FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
Crystalline Form of Ertapenem And Process for
Preparation
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400 601, India
The following specification particularly describes the nature of the invention and the manner in which it is performed:

FIELD OF INVENTION
The present invention relates to a novel crystalline form of 1β-methylcarbapenem antibiotic, Ertapenem and its process for the preparation.

Ertapenem is a sterile, synthetic, parenteral, 1-β methyl-carbapenem that is structurally related to beta-lactam antibiotics. It is marketed by Merck as Invanz®. It is structurally very similar to Meropenem in that it possesses a 1-β methyl group. Ertapenem is used as antibiotic agent in the treatment of moderate to severe complicated foot infection due to indicated pathogens in diabetic patients without osteomyelitis, and also useful in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynaecological, skin, and soft tissue infections, meningitis, septicaemia and febrile Neutrogena.
Crystalline forms of ertapenem are desirable due to improved purity and stability compared to amorphous form. PCT patent WO2003027067 specifically discloses three forms A and C of Ertapenem monosodium which are solvates and hydrates or mixed solvates/hydrates. WO2009150630 discloses Form D of Ertapenem. These forms are having some amount of residual solvents which are not desired for the formulation.
The present inventors have developed a novel crystalline form of Ertapenem monosodium which is a sesquihydrate.
SUMMARY OF THE INVENTION
Accordingly, the main aspect of the present invention is to provide a novel hydrate of Ertapenem monosodium which is Ertapenem monosodium sesquihydrate.
Another aspect of the present invention is to provide a novel crystalline form of Ertapenem monosodium sesquihydrate characterised by having X-ray powder diffraction

pattern as given in figure 1 and having a 2θ peaks at 4.41, 5.27, 7.45, 8.12, 10.97, 25.96, 29.04 and 29.96±0.2.
Another aspect of the present invention is to provide a process for the preparation of novel crystalline form of Ertapenem monosodium sesquihydrate comprising :
a) condensing the compound of formula II with compound of formula III in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;
b) optionally isolating monoprotected compound of formula IV or its sodium salt;
c) deprotecting the monoprotected compound of formula IV or its sodium salt in a solvent in presence or absence of a buffer and in presence or absence of a sodium ion source; and
d) extracting the product with optional pH adjustment to obtain Ertapenem monosodium sesquihydrate of formula I.
The above process is illustrated in below scheme:


Another aspect of the present invention is to provide a process for composition of sterile stable ertapenem monosodium comprising:
a) adding ertapenem monosodium sesquihydrate to an aqueous solution of carbondioxide producing compound or adding an aqueous solution of carbondioxide producing compound to ertapenem monosodium sesquihydrate while maintaining pH 7 to 7.5 by sodium hydroxide to obtain sterile ertapenem monosodium, and
b) lyophilizing the obtained solution in step (a) to obtain a pharmaceutical composition of sterile ertapenem monosodium.
Brief Description of the Diagram/Figure
Figure 1: X-Ray diffractogram of Ertapenem monosodium sesquihydrate Figure2: TGA of Ertapenem monosodium sesquihydrate
DETAIL DESCRIPTION OF THE INVENTION
In an embodiment of the present invention, the solvent used in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof, preferably N,N-dimethylformamide; and inorganic base used is selected from diisopropylethylamine (DIPEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0.]undec-7-ene (DBU) 1,5-diazabicydo[4,3.0Jnon-5-ene (DBN), N-methylpyrrolidine, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like preferably l,8-diazabicyclo[4.3.0.]undec-7-ene (DBU). The condensation reaction may optionally contain bases like N,N-dimethylaminopyridine, N,N-diethylamino pyridine to avoid impurity formation.
In another embodiment of the present invention the monoprotected compound of formula (IV) can be isolated as an acid or a sodium salt, using mixture of ethyl acetate, alcohol and isopropyl ether. The monoprotected acid or its sodium salt is subjected to de-

