AN IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE
CEFTRIAXONE SODIUM
The present invention is concerned with improvements in or relating to the production of the disodium salt of (6R,7R)-7-[[(2z)-(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-8-oxo-3-[[(l,2,5,6-tetrahydro-2-methyl-5, 6-dioxo-l,2,4-triazin-3-yl)-thio]methyl]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (hereina after referred to as Ceftriaxone) in crystalline hemiheptahydrate form.
BACKGROUND
Ceftriaxone, as disclosed in patent US 4,327,210 is a valuable third generation broad-spectrum antibiotic, characterized by high activity against a wide range of gram positive and gram negative microorganisms. It is highly stable to hydrolysis by most betalactamases and has greater activity than first or second generation cephalosporins against gram negative microorganism. Additionally, the compound is stable in body owing to its resistance to the action of mammalian esterases, and gives high serum levels following parenteral administration (e.g. in the form of the disodium salt) to human and animal subjects, while exhibiting low serum binding.
The disodium salt of Ceftriaxone (here in after referred to as Ceftriaxone Sodium) is of particular importance since it enable ceftriaxone to be formulated in pharmaceutical composition for injection. There is thus need to produce ceftriaxone sodium in as pure and homogeneous a condition as possible in order to fulfil exacting pharmaceutical requirements and specifications. The ceftriaxone sodium should be produced in the final stage in a sterile form this is advantageously achieved by conducting the operating processes of crystallization, recovery and drying under sterile conditions, preferably in a closed system.
It has proved difficult in practice to manufacture sterile ceftriaxone sodium industrially in a crystalline form having a combination of suitable properties such as solid state stability, purity, particle size, bulk density, flowability, filtration & drying characteristics.
The object of the invention is to obviate the above drawbacks.
The processes of the present invention enable crystalline ceftriaxone sodium to be readily recovered in a sterile form from a solution containg it, on an industrial scale, in a condition

, of sufficient purity, better flowability and bulk density for use in pharmaceutical preparations. This crystalline material has been found to have particularly good filtration and drying characteristics.
According to the present invention there is provided a process for the preparation of crystalline ceftriaxone sodium which comprises adding an aqueous solution of ceftriaxone sodium containing a dialkylamide (especially dimethyl formamide, N, N-dimethyl acetamide or N-methyl pyrrolidone) to a crystallizing medium at a temperature from 10° to 30°c.
The dialkylamide used in the aqueous solution of Ceftriaxone Sodium should be missible in water as well as in crystallizing medium i.e. lower ketones preferably acetone. A dialkylamide used in the process is preferably dimethyl formamide and N, N-dimethyl acetamide.
The aqueous solution of ceftriaxone sodium which is added to the crystallizing medium may have a concentration of 10 to 50%, preferably 20 to 30% w/v.
The concentration of dialkylamide in aqueous solution should be 10 to 30% v/v preferably 15 to 20%.
The aqueous solutions containing ceftriaxone sodium may it desired be diluted with a co-solvent e.g. a polar organic solvent such as a lower alkylketone, for example acetone.
The dialkylamide of the aqueous solution of ceftriaxone sodium is added at any stage it should be at the time of dissolution of ceftriaxone sodium or before or after charcolization but preferably before dispersion of aqueous solution in crystallization medium.
In order to ensure that the ceftriaxone sodium crystallizes out of the crystallizing medium in a satisfactory fashion, the crystallizing medium is maintained at a temperature of from 5° to 30°C, preferably from 10° to 20°C, the ceftriaxone sodium solution to be added is preferably at a temperature of, for example 5° to 30°C, advantageously 10 to 20°C.

The ceftriaxone sodium solution is advantageously treated with charcoal and filtered prior to addition to the crystallizing medium.
The ceftriaxone sodium solution is preferably added to the crystallizing medium over a period of 1 to 5 hours, particularly 2 to 3 hours. The ceftriaxone sodium in preferably added to the crystallizing medium in such a way that the ceftriaxone sodium crystallizes out in the crystallizing medium at a similar rate to that at which it added.
As the addition of solution proceeds, the crystallizing medium is desirably kept in a state of a agitation to facilitate the crystallization. This can be filtered off washed and dried.
The following examples illustrate the present invention.
Example 1
Ceftriaxone sodium (lO.Og) is dissolved in water (37.0ml) at 10-12°C, after complete dissolution, Acetone (25.0ml) and Charcoal (l.Og) is added, the mixture is stirred for 30 min. at 10 to 12°C, it was filtered and washed with mixture of water (5.2ml) and Acetone (1.7ml). To the filtrate, N, N-dimethylacetamide (1.0ml) is added and solution is then added in Acetone (160ml) at 10 to 12°C under stirring over a time period of 3 hours.
The mixture is then further stirred at 10 to 12°C for 2 hrs, filtered and the product washed with Acetone (3x20ml) and dried in vacuum. There were obtained 9.40g of ceftriaxone sodium as a white crystalline product with improved flowability (Bulk density : 0.51 w/v and tapped density at 100 taps : 0.56 w/v).
Example 2
Ceftriaxone sodium (lO.Og) is dissolved in water (37.0ml) at 10 to 12°C, after complete dissolution, Acetone (25.0ml) and Charcoal (l.Og) is added, the mixture is stirred for 30 min. at 10 to 12°C, it was filtered and washed with mixture of water (5.2ml) and Acetone (1.7ml). To the filtrate, N, N-dimethylacetamide (3.0ml) is added and solution is then added in Acetone (160ml) at 10 to 12°C under stirring over a time period of 3 hours.
The mixture is then further stirred at 10 to 12°C for 2 hrs, filtered and the product washed with Acetone (3x20ml) and dried in vacuum. There were obtained 9.43g of ceftriaxone

