The present invention relates to a cost effective and industrially advantageous process for the preparation of imipenem of high purity.
Imipenem monohydrate of Formula I, as shown in the accompanied drawings, is the N-formimidoyl derivative of thienamycin and is the first clinically available member of new class of ß-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits 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 the presence of ß-lactamases.
Imipenem was first obtained by lyophilization technique as disclosed in the U.S. Pat. No. 4,194,047. The product obtained by lyophilization is found to be largely amorphous and stated to be thermodynamically unstable. The process also involves an initial purification tnrough column chromatography using hydrophobic resins.
A thermodynamically stable crystalline monohydrate form of imipenem is disclosed in U.S. Pat. No. 4,260,543 which is obtained by crystallization of a lyophilized sample of imipenem. However, this process is not satisfactory at commercial scale as it requires isolation of the product via column chromatography, lyophilization, followed by crystallization. Moreover, the prolonged process for the isolation of the final product leads to the degradation of imipenem, thus affecting the purity of the product.
In U.S. Patent No. 4,292,436, crystalline imipenem is obtained by purifying the crude product by column chromatography. Another method for preparing imipenem having a high degree of crystallinity by freeze crystallization process has been reported by Connolly et. al. in J. Pharm. Sci, 85, 174(1996). However, these processes are tedious, cumbersome and unsuitable for industrial use.
Our pending Indian patent application No. 595/del/2001 provides a process for the isolation of crystalline imipenem monohydrate which comprises crystallizing imipenem monohydrate from a solution thereof in an organic or aqueous solvent or a mixture thereof, without using lyophilization, freeze drying or chromatographic techniques at any
stage.
However, it has been observed that imipenem obtained by methods which do not involve column chromatography contains polymeric and colored impurities. The polymeric impurities are side products formed during the synthesis of imipenem, which crystallize out along with imipenem. These impurities do not have any ultra violet absorption and hence, are difficult to detect. Although, the polymeric impurities are not reflected in the qualitative purity (by HPLC), quantitative determination (Assay) shows that the product has ~ 5-10% of content of these impurities.
Colored impurities are degradation products of imipenem formed during production or under storage, imipenem being inherently unstable in solution as well as 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.
Purification of imipenem is difficult due to its unstable nature. Crystalline imipenem has relatively low solubility in water at room temperature. A purification process thus requires dissolving imipenem in large volumes of water. Chromatographic purification also requires eluting with large volumes of water. The process of recovering the purified product is uneconomical as it requires concentration of water at low temperature thus necessitating the use of lyophilization, reverse osmosis, or freeze drying techniques.
In view of the above there is a need for a simple, practical and efficient method for the purification of imipenem. The object of the present invention is to provide a process for the preparation of pure crystalline imipenem monohydrate from crude imipenem containing polymeric and colored impurities.
The process of the present invention does not use capital intensive techniques of lyophilization or freeze crystallization as well as the time consuming purification process of column chromatography using expensive hydrophobic resins. The present invention thus fulfills the need for a process for the manufacture of imipenem that is convenient to operate on a plant scale.
In particular, the present invention provides a process for the preparation of pure crystalline imipenem monohydrate comprising: Dissolving crude imipenem in water,
Subjecting the resultant solution to activated carbon treatment at a pH of about 5 to
7, and
Adding a water miscible polar organic solvent to crystallize out pure imipenem
monohydrate.
The crude imipenem may have been obtained by any of the methods described in the prior art.
According to the present invention, crude crystalline imipenem is quickly dissolved in warm water to which some sodium bicarbonate has been added and the resulting solution is rapidly cooled to prevent any degradation. Addition of sodium bicarbonate ensures stability of imipenem in solution at high temperature by maintaining the pH around 7.5 to 8.5.
The water is preheated to a temperature of about 35 to 60°C. Around 30 to 60 volumes of water (with respect to imipenem, by weight) is sufficient to achieve effective purification without any need for concentration /removal of water for isolating the product.
The process is equally effective starting from crude amorphous imipenem though no special efforts may then be required for dissolving it in water.
The carbon treatment is carried out at an ambient temperature and at a pH of about 5 to 7 to facilitate adsorption of impurities. Optionally, sodium bisulfite is added during carbon treatment to obtain best results. Polymeric impurities remain undissolved in water and are filtered out along with carbon.
After carbon treatment a water miscible polar organic solvent is added to the clear colorless solution to crystallize out pure imipenem. The crystallization step is preferably carried out at temperatures below 25°C, for example at about 0°C to about 15°C.
