FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"A STABLE FEROPENEM SODIUM AND PROCESS FOR PREPARING THEREOF"
We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Gandhinagar-Sarkhej Highway, Ahmedabad - 380015, Gujarat, India;
The following specification describes the invention:


FIELD OF THE INVENTION:
The present invention relates to an improved method of identification and method of detection of purity by high performance liquid chromatography of Faropenem sodium and the process for the preparation thereof. The present invention further realates to improved process for preparing Feropenem sodium.
BACKGROUND OF THE INVENTION:
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
(5R,6S)-6-[(lR)-l-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza bicyclo [3.2.0]hept-2-ene-2-carboxylic acid, commonly known as faropenem of Formula I is a synthetic, broad-spectrum, Carbapenem antibiotic.

The sodium salt of faropenem shows potent antibacterial activity against me-thicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus pyrogenes and Streptococcus pneumonia and gram-positive bacteria such as penicillin-resistant pneumococci (PRSP), oral staphylococci and enterococci. It also shows a wide antibacterial spectrum covering gram-negative bacteria such as Haemophilus influenza and anaerobic bacteria such as the genus Bacteroides.
U.S. Patent No 4,997,829 provides a process for the preparation of sodium and potassium salts of faropenem, involving the deprotection of allyl faropenem in the presence of triphenylphosphine, palladium tetrakis-triphenylphosphine and sodium or potassium 2-ethylhexanoate. However, the process disclosed in the '829 patent does not result in stable and commercially useful hydrates of faropenem salts.
HP Patent No. 410,727 provides various processes for preparing the hemipentahydrate of faropenem salts, involving the deprotection of allyl faropenem in the presence of an alkali metal enolate of 1.3-diketone. The hemipentahydrate salt of faropenem salt is characterized


by Single Crystal X-ray analysis, 1H NMR, IR, specific optical rotation and elemental analysis. The faropenem formed in situ is converted into hemipentahydrate by the addition water. JP Patent No 2,949,363 B2 also provides a process for preparing hydrates of faropenem salts by treating deprotected faropenem with an alkali metal salt of a C1.4 carboxylic acid in the presence of water.
The water added to the reaction mixture to effect the formation of hydrates in the prior art processes is removed by distillation. However, the removal of water from the reaction mixture under reduced pressure consumes both time and energy. Additionally the solution stability of faropenem sodium in water is very poor and prolonged storage or heating results in impurity formation.
CN 1733771 A discloses the process for the preparation of Faropenem sodium from reaction by-products. Faropenem sodium prepared from 4-AA i.e. Acetic acid 3-[l-(tert-butyl)-dimethyl silanyloxy)-ethyl]-4-oxo-azetidinone-2-yl ester via allylation, intermolecular wittig reaction and deallylation results in Faropenem sodium also results in byproducts like below like syn and anti isomer. The reaction sequence is depicted in Scheme-1 as shown below.


SYN ANTI
CN 1884284 discloses the method for the preparation of Faropenem sodium, which comprises of: (1) performing reaction in the presence of the intermediate compound. I (R2 = H, halo, alkyl, or alkyoxy) with optical grade 2-(R)-tetrahydrofuran thiocarbonic acid in the presence of base to obtain compound II; (2) reacting with allyl glyoxylate by heating and re fluxing to obtain compound III; (3) converting to chloride and performing intramolecular Wittig reaction, after removing protective group to obtain sodium Faropenem. The invention also discloses the manufacture of the intermediate compound I.

CN 1733772 discloses one-pot synthesis of Faropenem sodium which involves (a) condensing (R)-tetrahydrofuran-2-thioformic acid and (3R,4R,1 'R)-4-acetoxy-3-(l-tert-butyldimethylsilicoxy)ethyl)azetidinone-2-one (4AA) in a solvent at -20°C to 60°C for 0.5-24 h in the presence of base; (b) condensing product of (a) with allyl chlorooxoacetate in solvent at -20°C to 60°C for 1-24 h in the presence of organic base like triethylamine or pyridine; (c) carrying out intramolecular Wittig or Wittig-Horner reaction of product of (b) with triphenylphosphine or tri-ethyl phosphite; (d) deprotecting with dil. HO of HF, or' tetrabutylammonium fiuroide; (e) reacting with sodium 2-ethylcaproate in the presence of Pd(PPh3)4 in ethyl ether at 10"C to 80°C for 2-36 h, filtering to obtain crude product, and recrystallizing with water/acetone to obtain pure product; wherein the operation a and b or c and d can be exchanged.
The main disadvantage associated with the one-pot process disclosed herein is use of different solvent as different stages. Also, the use of ethyl ether during deallylation is not industrially viable process. The continuos process like the one provided above would always


