FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
Title: - OLEMESARTAN MEDOXOMIL SUBSTANTIALLY FREE FROM DIMER IMPURITY
2. Applicant(s)
(a) NAME: CADILA HEALTHCARE LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: CADILA HEALTHCARE LTD; PLOT NO. 26-29 &31, DABHASA-UMARAYA ROAD, VILL. DABHASA-391440, TAL. PADRA, DIST. VADODARA, GUJARAT, INDIA
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The invention relates to a dimer impurity (I) of olmesartan medoxomil. In particular, the invention relates to a process for preparation olmesartan medoxomil substantially free from its dimer impurity. The invention also relates to /olmesartan medoxomil and pharmaceutical compositions comprising the olmesartan medoxomil.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Olmesartan medoxomil is chemically, (5-methyl-2-oxo-2H-l,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-({4-[2-(2H-l,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyI)-lH-imidazole-5-carboxylate having the structural Formula (II):


Olmesartan medoxomil was first disclosed in U.S. Patent No. 5,616,599. The synthetic method employed is depicted in the following reaction Scheme-1, where an imidazole derivative is condensed with a dioxolyl compound, then reacted with a substituted biphenyl methyl halide to obtain trityl olmesartan medoxomil, which is then deprotected to obtain olmesartan.


European Patent Application 1916246 A2 discloses a process for the preparation of ethyl-4-(l-hydroxy-l-methylethyl)2-propyl-l-[[2'-2-(tripheny
yl]methyl]imidazole-5-carboxylate (III) by reacting ethyl-4-(l-hydroxy-l-methylethyl)-2-propyIimidazole-5-carboxylate (V) with N-(triphenyl-methyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (IV) in an organic solvent in presence of a base and a phase transfer catalyst.

International (PCT) Publication No. WO 2007/047838 A2 discloses a process for the preparation of olmesartan medoxomil by condensation of dimethyl-2-propylimidazole-4,5-dicarboxylate (VI) compound with 4-[2-trityltetrazole-5-yl)phenyl}methyl benzyl bromide of Formula (IV) in a mixture of acetone and N,N-dimethylacetamide solvents in presence of potassium carbonate to obtain dimethyl 2-propyl-l-[4-(2-trityltetrazol-5-yl)phenyl]phenymethylimidazole-4,5-dicarboxylate and converting compound (VIII) to olmesartan medoxomil.

International (PCT) Publication No. WO 2007/017135 A2 discloses a process for the preparation of ethyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-[2-(triphenylmethyl)-2H-

tetrazol-5yljbiphenyl-4-yl]methyl] imidazole-5-carboxylate of Formula (III) by reacting ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (IV) in presence of K2CO3 in acetonitrile.
International (PCT) Publication No. WO 2007/048361 A2 discloses a process for the preparation of ethyl-4-(l-hydroxy-l-methylethyl)2-propyl-l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl] imidazole-5-carboxylate of Formula (III) by reacting ethyl-4-(l-hydroxy-l-rnethylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl) biphenyl-2-yl]tetrazole of Formula (IV) in the presence of potash in acetone in presence of PEG-400 as a phase transfer catalyst.
International (PCT) Publication No. WO 2007/148344 Al discloses an in-situ process for the preparation of ethyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl] imidazole-5-carboxylate of Formula (III) by condensing ethyI-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4,-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV) in the presence of potassium carbonate base in acetone solvent in presence of tetrabutylammonium bromide as a phase transfer catalyst.
International (PCT) Publication No. WO 2008/043996 A2 discloses a process for the condensation of ethyl-4-(l -hydroxy-1 -methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenyl methyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV) in the presence of a metal hydroxide/carbonate base in a polar aprotic solvent like N,N-dimethylacetamide in absence of phase transfer catalyst to provide ethyl-4-(l-hydroxy-1 -methylethyl)2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III).
International (PCT) Publication No. WO 2009/019304 Al also provides a process for the preparation of ethyl-4-( 1 -hydroxy-1 -methylethyl)2-propyl-1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl]imidazole-5-carboxylate of Formula (III) by condensation of ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with

N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV) in the presence of LiOH.H2O in N,N-dimethylacetamide solvent in absence of a phase transfer catalyst.
International (PCT) Publication No. WO 2010/134052 Al discloses eliminate and acetic acid ester impurities of Olmesartan. International (PCT) Publication No. WO 2006/073519 Al discloses preparation, of olmesartan medoxomil containing less than about 0.1% of one or more of the impurities OLM-Me, OLM-C1, and OLM-eliminate.
Reference article Analytical Chemistry: An Indian Journal (2007), 6(2), 78-81 discloses identification and characterization of impurity "5-methyl-2-oxo-[l,3]dioxo-4-yl methyl-4-(l-methoxy-l-methyl-ethyl)-2-propyl-l-{4-[2'(lH-tetrazol-5-yl)phenyl] phenyl} Me imidazole-5-carboxylate in olmesartan medoxomil bulk drug.
Reference articles Journal of Heterocyclic Chemistry (2008), 45(3), 917-920; Journal of Pharmaceutical and Biomedical Analysis (2008), 47(3), 553-559; Analytical Chemistry: An Indian Journal (2008), 7(8), 625-632; ARKIVOC (Gainesville, FL, United States) (2010), (2), 292-302 discloses various impurities of olmesartan medoxomil which are incorporated herein as reference.
The present inventors have found an improved process for preparation of olmesartan medoxomil, which is substantially free from dimer impurity generated during detritylation of trityl olmesartan medoxomil.
Applicants have found that olmesartan, often contains the impurity 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy)carbonyl)-2-propyl-1 H-imidazoI-4-yl)propan-2-yl-1 -((2'-(2H-tetrazol-5-yl)-biphenyl-4-yl)methyl-4-(2-hydroxypropan-2-yl)-2-propyl-1 H-imidazole-5-carboxylate "dimer impurity".
In the view of the foregoing, there is an unmet need for detecting, isolating and quantifying the dimer impurity, in samples comprising olmesartan medoxomil.

