PL193406B1 - Amorphous, stable form of cephetamet and its derivatives useful in obtaining pharmaceutic form, method of obtaining same and pharmaceutic agent containing it - Google Patents

Abstract

A method of obtaining an amorphous, stable form cefetameth salt useful for the preparation of pharmaceutical forms, characterized in that of the free acid cefetameth of the general formula I in which R1 is hydrogen make a solution in water or in a water mixture with an aliphatic alcohol containing from 1-3 atoms carbon, then added to the solution thus obtained sodium bicarbonate or sodium hydroxide or potassium or basic amino acid such as arginine, lysine or histidine to give a cefetamet salt solution of the general formula I in which R1 is a metal atom alkaline, such as Na or K, or a basic amino acid, such as arginine, lysine, or histidine, which is a solution optionally purified with activated carbon in the presence polar solvent and then preferably filtered through sterilizing filters and subjected to a drying process spray, resulting in essentially amorphous, permanent the salt form of cefetameth of general formula I, wherein R 1 is the basic amino acid specified above or specified above an alkali metal atom

Description

The invention relates to a process for the preparation of an amorphous, stable form of a cefetameth salt suitable for the preparation of pharmaceutical forms, and a pharmaceutical composition containing the same.

Cefetamet - free acid and its salts of general formula 1, where R 1 = H, and its derivatives, such as salts, esters and ester salts belong to the group of cephalosporins with a wide range of antibacterial activity, both against gram-positive and I play - negative.

In the known art, injection forms of the drug are prepared from cefetameth salts. The amorphous cefetamet sodium salt of the general formula I, in which R1 is sodium, prepared by lyophilization, was used to prepare the injectable form of the drug in accordance with the patent description No. PL 178281.

Other known methods for the preparation of said amorphous sodium salt or sodium salts of other cephalosporins having a 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamide moiety in the side chain consist, according to the patent description No. CZ242018, by precipitation of the product by the action of sodium salt of 2-ethyl caproic acid or according to the patent description No. PL 118475 on the evaporation of a large amount of the solution obtained after the purification of the given compound on the column.

The disadvantages of the methods for the preparation of sodium salts of the cephalosporins mentioned above are:

- high consumption of organic solvents in the case of concentrating the eluates from the column, and thus the high cost of the process, difficulties in purifying the product from the residual sodium salt of 2-ethylcaproic acid,

- obtaining a product with different sizes of molecules, which is characteristic of compounds obtained by dropping a solution into water or solvents. In order to obtain particles of a certain size, for example below 50 μ, it is necessary in this case to use a homogenizer, which, however, entails some product losses, especially when using a temperature-sensitive compound, as well as increasing costs and extending the process time.

- long time of the freeze-drying process,

- high tendency of the lyophilisate to absorb water, which is related to the low stability of this salt. For example, after leaving the lyophilisate of cefetameth sodium in the air for three days, the water content increased more than five times, i.e. from 1.5% to 8.0%.

Accordingly, it has proved to be expedient and beneficial to find a new method of producing the amorphous form of cefetamet salt. The aim of the invention was to obtain an amorphous, stable form of the new and known cefetameth salts, of the general formula I, in which R1 is an alkali metal or basic amino acid, which constitute a ready product for the preparation of an injectable drug form.

The method of the invention uses a spray-drying method which is free from the disadvantages of the prior art methods.

The essence of the invention is a method for the preparation of an amorphous, stable form of cefetameth salts, useful for the preparation of pharmaceutical forms. Those are:

amorphous, stable cefetameth sodium salt, amorphous, stable cefetamete potassium salt, amorphous, stable cefetameth arginine salt, amorphous, stable cefetameth lysine salt, amorphous, stable cefetameth histidine salt.

By said method, it is also possible to obtain an amorphous, stable form of a salt of cefetameth with ornithine.

According to the invention, an amorphous, stable cefetameth salt of general formula I is obtained; wherein R ₁ is sodium or potassium, or else a basic amino acid containing <3% impurities. These compounds are intended for the production of injection forms.

