CS195747B2 - 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. an acid

O H II i

CH-C-N- | -

OP C ⁷

O

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

N — V

COOP _m which has been described by Ryan in U.S. Patent 3 641 021. This parenteral antibiotic, cefamandole, has 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 into 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 e 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 a powder 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 ¹⁰ 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 antibiotic activity nor crystallinity were practically reduced when stored at 60 ° C for a week.

The invention also provides a crystalline methanolate form of cefamandole sodium. This new form can be used to prepare the crystalline anhydrous form as described in more detail below.

Crystalline methanolate, sometimes referred to as the methanol solvate, is characterized by its diffraction pattern of the X-ray powder sample,

as shown below. This pattern was obtained using nickel (Cu: Ni) filtered copper radiation with a wavelength of λ - 1.5405 10 - ^1θ m to calculate interplanar distances and relative intensities. distance d relative intensity l / Ιι. 15.22 0.06 14.24 1.00 12.99 0.25 8.75 0.18 7.92 0.19  7.65. ....... 0,45 ...... 7.16 0.46 6.93 0,25 i 6.62 0.18 5.48 0.15 5.30 0.07 5.11 0.26 4.98 0.47 4.79 0.40 4.64 0.19 4.22 0.08 4.15 0.07 3.76 0.11 3.89 0.28 3.70 0.18 3.58 0.19 3.49 0.22 3.35 0.13 3.12 0.09. 2.93 0.06 2.89 0,17,, 2.79 0.10 2.76 0,08 * 2.66 0.09 2.56 0.07

The methanolate form contains about 6.0% by weight of methanol, which corresponds to a molar ratio of methanol to cefamandole sodium of 1: 1.

The crystalline methanol solvate can be prepared by crystallizing substantially pure amorphous cefamandole sodium salt from methanol. Alternatively, the methanolate can be prepared from cefamandolic acid by converting the acid in methanol to the corresponding sodium salt using a weak acid sodium salt. The cefamandole sodium is precipitated from the solution as a crystalline methanolate. As the weak acid salts, for example, sodium acetate, sodium propionate, sodium 2-ethylhexanoic acid and similar sodium salts of weak carboxylic acids, when dissolved in methanol, can be used. ,

The crystalline form of the methanol solvate is preferably prepared using practically pure free cefamandolic acid as follows:

The acid was dissolved in methanol and an excess of sodium acetate in methanol solution was added. The sodium acetate solution is added slowly to avoid gel formation and the addition is stopped when the pH reaches about 6. The solution thus obtained (crystallization solution) is allowed to stand until crystallization is complete. The methanol solvate crystals are filtered off and washed with a suitable anhydrous organic solvent, for example ethanol or diethyl ether, and then allowed to dry.

The crystallization process for preparing the methanol solvate can be carried out at a temperature in the range of from 0 ° to about 50 ° C. The preferred crystallization temperature range is from 15 to 40 ° C. Within this preferred temperature range, crystalline methanolate yields range from about 90 to about 95%. At temperatures well above 40 ° C, yields are usually lower. For example, for. a crystallization temperature of about 50 ° C is a methanolate yield of about 60%.

The crystallization of the methanol solvate is preferably carried out in a substantially anhydrous medium. Although traces or minor amounts of water in the crystallization solution do not adversely affect the yield of the methanolate crystals, more water may result in the formation of a hydrated crystalline product together with the methanol solvate. Therefore, for best results, crystallization is performed in anhydrous methanol and using anhydrous sodium acetate. Methanol and anhydrous sodium acetate in chemically pure form are also preferably used.

The methanol solvate is obtained in the highest yields from the concentrated crystallization solution. Therefore, both a concentrated solution of free cefamandolic acid in methanol and a concentrated solution of anhydrous sodium acetate in methanol are used to prepare a concentrated crystallization solution of cefamandole sodium salt. A suitable concentration of cefamandolic acid in methanol is about 1 g of acid in 2-3 ml of methanol.

A concentrated solution of anhydrous sodium acetate in methanol, containing approximately 1 g of anhydrous sodium acetate per 12 ml of methanol, can be prepared conveniently at room temperature as follows: The excess anhydrous sodium acetate is stirred in methanol for several minutes, can be used together with a solution of cefamandolic acid in methanol to prepare a crystallization solution.

Methyl alcohol is irreplaceable for its ability to form a crystalline solvate with cefamandole sodium. Attempts to prepare crystalline forms of cefamandole sodium using other alcohols have resulted in the formation of an amorphous salt. For example, if, in the above procedure, methanol is replaced with ethanol to prepare the ethanolate, an amorphous cefamandole sodium salt is obtained, but not the ethanol solvate.

The methanol solvate is the starting crystalline form for the anhydrous crystalline salt as mentioned above. Methanol from the crystallization of the methanolate form can be removed under reduced pressure to give the crystalline anhydrous form.

The anhydrous crystalline form of cefamandole sodium salt as described above can be prepared from the methanol solvate. Methanol from the crystallization of the methanol solvate is removed under reduced pressure to give the anhydrous crystalline form.

Conversion of the methanol solvate to the anhydrous crystalline form is carried out under reduced pressure at a temperature in the range of 25 to 45 ° C, preferably at a temperature of about 40 ° C.

The crystalline anhydrous form can be stored in larger quantities in closed containers for subsequent formulation. Alternatively, it may be prepared in unit dosage form in sealed ampoules for parenteral administration in the treatment of infectious diseases. The crystalline methanol solvate is an intermediate for preparing the crystalline anhydrous form.

The following example illustrates the invention.

Example

Anhydrous form of cefamandole sodium

Dissolve 4.0 kg of cefamanedioic acid in 8.8 liters of methanol with stirring to prepare a solution of the acid. A solution of 0.98 kg of anhydrous sodium acetate in 9.0 liters of methanol was added to the resulting solution with vigorous stirring at a rate of approximately 0.25 liters per minute. After the addition was complete, the crystal suspension was stirred for 1 hour, then the methanol solvate crystals were filtered through a Buchner funnel and washed on the filter with a mixture of 1 liter of methanol and 1 liter of ethanol. The washed crystals are dried in a thin layer on slats, which are placed in a Stokes oven, where they are dried at a pressure of 50 psi at a temperature of about 40 ° C. The dry anhydrous form crystals are poured into yellowish glass containers in which the product is stored after closing.

Claims (1)

A process for the preparation of crystalline anhydrous sodium salt of cefamandole, i.e. 7- (D-2-hydroxy-2-phenyl-acetamido) -3- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3-cef em-4-carboxylic acid of formula I, characterized in that the crystalline methanol solvite of the sodium salt of 7- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl) -3-cep-4-carboxylic acid is subjected to reduced pressure at a temperature in the range of 25 to 45 ° C.