Examples of such water miscible polar organic solvents include lower alcohols such as methanol, ethanol, propanol and isopropanol: ketones such as acetone and methyl ethyl ketone or mixture(s) thereof. Particularly preferred are isopropanol and acetone.
In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit tne scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
PREPARATION OF CRYSTALLINE IMIPENEM MONOHYDRATE
Example 1
Distilled water (4.0L) to which sodium bicarbonate (2.6g) had been added was heated to 45 to 47°C under nitrogen atmosphere. Crude crystalline imipenem (100g, Assay = 90%) was added to the solution, stirred for 2 minutes at 45 to 47°C and then rapidly cooled to 5 to 10°C (within 10 to 15 minutes). Activated carbon "Eno Anticromos" (30g) was added at 20 to 25°C before cooling the solution to 5 to 10°C. The pH of suspension was adjusted to 6 with 3N hydrochloric acid and stirred for 45 minutes at 5 to 10°C under nitrogen. The carbon was filtered and washed with distilled water (500ml). The filtrate was cooled to 5 to 8°C and acetone (4.5L) was added with vigorous stirring maintaining the same temperature. The mixture was further stirred for 2-3 hours at 5 to 10°C (precipitation of crystalline imipenem monohydrate started within 15 to 20 minutes of acetone addition). Another lot of acetone (2.3L) was then added and the suspension stirred at 0 to 5°C for 3-4 hours. The crystalline solid was filtered, washed with acetone and dried under reduced pressure at 40°C for 3-4 hours to obtain white crystalline imipenem monohydrate (73g, Assay: 98.5%,).
Example 2
The process of Example 1 was repeated using crude crystalline imipenem (100g, Assay = 75%) to obtain white crystalline imipenem monohydrate (65g, Assay: 98.3 %).
Example 3
Distilled water (3.0L) to which sodium bicarbonate (2.6g) had been added was heated to 48°C under nitrogen atmosphere. Crude crystalline imipenem (100g, Assay = 92%) was added to the solution, stirred for 2 minutes at 48°C and then cooled to 20 to 25°C within 5 to 10 minutes. Activated carbon "Eno Anticromos" (20g) was added to the solution at the
same temperature. The pH of suspension was adjusted to 6 with 3N hydrochloric acid and stirred for 45 minutes at 5 to 10°C under nitrogen. The carbon was filtered and washed with distilled water (500ml). Acetone (3.5L) was added to the filtrate at 5 to 10°C. The mixture was stirred for 3 hours at 5 to 10°C. Another lot of acetone (5.0 L) was then added and the suspension stirred at 0 to 5°C for 4 hours. The crystalline solid was filtered, washed with acetone and dried under reduced pressure at 40°C to obtain white crystalline imipenem monohydrate (76 g, Assay: 99.0%).
Example 4
The process of Example 3 was repeated using isopropanol instead of acetone during crystallization. Crystalline imipenem monohydrate (71.5g, Assay: 98.0%) was obtained.6

CLAIMS:
1. A process for the preparation of pure crystalline imipenem monohydrate
comprising:
Dissolving crude imipenem in water,
Subjecting the resultant solution to activated carbon treatment at a pH of
about 5 to 7, and
Adding a water miscible polar organic solvent to crystallize out pure
imipenem monohydrate.
2. The process of claim 1, wherein crude crystalline imipenem is dissolved in water preheated to a temperature of about 35°C to 60°C.
3. The process of claim 2, wherein sodium bicarbonate is added to maintain the pH of the hot solution at around 7.5 to 8.5.
4. The process of claim 1, wherein crude imipenem is dissolved in about 30 to 60 volumes of water (with respect to imipenem, by weight).
5. The process of claim 1, wherein carbon treatment is carried out at an ambient temperature.
6. The process of claim 1, wherein carbon treatment is carried out at a pH of about 5 to 7.
7 The process of claim 1, wherein carbon treatment is carried out in the presence of
sodium bisulfite.
8. The process of claim 1, wherein the water-miscible polar organic solvent comprises a lower alcohoi, a ketone, or mixture(s) thereof.
9. The process of claim 8, wherein the lower alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, or mixture(s) thereof.
10. The process of claim 8, wherein the ketone is acetone, methyl ethyl ketone or a mixture of the two.
11. The process of claim 1, wherein the crystallization is carried out at a temperature below 25°C.
12. The process of claim 11, wherein the temperature is from about 0°C to about 15°C.
13. The process for the preparation of pure crystalline imipenem monohydrate as herein described and illustrated by the examples herein.