FIELD OF THE INVENTION

The present invention relates to an improved process for preparing Meropenem trihydrate of Formula I.

BACKGROUND OF THE INVENTION

Meropenem, chemically known as (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylamino) carbonyl-3-pyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, is a β-lactam antibiotic, having a carbapenem ring system and is being marketed as trihydrate under the Trade name MERREM I.V. Meropenem exhibits extremely broad antimicrobial spectrum and a strong antimicrobial activity and is useful as an antibiotic agent.

Meropenem was first disclosed in US 4,943,569. Example 2 of this patent specifically describes a process to prepare Meropenem, which comprises hydrogenating a solution of (4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(l-p-nitrobenzyloxycarbonyl-2-dimethylamine-carbonyl)pyrrolidinylthio]-4-methyl-6-(l-hydroxyethyl)-l-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate using Pd/C in tetrahydrofuran and ethanol. After the completion of the reaction, the residual solution obtained after filtration of Pd/C was subjected to polymer chromatography (CHP-20P) to obtain (4R,5S,6S,8R,2'S,4'S)-3-[4-(2-dimethylamine-carbonyl)pyrrolidinylthio]-4-methyl-6-(l-hydroxyethyl)-l-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylic acid from the fraction eluted with water.

US 4,888,344 discloses a process to prepare crystalline Meropenem trihydrate, which comprises dissolving the lyophilized product of non-crystalline Meropenem in water and
cooled in a water bath, whereupon precipitation of a small amount of crystals was observed. Acetone was added thereto, and the resultant mixture was stirred for 1 hour. The precipitated crystals were collected by filtration, washed with acetone and dried at room temperature under reduced pressure for 2 hours.

WO 2007/031858 A2 discloses a process to prepare sterile meropenem trihydrate, which comprises:

a) dissolving the meropenem or its hydrate salt in water in the presence of base and in the presence or absence of water-miscible organic solvents;

b) optionally filtering through micron filter;

c) adjusting pH to 4.0 to 7.0; and

d) optionally adding solvent to yield meropenem trihydrate.

However, this process suffers from poor yield and product of poor quality as the product gets degraded at acidic pH which leads to loss of product and contamination with impurities.

Accordingly, there has been a need to develop a simple and industrially viable process for the preparation of highly pure Meropenem trihydrate in higher yield.

We have now found an improved process for the preparation of Sterile Meropenem trihydrate using simple crystallization.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide an improved process for preparing sterile Meropenem trihydrate.
Yet another objective of the present invention is to provide an improved process for the preparation of sterile Meropenem trihydrate, which is simple, industrially applicable and economically viable.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of sterile Meropenem trihydrate of Formula I,

which comprises:

a) dissolving Meropenem trihydrate in water optionally in the presence of base;

b) adjusting the pH to 7.1-8.0 using aqueous N-Methylmorpholine formate solution and optionally with base;

c) optionally treating with carbon enoanticromos;

d) optionally adjusting the pH to 7.1 -8.0 with acid or base;

e) addition of organic solvent or mixture of organic solvents to crystallize sterile Meropenem trihydrate;

f) isolating and washing the product with 1:2 mixture of water and solvent; and

g) drying the obtained product at 25-40°C under reduced pressure.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of sterile Meropenem trihydrate, which comprises, dissolving Meropenem trihydrate in water; adjusting the pH to 7.1-8.0 using aqueous solution of N-Methylmorpholine formate; optionally treating the reaction mass with carbon and adding water miscible organic solvents or mixture of organic solvents to crystallize sterile Meropenem trihydrate, which is isolated and washed with mixture of water and water miscible organic solvent(s) or mixture of organic . solvents and dried the product under reduced pressure.

In one embodiment of the present invention, Meropenem trihydrate is dissolved in water in presence of base selected from aqueous ammonia or alkyl amines such as triethylamine, diethylamine or N-methyl morpholine and more specifically, in presence of aqueous ammonia.

In yet another embodiment of the present invention, pH of the aqueous solution of Meropenem trihydrate is adjusted to 7.1-8.0 using aqueous N-Methylmorpholine formate solution in presence of base. The base can be selected from ammonia or alkyl amines such as triethylamine, diethylamine or N-methyl morpholine.

