FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of amorphous Cilastatin sodium.

BACKGROUND OF THE INVENTION:

Cilastatin sodium, chemically known as [R-[R*,S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid mono sodium salt has the following structural Formula I.

Imipenem, a thienamycin derivative is a broad spectrum antibacterial agent and is indicated for the treatment of serious infections including lower respiratory tract infections, urinary tract infections, intra-abdominal infections, gynecologic infections, bone and joint infections, endocarditis, etc. Cilastatin sodium is a renal dehydropeptidase inhibitor and is co-administered with Imipenem in order to prevent renal metabolism of Imipenem. The Cilastatin sodium/Imipenem combination for intramuscular administration is marketed with the trade name PRIMAXIN®.

Cilastatin sodium was first disclosed in US 5,147,868, which describes various processes for the preparation of Cilastatin sodium. This patent also describes a lyophilization technique to obtain amorphous Cilastatin sodium.

US patent application US 2004/0152780 Al discloses a process for the preparation of pure Cilastatin sodium in an amorphous form, which comprises dissolving the crude Cilastatin sodium in methanol and by adding acetone to the solution so obtained, or by adding the solution so obtained into acetone to get a slurry. The slurry is subjected to vacuum distillation to recover some amount of solvent under reduced pressure and the product is recovered by filtration at ambient temperature after addition of fresh anti-solvent acetone. However, when the present inventors have repeated this method and isolated the product, impurity levels were high and it was very difficult to reduce the level of residual solvents in final product during drying due to formation of acetone solvate.

The prior art processes for the preparation of amorphous Cilastatin or its salts mainly involve lyophilization technique. This technique is not satisfactory for the process to be used on an industrial scale as it requires large volume of solvents. This technique also requires capital investment for creating technical infrastructure which makes the process highly unattractive from economical point of view.

A need remains for an improved and cost effective process for the preparation of amorphous Cilastatin sodium. Accordingly, present inventors have developed a simple, industrially applicable and cost effective process for the preparation of amorphous form of Cilastatin sodium.

OBJECTIVE OF THE INVENTION:

The main objective of the present invention is to provide a commercially viable process for the preparation of amorphous Cilastatin sodium, wherein the process is convenient to operate on a commercial scale.

Yet another objective of the present invention is to provide a process for the preparation of amorphous Cilastatin sodium, which is easy to handle, requires negligible repairs and maintenance and consumes less energy.

SUMMARY OF THE INVENTION:

The present invention provides a process for the preparation of amorphous Cilastatin sodium in pure form comprising obtaining a solution of Cilastatin sodium in solvent and isolating amorphous Cilastatin sodium; wherein the isolation of amorphous Cilastatin sodium is carried out by spray drying or by distillation.

In another aspect, present invention provides a process for the preparation of amorphous Cilastatin sodium comprising obtaining a solution of Cilastatin sodium in a solvent and isolation of amorphous Cilastatin sodium by adding anti-solvent to the solution or vice versa.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a process for the preparation of amorphous Cilastatin sodium.

In one embodiment of the present invention, process for the preparation of amorphous Cilastatin sodium comprises preparing a solution of Cilastatin sodium in a solvent and isolating the amorphous Cilastatin sodium by spray drying.

The solution of Cilastatin sodium is obtained either by dissolving crude Cilastatin sodium in a solvent or from the reaction mixture containing already dissolved crude Cilastatin sodium. The solvent is selected from water or lower alcohols such as methanol or mixtures thereof; preferably methanol.

The amorphous Cilastatin sodium is isolated from the solution by spray drying a solution of Cilastatin sodium. The spray drying is carried out by using a spray gun at an inlet temperature of 65-85°C and an outlet temperature of 50-70°C of the spray gun.
In another embodiment of the present invention, the isolation of the amorphous Cilastatin sodium from the solution is carried out by adding anti-solvent. The anti-solvent is selected from acetonitrile, ethanol, isopropanol, ethyl acetate, diisopropyl ether or mixtures thereof; preferably acetonitrile or ethanol. The amorphous Cilastatin sodium is obtained by adding an anti-solvent to a solution of Cilastatin sodium or by adding a solution of Cilastatin sodium to anti-solvent.

In yet another embodiment of the present invention, amorphous Cilastatin sodium is isolated from solution by distillation method. Cilastatin sodium is dissolved in different concentration of Solvent to obtain a clear solution. The solvent is preferably methanol. The solvent is distilled out under reduced pressure; preferably at 1-20 mm Hg and at temperature in the range of 40-65 °C, preferably at 50-65 °C to obtain amorphous Cilastatin sodium.

The crude Cilastatin sodium obtained for the preparation of amorphous Cilastatin can be prepared by the processes known in the prior art which are included herein by means of reference.