have impurities, unreacted starting materials etc. which is carry forwarded till the final step. Hence, the Faropenem sodium, pentahemihydrate resulted will not have every individual impurity less than 0.1 % as per ICH guidelines. Also, the yield factor will vary from step to step which will results in inconclusive yields. Thus, there is a need to isolate atleast one of the intermediate, which will by having better yield and purity. Thus, it is the scope of the present invention to obtain Allyl (5R,6S)-6-[(lR)-l-(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in better purity and yield. The present invention also provides a process for preparation of pentahemihydrate salt of Faropenem sodium from Allyl (5R,6S)-6-[(lR)-l-(t-buty Idimethy lsilicoxy)ethy 1] -7-oxo-3 - [(2R)-tetrahydro furan-2-yl] -4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate in one pot synthesis.
WO 2007/039885 Al discloses the process for the preparation of hydrate of an alkali metal salt of Faropenem wherein the process comprises reacting protected Faropenem with an alkali metal salt of a substituted or unsubstituted C5-10 carboxylic acid an a catalytic amount of a palladium in the presence of an organic solvent followed by treatment with water and a water miscible organic solvent and isolating a hydrate of an alkali metal salt of Faropenem from the reaction mixture wherein water is not removed from the reaction mixture.
The purity of the active substance is an important factor for manufacturing a safe and effective pharmaceutical formulation. Maximum possible purity of the product is of particular importance if the pharmaceutical product must be taken on a longer-term basis in the treatment. It is also important to know the level of impurities present in the pharmaceutical composition.
There are various analytical methods known in the art to identify and detect the level of impurities in the pharmaceutical composition as well as the active ingredients. The various techniques such as HPLC, GC, HPTLC, and Mass spectrum are well known in the field of pharmaceuticals to determine level of impurities.
The product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present. At certain stages during processing of the Faropenem contained in the product mixture into an active pharmaceutical ingredient


("API"), the Faropenem must be analyzed for purity, typically by HPLC or GC analysis, to determine if it is suitable for continued processing or ultimately for use in a pharmaceutical product. The Faropenem does not need to be absolutely pure. Absolute purity is a theoretical ideal that is unattainable. Rather, there are purity standards intended to ensure that an API is not made less safe for clinical use because of the presence of impurities. In the United States, the Food and Drug Administration guidelines recommend that applicants limit some impurities to below 0.1%.
Generally, side products, byproducts and adjunct reagents (collectively "impurities") are identified spectroscopically and by other physical methods and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). (Strobel p. 953) (Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach, 3 dd. (Wiley & Sons: New York 1989)). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time." This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRT") to identify impurities. (Strobel p. 922). The RRT of an impurity is its retention time divided by the retention time of some reference marker. In theory, Faropenem itself could be used as the reference marker, but as a practical matter it is present in such overwhelming proportion in the mixture that it tends to saturate the column, leading to irreproducible retention times, i.e., the maximum of the peak corresponding to Faropenem tends to wander (Strobel FIG. 24.8(b) p. 879, contains an illustration of the sort of asymmetric peak that is observed when a column is overloaded). Thus, it is sometimes desirable to select an alternative compound that is added to, or is present in, the mixture in an amount significant enough to be detectable and sufficiently low as not to saturate the column and to use that compound as the reference marker.
The purity of Faropenem was measured by HPLC by using the content measurement technique ol' Faropenem for injection using HPLC method in Xibei Yaoxue Zazhi, Journal written in Chinese, (2005), 20(5), 198-200 by Li, Bing and et. al, Institute of pharmaceuticals research. The conditions chosen in the present article demonstrated the use of ODS CI8 chromatographic column (4.6 mm X 250 mm), mobile phase: phosphate solution (Potassium