In yet another embodiment of the present invention, pH of the Meropenem trihydrate solution obtained after carbon treatment is adjusted to 7.1-8.0 using carboxylic acid or organic base or mixture(s) thereof. The carboxylic acid can be selected from the group of formic acid, acetic acid, oxalic acid or trifluoroacetic acid. The organic base can be selected from alkyl amines such as triethylamine, diethylamine or N-methyl morpholine.
In yet another embodiment of the present invention, the obtained sterile Meropenem trihydrate is washed with a mixture of water and organic solvent(s). The mixture of water with organic solvent can be used in the proportion of 1:5 to 1:1 (v/v), and more specifically in the proportion of 1:2 (v/v). The organic solvent can be selected from acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, tetrahydrofuran or mixture(s) thereof.

In yet another embodiment of the present invention, obtained sterile Meropenem trihydrate is dried under reduced pressure at 20-60° C and more preferably at 25-40° C.
The present 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

PREPARATION OF STERILE MEROPENEM TRIHYDRATE

Meropenem trihydrate (20 g) was suspended in DM water (200 ml) and treated with 10% w/w aqueous ammonia (10 ml) to obtain clear solution at 0-5°C. The pH of the resulting solution was adjusted to 7.1-8.0 with N-methylmorpholine formate solution, prepared by dissolving of N-methylmorpholine (6.75 g) and of formic acid (2.52 g) in DM water (10 ml), at 0-5°C. The resulting solution was treated with carbon enoanticromos (2 g) and then filtered. The filtrate was passed through 0.22 micron filter, seeded with Meropenem trihydrate (0.04 g) at 0-5°C and adjusted the pH to 7.1-7.3 with 10% w/w aqueous formic acid solution (22 ml). The contents were stirred for 1 h at 0-5°C, added isopropyl alcohol (360 ml) and further continued stirring for 1 h. Acetone (360 ml) was added to the contents, continued stirring for 2 h at 0-5°C, filtered the product, washed with a mixture of water and acetone (1:2, 78 ml) and dried at 30-35°C under reduced pressure (< 50 mm Hg) till the water content is between 11.4 and 13.4% w/w. Yield: 16.2 g Chromatographic Purity (By HPLC): 99.76%

EXAMPLE-2

PREPARATION OF STERILE MEROPENEM TRIHYDRATE

Meropenem trihydrate (20 g) was dissolved in DM water (700 ml) at 40-45°C, added N-methylmorpholine formate solution, prepared by dissolving of N-methylmorpholine (18.4 g) and of formic acid (8.4 g) in DM water (20 ml), adjusted the pH to 7.1-8.0 with N-methylmorpholine. The resulting solution was treated with carbon enoanticromos (2 g) and then filtered at 0-10°C. The filtrate was passed through 0.22 micron filter and seeded with Meropenem trihydrate (0.04 g) at 0-5°C. The contents were stirred for 2 h and acetone (2.28 It) was added at 20-30°C. Stirring further continued for 2 h and cooled to 0-5°C, filtered the product, washed with a mixture of water and acetone (1:2, 78 ml) and dried at 30-35°C under reduced pressure (< 50 mm Hg) till the water content is between 11.4 and 13.4% w/w. Yield: 17 g Chromatographic Purity (By HPLC): 99.95%

EXAMPLE-3

PREPARATION OF STERILE MEROPENEM TRIHYDRATE

Meropenem trihydrate (20 g) was dissolved in DM water (600 ml) at 40-45°C, added N-methylmorpholine formate solution, prepared by dissolving of N-methylmorpholine (18.4 g) and of formic acid (8.4 g) in DM water (20 ml), adjusted the pH to 7.1-8.0 with N-methylmorpholine. The resulting solution was treated with carbon enoanticromos (2 g) and then filtered at 20-30°C. The filtrate was passed through 0.22 micron filter and seeded with Meropenem trihydrate (0.04 g) at 0-5°C. The contents were stirred for 2 h and acetone (1.98 It) was added at 20-30°C. Stirring further continued for 2 h and cooled to 0-5°C, filtered the product, washed with a mixture of water and acetone (1:2, 78 ml) and dried at 30-35°C under reduced pressure (< 50 mm Hg) till the water content is between 11.4 and 13.4% w/w. Yield: 15.4 g Chromatographic Purity (By HPLC): 99.88%