protection to yield Ertapenem monosodium. The sodium salt of formula (IV) is more stable, and easy to handle in industrial point of view.
In another embodiment, monoprotected compound of formula (IV) or its sodium salt is optionally isolated by quenching the reaction mass from step (i) into a buffer solution selected from dipotassium hydrogen orthophosphate, or potassium dihydrogen orthophosphate, or water and the like followed by extracting the compound in an organic solvent like ethyl acetate, MDC (dichloromethane) preferably in MDC and precipitating the compound of formula (IV) directly from the resultant organic layer or by quenching the organic layer into a solvent selected from hexane, heptane, IPE (diisopropylether), methyl tert-butyl ether and the like or mixtures thereof. The intermediate of formula (IV) can be taken to next stage with or without isolation. Alternatively the intermediate of formula (IV) can be directly precipitated from the buffer solution or water.
In yet another embodiment of the present invention, the deprotection is preferably done by hydrogenolysis. The hydrogenolysis is usually done in presence of a metal catalyst, preferably in presence of hydrogen gas and palladium (Pd/C) catalyst. The solvent for deprotection in step (c) is selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof preferably aqueous MDC and n-propanol . The de-protection of protecting groups can be carried out using a mixture of solvents either in single phase or in biphasic medium. If required, the hydrogenation process can employ employs sodium ion source base such as sodium bicarbonate, sodium hydroxide, and sodium carbonate.
In yet another embodiment of the present invention, after completion of hydrogenation, the product is taken into aqueous medium, followed by optionally washing with organic solvents like MDC, butyl acetate, ethyl acetate, toluene, hexane, 1,2-dibromoethane and the like to remove reaction by-products and/or impurities. After hydrogenation, optionally carbon dioxide gas is purged to the reaction mass. The aqueous layer is subjected to degassing technique to remove the dissolved solvent if required. Further depending on the requirement, pH of aqueous layer optionally is adjusted using acid like acetic acid, formic acid, HC1, etc to obtain the compound of formula (1).
In yet another embodiment of the present invention, the pH of aqueous layer containing the Ertapenem monosodium was optionally reduced to 5 followed by quenching in to an alcohol yielding the compound of formula (I) as monosodium.

In yet another embodiment of the invention the crystalline form of Ertapenem monosodium sesquihydrate is novel and it is characterised by X-ray powder diffraction pattern same as given in figure 1 and having 20 peaks at 4.41, 5.27, 7.45, 8.12, 10.97, 25.96, 29.04 and 29.96±0.2. This novel crystalline form of Ertapenem monosodium sesquihydrate is very stable and the form doesn't change with time for a considerably long time. This novel ertapenem sodium sesquihydrate is further characterised by the TGA as given in figure 2.
In yet another embodiment of the invention the ertapenem monosodium sesquihydrate of formula 1 is further added to an aqueous solution of sodium bicarbonate at temperature 0 to 5°C while adjusting the pH 7 to 7.5 by adding sodium hydroxide. Then it is filtered through 0.2 micron filter and lyophlised to obtain a composition of sterile ertapenem monosodium.
In still further embodiment of the present invention, the starting material compound of formula (III) is prepared by utilizing technique known in the art.
Advantage of the process of the present invention:
a) The ertapenem monosodium sesquihydrate of the present invention is highly stable and pure for formulation
b) The use of monoprotected intermediate of Ertapenem gives higher yield 0.5w/w to 0.6w/w as compared to 0.2w/w to 0.3w/w obtained in prior art.
c) Hydrogenation using MDC gives faster layer separation & adds to the yield.
d) The present process avoids hydrogenation work up as described in innovator patent.
e) The present process avoids purification of final compound to obtain a purity of more than 98% whereas the prior art processes need a purification to achieve this purity.
f) Avoid consumption of more palladium carbon
The present invention is illustrated with the following non-limiting examples.
Example 1:
Step-I: Preparation of monoprotected Ertapenem monosodium
l-Azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, 3-[(diphenoxyphosphinyl)oxy]-6-( 1 -hydroxyethyl)-4-methy l-7-oxo-,(4-nitrophenyI)methyl ester, [4R-[4a,5b,6b(R*)]] (MAP) (25 g) cand Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido]benzoic acid hydrochloride (16 g) were dissolved in DMF (400 ml) at RT. Reaction mass was cooled to -50°C to -60°C. DBU was added at the same temperature and