dihydrogen phosphate 4.8 g, Sodium dihydrogen phosphate 5.4 g and tetrabutylammonium bromide 2.0 g were dissolved to 1000 mL water)-acetonitrile-methanol (70:10:20); flow rate: 1.0 ml./min; detection wavelength: 230 nm. The results show that, under the concentration appeared good linear relationship. The recovery rate was 100.0%, RSD was 0.20%.
Another such method for the determination of purity of Faropenem Sodium was disclosed in "An HPLC method for determination of related substances of Faropenem sodium" in Zhongguo Yaoxue Zazhi, Journal written in Chinese, (2005), 40(5), 385-387 by Zhao, Xia and et. al, National Institute for the control of Pharmaceutical and Biological Products. Faropenem sodium and its related substances were separated by using a mobile phase consisted of acetonitirle-0.02 mol/L, triethylamine (14.86. pH 2.5) at a flow rate of 1.0 mL/min on an Aglient Sorb Zelipse XDB - C18 Column and the detection wavelength of 247 nm. The resolution and sensitivity of related substances were acceptable. The detection limit was 2.4 ng.
A hydrate of the sodium salt of a penem carboxylic acid like Faropenem sodium is disclosed in Acta Crystallographica, Section C; crystal Structure communications (1994), C50(8), 1254-6. The crystalline nature of the compound is confirmed by single crystal analysis disclosing the hemipentahydrate of Faropenem sodium, a member of a new class of (3-lactam antibiotics, is orthorhombic, space group P2,2,2, with a 9.208 (1), b 32.454(2), c 5.495(3) A; Z = 4, dc = 1.43, R = 0.059, Rw = 0.110 for 1592 reflections.
To overcome the drawbacks of the prior art process the present invention relates to provide a simple, cost effective, non-hazardous and easily scaleable at large commercial production process for preparation of crystalline ammonium salt of (E)-7-[4-(4-flourophenyl) isopropyl-2-[methyl(methysulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid.
Moreover, there is a need to develop a new analytical method for identification and determination of level various impurities in Faropenem sodium of formula (I) prepared by process disclosed herein after. It is also an object of the present invention to prepare faropenem sodium substantially free of impurities when measured by high performance liquid chromatography.


OBJECT OF THE INVENTION:
It is an object of the present invention to provide an HPLC method for the determination and detection of purity with reference to RRT i.e. "relative retention time" of Faropenem sodium.
It is an object of the present invention in its preferred form to provide an improved process for preparation of Faropenem sodium and hydrate thereof.
Another object of the present invention is to provide a one-pot process for the preparation of Faropenem sodium and hydrate thereof.
According to another object of the present invention Faropenem sodium prepared by the process as disclosed herein after is relatively stable at 25°C/60% RH for 3 to 9 months when measured by HPLC.
Further object of the present invention is to overcome the problems associated with the prior art process and to prepare pure Faropenem sodium alkali metal salt and hydrate thereof by simple, cost effective, non-hazardous, easily scaleable and industrially viable process.
SUMMARY OF THE INVENTION:
There is provided a one-pot process for the preparation of alkali metal salts of Faropenem. The present inventors has developed advantageous processes for preparation of alkali metal salts of Faropenem and hydrates thereof in a one pot process avoiding the tedious work-up procedure and isolation of the intermediates at each stage.
According to one embodiment, the present process provides a common medium to obtain intermediate compounds finally to give alkali metal salt of Faropenem and hydrate thereof avoiding the use of different organic solvents at different stages and performing tedious work-up procedures, to obtain higher yield by checking the conversion of key intermediates by PLC. The total yield is approximately greater than 99% on TLC.
According to one another embodiment, the present invention provides directly insitu hydrate of alkali metal salt of Faropenem i.e. 2.5 hydrate whereby process doesn't involve the