EXAMPLE-4

PREPARATION OF STERILE MEROPENEM TRIHYDRATE

Meropenem trihydrate (20 g) was suspended in DM water (300 ml) and treated with 10% w/w aqueous ammonia (10 ml) to obtain clear solution at 0-5°C. The resulting solution was treated with carbon enoanticromos (2 g) and filtered. The filtrate was passed through 0.22 micron filter and adjusted the pH to 7.1-8.0 with N-methylmorpholine formate solution, prepared by dissolving of N-methylmorpholine (6.75 g) and of formic acid (2.52 g) in DM water (20 ml) at 0-5°C and then seeded with Meropenem trihydrate (0.04 g). Isopropyl alcohol (1.08 It) was added to the contents, continued stirring for 2 h at 0-5°C, filtered the product, washed with a mixture of water and isopropyl alcohol (1:2, 78 ml) and dried at 30-35°C under reduced pressure (< 50 mm Hg) till the water content is between 11.4 and 13.4% w/w. Yield: 14 g Chromatographic Purity (By HPLC): 99.63%

EXAMPLE-5

PREPARATION OF STERILE MEROPENEM TRIHYDRATE

Meropenem trihydrate (20 g) was suspended in DM water (300 ml) and treated with 10% w/w aqueous ammonia (10 ml) to obtain clear solution at 0 - 5°C. The resulting solution was treated with carbon enoanticromos (2 g) and filtered. The filtrate was passed through 0.22 micron filter and adjusted the pH to 7.1 - 8.0 with N-methylmorpholine formate solution, prepared by dissolving of N-methylmorpholine (6.75 g) and of formic acid (2.52 g) in DM water (20 ml) at 0 - 5°C and then seeded with Meropenem trihydrate (0.04 g). Acetone (1.08 It) was added to the contents, continued stirring for 2 h at 0 - 5°C, filtered the product, washed with a mixture of water and acetone (1:2, 78 ml) and dried at 30-35°C under reduced pressure (< 50 mm Hg) till the water content is between 11.4 and 13.4% w/w. Yield: 16 g Chromatographic Purity (By HPLC): 99.7%

WE CLAIM

1. A process for the preparation of Meropenem trihydrate of formula I

which comprises:

a) dissolving Meropenem trihydrate in water optionally in the presence of base;

b) adjusting the pH to 7.1-8.0 using aqueous N-Methylmorpholine formate
solution;

c) optionally treating resultant solution with carbon;

d) optionally adjusting the pH to 7.1 -8.0;

e) addition of organic solvent or mixture of organic solvents to crystallize
Meropenem trihydrate;

f) isolating and washing the product with a mixture of water and organic
solvent(s); and

g) drying obtained product under reduced pressure.

2. The process according to claim 1, wherein base is selected from aqueous
ammonia or alkyl amines selected from triethylamine, diethylamine or N-methyl
morpholine.

3. The process according to claim 1, wherein base is aqueous ammonia.

4. The process according to claim 1, wherein pH is adjusted to 7.1-7.3 using aqueous
N-Methylmorpholine formate solution.

5. The process according to claim 1, wherein the product is washed with mixture of water and organic solvent in the proportion of 1:2.

6. The process according to claim 1, wherein organic solvent is selected from the group of acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran or mixture(s) thereof.

7. The process according to claim 1, wherein step (d) is carried out by adding organic acid selected from carboxylic acids selected from formic acid or acetic acid or organic base selected from triethylamine, diethylamine, N-methyl morpholine or mixture(s) thereof.

8. The process according to claim 1, wherein obtained product is dried at 25-40°C under reduced pressure.

9. The process according to claim 1, wherein product obtained is sterile Meropenem tri hydrate.

10. A process for the preparation of sterile Meropenem trihydrate substantially as described herein.