A PROCESS FOR THE PREPARATION OF PURE MEROPENEM
TRIHYDRATE
Field of the Invention
The present invention relates to a process for the preparation of pure meropenem
trihydrate.
Background of the Invention
(4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(lR)-l-
hydroxyethyl]-4-methyl-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid of
Formula I, commonly known as meropenem, is a synthetic, broad- spectrum, carbapenem
antibiotic.
FORMULA I
Meropenem is commercially available as a trihydrate. Several processes for the
preparation of meropenem and meropenem trihydrate are described in U.S. Patent No.
4,888,344; WO Nos. 2006/035300; 2007/029084; 2007/104221; and 2005/118586.
Meropenem trihydrate is generally prepared by dissolving crude meropenem in
water followed by cooling and adding a water miscible organic solvent such as acetone or
isopropanol. This method requires heating of meropenem and water mixture to achieve
complete dissolution and subsequent cooling of the solution along with the addition of
water-miscible solvents, and optionally seed crystals, to maximize the precipitation or
crystallization of meropenem trihydrate. The present inventors have observed that
preparation of meropenem trihydrate from crude meropenem on a large scale results in a
increased impurity content, specifically relating to meropenemic acid of Formula II and
meropenem dimer of Formula III. The presence of impurities also impacts the yield.Formula III
The present inventors have not found that the problems associated with increased
impurities, and the corresponding reduced yields, is due to the higher residence time in the
batch mode reactors that are commonly employed during the scale-up. In batch mode
reactors, the reaction is allowed to proceed for a specified time period after which the
mixtures of unreacted materials and/or by-products, along with the desired end product,
are withdrawn. After the reactants or starting materials are fed into the batch mode
reactor, no further reactants or starting materials are added. The batch mode reactors have
more residence time, especially during the heating and subsequent cooling steps. In the
case of meropenem, the present inventors have observed that high residence time of
meropenem, along with water, leads to decomposition of meropenem and increases
impurity formation. On the other hand, the replacement of water with alternate organic
solvents, for example, methanol, in which meropenem is freely soluble and does not
require a heating step, results in higher residual solvent content.Summary of the Invention
In one general aspect, the present invention provides for a process for the
preparation of pure meropenem trihydrate, wherein the process includes:
a) heating crude meropenem to a temperature of about 40°C or above in water
to obtain a solution;
b) cooling the solution obtained in step a) to a temperature of about 30°C or
below;
c) treating the solution or partial solution obtained in step b) with a water-
miscible organic solvent; and
d) isolating pure meropenem trihydrate from the mixture thereof,
wherein steps a) and b) are carried out in a continuous mode reactor with a residence time
of about 5 minutes or less.
Embodiments of this aspect may include one or more of the following features.
For example, step a) may be carried out at a temperature of between about 60°C to about
75°C and the quantity of water in step a) is about 5 times to about 20 times the quantity of
crude meropenem.
Step b) may be carried out at a temperature of between about 15°C to about 25°C.
The water-miscible organic solvent may be acetone, acetonitrile, tetrahydrofuran, C1-3
alkanol, or mixture(s) thereof.
The pure meropenem trihydrate may be isolated from the reaction mixture by
filtration, solvent removal, decantation, or a combination thereof.
Detailed Description of the Invention
The present invention provides for a process for preparation of pure meropenem
trihydrate. The process includes:
a) heating crude meropenem to a temperature of about 40°C or above in water
to obtain a solution;
b) cooling the solution obtained in step a) to a temperature of about 30°C or
below;c) treating the solution or partial solution obtained in step b) with a water
miscible organic solvent; and
d) isolating pure meropenem trihydrate from the mixture thereof,
wherein steps a) and b) are carried out in a continuous mode reactor with a residence time
of about 5 minutes or less.
The crude meropenem may be prepared according to the methods described in U.S.