According to the invention, a substantially amorphous, stable form of the compounds of the general formula I in which R1 as defined above is prepared, essentially free of crystalline material, in the form of regular, spherical particles characteristic of products obtained by spray drying.

According to a first aspect of the invention, a method for preparing an amorphous, stable form of a cefetameth salt suitable for the preparation of pharmaceutical forms comprises that from the free acid cefetameth of the general formula I, in which R1 is a hydrogen atom, a solution in water or a mixture is prepared. water with an aliphatic alcohol containing from 1-3 carbon atoms, then sodium bicarbonate or sodium or potassium hydroxide or a basic amino acid such as arginine, lysine or histidine is added to the solution thus obtained to obtain a cefetamet salt solution of general formula 1, in which R1 is an alkali metal atom such as Na or K, or a basic amino acid such as arginine, lysine or histidine, which solution is optionally purified with activated carbon in the presence of a polar solvent, then filtered through sterilization filters and processed spray drying to give the substantially amorphous form of the cefetameth salt of the general formula I, wherein m R 1 is either the basic amino acid specified above or the alkali metal atom specified above.

For the preparation of the amorphous, stable form of the cefetameth salt, the above-mentioned cefetameth free acid of the general formula I in which R 1 is hydrogen is used as the starting material. It is also possible to use the alkali metal salts of cefetameth of the general formula I, in which R 1 is sodium or potassium, preferably the sodium or potassium salt of cefetamet, or else the salts of cefetamet with basic amino acids, preferably the salt of L-arginine, L-lysine, DL-ornithine or DL-histidine.

The above-mentioned compounds with an impurity content of <5% are used as starting materials to obtain the amorphous, stable form of the cefetameth salt of the general formula I, in which the meaning of R1 is given above, and which are then intended for injection forms.

In the process according to the invention, the solutions of the cefetameth salt of the general formula I, in which the meaning of R1 have been previously defined, which are then subjected to the spray-drying process, are used as a starting material in a crystalline, amorphous form or a mixture of crystalline and amorphous forms of the free acid of general formula 1.

In the process according to the invention, for the spray-drying process, the following solutions are used: cefetameth salt of the general formula I, in which R1 is defined above, with a concentration <25% w / v.

The obtained solution of cefetameth salt of the general formula I, where R1 is a sodium or potassium atom, or a basic amino acid, in water or in a mixture of water with an aliphatic alcohol, is purified with active carbon, then filtered through sterilizing filters and subjected to the process of spray-drying under sterile conditions .

The aliphatic alcohol used for the preparation of solutions of cefetameth and its salts is an alcohol with 1 to 3 carbon atoms, preferably ethyl alcohol.

In the spray drying process according to the invention, the dryer inlet temperature is> 60 ° C, and the outlet temperature> 50 ° C, and even with an inlet temperature in the range 145-150 ° C, no appearance of degradation products was observed in the final formulation. When using solutions containing organic solvents, it is necessary to use inert carrier gases, preferably nitrogen or carbon dioxide.

The method according to the invention, in relation to the methods known from the state of the art, has a number of significant advantages, such as:

- the possibility of using as substrates for the spray-drying process of a compound of general formula I, in which R1 has previously been defined as a crystalline, amorphous or a mixture of crystalline and amorphous forms,

- the possibility of using cefetameth as a substrate - free acid with impurity content <5%,

- the possibility of easy purification of an aqueous or hydroalcoholic solution of cefetameth free acid of general formula I in a polar organic solvent or in a mixture of organic solvents with water. Purification by the method according to the invention removes a large amount of impurities, similarly to the crystallization process, however, it is a process that is less time-consuming, simpler and cheaper than the crystallization method, especially since the solution after cleaning is directed directly to spray drying,

- a wide range of concentrations of up to 25% w / v of solutions intended for spray drying makes it possible to use various solvents, even those in which the solubility of cefetamet salts is low,

- the possibility of regenerating and recycling solvents to the process through the use of carbon absorbers in the spray dryer that absorb solvents from the stream of the carrier gas and by subsequent desorption of solvents from coal,

- a significant reduction in the process time compared to known methods, especially with regard to the lyophilization process,

- ensuring a low content of organic solvents <1%,

PL 193 406 B1

- low water content in products obtained by spray drying. For example, the water content in the cefetamet sodium salt obtained by the process of the invention is> 0.8%, and after being left in the air (unlike the cefetamet sodium lyophilisate), this content remains unchanged.

