FIELD OF THE INVENTION

The present invention relates to new polymorphic forms of Ertapenem sodium of Formula I, designated as Form Al, Form A2 and Form A3.

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-(l -hydroxyethyl)-4-methyl-7-oxo-l -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 with 15.5 to 19% water content. 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 is 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.

Polymorphism is the property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state. Crystalline forms of carbapenem antibiotics are desirable for improved purity and stability.

US RE40,794E discloses Ertapenem sodium as crystalline Form A and Form B and their processes. US 7,022,841 B2 discloses Ertapenem sodium as crystalline Form C and its process. WO 2009/150630 discloses crystalline Form D of Ertapenem monosodium.

We have now found new polymorphic forms of Ertapenem sodium, which are stable, reproducible and suitable for preparing pharmaceutical dosage forms.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide new polymorphic forms of Ertapenem sodium, which are stable and reproducible.

In yet another objective of the present invention is to provide a process for the preparation of new polymorphic forms of Ertapenem sodium.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Powder X-ray diffraction (PXRD) for Ertapenem sodium crystal Form Al

Figure 2 - Powder X-ray diffraction (PXRD) for Ertapenem sodium crystal Form A2

Figure 2 - Powder X-ray diffraction (PXRD) for Ertapenem sodium crystal Form A3

SUMMARY OF THE INVENTION

The present invention relates to new polymorphic forms of Ertapenem sodium of Formula I.

The present invention also provides processes for the preparation of new polymorphic forms of Ertapenem sodium viz. Form Al, Form A2 and Form A3.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, present invention provides a new polymorphic form of Ertapenem sodium (hereinafter Form Al) having powder X-ray diffraction (PXRD) °2 θ values (±0.2) at 14.63, 16.09, 18.89, 20.92, 30.61, 31.24, and 31.65. The novel polymorphic form, Form Al of Ertapenem sodium is further characterised by PXRD having °2 θ values (+ 0.2) at 4.92, 10.96, 14.63, 16.09, 17.08, 18.89, 19.22, 20.92, 22.13, 29.49, 30.61, 31.24, 31.65, 32.47 and 34.74. The Form Al of Ertapenem sodium is further characterized by a powder X-ray diffraction pattern substantially same as depicted in Figure-1.

In another embodiment, present invention provides a new polymorphic form of Ertapenem sodium (hereinafter Form A2) having powder X-ray diffraction (PXRD) °20 values (±0.2) at 18.88, 20.89, 22.33, 23.18 and 31.87. The new polymorphic Form A2 of Ertapenem sodium is further characterised by PXRD having °20 values (± 0.2) at 14.6, 16.07, 17.07, 18.88, 20.89, 22.33, 23.18, 25.92, 27.15, 29.43, 30.58, 31.2, 31.87, 32.82, 34.72 and 36.35. The Form A2 of Ertapenem sodium is further characterised by the PXRD pattern substantially same as depicted in Figure-2.

In yet another embodiment, present invention provides a new polymorphic form of Ertapenem sodium (hereinafter Form A3) having PXRD °20 values (±0.2) at 22.36, 23.16, 25.96, 31.87 and 32.84. The new polymorphic form, Form A2 of Ertapenem sodium is further characterised by °20 values (±0.2) at 22.36, 23.16, 25.96, 31.1, 31.87 and 32.84. The Form A3 of Ertapenem sodium is further characterised by powder X-ray diffraction pattern substantially same as depicted in Figure-3.

In other embodiments, present invention also provides processes for preparing polymorphic forms of Ertapenem sodium viz. Form Al, Form A2 and Form A3.

The process according to present invention to prepare Ertapenem sodium Form Al comprises:

i) treating the amorphous Ertapenem sodium with a base in the presence of an alcoholic solvent;

ii) adjusting the pH with an acid to 3 to 7;

iii) optionally seeding;

iv) adding tetrahydrofuran to precipitate, filtering; and

v) slurrying in acetone; and

vi) isolating Ertapenem sodium crystalline Form Al.

The amorphous Ertapenem sodium is treated with the base selected from alkali metal base, preferably with sodium bicarbonate. The alcoholic solvent used in the step (i) is selected from methanol, ethanol, and isopropyl alcohol or mixtures thereof and preferably methanol. The pH of the solution is adjusted using acid at 3 to 7 and more preferably at 5.5 to 6.0. The acid used for adjusting the pH is selected from mineral acid or organic acid. The resultant solution is optionally seeded with the crystals of the Form Al. Tetrahydrofuran is added at about -20°C to -30°C to the solution obtained from step (ii) or step (iii) to precipitate the Ertapenem sodium crystals followed by filtering the precipitate. The obtained precipitate is slurried in the acetone at about -20°C to -30°C to get Form Al of Ertapenem sodium.