Patent No. 4,888,344; WO Nos. 2006/035300; 2007/029084; 2007/104221; and
2005/1 18586. The crude meropenem may be in crystalline or amorphous form. The crude
meropenem has impurity content of greater than or equal to about 1.0%. The crude
meropenem is heated to a temperature of greater than or equal to about 40°C, for example,
about 60°C to about 75°C, in water to obtain a solution by heating. The quantity of water
may be present at about 5 times to about 20 times to the quantity of crude meropenem.
For example, about 1000 ml of water may be used for about 50 g to about 200 g of crude
meropenem.
The solution so obtained is cooled to a temperature of less than or equal to about
30°C, for example, about 15°C to about 25°C. The above steps are carried out in a
continuous mode reactor, for example, a helically coiled reactor, wherein the crude
meropenem is continuously fed in, contacted with water and the solution or partial
solution so obtained is continuously removed from the reactor. The residence time in the
continuous mode reactor is about 5 minutes or less, for example, about 2 minutes to about
3 minutes.
After cooling to less than or equal to about 30°C, the solution or a partial solution
so obtained may be transferred to a batch mode reactor, for example, a round bottom flask
and optionally subjected to carbon treatment. The solution or partial solution is optionally
seeded with crystals of meropenem trihydrate and treated with a water-miscible organic
solvent. Seed crystals of meropenem trihydrate can be prepared according to methods
described in WO 2006/035300.
The water-miscible organic solvent may be acetone, acetonitrile, tetrahydrofuran,
Ci-3 alkanol, for example, ethanol, isopropanol and 1-propanol, or mixture(s) thereof. The
treatment with the water-miscible organic solvent may be carried out at a temperature of
about 15°C or less, for example, about 0°C to about 10°C. The pure meropenemtrihydrate is isolated from the mixture by filtration, solvent removal, decantation, or a
combination thereof.
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.
Detailed Description of the Figures
Figure 1: depicts the XRPD (X-Ray powder diffractogram) of meropenem
trihydrate prepared according to Comparative Example 1.
Figure 1A: Table of values for XRPD pattern depicted in Figure 1.
Figure 2: depicts the XRPD (X-Ray powder diffractogram) of meropenem
trihydrate prepared according to Example 1.
Figure 2A: Table of values for XRPD pattern depicted in Figure 2.
Figure 3: depicts the XRPD (X-Ray powder diffractogram) of meropenem
trihydrate prepared according to Example 2.
Figure 3A: Table of values for XRPD pattern depicted in Figure 3.
Figure 4: depicts the XRPD (X-Ray powder diffractogram) of meropenem
trihydrate prepared according to Example 4 - Part A.
Figure 4A: Table of values for XRPD pattern depicted in Figure 4.
Figure 5: depicts the XRPD (X-Ray powder diffractogram) of meropenem
trihydrate prepared according to Example 4 - Part B.
Figure 5A: Table of values for XRPD pattern depicted in Figure 5.Comparative Example 1: Preparation of Meropenem Trihydrate by Batch Process
Crude meropenem (30g) (meropenemic acid: 0.37%; meropenem dimer: 0.56%;
total impurity content excluding meropenemic acid and meropenem dimer: 0.80%) was
dissolved in de-ionized water (450 ml) pre-heated to 68°C to 70°C in a round bottom
flask. The solution obtained was cooled to 20°C to 25°C over 25 minutes to 30 minutes,
treated with carbon, filtered and cooled to 5°C. Meropenem trihydrate seed (0.075g) was
added at 5°C and subjected to aging for 2 hours at 0°C to 5°C. Acetone (150 ml) was
added at -2°C to 5°C and the mixture was subjected to aging for further 3 hours at 0°C to
5°C. The mixture was filtered and washed with acetone (150 ml) and dried for 5 hours to
8 hours at 36°C to 38°C under vacuum to obtain the title compound.