removal of water and it provides the hydrate of Faropenem with higher yield, reduced time cycle and greater purity.
The process is avoiding the critical steps like distillation, change of solvent systems etc. thereby the process is economically and industrially viable.
The purity of Faropenem sodium in terms of HPLC, when measure by the method provided herein discloses that Faropenem sodium is relatively stable at 25°C/60% RH from 3 to 9 months with all the single individual impurities well within the limits.
Thus, it is one of the aspects of the present invention to provide Faropenem sodium with purity greater than or equal to 99.0%, preferably greater than or equal to 99.5% by HPLC.
Another embodiment of the invention encompasses methods to analyze Faropenem sodium of formula (I) purity comprising assaying Faropenem sodium to determine the presence and an amount, if any, of Faropenem sodium impurities. Yet another embodiment of the invention encompasses methods to determine Faropenem sodium stability comprising assaying Faropenem sodium to determine the presence and amount, if any, of Faropenem sodium impurities. Yet another embodiment of the invention encompasses methods to analyze Faropenem sodium purity comprising assaying a sample of Faropenem sodium by HPLC, and determining the presence and/or amount of compounds of formula (II), formula (III) or formula (IV) identified by an HPLC relative retention time.
DESCRIPTION OF THE INVENTION:
In one aspect, a one pot process for preparation allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II


wherein the process comprises:
a) condensing (3R,4R,l'R)-4-acetoxy-3-(l-(t-butyldimethylsilicoxy)ethyl)azetidin-2-one (4-AA) of formula III

and (2R)-tetrahydro-2-furancarbothioic S-acid; sodium salt of formula IV

in a solvent at -10°C to 20°C for 0.5 to 2.0 hrs in a molar ratio of 1:1.1 to 1:1.5 in presence of base;
b) condensing product of (a) with allyl chlorooxoacetate in a solvent at -25°C to 25°C for 1-10 hrs in a molar ratio of 1:1.2 to 1:1.8 with respect 4-AA of formula III in presence of organic base;
c) carrying out intramolecular Wittig of Wittig-Horner reaction of product (b) with triphenyl phosphine or tri-ethylphosphite in a solvent at retlux temperature for 0.5-10 hrs;
d) removing the solvent to obtain the residue;
e) treating the residue with suitable organic solvent and heated at 40°C to 80°C for 0.5-2 hrs;
f) gradually cooling to 0°C to 5°C to precipitate the product; and
g) isolating the product.
The condensation of compound azetidinone 4-AA of formula III and (2R)-tetrahydro-2-furancarbothioic S-acid; sodium salt of formula IV as in step (a) can be done in organic solvent selected from TIIF, Xylene, Toluene or mixture thereof with water, preferably in a mixture of toluene and water at -10°C to 20°C, preferably at 0°C to 10°C for 0.5-2,0 hrs, preferably for 0.5 hrs till the pll of the reaction mixture is 10.5 to 11.5.
The compounds azetidinone 4-AA of formula III and (2R)-tetrahydro-2-furancarbothioic S-acid, sodium salt of formula IV were taken in the molar ratio of 1:1.2 to 1:1.8 with respect 4-


AA of formula III, preferably 1:1.2 to 1:1.5, more preferably 1:1.25 in presence of base like inorganic base like carbonate, bicarbonate, hydroxides etc. carbonate like alkali metal carbonates, bicarbonates like alkali metal or alkaline earth metal bicarbonates etc. hydroxides like alkali metal hydroxides, preferably sodium or potassium hydroxide, more preferably sodium hydroxide.
The base used during the condensation reaction is 10% solution of sodium hydroxide to adjust the alkaline pH from about 10.5 to about 11.5.
The condensation of intermediate product of step (a) with allyl chlorooxoacetate as in step (b) can be done in can be done in organic solvent selected from THF, Xylene, Toluene or mixture thereof with water, preferably in a mixture of toluene and water at -25°C to 25°C, preferably at -25°C to -5°C, more preferably from -18°C to -22°C for 1-10 hrs preferably 1-5 hrs or till the completion of the reaction as checked by TLC.
Allyl chlorooxoacetate is used in the molar ratio of 1:1.2 to 1:1.8, preferably 1:1.25 to 1:1.6, more preferably 1:1.5 with respect 4-AA of formula III in presence of organic base selected from the group of alkyl amines or pyridine, more preferably alkyl amine like triethyl amine.
The intramolecular Wittig or Horner-Wittig reaction for the preparation of allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate of formula II is done by using triphenyl phosphite or triphenyl phosphine, preferably triphenyl phosphite in a solvent done in organic solvent selected from THF, Xylene, Toluene or mixture thereof with water, preferably in toluene at reflux temperature for 0.5-10 hrs.
The insitu product residue obtained after the removal of toluene i.e. allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl|-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II is treated with suitable organic solvent selected from the group of C1-C.4 alcohols like methanol, ethanol, propanol, isopropanol and butanol, ethers like dioxane, 1111'' etc. esters like methyl acetate, ethyl acetate etc. ketones like methyl isobutyl ketone, methyl ethyl ketone, acetone etc. preferably with alcoholic solvent like isopropanol at heated at 4()°C to 80°C, preferably at 50°C to 55°C for 0.5-2 hrs and is gradually cooled to ()°C to 5°C to obtain pure allyl (5R,6S)-6-[(lR)-l(t-


butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate having purity greater than or equal to 99% by HPLC.
The product allyl (5R,6S)-6-[(1 R)-1 (t-butyldimelhylsilicoxy)cthy1]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-fhia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II is an important precursor for the preparation of antibiotics like Faropenem. Hence, it is further aspect of the present invention to provide hydrate of alkali metal salt of Faropenem in high yield and purity by using the pure intermediate of formula II.
The present invention relates to analytical methods to determine the purity and/or the stability of Faropenem Sodium.
As used herein, the term "relative response factor" refers to the ratio of the absorbency between two compounds as a predetermined wavelength.
As used herein, the term "substantially free of impurities" refers to the individual impurities less than or equal to 0.1% when measure by HPLC.
As used herein, the term "substantially free of impurities" refers to the individual impurities less than or equal to 0.5% when measure by HPLC at RRT 1.07.
As used herein, the term "substantially free of impurities" refers to the individual impurities less than or equal to 0.5% when measure by HPLC at RRT 1.07, with real-time stability at 25°C/60% RH for 9 months.
In another aspect, there is provided one-pot process for the preparation of hydrate of alkali metal salt of Faropenem of formula I


wherein R is alkali metal or alkaline earth metal salt and n is 2.5 comprises:
a) reacting allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydro-
furan-2-yl]-4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II

with deprotecting reagent in a molar ratio of 1:1.2 to 1:1.8 with respect to compound of formula II in presence of an acid in a suitable organic solvent at 20°C to 80°C for 1-20 hrs;
b) cooling the reaction mixture;
c) treating with a mixture of water and water immiscible organic solvent;
d) removal of organic solvent to obtain the residue;
e) reacting the residue with sodium 2-ethylcaproate in the presence of Pd(PPh3)4 and
triphenyl phosphine in suitable organic solvent at an ambient temperature;
f) isolating the technical Faropenem sodium;
h) optionally purifying technical Faropenem sodium in alcoholic solvent; i) removal of alcoholic solvent to obtain the residue; and
j) treatment of residue with mixture of water and acetone and isolating pentahemihydrate of Faropenem sodium.
The compound allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclb[3.2.0] hept-2-ene-2-carboxylate of formula II is ' treated with a deprotecting agent to remove the hydroxy protecting group like t-butyldimethylsilicoxy, where the suitable deprotecting agents can be selected from dil HC1, HF or tetrabutyl ammonium fluoride (TBAF), more preferably tetrabutyl ammonium-fluoride in a molar ratio of 1:1.2 to 1:1.8, preferably 1:1.4 to 1:1.6, more preferably 1:1.47 with respect to compound of formula II.