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 AMORPHOUS CILASTATIN SODIUM

Sodium hydroxide (18.30 g) was dissolved in DM water (165 ml) at 25-30°C. Cooled
the solution to 18-25°C and L-cysteine (28.50 g) was added at 18-25°C under
nitrogen atmosphere and maintained it throughout the process. Separately dissolved
(+)-(Z)-7-Chloro-2-(2,2-dimethyl-cyclopropanecarboxamido)-2-heptenoic acid,
sodium salt (50 g) in DM water (210 ml) and added to the reaction mass at 18-25°C for 30 min under nitrogen atmosphere and stirred the reaction mass under nitrogen atmosphere up to completion of reaction. After completion of the reaction, pH was adjusted to 1.8-2.0 with cone, hydrochloric acid at 18-25°C.

Loaded the reaction mixture obtained as above on a column packed with activated diaion HP-20 resin (600 g). Recycle the eluant through the resin column till the eluant shows complete adsorption of product on resin. The resin column was washed with distilled water. Thereafter, eluted the product with aqueous methanol. Analyzed the fractions by qualitative HPLC and combined the fractions containing pure product (HPLC purity >99.0%).

The pH of the combined pure fractions was adjusted to 7.6-7.8 with aqueous sodium hydroxide (10% w/w) solution at 20-3 0°C. Concentrated the solution of Cilastatin sodium to ~400 ml under reduced pressure (3-5 mm of Hg) at below 48°C. Filtered the concentrated solution under nitrogen through 0.22 um filter. An aqueous solution of pure Cilastatin sodium was spray dried to obtain the title compound. Yield: 36 g Chromatographic purity (by HPLC): 99.37%

EXAMPLE 2:

PROCESS TO PREPARE AMORPHOUS CILASTATIN SODIUM

Sodium hydroxide (18.30 g) was dissolved in DM water (165 ml) at 25-30°C. Cooled
the solution to 18-25°C and L-cysteine (28.50 g) was added at 18-25°C under
nitrogen atmosphere and maintained it throughout the process. Separately dissolved
(+)-(Z)-7-Chloro-2-(2,2-dimethyl-cyclopropanecarboxamido)-2-heptenoic acid,
sodium salt (50 g) in DM water (210 ml) and added to the reaction mass at 18-25°C for 30 min under nitrogen atmosphere and stirred the reaction mass under nitrogen atmosphere up to completion of reaction. After completion of the reaction, pH was adjusted to 1.8-2.0 with cone, hydrochloric acid at 18-25°C.

Loaded the reaction mixture obtained as above on a column packed with activated diaion HP-20 resin (600 g). Recycled the eluant through the resin column under nitrogen atmosphere till the eluant shows complete adsorption of product on resin. The resin column was washed with distilled water. Thereafter, eluted the product with aqueous methanol. Analyzed the fractions by qualitative HPLC and combined the fractions containing pure product (HPLC purity >99.0%).

The pH of the combined pure fractions was adjusted to 7.6-7.8 with aqueous sodium hydroxide (10% w/w) solution under nitrogen atmosphere at 20-30°C. Concentrated the solution of Cilastatin sodium up to thick oil under reduced pressure (3-5 mm of Hg) at below 48°C. Methanol (260 ml) was added and stirred for 15-20 min at 40-45°C to obtain a clear solution. Concentrated the methanol solution of Cilastatin sodium up to thick oil by distilling mixture of methanol and trace amount of water under reduced pressure (3-5 mm of Hg) at below 48°C. Methanol (260 ml) was added and stirred for 15-20 min at 40-48°C to obtain a clear solution. Filter the methanol solution under nitrogen through 0.22 um filter. Filtrate (methanol solution of Cilastatin sodium) was spray dried by a spray gun to obtain the title compound. Yield: 36 g Chromatographic purity (by HPLC): 99.13%

EXAMPLE-3:

PROCESS TO PREPARE AMORPHOUS CILASTATIN SODIUM

Sodium hydroxide (18.30 g) was dissolved in DM water (165 ml) at 25-30°C. Cooled
the solution to 18-25°C and L-cysteine (28.50 g) was added at 18-25°C under
nitrogen atmosphere and maintained it throughout the process. Separately dissolved
(+)-(Z)-7-Chloro-2-(2,2-dimethyl-cyclopropanecarboxamido)-2-heptenoic acid,
sodium salt (50 g) in DM water (210 ml) and added to the reaction mass at 18-25°C for 30 min under nitrogen atmosphere and stirred the reaction mass under nitrogen atmosphere up to completion of reaction. After completion of the reaction, pH was adjusted to 1.8-2.0 with cone, hydrochloric acid at 18-25°C.

Loaded the reaction mixture obtained as above on a column packed with activated diaion HP-20 resin (600 g). Recycled the eluant through the resin column under nitrogen atmosphere till the eluant shows complete adsorption of product on resin. The resin column was washed with distilled water. Thereafter, eluted the product with aqueous methanol. Analyzed the fractions by qualitative HPLC and combined the fractions containing pure product (HPLC purity >99.0%).

