The present invention relates to a process for the preparation of sterile Doripenem.
(4R,5S,6S)-3-[[(3S,5S)-5-[[(Aminosulfonyl)amino]methyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-
hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid,
Commonly known as doripenem of Formula I is a synthetic, broad-spectrum, carbapenem antibiotic.

(Formula Removed)



FORMULA I
Doripenem is presently available in the market as a monohydrate and it exhibits potent, broad and well-balanced antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.
US 5,317,016 provides a process for the isolation of doripenem by lyophilization. Similar processes for preparing lyophilized doripenem have also been described in Yasuyoshi Iso et al, J. Antibiot. 1996, 49, 199-209 and Yasuyoshi Iso et al, J. Antibiot. 1996, 49, 478-484. WO 06/117763 provides a process for the preparation of amorphous doripenem using water and ethanol as solvents. US 6,111,098 and US 5,703,243 provide processes for preparing crystalline and amorphous forms of lyophilized doripenem. US 2003/0153191 provides processes for preparing Type III and Type IV crystals of doripenem using water and alcohols.
Yutaka Nishino et al, Org. Process Res. Dev. 2003, 7, 846-850 provide a process for the preparation of sterile crystalline doripenem wherein, crude doripenem is dissolved in water by heating at 55°C, filtered through a funnel pre-coated with activated carbon, a membrane filter (0.2 mm), a membrane for ultrafiltration and a filter for the sterilization. The solution is cooled to room temperature, and stirred at 2°C for 2 h.

Jsopropanol is then added and stirred at -5°C for 4 h and at -10°C overnight to obtain Sterile doripenem.
The present inventors have observed that the prior art processes for preparing sterile doripenem involve dissolving doripenem in water by heating to a temperature above 50°C and requires membrane filtration at hot conditions. The present inventors have observed that carrying out sterilization process of sensitive compounds such as doripenem at high temperature conditions result in the formation of degradation impurities.
The present inventors have developed an advantageous process for the preparation of sterile doripenem, which can be carried out at low temperature conditions and thereby avoiding any degradation. By employing the process of the present invention, doripenem can be isolated as a monohydrate. Further, the present process is simple and efficient to prepare sterile doripenem at industrial scale.
A first aspect of the present invention provides a process for preparation of sterile doripenem, wherein the process comprises,
a) dissolving doripenem in water in the presence of a base,
b) filtering the solution obtained in step a) using a filter for sterilization, and
c) isolating sterile doripenem from the filtered solution thereof.
Doripenem, which is used as the starting material, can be prepared according to the methods provided in US 5,317,016, US 6,111,098 or Yutaka Nishino et al, Org. Process Res. Dev. 2003, 7, 846-850. Doripenem, which is used as the starting material, can exist in any solid form known in the art. Doripenem is dissolved in water in the presence of a base. The base is selected from the group consisting of hydroxides, bicarbonates or carbonates of alkali metals or alkaline earth metals, alkoxides and amines. The water is used in a quantity of about 5 times to 15 times to the weight of doripenem. The base can be used in an amount to attain a pH of about 8 to about 12 at a temperature of about 30°C or below, preferably at a temperature of about 5°C to about 25°C. The solution so obtained is optionally treated with activated

Carbon and filtered using a filter for sterilization. The filter for sterilization is preferably a membrane having a pore diameter of about 0.25 microns or below. Sterile doripenem is isolated from the filtered solution. The isolation is carried out by adjusting the pH of the filtered solution to about 4 to about 6. The pH adjustment can be carried out by the addition of an acid. The acid can be an organic or inorganic acid. The acid Can be used in concentrated form or as diluted solutions. The mixture so obtained is optionally seeded with sterile doripenem and stirred at about 0° to about 30°C. The Stirring can be carried out for about 10 minutes to about 100 h, preferably for about 1 to 6 h. Sterile doripenem is isolated from the mixture by filtration, concentration, distillation, treating with water miscible organic solvent or a combination thereof. Sterile doripenem is preferably isolated by treating the mixture with a water miscible organic solvent. The water miscible organic solvent is selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methanol, ethanol, propanol, dimethylformamide and dioxane. The mixture is optionally stirred and filtered to obtain sterile doripenem. Sterile doripenem is preferably isolated as a monohydrate.
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 STERILE DORIPENEM
Doripenem (50 g) was dissolved in water (300 ml) by adding ammonia drop-wise to attain a pH of 8.5 to 9 at 15° to 20°C. The solution was treated with activated carbon (5 g) followed by micron filtration using a membrane (0.25 microns). The pH of the filtrate was adjusted to 5 to 5.5 with aqueous formic acid at 10° to 20°C. The mixture was stirred at 0° to 5°C for 4 to 5 h. Isopropyl alcohol (150 ml) was added slowly to the mixture and stirred about 12 h at 0°to 5°C. The mixture was filtered and dried 40° to 50°C at to obtain the title compound. Yield: 80% w/w Purity: 98%

WE CLAIM:
1. A process for preparation of sterile doripenem, wherein the process comprises,
a) dissolving doripenem in water in the presence of a base,
b) filtering the solution obtained in step a) using a filter for sterilization, and
c) isolating sterile doripenem from the filtered solution thereof.

2. A process according to claim 1, wherein the base is selected from the group
consisting of hydroxides, bicarbonates or carbonates of alkali metals or alkaline
earth metals, alkoxides and amines.
3. A process according to claim 1, wherein the water is used in a quantity of about
5 times to 15 times to the weight of doripenem.
4. A process according to claim 1, wherein the base is used in an amount to attain
a pH of about 8 to about 12 at a temperature of about 30°C or below.
5. A process according to claim 4, wherein the base is used in an amount to attain
a pH of about 8 to about 12 at a temperature of about 5°C to about 25°C.
6. A process according to claim 1, wherein the filter for sterilization is preferably a
membrane having a pore diameter of about 0.25 microns or below.
7. A process according to claim 1, wherein the isolation of sterile doripenem is
carried out by adjusting the pH of the filtered solution to about 4 to about 6.
8. A process according to claim 7, wherein the pH adjustment is carried out by the
addition of an acid.

9. A process according to claim 8, wherein the sterile doripenem is isolated by treating with a water miscible organic solvent.