The deprotection of silylprotected hydroxy group is done in presence of acid like acetic acid in a suitable organic solvent selected from the group of C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and butanol, ethers like dioxane, THF etc. esters like methyl acetate, ethyl acetate etc. ketones like methyl isobutyl ketone, methyl ethyl ketone, acetone etc. preferably in acetone at 20°C to X0°C, preferably ul 45nC to 50°C for 1-20 hrs, more preferably for 16-18 hrs. The reaction mixture was cooled and treated with mixture of water and water immiscible organic solvent like toluene, methylene dichloride, ethyl acetate etc. more preferably mixture of water and methylene dichloride.
The unisolated desilylated derivative of compound of formula II is treated with sodium 2-ethylcaproate in the presence of Pd(PPh3)4 and triphenyl phosphine in suitable organic solvent like THF at an ambient temperature to obtain the technical Faropenem sodium which can be optionally purified by alcoholic solvents like C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and butanol, preferably methanol.
The hydrate s of alkali metal salt of Faropenem i.e. Faropenem sodium is prepared by treating the technical Faropenem sodium with mixture of water and acetone. The hydrate thus obtain is pentahemihydrate of Faropenem sodium. The pentahemihydrate of Faropenem sodium thus obtained is having purity greater than 99.0% and all individual impurities less than 0.1%. The total impurities is less than 0.5%.
Apart from the purity of Faropenem sodium, the stability is the key aspect for any pharmaceutical substances. Hence, it is one of the preferred aspect of the present invention to provide the Stable Faropenem sodium with all the individual impurities well within their limits and real-time stability at 25°C/60% RH as disclosed in Table-1. According to yet another aspect of the present invention the stability of Faropenem with different pH conditions were verified under different sets of conditions as disclosed in Table-2. It is preferred that the Faropenem sodium particles D50 not exceeding 100 /um. It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. Thus a D50 of 100 mrn means that 50% of the particles in Faropenem sodium preferably have a diameter less than 100 mm, preferably D50 is less than 75 mm.
A preferred mean particle size of Faropenem sodium particles is equal to or less than 75 mm. The range of mean particle sizes preferred for use in the invention is 30 to 75 mm, more


preferably 35 to 70 mm, and most preferably 45 to 65 mm, The particle sizes stipulated herein and refer to particle sizes determined with Malvern light scattering.
The term "particles" refers to individual particles whether the particles exist singly or are agglomerated. Thus, Faropenem sodium comprising particulate Faropenem sodium pentahemihydrate may contain agglomerates that are well beyond the size limit of about 75 mm specified herein. However, if the mean size of the primary drug substance particles (i.e., feropenen sodium or Faropenem sodium pentahemihydrate) comprising the agglomerate are less than about 75 mm. individually, then the agglomerate itself is considered to satisfy the particle size constraints defined herein and the composition is within the scope of the invention.
Reference to Faropenem sodium or to Faropenem sodium pentahemihydrate particles having "a mean particle size" (herein also used interchangeably with "VMD" for "volume mean diameter") equal to or less than a given diameter or being within a given particle size range means that the average of all Faropenem sodium particles in the sample have an estimated volume, based on an assumption of spherical shape, less than or equal to the volume calculated for a spherical particle with a diameter equal to the given diameter i.e. VMD D[4,3] < 175 mm, preferably < 150 fivo. Particle size distribution can be measured by Malvern light scattering as known to those skilled in the art and as further disclosed and discussed below.
Faropenem sodium prepared by the process as disclosed herein with the suitable examples is relatively stable in real-time stability at 25°C/60%RH after 3 months with impurity at RRT 1.07 less than or equal to 0.5%, preferably less than or equal to 0.25% more preferably less than equal to 0.20%.
Faropenem sodium prepared by the process as disclosed herein with the suitable examples is relatively stable in real-time stability at 25°C/60%RH after 6 months with impurity at RRT 1.07 less than or equal to 0.5%, preferably less than or equal to 0.25% more preferably less than equal to 0.20%.
faropenem sodium prepared by the process as disclosed herein with the suitable examples is relatively stable in real-time stability at 25"C760%RH after 9 months with impurity at RRT


1.07 less than or equal to 0.5%, preferably less than or equal to 0.25% more preferably less than equal to 0.20%.
The chromatography used in the methods of the invention include, but are not limited to, thin layer chromatography, column chromatography, flash chromatography, or high pressure liquid chromatography (HPLC). Typically, the impurities Faropenem Sodium were isolated by using HPLC, MS, or both.
Typically, the HPLC is performed using a column of Inertsil ODS-3 (250 mm x 4.6 mm, 5u) or equivalent and an eluent of buffer : Methanol 65:35. The flow rate may be 1.0 ml / minute, the detector set at 305 nm, and column temperature about 30°. The column packing material of the HPLC may be Inertsil ODS-3.
Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.
The process of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be constructed as limit to the scope of the claims in any manner.


