losing high efficiency.

In some of the following examples, an unstable zwitterion is used as the starting material. The preparation of this zwitterion is described in Examples 1-3 of U.S. Patent No. 4,406,899 to Aburaki et al. Aburaki et al. describe this zwitterionic ion as 7- (Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1-pyrrolidinium) methyl] -3-cephem-4 -carboxylate.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of sulfuric acid addition salt (sulphate)

To 10 ml of vigorously stirred 1N sulfuric acid (1.59 mol equivalents), 1.5 g of zwitterion is slowly added at 20-26 ° C. The resulting solution was seeded with a sulfuric acid addition salt crystal and allowed to crystallize for 0.5 hours. The crystalline material was collected by vacuum filtration, washed with 3 mL of 50% (v / v) aqueous acetone and twice with 5 mL of acetone each, then dried in vacuo at 40-50 ° C overnight.

1.3 g of sulfuric acid addition salt are obtained.

^{For C} 19 ^H 24 ^N 6 ° 5 ^S 2 ' ^H 2 ^SO 4 calculated: 39.44% C, 4.53% H, 14.52% N, 16.62% S, 0% H 10 O; Found: 38.91% C, 4.57% H, 14.64% N, 16.71% S, 1.42% H ₂ 0

Example 2

Preparation of sulfuric acid addition salt

Dissolve 1.5 g of zwitterion in 5 ml of water and slowly add 5 ml of 1M sulfuric acid to the solution. Inoculation with a crystal of the corresponding acid addition salt induced crystallization and the mixture was allowed to crystallize for 0.5 hours. The precipitated crystals are then filtered off under vacuum, washed with 3 ml of 50% (v / v) aqueous acetone and twice with 5 ml of acetone each, and then dried under vacuum at 40 to 50 ° C overnight.

1.3 g of the sulfuric acid addition salt are obtained.

Example 3

Preparation of nitric acid addition salt (dinitrate)

Dissolve 300 mg of zwitterion in 0.5 ml of 2N nitric acid. Scratching the vessel walls under a glass rod solution induces crystallization, dilute the mixture with 0.4 mL of 2-panole and cool. The crystalline title compound was collected and washed successively with 0.4 mL of a mixture of equal parts of 2-propanol and water, 2-propanol and ether. 127 mg of the desired dinitrate is obtained.

For C ₁₉ H ₂₄ N ₆ ^O 5 S ₂ .2HNO ₃ calculated: 37.62% C, 4.32% H, 18.47% N, 10.57% S;

Found: C 36.92, H 4.10, N 18.08, S 10.67 (0.90% water content).

Example 4

Preparation of the addition salt with 1 mol of hydrochloric acid (monohydrochloride) g of zwitterionic ion at 20-25 ° C is dissolved in 2.08 ml (1 mol equivalents) of 1N hydrochloric acid and 30 ml of acetone are added under vigorous stirring over 15 minutes. The crystals are isolated by vacuum filtration, washed with 10 ml of acetone and dried under vacuum at 50 DEG C. for 2 hours.

0.9 g of crystalline monohydrochloride is obtained.

For C ₁₉ H ₂₄ N ₆ O ₅ S ₂ .HC1: calculated: 41.37% C, 4.75% H, 15.2% N, 11.63% S, 12.86% Cl; found: 39.32% C, 4.88% H, 13.95% N, 11.28% S, 12.44% Cl, 4.5% H ₂ O after correcting for water content:

C, 41.17; N, 14.61; S, 11.82; Cl, 13.03.

Example 5

Preparation of addition salt with 2 mol of hydrochloric acid (dihydrochloride)

350 mg of zwitterion are dissolved in 2 ml of 1N hydrochloric acid and 10 ml of acetone are added with vigorous stirring over 5 minutes, whereupon crystals are formed. Stirring was continued for a further 5 minutes, then an additional 10 ml of acetone was added and the mixture stirred for a further 0.5 hours. The crystals were isolated by vacuum filtration, washed twice with 5 ml of acetone each, and dried under vacuum at 40-45 ° C for 24 hours.

300 mg of crystalline dihydrochloride are obtained.