The process to prepare Ertapenem sodium Form A2, which comprises:

i) treating the amorphous Ertapenem sodium with a base in the presence of an alcoholic solvent; ii) adjusting the pH with an acid 3 to 7; iii) adding acetone; iv) optionally seeding; v) filtering the product; and vi) slurrying in acetone.

The amorphous Ertapenem sodium is treated with the base selected from alkali metal base and preferably with sodium bicarbonate. The alcoholic solvent used in the step (i) is selected from methanol, ethanol, and isopropyl alcohol or mixtures thereof and preferably methanol. The pH of the solution is adjusted using acid at 3 to 7 and more preferably at 5.5 to 6.0. The acid used for adjusting the pH is selected from mineral acid or organic acid. Acetone is added to the resultant solution followed by filtering the product. The obtained product is slurried in the acetone at about -20°C to -30°C to get Form A2 of Ertapenem sodium.

The process according to present invention to prepare Ertapenem sodium Form A3 comprises:

i) treating the amorphous Ertapenem sodium with a base in the presence of an alcoholic solvent;

ii) adjusting the pH with an acid 3 to 7;

iii) adding tetrahydrofuran to precipitate;

iv) filtering the product; and

v) slurrying in acetone.

The amorphous Ertapenem sodium is treated with the base selected from alkali metal base and preferably with sodium bicarbonate. The alcoholic solvent is selected from methanol, ethanol, and isopropyl alcohol or mixtures thereof and preferably methanol. The pH of the resultant solution is adjusted using acid at 3 to 7 and more preferably at 5.5 to 6.0. The acid used for adjusting the pH is selected from mineral acid or organic acid. Tetrahydrofuran is added to the resultant solution followed by filtering to obtain the product. The obtained product is slurried in the acetone to get Form A3 of Ertapenem sodium.

The process to prepare Ertapenem sodium Form A3, which comprises treating the Ertapenem sodium Form Al with acetone.

The amorphous Ertapenem sodium is prepared by the process known in the prior-art.

POWDER X-RAY DIFFRACTION fPXRD)

The X-ray powder diffractogram is obtained using a Seifert, XRD 3003 TT system. The X-ray generator was operated at 45 kv and 40 mA, using the Ka line of copper at 1.540598 A° as the radiation source. It is scanned in the diffraction range of 2.0° to 40° 20 at a scan rate of 0.03° 29 per second.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PROCESS TO PREPARE POLYMORPHIC FORM OF ERTAPENEM SODIUM FORM Al

Amorphous Ertapenem Sodium (5.0 g) was dissolved in 2.5% w/w aqueous sodium bicarbonate (43 ml) at 0-5°C. To the solution, methanol (10 ml) was added and adjusted the pH to 5.5-6.0 with acetic acid at 0 - 5°C. The resulting solution was treated with activated carbon (0.2 g) at 0 - 5°C, filtered and washed with a mixture of water and methanol (15 ml; 2:1). The filtrate was cooled to -20 to -30°C and then added Tetrahydrofuran (25 ml) followed by mixture of tetrahydrofuran and methanol (150 ml; 1:1) in 1 h at -20 to -30°C. The slurry was stirred for 4 h, filtered and washed with acetone. The wet product was slurried in acetone (25 ml), filtered and dried under nitrogen atmosphere at < 25 °C to obtain Ertapenem Sodium Form Al. Yield: 2.75 g

EXAMPLE-2

PROCESS TO PREPARE POLYMORPHIC FORM OF ERTAPENEM SODIUM FORM Al

Amorphous Ertapenem sodium (2.0 g) was dissolved in 2.5% w/w aqueous sodium bicarbonate (17 ml) at 0-5°C. To the aqueous solution, methanol (4 ml) was added and adjusted the pH to 5.5-6.0 with acetic acid at 0 - 5°C. The resulting solution was treated with activated carbon (0.1 g) at 0 - 5°C, filtered and washed with a mixture of water and methanol (6 ml; 2:1). The filtrate was cooled to -20 to -30°C and seeded with Ertepenem Sodium Form Al (0.01 g) and then added Tetrahydrofuran (10 ml) followed by mixture of tetrahydrofuran and methanol (60 ml; 3:1) in 1 h at -20 to -30°C. The slurry was stirred for 4 h, filtered and washed with acetone. The wet product was slurried in acetone (10 ml), filtered and dried under nitrogen atmosphere at < 25°C to obtain Ertapenem Sodium Form Al. Yield: 1.04 g

