FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of crystalline form Ertapenem sodium of Formula I,

which is substantially free of residual solvents.

BACKGROUND OF THE INVENTION

Carbapenem-type antibacterial agents are excellent antibacterials having strong antibacterial activity against a wide spectrum of bacteria ranging from gram-positive bacteria to gram-negative bacteria including Pseudomonos aeruginosa. Ertapenem sodium is a carbapenem antibiotic, which is chemically known as [4R-[3(3S*,5S*),4a,5p,6P(R*)]]-3-[[-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-( 1 -hydroxyethyl)-4-methyl-7-oxo-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt.

Ertapenem Sodium is marketed under the trade name INVANZ®. It is reported that Ertapenem Sodium is white to off-white hygroscopic, weakly crystalline powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble in ethanol, isopropyl acetate and tetrahydrofuran. Ertapenem Sodium is unstable at ambient temperature and humidity and requires storage in moisture impermeable containers at -20°C over the retest period of 18 months. In solution, degradation of Ertapenem is very rapid outside a very narrow pH range.

Ertapenem Sodium was disclosed for the first time in US 5,478,820 by Zeneca Limited. This patent also discloses a process for the preparation of Ertapenem sodium. However, this patent does not disclose the nature of the product.

US RE40,794 E discloses Ertapenem sodium as crystalline Form A and Form B and processes for preparing these forms. US 7,022,841 B2 discloses Ertapenem sodium as crystalline Form C and its process. This patent also discloses a process for reducing the levels of organic solvents in crystalline carbapenem to pharmaceutically acceptable levels, comprising washing the crystalline carbapenem containing organic solvent with an organic solvent containing water to produce a washed carbapenem solid containing residual organic solvent; wherein throughout the washing the water content of the crystalline carbapenem solids, correcting for residual organic solvents, is maintained at about 13% to about 25% and evaporating the residual organic solvent in the washed carbapenem solid using vacuum and/or inert gas at low temperature. This process requires continuous monitoring and is not suitable for large scale production.

WO 2009/150630 A2 discloses crystalline Form D of Ertapenem monosodium, which is prepared by a process comprising treating Ertapenem sodium with methanol and water to form a solution, adding n-propanol and stirring the solution at low temperature to obtain a solid and thereafter treating with acetone.
CN 102363617 A discloses crystalline form of Ertapenem sodium, which is prepared by process comprising dissolving Ertapenem sodium in aqueous solution at 0°C; cooling the solution to -2 to -10°C; adding methanol and n-propanol to obtain crystalline Ertapenem sodium. WO 2012/089058 Al discloses crystalline Form E of Ertapenem sodium and its process.

However, the Ertapenem sodium prepared according to above processes contains more residual solvent content, which cannot be removed/controlled in the later stages and is not suitable for preparing pharmaceutical dosage forms. Further, the crystalline forms obtained according to prior art processes are not stable. Present inventors have now developed an improved process for the preparation of stable crystalline Form of Ertapenem sodium having purity not less than 98% (by HPLC), which is reproducible, substantially free of residual solvents and suitable for preparing pharmaceutical dosage forms.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a process for the preparation of Ertapenem sodium, which is free of residual solvents.

Yet another objective of the present invention is to provide a process for the preparation of stable crystalline form of Ertapenem sodium having purity not less than 98% (by HPLC).

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of crystalline form of Ertapenem sodium of formula I,

which comprises:

a) dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain aqueous solution;
b) optionally seeding with a crystalline form of Ertapenem sodium;
c) adding water miscible solvent to the solution at -5 to 25 °C to crystallize the product; and
d) isolating crystalline Ertapenem sodium.