For _Ig C H ₂₄ N ₆ O ₅ S ₂ .2HC1 calculated: 41.38% C, 4.75% H, 15.2% N, 11.62%, 12.8% Cl; Found: C 40.78, H 4.98, N 14.7%, S 11.25%, H ₂ O 1.25 corrected for water content:

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

Example 6 f Preparation of an addition salt with 2 moles of orthophosphoric acid (di-orthophosphate) g of zwitterionic ion at 15 ° C is dissolved in 3.4 ml of a solution containing 144 mg of phosphoric acid (H ₃ PO ₄ ; 2.2 mol equivalents) in 1 ml. The resulting solution was clarified by filtration, and 12 ml of acetone was added with vigorous stirring over 10 minutes, forming crystals, with vigorous stirring. Stirring was continued for 10 minutes, then an additional 30 ml of acetone was added over 10 minutes and stirring was continued for 15 minutes. The crystals were collected by vacuum filtration, washed twice with 5 ml of acetone and twice with 5 ml of ether each, and then dried under high vacuum for 16 hours.

In this type of preparation, the typical yield of crystalline di-orthophosphate is 1.1 g.

For C ₁₉ H ₂₄ ^N 6 ° 5 ^N 2 ' .28 I ₃ PC '4 calculated: 33.72 % C, 4.47 % H, 12.42 % N; found: 33.43 % C, 4.65 % H, 12.02 % N, 1.82% H ₂ O

after correction for water content:

34.0% C, 12.2% N.

The sesqui-orthophosphate is prepared in the same manner as above except that 1.5 mol equivalents are used instead of 2.2 mol equivalents of orthophosphoric acid.

• 7

Example 7

Stability at elevated temperature

The stability at elevated temperature is determined by storing the individual preparations in dry containers at certain temperatures and for a period of time, as shown in the following table, and then detecting or increasing the efficacy by high resolution liquid chromatography. The efficiency gain in% is indicated by a + sign in front of the corresponding value. A 10% loss in potency after two to four weeks of storage at 45 to 56 ° C usually indicates less than a 10% loss in potency after two to three years of storage at room temperature.

TABLE

test form 45 'C (weeks) loss 1 efficiency 56 C (weeks) 2 during storage 4 100 c (days) 1 1 2 4 6 zwitterion 37 51 71 - 57 - 100 ALIGN!

sulfate 2,4 to

+ 5 3 +5 1.4 5 to +6 +3 0 to +6 0 - 10 dinitrate 8.8 3.4 0.68 10.3 3.7 2.4 - - monohydro- chloride 4.8 2.3 6.0 6.4 6.4 - dihydrochloride O - 7.4 - 0 7.2 12.4 di-orthophosphate O 3.0 1.0 - 2 ‘, 7 5.0 - -

Example 8

Testing of physical mixtures

Physical mixtures of crystalline sulfate with (a) trisodium orthophosphate (b) sodium bicarbonate (c) L (+) - lysine and (d) L (+) - arginine are prepared.

The individual bases are added in an amount such that after dilution of the mixture with water to a concentration (activity) of zwitterion of 250 mg / ml (as determined by high-resolution liquid chromatography) the individual preparations have the following pH values:

trisodium orthophosphate - pH 6.0 sodium bicarbonate - pH 6.0 L (+) - lysine - pH 6.0 L (+) - arginine - pH 6.0

Injectable preparations are obtained by reconstituting the mixture with sterile water to obtain a 250 mg / ml oboCS 276717 B6 activity (as determined by high resolution liquid chromatography). There are no problems with solubility. Injections at 100 mg / kg are administered intramuscularly to rabbits, with pain within acceptable limits. The arginine-containing composition has the lowest pain.

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

X-ray diffraction pattern of 7- [alpha] - (2-aminothiazol-4-yl) - N - (Z) -methoxyiminoacetamido] -3- [(1-methyl-1-pyrrolidinio) methyl] -3-cefem-4 crystalline sulfate powder sample The carboxylate prepared according to Example 1 or 2, from which the interplanar distances (d) and relative intensities (I / l ') shown in the following table were calculated, was determined on a Rigaku powder diffractometer using a copper anticatode, nickel filter and pattern on glass dish. Scanning speed 2 '/ min ranging from 5 * to 40', with the diagram being mechanically recorded to show the maximum diffraction angles.

d (10 ~ ^10m ) 1/1 '(¾)

9,20 100 ALIGN! 6.80 50 5.50 28 5.09 22nd 4.50 38 4.41 44 4.19 63 3.78 38 3.64 44 3.39 25 3.31 31 3.15 47

