CS195748B2 - Process for preparing crystalline anhydrous natrium salt of cephamandole - Google Patents

Description

The present invention provides a process for the preparation of crystalline anhydrous sodium salt of cefamandole. This name refers to an antibiotic of the cephalosporin family, i.e. acid 72

- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid of structural formula I,

This parenteral antibiotic, cefamandole, is characterized by a very broad spectrum and excellent activity against infectious microorganisms of the gram-negative type. Although cefamandole is relatively easy to prepare, it is very difficult to obtain a pharmaceutically acceptable salt of cefamandole in crystalline form that is sufficiently stable and sufficiently pure for parenteral administration.

After extensive research into this antibiotic, cefamandole O-formate was prepared in χ-crystalline form as described in Belgian patent 840 179. This crystalline form of cefamandole O-formate is suitable for parenteral administration but is best administered, when formulated in a pharmaceutical composition together with a weak base such as sodium carbonate. Such compositions are described in U.S. Patent 3,928,592 (1975).

A stable, crystalline form of sodium salt of cefamandole, suitable for industrial scale production and easy application, would eliminate the need for the preparation of the O-formyl derivative and thus greatly simplify the production of this antibiotic.

Accordingly, the present invention provides a process for producing a crystalline anhydrous form of cefamandole sodium; this form of cefamandole anhydrous sodium is easy to prepare and is stable as desired for compositions containing the antibiotic.

The invention also provides crystalline cefamandole sodium methanolate. This form is a suitable crystalline intermediate in the preparation of anhydrous cefamandole sodium crystals by the process of the invention.

Crystalline anhydrous cefamandole sodium is prepared by removing the solvent from the crystalline cefamandole sodium solvate under reduced pressure.

Crystalline anhydrous sodium salt of cefamandole is a white, microcrystalline solid that is best characterized by the X-ray diffraction pattern of the powdered sample as shown below. The diffraction pattern was obtained by copper radiation filtered through nickel (Cu: Ni) at a wavelength of λ - 1.5405 10 ^_1 ° m. ".

distance relative Intensity d I / Ii

14.24 0.61 12.70 0.22 8.14 0.15 7.92 0.23 7.25 0.71 6.60 0.15 6.43 0.30 5.33 0.13 5.06 0.12 4.83 0.55 4.29 0.29 4.17 0.15 4.02 0.26 3.64 0.12 3.60 0.13 3.58 0.12 3.50 0.05 3.42 0.06 3.28 0.07 3.20 0.08 3.14 0.06 2.96 0.09 2.87 0.21 2.80 0.06 2.72 0.15 2.67 - 0,08 2.57 0.07 2.52 0.04 2.41 0.12 2.29 0.15

Examination of the stability of the crystalline anhydrous salt showed that neither the antibiotic activity nor the crystalline activity was practically reduced when the salt was stored at 60 ° C for a week.

The invention also provides a crystalline monohydrate form of cefamandole sodium. This novel form can be used to prepare the crystalline anhydrous form according to the process of the invention, as described in more detail below.

The crystalline cefamandole sodium monohydrate contains approximately 4% by weight of water, which corresponds to a water: cefamandole sodium ratio of 1: 1.

The crystalline structure of the monohydrate differs from the crystalline structure of both the anhydrous form and the methanolate. The X-ray diffraction pattern of the monohydrate powder sample is shown below. The diffraction pattern was obtained using nickel-filtered copper radiation with a wavelength of λ - 1.5405 10-θθ _m .

interplanar distance relative intensity d I / Ii

13.79 0.57 12.23 0.40 8.23 0.12 7.52 0.09 7.21 0.40 7.02 0.60 6.67 0.15 6.19 0.25 5.09 0.10 4.84 0.42 4.70 0.33 - 4,15 0.37 3.99 0.26 3.84 0.08 3.76 0.09 3.65 0.12 3.55 0.10 3.40 0.08 3.25 0.10 3.07 0.11 2.92 0.06 2.76 0.16 2.65 0.11 2.62 0.05 v 2.49 0.15 2.41 0.05 2.36 0.07 2.23 0.11

The monohydrate is prepared from the methanol solvate by replacing the crystal methanol with water in the methanol crystals. The monohydrate is produced by exposing the methanolate crystals to moist air. The replacement of methanol with water is at an acceptable rate at a relative air humidity of about 40 to 60% at a temperature of about 20 to 30 ° C. The preferred relative humidity is 50% humidity at 25 ° C. The crystalline monohydrate is conveniently prepared in a humidifying chamber.

The monohydrate is less stable than the anhydrous form. It becomes discolored and partially loses its antiblottic activity; in a standard stability test conducted at 60 ° C for 1 week, the crystal structure also collapsed.

The anhydrous crystalline form of cefamandole sodium salt as described above can be prepared from the monohydrate. The crystal water of the monohydrate is removed under reduced pressure to give the anhydrous crystalline form.

The monohydrate crystalline form may be dehydrated under reduced pressure at a temperature in the range of about 45 to 50 ° C to form the anhydrous form. Preferably, a drying agent is introduced into the vacuum dryer in order to increase the anhydrous mold formation rate.

The monohydrate loses water at room temperature under zero relative humidity; however, the rate of water loss is much lower than when dehydration is carried out as described above.

The anhydrous form of cefamandole sodium is converted to the monohydrate crystalline form when exposed to moist air. For example, at a relative humidity of about 55% and a temperature of about 25 ° C, the anhydrous form absorbs about 40% by weight of water in less than 1 hour. Therefore, the anhydrous crystalline form is stored in sealed containers or in a dry atmosphere before use to prevent the formation of a less stable monohydrate form.

The crystalline anhydrous form of cefamandole sodium may be stored in larger quantities in sealed containers for subsequent formulation. Alternatively, it may be prepared in unit dosage form in closed amules for parenteral administration in the treatment of infectious diseases. Crystalline monohydrate is an intermediate for the preparation of the crystalline anhydrous form.

The following examples illustrate the invention.

Example 1

Preparation of cefamandole sodium monohydrate g of crystalline cefamandole sodium methanolate prepared as described in Example 2 is exposed to air at 50 + 10% RH for about 16 hours to give 9.8 g (quantitative yield). ) of cefamandole sodium monohydrate crystals.

Example 1 a d 2

Preparation of crystalline cefamandole sodium methoxide

To a solution of 100 g of cefamandolic acid in approximately 200 ml of methanol is slowly added a solution of 25 g of anhydrous sodium acetate in 300 ml of methanol until the pH of the solution reaches 6. The resulting solution is allowed to stand at room temperature. The crystals were filtered through a Buchner funnel and washed with anhydrous ethyl alcohol and diethyl ether.

Example 1 a d 3

Preparation of the anhydrous crystalline form of cefamandole sodium

The crystalline cefamandole sodium monohydrate, prepared as described in Example 1, is subjected to reduced pressure at a temperature in the range of 45-50 ° C to remove crystalline water. An adsorbent is introduced into the vacuum dryer in which the process is carried out to retain the water released, thereby speeding up the process.

An anhydrous crystalline form of cefamandole sodium is obtained in quantitative theoretical yield.

Claims (1)

A process for preparing crystalline anhydrous sodium salt of cefamandole, i.e. 7- (D-2-hydroxy-2-phenyl-acetamido) -3- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid formula I, -Cu-C- N \ - = / λ COOU characterized in that the crystalline sodium salt of 7- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3-cefem-4 is the monohydrate the carboxylic acids are subjected to reduced pressure at a temperature in the range of 45 to 50 ° C.