- significant technical facilitation of obtaining small particles of the product (below 50 μ) directly during spray drying, without the need for additional use of a homogenizer,

- increasing the stability of the substance in relation to the product obtained by lyophilization. For example, the difference in the content of cefetameth potassium salt obtained by freeze drying and by spraying and stored for 5 months at 37 ° C was 2% in favor of the product produced by the spray drying process.

The products obtained according to the invention were examined by X-ray method and it was found that each time they were essentially amorphous. Moreover, the shifts in the IR spectra of the amorphous form towards higher frequencies of the C = O groups in the range of 2950 - 3450 cm ^-1 as compared to the crystalline form of the discussed compounds, became helpful in the identification of the form obtained by the method according to the invention.

Another aspect of the invention is a pharmaceutical composition, characterized in that it contains as biologically active substance from 0.1-99.9% of a stable cefetameth salt of the general formula I, in which R1 is an alkali metal atom such as K or Na, or a basic amino acid , such as arginine, lysine, or histidine prepared so that the cefetameth of the free acid of general formula I, wherein R1 is hydrogen, is dissolved in water, or in a mixture of water with an aliphatic alcohol containing 1-3 carbon atoms, whereby sodium bicarbonate or sodium or potassium hydroxide or a basic amino acid such as arginine, lysine or histidine is added to the solution thus obtained to obtain a cefetamet salt solution of the general formula I, in which R1 is an alkali metal atom, such as Na or K, or basic an amino acid such as arginine, lysine, or histidine, which solution is optionally purified with activated carbon in the presence of a polar solvent, and then The soils are filtered through sterilizing filters and subjected to a sterile spray-drying process to give a substantially amorphous, stable form of the cefetameth salt of the general formula I wherein R 1 is the above-mentioned basic amino acid or the above-mentioned alkali metal atom.

The obtained pharmaceutical agent can be dispensed under sterile conditions into the vials with direct injection into the drug form.

In the pharmaceutical composition, in addition to the cefetamet salt in an amount of 0.1 - 99.9%, which is the actual active ingredient, preferably known pharmaceutically acceptable excipients are present. Their quantity and quality depends primarily on the type of pharmaceutical form and the properties of the antibiotic itself.

Suitable carriers and diluents in the pharmaceutical composition according to the invention are substances conventionally used for this purpose in pharmaceutical practice, depending on the form of the finished drug, for example mainly water.

In the embodiments of the invention relating to pharmaceutical forms of cefetameth and its salts for injection, the amorphous, stable form of the said compounds obtained by the method of the invention is used.

The examples provided illustrate the invention without limiting its scope in any way.

Example I. 63.6 g (0.16 mol) of crystalline cefetameth free acid with purity as determined by HPLC 97.8% was suspended in 360 cm ³ of apyrogenic water and, after cooling to 8-10 ° C, was added in for 1.5 hours in five portions of 13.80 g (0.164 mol) of sodium bicarbonate. After the completion of the carbonate addition, the resulting solution was stirred for an additional 45 minutes, then the resulting solution, having a pH value of 7.0 and a concentration of 18.6% w / v, was filtered through a sterilizing filter and subjected to a sterile spray-drying process using an outlet temperature of 115 ° C C and the inlet 95 ° C. 62.2 g of the apyrogenic and sterile sodium salt of cefetameth was obtained, which is 92.8% of the theoretical yield.