Yield: 74%
Meropenemic acid content: 0.234%
Meropenem dimer content: 0.357%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.106%
Comparative Example 2: Preparation of Meropenem Trihydrate by Batch Process
Crude meropenem (30g) (meropenemic acid: 0.37%; meropenem dimer: 0.56%;
total impurity content excluding meropenemic acid and meropenem dimer: 0.80%) was
dissolved in methanol (120 mL) at 10°C to 15°C in a round bottom flask. The solution
obtained was treated with carbon (lOg), filtered and cooled to about 10°C to 15°C
followed by addition of meropenem trihydrate seed crystals (0.075g) at 12°C. Isopropyl
alcohol (200 ml) was added at 0°C to 10°C and the filtrate was subjected to aging for
further 4 hours at 0°C to 2°C. The mixture was filtered and washed with acetone (60 ml)
and dried for 4 hours to 5 hours at 36°C to 38°C under vacuum to obtain the title
compound.
Yield: 78%
Meropenemic acid content: 0.072%
Meropenem dimer content: 0.094%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.191%
Methanol content: 1.06%Example 1: Preparation of Pure Meropenem Trihydrate
Crude meropenem (50g) (meropenemic acid: 0.37%; meropenem dimer: 0.56%;
total impurity content excluding meropenemic acid and meropenem dimer: 0.80%) was
dissolved in de-ionized water (700 ml) by heating the mixture to 68°C and cooled to 20°C
to 25°C in 2 minutes in a helically coiled reactor. The solution so obtained was treated
with carbon (10 g) and filtered. The filtrate obtained was cooled to about 5°C in a round
bottom flask, followed by addition of meropenem trihydrate seed crystals (0.125 g). The
mixture was subjected to aging for 2 hours at 0°C to 5°C. Isopropyl alcohol (500 ml) was
added at 0°C to 5°C and the mixture was subjected to aging for further 3 hours at 0°C to
10°C. The mixture was filtered, washed with acetone (150 ml) and dried for 6 hours to 8
hours at 36°C to 38°C under vacuum to obtain the title compound having XRPD pattern as
depicted in Figure 2.
Yield: 78%
Meropenemic acid content: 0.017%
Meropenem dimer content: 0.045%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.074%
Example 2: Preparation of Pure Meropenem Trihydrate
Crude meropenem (15g) (meropenemic acid: 0.37%; meropenem dimer: 0.56%;
total impurity content excluding meropenemic acid and meropenem dimer: 0.80%) was
dissolved in de-ionized water (210 ml) by heating the mixture to 68°C and cooled to 20°C
to 25°C in 2 minutes in a helically coiled reactor. The solution so obtained was treated
with carbon (1.5 g) and filtered. The filtrate obtained was cooled to about 5°C in a round
bottom flask, followed by addition of meropenem trihydrate seed crystals (0.0375 g). The
mixture was subjected to aging for 2 hours at 0°C to 5°C. Isopropyl alcohol (500 ml) was
added at 0°C to 5°C and the mixture was subjected to aging for further 3 hours at 0°C to
10°C. The mixture was filtered, washed with acetone (150 ml) and dried for 6 hours to 8
hours at 36°C to 38°C under vacuum to obtain the title compound having XRPD pattern as
depicted in Figure 3.
Yield: 79%Meropenemic acid content: 0.056%
Meropenem dimer content: 0.078%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.181%
Example 3: Preparation of Pure Meropenem Trihydrate
Crude meropenem (lOOg) (meropenemic acid: 0.37%; meropenem dimer: 0.56%;
total impurity content excluding meropenemic acid and meropenem dimer: 0.80%) was
dissolved in de-ionized water (1400 ml) by heating the mixture to 68°C and cooled to
20°C to 25°C in 2 minutes in a helically coiled reactor. The solution so obtained was
treated with carbon (10 g) and filtered. The filtrate obtained was cooled to about 5°C in a
batch mode reactor (round bottom flask), followed by addition of meropenem trihydrate
seed crystals (0.025 g). The mixture was subjected to aging for 2 hours at 0°C to 5°C.