Example 9

Preparation of sesquiphosphate

0.70 g of zwitterion is dissolved with vigorous stirring in 2.2 to 2.4 ml of 85% phosphoric acid (2.1 to 2.2 mol equivalents), which was diluted 1: 10 (v / v) with water. The solution is clarified by filtration through a 0.22-0.45 µm membrane filter. 5-7 volumes (15-20 ml) of methanol are added to the filtrate with vigorous stirring over 30-60 minutes, forming crystals. Stirring is continued for a further 1.5 to 2 hours, the crystalline product is isolated by vacuum filtration and the product is first washed on the filter with 6-8 ml of a mixture of equal volumes of methanol and acetone (taking care that the filter cake is constantly tightly packed) and then with acetone. After drying under vacuum at 50 DEG C. for 2 hours, the desired product is obtained in a yield of 0.7 to 0.75 g.

The following overview gives an interpretation of the IR spectrum (KBr technique) of the product.

maximum position t 'li (cm) functional group

2800 to 3400

1780

1680

1660

1630

1550

980, 1040

NH, ^NH-4, OH, carboxyl &-lactam carbonyl carbonyl carbonyl group of the carboxylic amide group C = N, C = C

OH amide

Heating behavior

Exotherm at 171.8 ° C was detected in the differential scanning calorimeter.

X-ray diffraction

The X-ray diffractogram of the powder sample of the prepared sesquiphosphate is measured on a Rigaku powder diffractometer in the same manner as described above with respect to sulfate. The evaluation is presented in the following overview.

d (10 ~ ^10m ) 1/1 '(%)

11.04 32 9.2 16 7.89 24 7.02 42 6.7 32 5.5 26 4.64 100 ALIGN! 4,456 53 4.3 58 3.88 26 3.75 89 3.56 21 3.31 26 3.05 16

Interpretation of NMR spectrum

H-NMR spectrum measured at 90 MHz in deuterium oxide:

chemical shift

(dpv values versus trimethylsilylpropanesulfonic acid) signal shape integration assignment 2.0 to 2.4 multiplet 4 14CH ₂ , 14'CH. 3.04 singlet 3 12CH ₃ 3.3 to 3.6 multiplet 5 2CH, 13CH ₂ ,: 3.94 doublet 1 2CH 4.12 singlet 3 20CH ₃ 4.12 doublet 1 UCH 4.8 doublet 1 UCH 5.42 doublet 1 6CH 5.88 doublet 1 7CH 7.21 singlet 1 18CH

Stability time - temperature loss (%, 1. day; 100 ALIGN! C 10.9 3 days; 70 ’ C 0 7 days; 70 ' C 1.9 1 week; 56 'C 1.0 2 weeks; 5 6 *C 1.4 4 weeks; 56 'C 0 1 week; 45 'C 0 2 weeks; 4 5 'C 1.4 4 weeks; 45 'C 0.7 8 weeks; 4 5 'C 1.6 1 Moon; 37 *C 2.5

and

Elemental analysis (% by weight) dry base theory (sesquiphosphate) found 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 ^x) - monohydrate = 2.8% Hj ^{* 1 2 3 4} h ₃ Mon ₄ 23.06 23.6 23.6

Legend:

(x) Karl Fischer method

PATENT CLAIMS

Claims (12)