In another embodiment, present invention relates to a process for the preparation of crystalline Ertapenem sodium substantially free of residual solvents, which comprises:

a) washing crystalline Ertapenem sodium containing residual solvents with anhydrous solvent; and
b) drying the product under dry nitrogen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of crystalline form of Ertapenem sodium having powder X-ray diffraction (PXRD) °20 peaks (±0.2) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01, 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06, and 19.21, which comprises dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain an aqueous solution; optionally seeding with crystalline Ertapenem sodium; adding water miscible solvent, selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile or mixtures thereof, to the solution at -5 to 25°C to crystallize the product; and isolating the obtained crystalline Ertapenem sodium.

The process further comprises, optionally addition of water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile or mixture thereof to form the aqueous solution before seeding.

The process further comprises, optionally adjusting the pH of the solution after addition of water miscible organic solvent to about 5.0 to 6.0 by adding dilute acetic acid and optionally treating with the activated carbon.

In yet another embodiment the present invention relates to a process for the preparation of crystalline form of Ertapenem sodium having powder X-ray diffraction (PXRD) °20 peaks (±0.2) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01, 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06, and 19.21, which comprises dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain an aqueous solution; addition of water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile; seeding with crystalline Ertapenem sodium; adjusting the pH of the solution after addition of water miscible organic solvent to about 5.0 to 6.0 by adding dilute acetic acid; treating with activated carbon; adding water miscible solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile or mixtures thereof to the solution at -5 to 25°C to crystallize the product; and isolating the obtained crystalline Ertapenem sodium.

The seed of the crystalline Ertapenem sodium can be prepared by the process of the present invention.
Another aspect of the present invention relates to a process for the preparation of crystalline Ertapenem sodium substantially free of residual solvents, which comprises washing Ertapenem sodium containing residual solvents with an anhydrous solvent selected from acetone, methyl tert-butyl ether, methyl acetate, ethanol or mixtures thereof; and drying the product under dry nitrogen, wherein drying is carried out at temperature less than 25°C; preferably at -5 to 10°C.

The residual content of the crystalline Ertapenem sodium before washing with anhydrous solvent is about 5%(w/w), which is reduced to about 1.5%(w/w) after washing with anhydrous solvent.

In the present invention, one of the residual solvent is methyl acetate, which is classified under ICH as class-3 solvent and is regarded as less toxic and lower risk to human health. Hence, residual methyl acetate in Ertapenem sodium prepared according to the present invention is within the pharmaceutically acceptable levels.

An amorphous Ertapenem sodium used herein is prepared according to the processes known in the prior art.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE-1

PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (20 g) was dissolved in aqueous sodium acetate solution (2%w/w; 200 ml) at 0-5°C. Methanol (40 ml) was added to the solution and adjusted the pH to 5.0-6.0 with acetic acid.

The solution was treated with activated carbon (2 g), filtered, seeded with crystalline Ertapenem Sodium (0.4 g) and added mixture of methanol and acetone (1:3 ratio; 600 ml) to obtain crystalline Ertapenem
sodium.

Yield: 10.5 g.
Chromatographic Purity: 98.33% (by HPLC).

EXAMPLE-2

PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (20 g) was dissolved in aqueous sodium bicarbonate solution (2.0% w/w; 200 ml) at 0-5°C. Methanol (40 ml) was added to the solution and adjusted the pH to 5.0-6.0 with acetic acid. The solution was treated with activated carbon (2g), filtered, seeded with crystalline Ertapenem Sodium (0.4g) and added mixture of methanol and acetone (1:3 ratio; 600 ml) to obtain crystalline Ertapenem Sodium. Yield: 11 g. Chromatographic Purity: 98.07% (by HPLC).

EXAMPLE-3

PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (10 g) was dissolved in aqueous sodium bicarbonate solution (2.0% w/w 100 ml) and adjusted the pH to 5.0-6.0 with diluted acetic acid at 0-5°C. The solution was treated with activated carbon (1 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran (1:3 ratio; 50 ml). The resulting solution was seeded with crystalline Ertapenem Sodium (0.2 g) and added mixture of methanol and tetrahydrofuran (1:3 ratio; 250 ml) at 0 to -20°C to obtain crystalline Ertapenem Sodium. Yield: 6 g. Chromatographic Purity: 98.75% (by HPLC).