Cefetameth sodium content (HPLC) - 97.8%

Impurity content - 0.8%

Water content - 0.8%

Characteristic infrared bands (KBr):

CH, NH and NH2 - 3400, 3300, 3180 and 2930 cm ^-1

C = O (β-lactam) - 1750 cm ^-1

PL 193 406 B1

C = O (CONH)

C = O ^(COO: j ^1H NMR (200 MHz, D2O)

1.94 ppm

3.34, 3.58 ppm

3.94 ppm

5.19 ppm

5.69 ppm

6.99 ppm

9.60 ppm

- 1660 cm ^-1

- 1590 cm ^-1

- 3H, s, 3-CH3

- 2H, 2d, 2-CH2

- 3H, s, OCH3

- 1H, d, J = 4.6,6-H

- 1H, dd, J = 4.6, J = 8.0, 7-H

- 1H, s, 5-H (thiazolyl ring) - 1H, d, J = 8.0, CONH

Example II. 15.9 g (0.04 mol) of amorphous cefetameth free acid, purity _3, as determined by HPLC, 93.9% was added to 110 cm of the apyrogenic mixture of water and ethanol, and after cooling to 5-6 ° C, it was gradually added in within 1 hour 2N potassium hydroxide solution. After adjusting the pH to 6.2, the resulting solution was purified with activated carbon for minutes, and then a further 2N KOH solution was added under the indicated conditions until pH = 7.0. The resulting solution was filtered through a sterilizing filter, and then subjected to a sterile spray-drying process with a dryer inlet temperature of 125 ° C and an outlet temperature of 105 ° C. 15.9 g of sterile, apyrogenic potassium salt of cefetameth were obtained, which is

91.2% of theory.

Cefetameth Potassium Salt Content (HPLC) - 96.9%

Water content - 0.8%

Ethanol content - 0.6%

Characteristic infrared bands (KBr):

CH, NH and NH2 - 3400, 3300, 3190 and 2935 cm ^-1

C = O (β-lactam) - 1755 cm ^-1

C = O (CO-NH) - 1660 cm ^-1

C = O (COO ^ - 1595 cm ^-1

Example III. 11.9 g (0.03 mol) of crystalline cefetameth - free acid with purity as determined by HPLC - 96.0% was added to 150 cm ^{3 of} the water-ethyl alcohol mixture, and after cooling to 6-8 ° C, it was added within 1 hours, in four portions of 5.23 g (0.03 mol) L-arginine. The resulting solution with a concentration of 11.4% m / v and pH = 6.5 was filtered through a sterilizing filter, then it was spray dried under sterile conditions at an inlet temperature of 115 ° C and an outlet temperature of 95 ° C.

The obtained yield was 15.6 g of cefetameth salt with L-arginine, which is 91.3% of the theoretical yield.

Cefetameth-free acid content (HPLC) L-arginine content Water content Ethanol content

Characteristic infrared bands (KBr): CH, NH and NH2

C = O (β-lactam)

C = O (CONH)

C = O (CONH) ¹ H NMR (200MHz, DMSO)

1.40 - 1.85 ppm

1.90 ppm

3.0-3.5 ppm

4.96 ppm}

5.57 ppm}

6.72 ppm

7.21 ppm

8.01 ppm

9.0 ppm

9.47 ppm

- 69.4%

- 28.0%

- 0.7%

- 1.1%

- 3340, 3160, and 2930 cm ^-1

- 1750 cm ^-1

- 1660 cm ^-1

- 1640 - 1610 cm (wide band)

- 4H, m (CH2) 2 of arginine

- 3H, s 3 -CH3

- 5H, m, 2H from 2-CH ₂ and CH ₂ NH and CHNH ₂ from arginine

- 1H, 1H, 6-H and 7-H, J = 4.6

- 1H, s, 5-H (thiazolyl ring)

- 2H, s, NH2 (thiazolyl ring)

- 5-H (broad band), NH2 and NH groups from arginine

- 1H, (broad band), = NH of arginine

- 1H, s, (broad band), CONH

PL 193 406 B1

IV. Proceeding analogously to example III, but using instead of L-lysine, the cefetamet salt with L-lysine was obtained with the yield of 90.5% of the free acid (HPLC)

- 72.8%

- 25.5%

- 0.8%

- 0.7%

- 3390, 3140 and 2940 cm ^-1

- 1750 cm ^-1

- 1665 cm ^-1

- 1630-1600 cm ^-1

- 4H, m, (CH2) 2 from lysine

- 3H, s, 3-CH3

- 6H, m, CH ₂ NH ₂ , CH ₂ CH (NH ₂₎ and 2-CH ₂

- 3H, s, OCH ₃

- 1H, d} 6-H and 7-H, J = 4.6

- 1H, d}

- 1H, s, 5-H (thiazolyl ring)

- 2H, s, NH2 (from the thiazolyl ring)

Example of L-arginine (0.03 mol) of theoretical value.