A process for the preparation of thermally stable crystalline addition salts of 7- [ec- (2-aminothiazol-4-yl) -O- (Z) -methoxyiminoacetamido] -3- (1-methyl-1-pyrrolidinio) methyl] -3-cephem-4- a carboxylate with acids selected from the group consisting of sulfate, dinitrate, monohydrochloride, dihydrochloride and orthophosphoric acid addition salts containing 1.5 to 2 moles of orthophosphoric acid, and solvates thereof, characterized in that the zwitterionic corresponding to said salts is treated with by crystallization of the aforementioned salt, and the resulting thermally stable crystalline acid addition salt is isolated. 2. The process of item 1, for the preparation of thermally stable crystalline 7-β- (2-aminothiazol-4-yl) -O- (Z) -methoxyiminoacetamido-3 - [(1-methyl-1-pyrrolidinio) methyl] - 3-Cephem-4-carboxylate, characterized in that (a) an aqueous mixture of (i) at least one mole equivalent of sulfuric acid and (ii) a zwitterionic ion corresponding to said salt is prepared, (b) inducing crystallization of said sulfate with that if the zwitterion 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) isolating the aforementioned crystalline sulfuric acid addition salt. 3. The process of item 1, for the preparation of a thermally stable crystalline 7- [beta] - (2-aminothiazol-4-yl) -CG- (z) -methoxyiminoacetamido] -3- [(1-methyl-1-pyrrolidinio) methyl] methyl- 3-Cephem-4-carboxylate, characterized in that (a) a mixture of (i) at least two mol equivalents of nitric acid and (ii) a zwitterionic ion corresponding to said salt is prepared such that the ion is present in the mixture at a concentration greater than 100 mg / ml, (b) inducing crystallization of the aforementioned salt, preferably by seeding or scratching the vessel walls with a glass rod followed by dilution with 2-propanol and cooling, and (c) isolating the stable crystalline dinitrate, preferably by filtration, washing and drying under vacuum. 4. The process of item 1, for producing a thermally stable crystalline monohydrochloride 7- [° C- (2-aminothiazol-4-yl) -O- (Z) -methoxyiminoacetamido] -3-Q (1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate, wherein (a) the zwitterion corresponding to the above salt is dissolved in 1 mol equivalent of the acid CS 276717 336 hydrochloride, inducing crystallization of the aforementioned salt, preferably by adding acetone with stirring, and the aforementioned stable crystalline monohydrochloride is isolated, preferably by vacuum filtration followed by washing with acetone and drying under vacuum. 5. The method of item 1, for the preparation of a thermally stable crystalline 7- (2-aminothiazol-4-yl) -Λ- (Z) -methoxyiminoacetamido dihydrochloride -3-C (1-methyl-1-pyrrolidinio) methyl -3- cefem-4-carboxylate, characterized in that the zwitterion corresponding to the above dihydrochloride is dissolved in at least 2 mol equivalents of hydrochloric acid, inducing crystallization of the above dihydrochloride, preferably by adding acetone, and isolating the crystalline product, preferably by vacuum filtration followed by washing with acetone and drying in vacuo. 6. The process of item 1, for the preparation of a thermally stable crystalline 7- [ee- (2-aminothiazol-4-yl) - o - (Z) -methoxyiminoacetamido] -3- [- (1-methyl) di- or sesquiorthothosphate 1-pyrrolidinio) methyl-3-cephem-4-carboxylate, characterized in that the zwitterion corresponding to the desired orthophosphoric acid addition salt is dissolved in at least 2 mol equivalents of phosphoric acid in the preparation of di-orthophosphate or in 1.5 mol phosphoric acid For example, the crystalline product is isolated, preferably by vacuum filtration followed by successive washing with acetone and ether, and drying under vacuum. 7. The process of claim 1 wherein step (b) is carried out in an aqueous solvent-free aqueous medium. 8. The method of claim 7, wherein the zwitterion 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. 9. The method of claim 1, wherein the zwitterion is used in step (a) in an amount such that it is present in the mixture at a concentration of greater than 25 mg / ml. 10. The method of claim 7, wherein the zwitterion is used in step (a) in an amount such that it is present in the mixture at a concentration ranging from 100 mg / ml to 200 mg / ml. 11. A process according to any one of Claims 1 and 7 to 10, wherein the corresponding starting materials and processes are used to form crystalline 7- [2- (2-aminothiazol-4-yl) -o-O-sulfate]. (Z) -methoxy iminoacetamido-3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4-carboxylate with the following X-ray powder diffraction pattern d (10 ¹⁰ m) I / X * (%) 9,20 100 ALIGN! 6.86 50 5.50 28 5.09 22nd 4.50 38 4.41 44 4.19 63 3.78 38 3.64 44 3.39 25 3.31 31 3.15 47 12. The process of claim 6, wherein the corresponding starting materials and procedures are used to form crystalline 7- ^C10 - (2-aminothiazol-4-yl) - (Z) -methoxyiminoacetamido] -3- [ (1-methylpyrrolidinio) methyl 3-cephem-4-carboxylate with the following powder X-ray diffraction pattern d (10 ~ ¹⁰ m) 1/1 '(¾) 11.04 32 9.2 16 7.89 24 7.02 42 6.7 32 5.5 26 4.64 100 ALIGN! 4,456 53 4.3 58 3.88 26 3.75 89 3.56 21 3.31 26 3.05 16