EXAMPLE-3

PROCESS TO PREPARE POLYMORPHIC FORM OF ERTAPENEM SODIUM FORM A2

Amorphous Ertapenem Sodium (5.0 g) was dissolved in 2.5% w/w aqueous sodium bicarbonate (43 ml) at 0 - 5°C. To the aqueous solution, methanol (10 ml) was added and adjusted the pH to 5.5-6.0 with acetic acid at 0 - 5°C. The resulting solution was treated with activated carbon (0.2 g) at 0 - 5°C, filtered and washed with a mixture of water and methanol (15 ml; 2:1). To the filtrate, acetone (25 ml) was added at 0 - 5°C, seeded with Ertepenem Sodium Form A2 (0.05 g) at -20 to -30°C and then mixture of acetone and methanol (150 ml; 1:1) was added in 1 h at -20 to -30°C. The slurry was stirred for 4 h, filtered and washed with acetone. The wet product was slurried in acetone (25 ml), filtered and dried under nitrogen atmosphere at < 25°C to obtain Ertapenem Sodium Form A2. Yield: 2.0 g

EXAMPLE-4

PROCESS TO PREPARE POLYMORPHIC FORM OF ERTAPENEM SODIUM FORM A3

Ertapenem Sodium amorphous (5.0 g) was dissolved in 2.5% w/w aqueous sodium bicarbonate (43 ml) at 0 - 5°C. To the aqueous solution, methanol (10 ml) was added and adjusted the pH to 5.5-6.0 with acetic acid at 0 - 5°C. The resulting solution was treated with activated carbon (0.2 g) at 0 - 5°C, filtered and washed with a mixture of water and methanol (15 ml; 2:1). To the filtrate, tetrahydrofuran (25 ml) followed by mixture of tetrahydrofuran and methanol (150 ml; 3:1) were added in 1 h at -20 to -30°C. The slurry was stirred for 4 h, filtered and washed with acetone. The wet product was slurried in acetone (25 ml), filtered and dried under nitrogen atmosphere at < 25°C to obtain Ertapenem Sodium Form A3. Yield: 2.85 g

EXAMPLES-5

PROCESS TO PREPARE POLYMORPHIC FORM OF ERTAPENEM SODIUM FORM A3

Ertapenem sodium Form Al (1.0 g) obtained from example-1 was added to cold acetone (10 ml) at 0 - 5°C and stirred for 5 h. The product was filtered, slurried in acetone and dried under nitrogen at < 25°C to obtain Ertapenem Sodium form A3. Yield: 0.8 g

We Claim:

1. Ertapenem sodium crystalline Form Al having powder X-ray diffraction pattern containing °2 θ values (±0.2) at 14.63, 16.09, 18.89, 20.92, 30.61, 31.24, and 31.65.

2. Ertapenem sodium crystalline Form A2 having powder X-ray diffraction pattern containing °2 θ values (±0.2) at 18.88,20.89,22.33,23.18 and 31.87.

3. Ertapenem sodium crystalline Form A3 having powder X-ray diffraction pattern containing °2 θ values (±0.2) at 22.36,23.16,25.96, 31.87 and 32.84.

4. A process to prepare Ertapenem sodium crystalline Form Al comprising:

i) treating the amorphous Ertapenem sodium with a base in the presence of an alcoholic solvent;

ii)adjusting the pH with an acid at 3 to 7; iii)optionally seeding; iv)adding tetrahydrofuran to precipitate,

v)filtering the product; vi)slurrying in acetone; and vii)isolating Ertapenem sodium crystalline Form Al.

5. The process according to claim 4, wherein base is selected from alkali metal base; alcoholic solvent is selected from methanol, ethanol, and isopropyl alcohol and mixtures of thereof.

6. A process to prepare Ertapenem sodium crystalline Form A2 comprising:

i) treating the amorphous Ertapenem sodium with a base in the presence of an alcoholic solvent;

ii) adjusting the pH with an acid at 3 to 7;

iii) adding acetone;

iv) optionally seeding;

v) filtering the product;

vi) slurrying in acetone; and

vii) isolating Ertapenem sodium crystalline Form A2.

7. The process according to claim 6, wherein base is selected from alkali metal base; alcoholic solvent is selected from methanol, ethanol, and isopropyl alcohol and mixtures of thereof.

8. A process for to prepare Ertapenem sodium crystalline Form A3 comprising:

i) treating the amorphous Ertapenem sodium with a base in the presence of an alcoholic solvent;

ii) adjusting the pH with an acid at 3 to 7;

iii) adding tetrahydrofuran;

iv) filtering the product;

v) slurrying in acetone; and

vi) isolating Ertapenem sodium crystalline Form A3.

9. The process according to claim 8, wherein base is selected from alkali metal base; alcoholic solvent is selected from methanol, ethanol, and isopropyl alcohol and mixtures of thereof.

10. A process to prepare Ertapenem sodium crystalline Form A3 comprising treatment of Ertapenem sodium Form Al with acetone.