PROCESS FOR ISOLATING PURE CRYSTALLINE IMIPENEM

Field of the Invention
In general, this invention relates to a process for isolating pure crystalline Imipenem. More particularly, the present invention provides an improved and cost effective process for isolation of highly pure crystalline Imipenem monohydrate with reduced thienamycin content and other impurities on commercial scale.

Background of the Invention
Imipenem monohydrate i.e. the N-formimidoyl derivative of thienamycin and has the structure Formula I, is an intravenous ß-lactam antibiotic that belongs to the subgroup of carbapenems. Imipenem has an extremely 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 b-lactamases.

Imipenem was first disclosed in US Patent No. 4,194,047 and obtained by lyophilization technique. The compound obtained by lyophilization is found to be largely amorphous and stated to be thermodynamically unstable. The US’047 process of imipenem production was found to give a product in low yield and of poor quality. In addition, the process is tedious and time consuming involving column chromatography using hydrophobic resins.

US patent no. 4,260,543 discloses thermodynamically stable form of crystalline imipenem monohydrate obtained by lyophilization followed by crystallization of imipenem. However this process is tedious involving multiple steps, thereby making it uneconomical for large scale production. Moreover, the prolonged process of isolation results in degradation of imipenem, thus affecting the purity of the product.

US patent no. 4,292,436 discloses an alternate process for the preparation of imipenem wherein crude imipenem is purified by column chromatography using Dowex -50 to give crystalline imipenem. Still another process for the preparation of highly crystalline imipenem by freeze crystallization is disclosed in J. Pharm. Sci, 85, 174(1996) by Connolly et. al. However, the above processes are tedious, cumbersome and unsuitable for industrial use.

US patent no. 7,241,885 and US patent no. 7,332,600 disclosed the crystallization of pure imipenem by treating an aqueous solution containing crude imipenem with organic solvent and isolating the pure crystalline imipenem monohydrate form the mixture. The product so obtained results in the formation of the side products during the reaction viz polymeric impurities and colored impurities. These impurities are difficult to detect as they don’t have any ultra-violet absorption. Moreover, the polymeric impurities are not reflected in the qualitative determination of purity by HPLC, but the quantitative determination shows that the product contains 5-10% of these impurities.

The colored impurities are degradation products of imipenem formed during production or under storage, imipenem being inherently unstable in solution and sensitive to heat and light. These colored impurities adversely affect the appearance of imipenem, which may appear from pale yellow to brownish powder instead of the desired white crystalline powder. However the product obtained by the process contains thienamycin content more than 1 %. As per US’600, crude imipenem is added to warm water at 45-470C containing the base, followed by rapidly cooling to 5 to 10oC within 10 to 15 min, which is extremely difficult to achieve during large scale production. This uncontrolled temperature may leads to generation of thienamycin impurities on industrial scale, thus affecting the purity of final product.

Further, the purification of imipenem is difficult due to its unstable nature. The crystalline imipenem has relatively low solubility in water at room temperature, as a result the purification and chromatographic process requires large volumes of water for dissolving imipenem and also it involves tedious process for removing the water.

In light of the existing processes there still exists a need to develop an alternate process for large scale production of imipenem that is economical, less tedious and time consuming. Further, there is need to develop a simple process for producing imipenem that involves fewer steps and generates minimal impurities.

Objects and summary of the Invention
It is an object of the present invention to provide a simple, cost-effective process for isolation of highly pure crystalline imipenem free from impurities that includes polymeric, colored and thienamycin.

It is another object of the present invention to provide a process for isolating pure crystalline imipenem with high purity and yield at large scale industrial production.

It is another object of the present invention to provide a process for isolating pure crystalline imipenem, wherein the process does not involves use of sophisticated, time consuming and costly techniques like lyophilization and column chromatography etc.

The above and other objects of the present invention are attained according to following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.

In accordance with one embodiment of the present invention, there is provided a process for isolating pure crystalline imipenem comprises of dissolving crude imipenem in water at a room temperature, wherein the water having a pH adjusted in a manner to control the impurity formation, treating the resultant solution with activated carbon at low temperature, and isolating the pure crystalline imipenem monohydrate employing an organic solvent.

In accordance with one embodiment of the present invention, there is provided a process for isolating pure crystalline imipenem, wherein the ratio of crude imipenem and water is 1:50-100 (w/v), preferably the ratio is 1:70 (w/v).

In accordance with one embodiment of the present invention, there is provided a process for isolating pure crystalline imipenem, wherein the resultant product is having impurity content less than 0.25%.

In accordance with one embodiment of the present invention, there is provided a process for isolating pure crystalline imipenem, wherein the pH of water is adjusted to 6.0-7.5 by adding base and treating the same with either acid or buffer or purging carbon dioxide gas, preferably, pH of water is adjusted to 6.5-7.3, most preferably the pH of water is adjusted to 6.8-7.2.

In accordance with one embodiment of the present invention, there is provided a process for isolating pure crystalline imipenem, wherein the said process is feasible for large-scale industrial manufacture of pure crystalline imipenem.

Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The disclosed embodiment of the present invention deals with a process for isolating pure crystalline imipenem. The process of the present invention is advantageous over the prior art due to the use of specific temperature range and pH, thereby reducing undesired processing steps and controlling the formation of impurities. This makes the process economical, commercially viable and feasible for large-scale manufacture of pure crystalline imipenem.

Accordingly, the present invention provides a process for isolating pure crystalline imipenem comprising dissolving crude imipenem in water at a room temperature, wherein the water having a pH adjusted in a manner to control the impurity formation, treating the resultant solution with activated carbon at low temperature, and isolating the pure crystalline imipenem monohydrate employing an organic solvent.