Cefetamete content

L-lysine content

Water content

Ethanol content

Characteristic infrared bands (KBr):

CH, NH and NH2

C = O (β-lactam)

C = O (CONH)

C = O (COOH) ¹ H NMR (200MHz, DMSO)

1.25-1.80 ppm

1.88 ppm

2.65-2.80 ppm}

3.05-3.50 ppm}

3.82 ppm

5.07 ppm}

5.58 ppm}

6.72 ppm

7.22 ppm

EXAMPLE V. 11,9g (0.03 mol) of crystalline cefetametu - free acid with a purity in debt ₃ determinations by HPLC - 95.9% was added to 260 ml of water at room temperature was added steadily over 1 hour 4.65 g (0.03 mol) DL-histidine. The resulting solution at a concentration of 6.36% m / v and pH = 6.4 was spray-dried under the conditions described in Example 4, obtaining 15.0 g of cefetameth sodium with DL-histidine, which is 90.6% of theoretical yield.

Cefetameth Free Acid Content (HPLC) Water content

Characteristic infrared bands (KBr): CH, NH and NH2 C = O (β-lactam)

C = O (CONH)

C = O (COOH) ¹ H NMR (200MHz, DMSO)

1.97 ppm 2.87-3.7 ppm 1.82 ppm 5.04 ppm 5.63 ppm

6.73 ppm 6.95 ppm 7.25 ppm 7.60-8.10 ppm

- 71.6%

- 0.7%

- 3400, 3140, and 2930 cm ^-1

- 1752 cm ^-1

- 1655 cm ^-1

- 1630-1600 cm (wide range)

- 3H, s, 3-CH3

- 6H, s, CH-CH2-CH (COOH) from histidine and 2-CH2

- 3H, s, OCH3

- 1H, d, J = 4.6,6-H

- 1H, dd, J-4.6, J = 8.0, 7-H

- 1H, s, 5-H (thiazolyl ring)

- 1H, s, NH-CH = N

- 2H, s, NH ₂ from the thiazolyl ring

- 3H, m, NH and NH2 from the histidine

- 1H, d, J = 8.0, CONH

9.55 ppm

P r x l a d VI. By proceeding analogously to example 5, but using DL-ornithine, the cefetameth salt with DL-ornithine was obtained with the yield of 88.0% of theory.

Cefetameth Free Acid Content (HPLC) Water content

Characteristic infrared bands (KBr): CH, NH and NH2 C = O (β-lactam)

C = O (CONH)

C = O (COOH)

- 74.0%

- 0.9%

- 3495, 3140, and 2935 cm ^-1

- 1755 cm ^-1

- 1655 cm ^-1

- 1625-1595 cm ^-1 (wide band)

PL 193 406 B1

Example VII. 7.95 g (0.02 mol) of crystalline cefetameth - free acid with HPLC purity - 95.8% was gradually added to the water - acetone - ethanol mixture at 30 ° C. The resulting 1.5% solution was purified with activated carbon and then spray dried with an inlet temperature of the dryer 125 ° C and an inlet temperature of 108 ° C. 7.1 g of amorphous cefetameth free acid were obtained, which is 89.3% of theoretical yield.

Cefetameth Free Acid Content (HPLC) - 97.1%

Impurity content - 1.5%

Water content - 0.4%

The content of ethanol - 0.5% ¹ H NMR (200MHz, DMSO)

2.00 ppm - 3H, s, 3-CH3

3.33 ppm}

3.57 ppm} - 2H, 2d, J = 18.3,2-CH2

3.84 ppm - 3H, s, OCH3

5.08 ppm - 1H, d, J = 4.6

5.67 ppm - 1H, dd, J = 4.6 and J = 8.0

6.77 ppm - 1H, s, 5-H (thiazolyl ring)

7.50 ppm - 2H, (broad band) NH2 from the thiazolyl ring

9.59 ppm - 1H, d, J = 8.0, CONH.