Examples:
Example-1: One-pot preparation of Allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)
ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-
carboxylate

1.0 Kg of (3R,4R,1’R)-4-acetoxy-3-(l-t-butyldimethylsilicoxy)ethyl)azetidin-2-one (4-AA) was taken in mixture of 15.0 L toluene and 5.0 L water at 25°C to 35°C. The reaction mixture was cool down up to 0°C to 10°C and 0.67 Kg of (2R)-tetrahydro-2-furancarbothioic S-acid; sodium salt was added. The reaction was proceeded in basic pH of 10.5 toll.5 by adding 10% sodium hydroxide solution. The extracted organic layer of toluene was washed with water and filtered. The toluene layer was distilled and cooled after distillation. 0.524 Kg of triethylamine was added at 25°C to 35°C and cooled down below -20°C. 0.770 Kg of allyl chlorooxoacetate in 2.48 L of toluene was added within 3 hrs and stirred. The reaction mixture was treated with 9.5 L of water at -18°C to 22°C. The organic layer was washed with water and filtered through hyflow bed. The toluene layer was distilled and the reaction mass was cooled. 1.60 L of triethyl phosphite was added and heated to reflux for 6-8 hrs. The toluene was distilled to obtain the residue which was treated with 3.20 L of isopropanol and heated and gradually cooled to 0°C to 5°C. The product was filtered and washed with chilled


isopropanol to obtain Allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

100 gm Allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydro furan-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, 820 mL acetone, 57.6 gm of acetic acid were taken 1L of round bottom flask. 87.4 gm of tetrabutyl ammonium fluoride solution in 340 mL acetone was added dropwise within 30 min. The reaction mixture was heated upto 45°C-50°C for 16-18 hrs. The cooled reaction mixture was treated with mixture of 1L of water and 1L of methylene dichloride and stirred for 30 min. The separated organic layer was washed with water. Methylene dichloride was completely distilled to obtain 80.90 gm of Allyl (5R,6S)-6-[(lR)-l-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo [3.2.0]hept-2-ene-2-carboxylate as wet residue.
500 mL THF was added to above residue and stirred. 16.0 gm triphenyl phosphine, 4.2 gm of tetra kis(triphenylphosphine)Palladium, 34.0 gm sodium 2-ethylhexanoate within 15-20 min and 20.4 gm of water were added and stirred. Solid thus obtained was filtered and washed with THF. The product was dried under vacuum at 45°C to 50°C to obtain 64.0 gm technical Faropenem Sodium.
62.0 gm of technical Faropenem Sodium was taken in 200 mL of methanol to obtain clear solution. The reaction mixture was charcoalized, filtered and washed with methanol. Methanol was distilled. The residue 69.64 gm was treated with mixture of 30.0 mL of water and 90.0 mL of acetone at 25°C to 30°C. The reaction mixture was stirred for 2 hrs and cooled to 0°C to 5°C. The product was filtered and washed with chilled acetone. The product was dried at 45°C to 50°C under vacuum to obtain 53.0 gm of Faropenem Sodium Pentahemihydrate.


Example 3
Faropenem Sodium Related Substance analysis using HPLC:
A) Preparation of standard solution:
Weigh accurately about 25 mg Faropenem Sodium primary standard and transfer it into a 25.0 ml volumetric flask. Add about 10 ml diluent into the volumetric flask, sonicate the volumetric flask to dissolve the contents and make the volume upto the mark with diluent to obtain 1000 mg/ml Faropenem Sodium
B) Preparation of test solution:
Weigh accurately about 25 mg test sample and transfer it into a 25.0 ml volumetric flask. Add about 10 ml diluent to the volumetric flask, sonicate the volumetric flask to dissolve the contents and make the volume upto the mark with diluent to obtain 1000 ug/ml Faropenem Sodium test solution.
C) Preparation of Ammonium acetate buffer:
Weigh accurately about 2.7 g ammonium acetate into a 1000.0 ml volumetric flask. Add about 500 ml water to this flask and mix the contents. Make the volume to mark with water and mix the contents. Adjust the pH of the resulting solution to 4.0 ± 0.05 with controlled addition of acetic acid. Filter the solution through 0.2 um filter paper.
D) Chromatographic conditions:
Equipment : Shimadzu LC2010C HPLC system equipped with a dual wavelength
UV- Vis detector or equivalent.
Column : Inertsil ODS-3 (250 mm x 4.6 mm, 5u) or equivalent
Flow Rate : 1.0 ml / minute
Column oven temp. : 30°C
Wavelength : 305nm
Injection Volume : 20 ml
Run time : 50 minutes


Gradient Elution Program:

Procedure & Calculations:
Inject blank, standard and test solution into the chromatograph and record the results. The appropriate retention time of Feropenem Sodium is about 25 minutes.
Calculate the related substances by percent area normalization method and report the results.