Isopropyl alcohol (500 ml) was added at 0°C to 5°C and the mixture was subjected to
aging for further 3 hours at 0°C to 10°C. The mixture was filtered, washed with acetone
(150 ml) and dried for 6 hours to 8 hours at 36°C to 38°C under vacuum to obtain the title
compound.
Yield: 79%
Meropenemic acid content: 0.049%
Meropenem dimer content: 0.050%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.173%
Example 4: Preparation of Pure Meropenem Trihydrate
Step 1:
Crude meropenem (lOOg) (meropenemic acid: 0.37%; meropenem dimer: 0.56%;
total impurity content excluding meropenemic acid and meropenem dimer: 0.80%) was
dissolved in de-ionized water (1400 ml) by heating the mixture to 68°C and cooled to
20°C to 25°C in 2 minutes in a helically coiled reactor. The solution so obtained was
treated with carbon (10 g) and filtered.Step 2 : Part A
Solution equivalent to 25 g of input crude meropenem, obtained according to step
1, was cooled to about 5°C in a round bottom flask, followed by addition of meropenem
trihydrate seed crystals (0.0625 g) at 5°C. The mixture was subjected to aging for 2 hours
at 0°C to 5°C. Mixture of isopropyl alcohol (125 ml) and acetone (125 ml) was added at
0°C to 10°C and the mixture was subjected to aging for further 3 hours at 0°C to 10°C.
The mixture was filtered, washed with acetone (75 ml) and dried for 6 hours to 8 hours at
36°C to 38°C under vacuum to obtain the title compound having XRPD pattern as
depicted in Figure 4.
Yield: 78%
Meropenemic acid content: 0.031%
Meropenem dimer content: 0.066%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.122%
Step 2 : Part B
Solution equivalent to 25 g of input crude meropenem, obtained according to step
1was cooled to about 0°C to 5°C in a round bottom flask, followed by addition of
meropenem trihydrate seed crystals (0.0625 g) at 5°C. The mixture was subjected to aging
for 2 hours at 0°C to 5°C. Acetone (500 ml) was added at 0°C to 10°C and the mixture
was subjected to aging for further 3 hours at 0°C to 10°C. The mixture was filtered,
washed with acetone (75 ml) and dried for 6 hours to 8 hours at 36°C to 38°C under
vacuum to obtain the title compound having XRPD pattern as depicted in Figure 5.
Yield: 80%
Meropenemic acid content: 0.036%
Meropenem dimer content: 0.071%
Total impurity content (excluding meropenemic acid and meropenem dimer): 0.133%.We claim:
1. A process for the preparation of pure meropenem trihydrate, wherein the process
comprises:
a) heating crude meropenem to a temperature of about 40°C or above in water
to obtain a solution;
b) cooling the solution obtained in step a) to a temperature of about 30°C or
below;
c) treating the solution or partial solution obtained in step b) with a water-
miscible organic solvent; and
d) isolating pure meropenem trihydrate from the mixture thereof,
wherein steps a) and b) are carried out in a continuous mode reactor with a
residence time of about 5 minutes or less.
2. The process according to claim 1, wherein step a) is carried out at a temperature of
between about 60°C to about 75°C.
3. The process according to claim 1, wherein the quantity of water in step a) is about
5 times to about 20 times to the quantity of crude meropenem.
4. The process according to claim 1, wherein step b) is carried out at a temperature of
between about 15°C to about 25°C.
5. The process according to claim 1, wherein the water-miscible organic solvent
comprises acetone, acetonitrile, tetrahydrofuran, C1-3
alkanol, or mixture(s) thereof.
6. The process according to claim 1, wherein the pure meropenem trihydrate is
isolated from the reaction mixture by filtration, solvent removal, decantation, or a
combination thereof.