CS276849B6 - Process for preparing heat stable crystalline mono chloride - Google Patents

Description

(57)

A process for the preparation of heat stable crystalline crystalline monohydrochloride 7 - [[1- (2-aminothiazol-4-yl)] - (- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem- 4-carboxylate, characterized in that 7- (4- (2-aminothiazol-4-yl)) - (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-dihydrochloride The cephem-4-carboxylate is suspended in methylene chloride, 1 mol equivalent of triethylamine is added under stirring, then the monohydrochloride formed is isolated, preferably by vacuum filtration, washing with methylene chloride and drying under vacuum. compositions which, when diluted with water to a concentration suitable for injection, have a favorable pH.

SUMMARY OF THE INVENTION The present invention provides a thermally stable semisynthetic salt of cephalosporin, the preparation of which has not been previously described in the literature, a process for the preparation of said salt and a mixture comprising said salt.

Aburaki et al. U.S. Pat. No. 4,406,899 discloses 7- [4- (2-aminothiazol-4-yl) -N- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] - 3-cefem-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, or how these salts are produced, or whether any of these salts are stable in dry powder form. Kessler et al., Comparison of New Cephalosporin, BMY 28142, with Other Broad-Spectrum β-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 - [* - (2-aminothiazol-4-yl) - (Z) -methoxy iminoacetamidol -3-t (1-methyl-1-pyrrolidinio) The methyl 3-cephem-4-carboxylate with acids exhibit excellent stability at room temperature in the form of a dry powder and have better stability at elevated temperature compared to the zwitterion. 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- [N - (2-aminothiazol-4-yl) - N - (Z) -methoxyiminoacetamido] -3-1 (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. In this case, the term crystalline is used to denote at least a partial characterizing arrangement of the molecule. While sulphate, dinitrate, dihydrochloride and orthophosphoric acid addition salts are prepared in a clearly crystalline form (as evidenced by refraction under a polarizing microscope) with precisely arranged molecules, the monohydrochloride is obtained with only a certain degree of regularity in the molecular arrangement (as evident from the poor) dvojCS 276849 B6 under a polarizing microscope) and it cannot be predicted precisely - it is poorly crystalline. The term crystalline used includes not only clearly crystalline salts but also poorly crystalline monohydrochloride.

The acid addition salts described above, when converted into injectable aqueous preparations, form a zwitterion in solution having the structure of the formula:

The broad spectrum of use of this zwitterionic ion, and thus of 1 aqueous formulations prepared from the aforementioned salts, against various organisms results from the data reported by Aburakl et al. in U.S. Patent No. 4,406,899.

Aqueous formulations prepared from the addition salts mentioned above simply by the addition of sterile water form acidic solutions which, when administered intravenously to rabbits, cause unacceptable irritation and, when administered to rabbits, are highly painful. 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) with 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.

Our co-pending Czechoslovak patent specification No. 276,717 discloses a process for preparing all of the aforementioned thermally stable acid addition salts by reacting the aforementioned zwitterion with an appropriate amount of the corresponding acid, causing crystallization of the resulting salt and isolating it.

In accordance with the invention, it has been found that monohydrochloride

- (2-Aminothiazol-4-yl) - N - (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolinedinio) methyl] -3-cephem-4-carboxylate can also be obtained from the corresponding dihydrochloride .

Accordingly, the present invention provides a process for the preparation of thermally stable crystalline 7-E - (2-aminothiazol-4-yl- (Z) -methoxyiminoacetamido-1-3-l- (1-methyl-1-pyrrolidinio) methyl) -3-monohydrochloride.

CS 276849 86 ·>

-cephem-4-carboxylate, characterized in that it is a dihydrochloride

7- [β - (2-aminothiazol-4-yl- <Z) -methoxyiminoacetamido] -3-1 Cl-A

The methyl-1-pyrrolidinio) methyl-3-cephem-4-carboxylate is suspended in methylene chloride, 1 mol equivalent of triethylamine is added with stirring, then the resulting monohydrochloride is isolated, preferably by vacuum filtration, washing with methylene chloride and drying under vacuum.