stirred for 1 hour. After completion of the reaction, the reaction mass was quenched into buffer solution {(KH2PO4(15 gm) in water (300 ml)}. The pH was adjusted to 5-5.5 by using phosphoric acid. The product has been extracted with MDC and washed with water. The combined MDC layer was further taken for next step.
Step-II: Preparation of Ertapenera mono sodium NS
The above MDC layer of Monoprotected Ertapenem acid, water (250 ml), sodium bicarbonate (3.5 gm) and n-propanol (100 ml) were charged into a flask. Pd/c was slurryfied in water and added to it, stirred under 5-8 kg of H2 pressure for 3 hours at -2 to 5°C. Reaction mass was filtered at 0-2°C and MDC layer was degaussed under carbon at 5-10°C. The aqueous layer was filtered and methanol was added to it at -5°C. 1-Propanol was added into it at -20°C and stirred for 6-8 hours, filtered and suck dried. The obtained mass is washed with a mixture of water, methanol and absolute alcohol(l:l:3 vol) at 0-5°C.lt is further washed with absolute alcohol and dried und vacuum and nitrogen for 5-10 hours to obtain Ertapenem monosodium sesquihydrate.
Yield : 11-12 g; purity: 98.5%; M/C: 5.5 to 6%
Step-III: Preparation of Ertapenem Sterile
Ertapenem monosodium sesquihydrate (10 gm) was dissolved in aqueous solution of sodium bicarbonate (1.5 gm in 50 ml of water) at 0-5°C and pH was adjusted to 7 -7.5 using 5% sodium hydroxide at 0-5°C.The clear filtrate was filtered through 0.2micron and lyophilized according to the condition provided below:

Thermal Treatment Steps
Temp Time Ramp/Hold
Step# 1 -25 60 H
Step# 2 -40 90 R
Step# 3 -40 210 H
Step# 4 0 0 H
Step # 5 0 0 R
Step# 6 0 0 R
Step## 7 0 0 R
Step# 8 0 0 R
Step# 9 0 0 R
Step #10 0 0 R
Step # 11 0 0 R
Step # 12 0 0 R
Freeze Temp -35 °C
Additional Freeze 10 min
Condenser Setpoint -50 oc
Vacuum Setpoint 250 mTorr

Primary Drying Steps
Temp Time Vac Ramp/Hold
Step # 1 -40 90 250 H
Step# 2 -30 60 250 R
Step# 3 -30 150 250 H
Step# 4 -20 120 250 R
Step# 5 -20 450 250 H
Step# 6 -10 60 100 R
Step# 7 -10 430 100 H
Step# a 0 60 100 R
Step# 9 0 480 100 H
Step # 10 10 60 100 R
Step # 11 10 120 100 H
Step # 12 20 60 100 R
Step #13 20 90 100 H
Step #14 26 60 50 R
Step# 15 0 0 0 R
Step #16 0 0 0 R
Post Heat 26 480 50
Secondary Temperature 30 oC

We claim:
1. Ertapenem monosodium sesquihydrate.
2. A crystalline form of Ertapenem monosodium sesquihydrate characterised by having X-ray powder diffraction pattern as given in figure 1 or having a 29 peaks at 4.41, 5.27, 7.45, 8.12,10.97,25.96, 29.04 and 29.96±0.2.
3. A process for the preparation of crystalline form of Ertapenem monosodium sesquihydrate as claimed in claim 2, comprising :
a) condensing the compound of formula II with compound of formula III in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;


c) deprotecting the monoprotected compound of formula IV or its sodium salt in a solvent in presence or absence of a buffer and in presence or absence of a sodium ion source; and
d) extracting the product with optional pH adjustment to obtain Ertapenem monosodium sesquihydrate of formula I.

4. A process according to claim 1, wherein solvent in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichlororoethane, 1,2-dichloroethane, N,N-dirnethylformamide, dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof.
5. A process according to claim 1, wherein base in step (a) is selected from the group consisting of diisopropylethylamine (DIPEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo[4,3.0.]undec-7-ene (DBU) 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylpyrrolidine, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like.
6. A process according to claim 1, wherein the monoprotected compound of formula (IV) in step (b) is isolated as an acid or a sodium salt, using mixture of ethyl acetate, alcohol and isopropyl ether.
7. A process according to claim 1, wherein the deprotection of compound of formula (IV) in step (c) is done by hydrogenolysis in presence of hydrogen gas and palladium (Pd/C) catalyst and a solvent selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof and sodium ion source base selected from sodium bicarbonate, sodium hydroxide, and sodium carbonate.

8. A process according to claim 1, wherein the pH of aqueous layer in step (d) is adjusted using acid selected from acetic acid, formic acid, or hydrochloric acid.
9. A composition of sterile stable ertapenem monosodium comprising:

a) adding ertapenem monosodium sesquihydrate to an aqueous solution of carbondioxide producing compound or adding an aqueous solution of carbondioxide producing compound to ertapenem monosodium sesquihydrate while maintaining pH 7 to 7.5 by sodium hydroxide to obtain sterile ertapenem monosodium, and
b) lyophilizing the obtained solution in step (a) to obtain a pharmaceutical composition of sterile ertapenem monosodium.
10. A process according to claim 9, wherein ertapenem monosodium sesquihydrate after
pH adjustment filtered through 0.2 micron filter.