According to the present invention, the pH of water is adjusted first to about 7.5 to 8.5 by using suitable base, preferably by sodium bicarbonate or sodium carbonate. To the above basified water, pH is again adjusted to 6.0-7.5, preferably 6.5-7.3 and more preferably 6.8-7.2 by either treatment with acid and buffer or by purging carbon dioxide gas into the solution. The acid used herein is selected from the group consisting of inorganic acid or organic acid. The organic acid used herein is selected from the group consisting of but not limited to acetic acid, formic acid whereas inorganic acid used herein is selected from the group consisting of but not limited to hydrochloric acid. The buffer used herein is selected from the group consisting of but not limited to N-methylmorpholine or Morpholinopropane sulphonic acid buffer.

To above obtained solution, crude imipenem (containing polymeric, colored and thienamycin impurities) is added under inert atmosphere at room temperature. The crude imipenem: water ratio can be 1:50-100 (w/v) preferably 1:70 (w/v). It is observed that in case of ratio less than 1:50 (w/v) crude imipenem does not get dissolved properly and to dissolve imipenem in the particular ratio temperature need to be increased to 40-50o C, which leads to impurity generation in final product, whereas if the ratio is above 1:100 (w/v) the organic solvent requirement is very large to precipitate the pure imipenem, which makes it unfavorable for commercial scale production. To dissolve crude imipenem at room temperature the optimum ratio is 1:70 (w/v). In this optimized ratio quantity of organic solvent required for precipitation is also very low when compared with other ratios, thus making it economical for industrial scale production.

The mixture is stirred for a time period of 5-25 min and obtained clear solution is subjected to activated carbon treatment along with cooling to a temperature of -5 to15oC preferably 5-10oC. During cooling operation pH is adjusted to 5.8–6.2 by adding suitable acid like hydrochloric acid and stirred for 15-45 min followed by filtration. The filtrate is passed through 0.2 µ filter and cooled to 0-10oC followed by adding prechilled organic solvent. The precipitated product is filtered out and washed with organic solvent and dried under vacuum to get the imipenem monohydrate crystalline having HPLC purity of >99% and thienamycin content about 0.25%. The organic solvent used herein is selected from the group consisting of lower alcohol such as methanol, ethanol, propanol and isopropanol; ketones such as acetone, methyl ethyl ketone; or mixture thereof.

The crude imipenem is obtained by any process known in the art like disclosed in US4194047, 4292436, 4374772, 4894450, EP1670806 and are incorporated herein for reference and the crude imipenem so obtained by said mention process is subjected to crystallization process.

Further details of the invention will be apparent form examples. However, these are not intended in any way to limit the scope of the present invention.

Example-1
To a basified water solution (mixture of 0.625 gm of Sodium bicarbonate in 1750 ml water) carbon dioxide gas was purged at room temperature to adjust the pH 6.8-7.2. Crude imipenem (25 gm) (purity 95 %) was added to the above solution under inert atmosphere and stirred at room temperature followed by treatment with activated carbon (7.5 gm) at low temperature. Further pH of the solution was again adjusted to 5.8-6.2 using 10% aq hydrochloric acid. The obtained reaction mass was filtered and washed repetitively with water, the filtrate obtained was again filtered through 0.2µ filter followed by cooling the filtrate. The filtrate was then subjected to precipitation using chilled acetone (3500 ml) and the solid obtained was filtered. The dry product with a yield of 0.65-0.75 w/w imipenem of more than 99% purity is obtained with thienamycin content less than 0.25%.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We Claim:
1. A process for isolating pure crystalline imipenem comprising:
dissolving crude imipenem in water at a room temperature, wherein the water having a pH adjusted in a manner to control the impurity formation;
treating the resultant solution with activated carbon at low temperature, and isolating the pure crystalline imipenem monohydrate employing an organic solvent.

2. The process according to claim 1, wherein the ratio of crude imipenem and water is 1:50-100 (w/v).

3. The process according to claim 1, wherein the ratio of crude imipenem and water is 1:70 (w/v).

4. The process according to claim 1, wherein the impurity content is less than 0.25%.

5. The process according to claim 1, wherein the pH of water is adjusted to 6.0-7.5 by adding base and treating the same with either acid or buffer or purging carbon dioxide gas.

6. The process according to claim 5, wherein the pH of water is adjusted to 6.5-7.3.

7. The process according to claim 6, wherein the pH of water is adjusted to 6.8-7.2.

8. The process according to claim 5, wherein the base used is sodium carbonate or sodium bicarbonate.

9. The process according to claim 1, wherein activated carbon treatment is carried out at temperature range of 5-10 °C and pH 5.8-6.2.

10. The process according to claim 1, wherein the organic solvent used is selected from group consisting of lower alcohols or ketones or mixture thereof.

11. The process according to claim 11, wherein the organic solvent used is selected from group consisting of methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone or mixture thereof.

12. The process according to claim 1, wherein the said process is feasible for large-scale industrial manufacture of pure crystalline imipenem.

Dated this the 21st day of July, 2010

PROCESS FOR ISOLATING PURE CRYSTALLINE IMIPENEM

Abstract of the Invention

The present invention discloses the cost effective and industrially viable process for the isolation of highly pure crystalline imipenem, which comprises adjusting the pH of basified water followed by addition of crude imipenem to it at room temperature and precipitating imipenem monohydrate as crystalline material using suitable organic solvent.