The present invention provides a process for the preparation of crystalline imipenem by reverse osmosis.
Imipenem monohydrate, the crystalline monohydrate of N-formimidoyl derivative of thienamycin, is the first clinically available member of a p-lactam antibiotic having carbapenem ring system. Imipenem exhibits a broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species, which is partly due to its high stability in presence of p-lactamases.
US Patent No 4,194,047 provides a process for preparing imipenem, wherein the final product is isolated by column chromatography and subsequent lyophilization. US Patent Nos 4,329,481 and 4,292,436 provide a process for obtaining crystalline imipenem from a crude imipenem by column chromatography. US Patent No 4,374,772, 4,894,450 and PCT Publication No WO 02/094828 provide processes for preparing imipenem, but no method is provided in these patents or applications for isolating the final product from the reaction mixture.
US Patent No 4,260,543 provides a process for crystallizing imipenem monohydrate from a solution of amorphous product in water and ethanol by adding seed crystals of crystalline monohydrate. Connolly et al., J. Pharm. Sci., (1996), 85, 2, 174-177 provide a freeze crystallization process for preparation of crystalline imipenem.
PCT Publication No WO 03/042215 involves crystallization of pure imipenem monohydrate from a crude imipenem, wherein the said process involves the use of a base to effect dissolution and the isolation is carried out by subsequent neutralization with hydrochloric acid.
PCT Publication No WO 02/36594 provides a process for isolating crystalline imipenem directly from a reaction mixture, wherein the process involves chromatographic purification of the reaction mixture prior to crystallization.

The processes known in the art for preparing a pure crystalline imipenem are not simple. The prior art processes involve the use of chromatographic purification; freeze crystallization, strong acids, or heating.
The present inventors have developed a simple process for preparing imipenem in a crystalline form having purity more than 99%. The present process employs reverse osmosis technique and therefore can be carried out at temperatures equal to or less than room temperature so that the stability of imipenem is maintained with high and consistent yield.
A first aspect of the present invention provides a process for the preparation of crystalline imipenem wherein the process comprises of,
a) concentrating an aqueous solution of imipenem by reverse osmosis,
b) isolating crystalline imipenem from the concentrated mass thereof.
The imipenem used as a starting material can be prepared by any of the methods disclosed in the prior art and it can be in crystalline or amorphous form. Imipenem is dissolved in water optionally containing 0.5 to 50% v/v of water miscible organic solvent at ambient temperature. The solution comprising water and imipenem can be treated with activated carbon to remove coloring impurities. The resultant solution is concentrated by reverse osmosis. Reverse osmosis membrane can be selected from a group consisting of hollow fiber membrane elements, tubular membrane elements, spiral-wound membrane elements, plate and frame membrane elements or combinations thereof.
The concentrated mass so obtained is then stirred at a temperature of about 0° - 5°C and the crystalline imipenem is isolated from the mass by suitable means such as filtration. Alternatively, the concentrated mass is treated with a water miscible organic solvent and the resultant mass is stirred at a temperature of about 0° - 5°C and the crystalline imipenem is isolated from the mass.

The water miscible organic solvent is selected from a group comprising of methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1 PREPARATION OF CRYSTALLINE IMIPENEM:
Crystalline imipenem (100 g) was dissolved in water (10 L) at ambient temperature. The resultant solution was treated with activated carbon (5 g) and filtered. The solution so obtained was concentrated at about 5° to 25°C using Millipore Namomax-50 Helicon R060 membrane to give a solution containing about 25 g of imipenem per liter of water. Absolute ethanol (4 L) was added to the concentrated solution and stirred for 60 minutes at 0° to 5°C, followed by filtration to obtain the title compound. Yield: 75 g HPLC Purity: 99.5%
EXAMPLE 2 PREPARATION OF CRYSTALLINE IMIPENEM:
Crystalline imipenem (100 g) was dissolved in water (10 L) at ambient temperature in the presence of sodium bicarbonate (2 g). The resultant solution was treated with activated carbon (5 g) and filtered. The solution so obtained was concentrated at about 5° to 25°C using Millipore Namomax-50 Helicon RO60 membrane to give a solution containing about 30 g of imipenem per liter of water. Isopropyl alcohol (3.5 L) was added to the concentrated solution and stirred for 2 h at 0° to 5°C, followed by filtration to obtain the title compound. Yield: 72 g HPLC Purity: 99 %
EXAMPLE 3 PREPARATION OF CRYSTALLINE IMIPENEM:
Crystalline imipenem (100 g) was dissolved in water (10 L) at ambient temperature in the presence of sodium bicarbonate (2 g). The resultant solution was treated with activated carbon (5 g) and filtered. The solution was so obtained concentrated at about 5° to 25°C using Millipore Namomax-50 Helicon R060 membrane to give a solution containing about 30 g of imipenem per liter of water. Acetone (3.5 L) was added to the concentrated solution and stirred for 2 h at 0° to 5°C, followed by filtration to obtain the title compound. Yield: 75 g HPLC Purity: 99 %
EXAMPLE 4 PREPARATION OF CRYSTALLINE IMIPENEM:
Crystalline imipenem (100 g) was dissolved in water (10 L) at ambient temperature. The solution so obtained was concentrated at about 5° to 25°C using Millipore Namomax-50 Helicon RO60 membrane in 30 to 40 minutes to give a solution containing about 20 - 25 g of imipenem per liter of water. The resultant solution was stirred at 0° to 5°C, followed by micron filtration to obtain the title compound. Yield: 50 g HPLC Purity: 99 %

WE CLAIM:
1. A process for the preparation of crystalline imipenem wherein the process
comprises
a) concentrating an aqueous solution of imipenem by reverse osmosis
b) isolating crystalline imipenem from the concentrated mass thereof.

2. A process as claimed in claim 1, wherein the aqueous solution contains 0.5 to 50%
v/v of water miscible organic solvent.
3. A process as claimed in claim 2, wherein the water miscible organic solvent is
selected from a group comprising of methanol, ethanol, 1-propanol, 2-propanol,
acetone and acetonitrile
4. A process as claimed in claim 1, wherein the reverse osmosis membrane is
selected from a group comprising of hollow fiber membrane elements, tubular
membrane elements, spiral-wound membrane elements, plate and frame
membrane elements or combinations thereof.
5. A process as claimed in claim 1, wherein the concentrated reaction mixture of step
a) is stirred at a temperature of about 0° - 5°C.
6. A process as claimed in claim 5, wherein the concentrated reaction mixture is
treated with a water miscible organic solvent prior to cooling.

7. A process as claimed in claim 6, wherein the water miscible organic solvent is selected from a group comprising of methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.