The preparation of the starting dihydrochloride is the subject of our above-cited related Czechoslovak patent specification and is further described below in an exemplary embodiment.

The salt of the invention is 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 ranging from about 750 to 3000 mg, which is administered in several divided doses.

It is not desirable to process the salt of the invention into injectable formulations by simply adding sterile water, since upon dissolution of this salt formulations having a very low pH value (8 to 2.5) are obtained which are painful for injection. As mentioned above, this drawback can be remedied by preparing a physical (i.e., solid) mixture of these salts with a pharmaceutically acceptable, non-toxic, basic, organic or inorganic alkaline agent under normal conditions, in such a ratio that after diluting the mixture with water to a zwitterionic concentration. of the ionic composition 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 about 4 to 6.

The exact proportions of the ingredients in this physical mixture vary from batch to batch, as the purity of the salt varies from batch to batch. The necessary proportions of the individual components are determined for the respective 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, taking advantage of the stability of the salts of the invention, and easily converted into an injectable formulation by simply adding water just prior to use by the attending staff or physician.

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

As mentioned above, the bases useful in the preparation of the physical compositions of the invention include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylgluCS 276849 B6, carboxylate, 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 a ratio such that diluting the resulting mixture with water yields a zwitterionic concentration of 250 mg / ml (as determined by liquid chromatography with high resolution) having a pH in the range of 3.5 to 6.

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

The invention is illustrated by the following non-limiting example. This example uses a zwitterion, the preparation of which is described in Examples 1-3 of U.S. Patent No. 4,406,899 to Aburakl et al. Aburaki et al. describe this zwitterionic ion as 7- [o - (2-aminothiazol-4-yl) - N - (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4- carboxylate.

Example

Preparation of the addition salt with 2 mol of hydrochloric acid (dihydrochloride) followed by preparation of the monohydrochloride

350 mg of zwitterion are dissolved in 2 ml of 1N hydrochloric acid and 10 ml of acetone are added under vigorous stirring over 5 minutes to form crystals. Stirring was continued for a further 5 minutes, then an additional 10 ml of acetone was added and the mixture was 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.

Analysis: for C 19 H 24 N 6 O 5 S 2. H, 4.75; N, 15.2; N, 11.62; Cl, 12.8;

Found: C 40.78, H 4.98, N 14.7, S 11.25, H 2 O 1.25;

after correction for water content:

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

g of the dihydrochloride prepared as described above is suspended in 20 ml of methylene chloride in a sealed vessel at 20-25 ° C and 0.28 ml of triethylamine is added to the suspension over 15 minutes. After five hours of crystallization, the precipitated monohydrochloride crystals are isolated by vacuum filtration, washed twice with 5 ml of methylene chloride each time and dried under vacuum at 50 DEG C. for 2 hours. Yield 800 mg.

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, then using high-resolution liquid chromatography to detect losses or gains in potency. Increment of efficiency in% is indicated by a + before the corresponding value. A 10¾ loss of efficacy after two to four weeks of storage at 45 to 56 ° C usually indicates less than a 10¾ loss of efficacy after two to three years of storage at room temperature.

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PATENT CLAIMS

Claims (1)

A process for the preparation of thermally stable crystalline monohydrochloride 7-l- (2-aminothiazol-4-yl) -3- [beta] - (3-methoxyiminoacetamidol-3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem-4- carboxylate, characterized in that 7- N - (2-aminothiazol-4-yl) -o - (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-dihydrochloride The cephem-4-carboxylate is suspended in methylene chloride, 1 mol equivalent of triethylamine is added with stirring, then the resulting monohydrochloride is isolated, preferably by vacuum filtration, washing with methylene chloride and drying in vacuo. End of document