EXAMPLE-4
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (lOg) was dissolved in DM water (100ml). The solution was treated with activated carbon (lg) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran (1:3 ratio; 280ml). The resulting solution was seeded with crystalline Ertapenem Sodium (0.2g) and added mixture of methanol and tetrahydrofuran (1:3 ratio; 120ml) at 0 to -20°C to obtain crystalline Ertapenem
Sodium.

Yield: 7 g.
Chromatographic Purity: 99.16% (by HPLC).

EXAMPLE-5

PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (20g) was dissolved in DM water (200ml) at 0 to 10°C. The solution was treated with activated carbon (2 g), filtered and added mixture of methanol and tetrahydrofuran (1:3 ratio; 560 ml). The resulting solution was seeded with Ertapenem Sodium (0.4 g) and added mixture of methanol and tetrahydrofuran (1:3 ratio; 240 ml) at 0 to -20°C. The solid product was filtered,
washed with anhydrous acetone and dried with dry nitrogen at less than 25°C to obtain title compound.

Yield: 13.80 g Residual solvents (by GC): Methanol: 2856 ppm; Tetrahydrofuran: 57 ppm;
Acetone: 13000 ppm
Chromatographic purity (by HPLC): 98.13%

EXAMPLE-6

PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (25 g) was dissolved in DM water (250 ml) at 0 to 10°C. The solution was treated with activated carbon (2.5 g), filtered and added mixture of methanol and tetrahydrofuran (1:3 ratio; 700 ml). The resulting solution was seeded with Ertapenem Sodium (0.5 g) and added mixture of methanol and tetrahydrofuran (1:3 ratio; 300 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous methyl tert-butyl ether and dried with dry nitrogen at less than 25°C to obtain title compound. Yield: 15.75 g

Residual solvents (by GC): Methanol: Not Detected, Tetrahydrofuran: 6559 ppm andMTBE: 3114 ppm
Chromatographic purity (by HPLC): 98.96%

EXAMPLE-7

PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM

Amorphous Ertapenem sodium (50 g) was dissolved in DM water (500 ml) at 0 to 10°C. The solution was treated with activated carbon (5 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran (1:3 ratio; 1400 ml). The resulting solution was seeded with Ertapenem Sodium (l.Og) and added mixture of methanol and tetrahydrofuran (1:3 ratio; 600 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous methyl acetate and dried with dry nitrogen at less than 25°C to obtain title compound.

Yield: 28.3 g

Residual solvents (by GC): Methanol: Not Detected, Tetrahydrofuran: Not Detected and Methyl acetate: 15630 ppm Chromatographic purity (by HPLC): 98.24%.

We Claim

1. An improved process for preparing crystalline Ertapenem sodium of formula I, which comprises:

a) dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain aqueous solution;
b) optionally, seeding with a crystalline form of Ertapenem sodium;
c) adding water miscible solvent to the solution at -5 to 25°C to crystallize the product; and
d) isolating crystalline Ertapenem sodium.

2. The process according to claim 1, wherein water miscible solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile and mixtures thereof.

3. The process according to claim 1, wherein Ertapenem sodium crystalline form is characterised by powder X-ray diffraction (PXRD) containing 20 peaks (±0.2°) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01, 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06 and 19.21.

4. A process for preparing Ertapenem sodium substantially free of residual solvents, which comprises:

a) washing Ertapenem sodium containing residual solvents with anhydrous solvent; and
b) drying the product under dry nitrogen.

5. The process according to claim 4, wherein anhydrous solvent is selected from group comprising of acetone, methyl tert-butyl ether, methyl acetate, ethanol and mixtures thereof.

6. The process according to claim 4, wherein residual solvent content in Ertapenem sodium after drying is about 1.5%(w/w).

7. The process according to claim 4, wherein obtained Ertapenem sodium is in crystalline form.

8. A process for the preparation of crystalline Ertapenem sodium substantially as described herein.