The pH of the combined pure fractions was adjusted to 7.6-7.8 with aqueous sodium hydroxide (10% w/w) solution under nitrogen atmosphere at 20-30°C. Concentrated the solution of Cilastatin sodium up to thick oil by distilling mixture of methanol and water under reduced pressure (3-5 mm of Hg) at below 48°C. Methanol (260 ml) was added and stirred for 15-20 min at 40-45°C to obtain a clear solution. Concentrated the methanol solution of Cilastatin sodium up to thick oil under reduced pressure (3-5 mm of Hg) at below 48°C. Methanol (260 ml) was added and stirred for 15-20 min at 40-48°C to obtain a clear solution. Filter the methanol solution under nitrogen through 0.22 um filter. Filtrate (methanol solution of Cilastatin sodium) was concentrated on a Buchi Rotavapour at bath temperature 65 °C under vacuum to a residue. Kept the flask under vacuum at bath temperature 65°C for 2 h to obtain title compound.

Yield: 38 g Chromatographic purity (by HPLC): 99.32%

EXAMPLE-4:

PROCESS TO PREPARE AMORPHOUS CILASTATIN SODIUM

Sodium hydroxide (18.30 g) was dissolved in DM water (165 ml) at 25-30°C. Cooled
the solution to 18-25°C and L-cysteine (28.50 g) was added at 18-25°C under
nitrogen atmosphere and maintained it throughout the process. Separately dissolved
(+)-(Z)-7-Chloro-2-(2,2-dimethyl-cyclopropanecarboxamido)-2-heptenoic acid,
sodium salt (50 g) in DM water (210 ml) and added to the reaction mass at 18-25°C for 30 min under nitrogen atmosphere and stirred the reaction mass under nitrogen atmosphere up to completion of the reaction. After completion of the reaction, pH was adjusted to 1.8-2.0 with cone, hydrochloric acid at 18-25°C.

Loaded the reaction mixture obtained as above on a column packed with activated diaion HP-20 resin (600 g). Recycled the eluant through the resin column under nitrogen atmosphere till the eluant shows complete adsorption of product on resin. The resin column was washed with distilled water. Thereafter, eluted the product with aqueous methanol. Analyzed the fractions by qualitative HPLC and combined the fractions containing pure product (HPLC purity >99.0%).

The pH of the combined pure fractions was adjusted to 7.6-7.8 with 10% w/w aqueous sodium hydroxide solution under nitrogen atmosphere at 20-3 0°C. Concentrated the solution of Cilastatin sodium up to thick oil under reduced pressure (3-5 mm of Hg) at below 48°C. Methanol (260 ml) was added and stirred for 15-20 min at 40-45°C to obtain a clear solution. Concentrated the methanol solution of Cilastatin sodium up to thick oil by distilling mixture of methanol and trace amount of water under reduced pressure (3-5 mm of Hg) at below 48°C. Methanol (260 ml) was added and stirred for 15-20 min at 40-48°C to obtain a clear solution. Filtered the methanol solution under nitrogen through 0.22 urn filter and washed the residue with methanol (35 ml). Add the filtrate (methanol solution of Cilastatin sodium) in to the Acetonitrile (1400 ml) slowly at 0-5°C during 30 min under nitrogen. Filter the product after 1 hr under nitrogen at 0-5 °C followed by washing with Acetonitrile and drying to obtain the title compound.

Yield: 35 g Chromatographic purity (by HPLC): 99.19%

WE CLAIM:

1. A process for the preparation of amorphous Cilastatin sodium comprising obtaining a solution of Cilastatin sodium in a solvent and isolation of amorphous Cilastatin sodium from the solution; wherein isolation is carried out by spray drying or distillation.

2. A process for the preparation of amorphous Cilastatin sodium comprising obtaining a solution of Cilastatin sodium in a solvent and adding an anti-solvent to the solution or vice versa to obtain amorphous Cilastatin sodium.

3. The process according to claim 1 or 2, wherein solvent is selected from water or methanol or mixture thereof.

4. The process according to claim 1 or 2, wherein solvent is methanol.

5. The process according to claim 1, wherein spray drying is carried out by using a spray gun at an inlet temperature of 65-85°C and an outlet temperature of 50-70°C of the spray gun.

6. The process according to claim 1, wherein distillation is carried out at temperature in the range of 60 to 110°C.

7. The process according to claim 2, wherein anti-solvent is selected from acetonitrile, ethanol, isopropanol, ethyl acetate, diisopropyl ether or mixtures thereof.

8. The process according to claim 2, wherein anti-solvent is acetonitrile or ethanol.

9. The process according to claim 1 or 2, wherein solvent is added in different concentrations to obtain a clear solution of Cilastatin sodium.

10. A process for the preparation of amorphous Cilastatin sodium substantially as described herein.