Example VIII. The sterile and apyrogenic cefetameth sodium salt prepared according to Example 1, ₃ is sterile dispensed 0.5 g into 10 cm ³ vials and 1.0 g into ₃ cm ₃ vials. After closing the vials with sterile rubber stoppers and after capping, an injection form of cefetamet is obtained.

Claims (9)

A method for the preparation of an amorphous, stable form of a cefetameth salt suitable for the preparation of pharmaceutical forms, characterized in that the cefetameth free acid of the general formula 1, in which R 1 is a hydrogen atom is prepared into a solution in water or in a mixture of water with an aliphatic alcohol containing from 1-3 carbon atoms, then sodium bicarbonate or sodium or potassium hydroxide or a basic amino acid such as arginine, lysine, or histidine is added to the thus obtained solution to obtain a cefetameth salt solution of general formula 1, in which R1 is an alkali metal atom, such as such as Na or K, or a basic amino acid such as arginine, lysine, or histidine, which solution is optionally purified with activated carbon in the presence of a polar solvent, then preferably filtered through sterilization filters and spray-dried to give a substantially amorphous, stable the salt form of cefetameth of the general formula I in which R1 is as defined above in an amino acid or an alkali metal atom as defined above. 2. The method according to p. 3. The method of claim 1, wherein the above-mentioned cefetameth free acid of the general formula 1 in which R1 is defined above with an impurity content <5 is used as a starting material for the preparation of an amorphous, stable form of the cefetameth salt of the general formula 1 in which R 1 is defined above. %. 3. The method according to p. A process as claimed in claim 1, characterized in that for the preparation of the solutions of the cefetameth salt of the general formula I, in which R1 is defined above, which are then subjected to a spray-drying process, a crystalline, amorphous form or a mixture of crystalline and amorphous forms of the above-mentioned compound are used as the starting material. 4. The method according to p. The method of claim 1, characterized in that solutions of cefetameth salt of the general formula I, as previously mentioned, with a concentration of <25% w / v are used for the spray-drying process. 5. The method according to p. The process of claim 1, wherein the aliphatic alcohol having 1 to 3 carbon atoms is preferably ethyl alcohol. 6. The method according to p. 3. A method according to claim 1, characterized in that the obtained solution of cefetameth salt of general formula I, wherein R 1 is sodium or potassium atom, or the above-mentioned basic amino acid, in water or in a mixture of water with an aliphatic alcohol is purified with activated carbon, It is preferably filtered through sterilizing filters and subjected to a spray-drying process under sterile conditions. 7. The method according to p. The process of claim 1, wherein the inlet temperature of the spray dryer is> 60 ° C, and the outlet temperature is> 50 ° C, respectively. 8. The method according to p. The process of claim 1, wherein nitrogen or carbon dioxide is used as carrier gas in the spray drying of the solutions containing organic solvents. 9. A pharmaceutical composition, characterized in that, as the biologically active substance, it contains from 0.1 to 99.9% of a stable cefetameth salt form of the general formula I, in which R1 is an alkali metal atom, such as K or Na, or a basic amino acid, such as such as arginine, lysine, or histidine prepared so that the cefetameth of the free acid of general formula I, wherein R 1 is hydrogen is dissolved in water, or in a mixture of water with an aliphatic alcohol containing from 1 to 3 carbon atoms, then to the solution thus obtained is added sodium bicarbonate or sodium or potassium hydroxide, or a basic amino acid such as arginine, lysine, or histidine to obtain a cefetamet salt solution of the general formula I, in which R1 is an alkali metal atom, such as Na or K, or a basic amino acid, such as arginine, lysine, or histidine, which solution is optionally purified with activated carbon in the presence of a polar solvent and then preferably filtered through sterilization filters and subjected to a spray-drying process under sterile conditions to obtain a substantially amorphous, stable form of the cefetameth salt of general formula I, wherein R 1 is the above-mentioned basic amino acid or the above-mentioned alkali metal atom.