TABLE!: FEROPENEM SODIUM LONG TERM STABILITY AT 25°C /RH 60%

Batch No's
FR/001/6001 FR/001/6002
RRT Initial 3 Months 6 Months 9 Months Initial 3 Months 6 Months 9 Months
0.11 - - 0.01 0.01 - - 0.01 0.01
0.12 - - 0.03 0.05 - - 0.05 0.05
0.15 - - - - - - - -
0.28 0.01 0.03 r - 0.01 0.04 - -
0.70 0.06 0.02 - - 0.07 - - -
0.72 0.02 0.02
0.80 - 0.08 0.02 - 0.02 0.01
0.84 - 0.05 0.01 - 0.06 0.01
1.00 99.88 99.93 99.75 99.81 99.85 99.95 99.80 99.82
1.07 0.01 - 0.02 0.01 0.01 0.01 0.01 0.01
1.11 0.01 - 0.02 0.02 0.01 - 0.02 0.02
1.14 0.01 0.01 0.02 0.02 0.01 - 0.01 0.01
1.18 - - 0.01 0.01 - - 0.01 -
1.21 - - 0.01 0.01 - - 0.01 0.01
1.51 - - - 0.03 - - 0.05


TABLE-2: FEROPENEM SODIUM STABILITY AT DIFFERENT pH CONDITIONS
Faropenem sodium Solution stability

Study pH pH solution used Time of study Main peak purity Impurity at RRT 0.11 Impurity at RRT 0.15 Impurity at RRT 0.18 Impurity at RRT 0.25 Impurity at RRT 1.08
A 6.74 Methanol(as per STP) Initial 99.82 0.01 Not detected Not detected Not detected 0.05
B 3.10 0.1% aceticacid Initial 99.79 0.01 0.02 Not detected Not detected 0.06
After 6 hrs 99.53 0.07 0.19 0.01 Not detected 0.06
After 12hrs 99.30 0.15 0.31 0.01 Not detected 0.06
C 4.0 0.01 MAmm.acetate, pHadjusted to 4.0 withacetic acid Initial 99.82 Not detected 0.03 Not detected Not detected 0.06
After 6 hrs 99.53 0.05 0.13 Not detected Not detected 0.06
After12hrs 99.47 0.09 0.21 Not detected Not detected 0.0.6
D 6.0 0.01 MAmm.acetate, pHadjusted to 6.0 withammonia solution Initial 99.80 0.02 0.03 Not detected Not detected 0.05
After 6 hrs 99.68 0.07 0.06 0.01 0.01 0.06
After 12hrs 99.60 0.13 0.08 0.01 0.02 0.06
E 7.0 0.01 M Amm.acetate, pHadjusted to 7.0 withammonia solution Initial 99.81 0.02 0.03 Not detected Not detected 0.06
After 6 hrs 99.61 0.09 0.06 0.05 0.02 0.06
After 12hrs 99.43 0.17 0.09 0.11 0.04 0.06
F 8.0 0.01 M Amm.acetate, pHadjusted to 8.0 withammonia solution Initial 99.77 0.02 0.04 0.01 0.01 0.06
After 6 hrs 99.06 0.18 0.1 0.35 0.14 0.06
After 12hrs 98.21 0.38 0.18 0.78 0.3 0.06
G 9.0 0.01 M Amm.acetate, pHadjusted to 8.0 withammonia solution Initial 99.76 0.01 0.04 0.01 Not detected 0.06
After 6 hrs 91.49 0.90 0.48 4.40 2.33 0.05
After 12hrs 82.94 2.13 1.10 9.02 4.19 0.04

The present invention is not to be construed to be limited to any specific embodiment claimed. IL will be apparent to a person skilled in the are that various modifications of the invention may be possible without departing from the scope thereof.