sodium as a white crystalline product with improved flowability (Bulk density : 0.54 w/v and tapped density at 100 taps : 0.60 w/v).
Example 3
Ceftriaxone sodium (lO.Og) is dissolved in water (37.0ml) at 10 to 12°C, after complete dissolution. Acetone (25.0ml) and Charcoal (l.Og) is added, the mixture is stirred for 30 min. at 10 to 12°C, it was filtered and washed with mixture of water (5.2ml) and Acetone (1.7ml). To the filtrate, Dimethyl Formamide (1.0ml) is added and solution is then added in Acetone (160ml) at 10 to 12°C under stirring over a time period of 3 hours.
The mixture is then further stirred at 10 to 12°C for 2 hrs, filtered and the product washed with Acetone (3x20ml) and dried in vacuum. There were obtained 9.35g of ceftriaxone sodium as a white crystalline product with improved flowability (Bulk density : 0.50 w/v and tapped density at 100 taps : 0.55 w/v).
Example 4
Ceftriaxone sodium (lO.Og) is dissolved in water (37.0ml) at 10 to 12°C, after complete dissolution, Acetone (25.0ml) and Charcoal (l.Og) is added, the mixture is stirred for 30 min. at 10 to!2°C, it was filtered and washed with mixture of water (5.2ml) and Acetone (1.7ml). To the filtrate, N, N-dimethyformamide (3.0ml) is added and solution is then added in Acetone (160ml) at 10 to 12°C under stirring over a time period of 3 hours.
The mixture is then further stirred at 10 to 12°C for 2 hrs, filtered and the product washed with Acetone (3x20ml) and dried in vacuum. There were obtained 9.40g of ceftriaxone sodium as a white crystalline product with improved flowability (Bulk density : 0.52 w/v and tapped density at 100 taps : 0.58 w/v).

We claim:
1. A process for the preparation of crystalline ceftriaxone sodium comprising the steps
of adding an aqueous solution containing 10 to 50% w/v of ceftriaxone sodium and
dialkylamide 10 to 50%v/v; to an non-aqueous crystallizing medium, the
crystallizing medium being at a temperature of from 15 to 30°C and the aqueous
solution of the ceftriaxone sodium containing at dialkylamide is added substantially
at constant volume rate, whereby ceftriaxone sodium continuously crystallizes out of
the crystallizing medium.
2. A process as claimed in claim 1 wherein in the aqueous solution containing
dialkylamide, a compound selected from group consisting of N, N-dimethyl
acetamide and dimethyl formamide.
3. A process as claimed in claim 1 wherein the crystallizing medium is an lower alkyl
ketones preferably acetone in an amount sufficient to prevent the solid ceftriaxone
sodium form going into solution.
4. A process as claimed in claim 1 wherein the aqueous solution of ceftriaxone sodium
is to be added at a temperature from 10 to 20° C.
5. A process as claimed in claim 1 wherein the aqueous solution containing ceftriaxone
sodium and dialkylamide is added to the crystallizing medium over a period of 2 to 3
hours.
6. A process as claimed in claim 1 wherein the crystallizing medium is at temperature
from!5to30°C.
7. The process as defined in claim 1 wherein the amount of ceftriaxone sodium in the
aqueous solution is from 20 to 30 % w/v and the amount of dialkylamide in the same
aqueous solution is from 10 to 15% v/v.
8. The process as defined in claim 1 wherein the aqueous solution containing
ceftriaxone sodium and dialkylamide is at a temperature from 5° to 30° C.

9. The process as defined in claim 8 wherein the temperature of aqueous solutic
containing ceftriaxone sodium and dialkylamide is from 10° to 20° C and tl
temperature of crystallizing medium is from 10°C to 20°C.
10. A process for the preparation of crystalline ceftriaxone sodium substantially i
herein described with reference to the foregoing examples.
11. Crystalline ceftriaxone sodium whenever prepared by the preceding claims wi
reference to the examples.