SUMMARY OF THE INVENTION
The invention provides dimer impurity of olmesartan medoxomil, a process for preparing dimer impurity of olmesartan medoxomil and use thereof, as a reference marker and reference standard for analyzing samples comprising olmesartan medoxomil.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an HPLC chromatogram of Olmesartan Medoxomil with dimer impurity at -RRT 2.44
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have found that a compound of Formula (I), 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy) carbonyl)-2-propyl-1 H-imidazol-4-yl)propan-2-yl-1 -((2'-(2H-tetrazol-5-yl)-biphenyl-4-yl) methyl-4-(2-hydroxypropan-2-yl)-2-propyl-lH-imidazoIe-5-carboxylate i.e. dimer impurity, is one of the potential impurity generated during the detritylation of olmesartan medoxomil to obtain olmesartan medoxomil.

The dimer impurity (I) is generated during the preparations of olmesartan as a side product through esterification between hydroxyl group in olmesartan medoxomil and acid group of olmesartan acid as shown in the scheme given below.


In preparation of olmesartan the present inventors have found that compound (I) is formed as an impurity, which as compared with olmesartan, has similar structure and physical properties and it is difficult to detect, remove during crystallization of olmesartan medoxomil and quantify the level of impurity.
The invention provides a compound 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-memyl-2-oxo-l,3-dioxol-4-yl)methoxy)carbonyl)-2-propyl-lH-imidazol-4-yl)propan-2-yl-l-((2'-(2H-tetrazol-5-yl)-biphenyl-4-yl)methyl-4-(2-hydroxypropan-2-yl)-2-propyl-lH-imidazole-5-carboxylate i.e. dimer impurity of Formula (I).

In another general aspect, the invention provides an isolated compound 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy)carbonyl)-2-propyl-lH-imidazol-4-yl)propan-2-yl l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-lH-irnidazole-5-carboxylate i.e. dimer impurity of Formula
(I).
In another general asepct, the invention provides an isolated compound of Formula (I) having a purity higher than 80%, particularly having a purity higher than 90%, and more particularly having a purity higher than 99%, as measured by HPLC.
In another general aspect, there is further provided, therefore, use of compound of Formula (I), as a reference marker to detect the presence of compound (I), in a sample comprising olmesartan, and/or as a reference standard to quantify the amount of compound (I) in a sample comprising olmesartan, and/or as a reference standard to ensure the purity of a sample comprising olmesartan, so as to ensure that olmesartan, particularly olmesartan free base or olmesartan medoxomil, as present in said sample has less than 0.15%, particularly less than 0.08%, as measured by HPLC of a compound of Formula (I).
In another general aspect, there is provided, a method of use of compound of Formula (I), as a reference standard to detect the presence of compound (I), in a sample comprising olmesartan, and/or as a reference standard to quantify the amount of compound (I) in a sample comprising olmesartan, and/or as a reference standard to ensure the purity of a sample comprising olmesartan, so as to ensure that olmesartan, particularly olmesartan free base or olmesartan medoxomil, as present in said sample has less than 0.15%, particularly less than 0.08%, as measured by HPLC of a compound of Formula (I).
The term "reference marker", as used herein, refers to a compound that is used in qualitative analysis to identify components of a mixture based on their position, e.g. in a HPLC or a GC chromatogram or on a Thin Layer Chromatography (TLC) plate.
The term "reference standard", as used herein, refers to a compound that is used in quantitative analysis to determine the amount of a compound present in a sample.

Furthermore, there is provided a method for determining the presence of a compound (I), in a test sample comprising olmesartan, particularly olmesartan free base or olmesartan medoxomil, the method comprising:
(a) providing a reference sample comprising (i) olmesartan, or olmesartan medoxomil, and (ii) a reference marker which is a compound of Formula (I);
(b) carrying out chromatographic separation on said reference sample to obtain a reference chromatographic result of said reference marker relative to said olmesartan or olmesartan medoxomil;
(c) carrying out chromatographic separation on said test sample to obtain a test
chromatographic result;
(d) comparing the chromatographic results obtained in steps (b) and (c); wherein if the test
chromatographic result is substantially the same as the reference chromatographic result for
said reference marker, then a compound of Formula (I), is present in said test sample.
By "substantially the same results", as used herein, is meant to refer that the chromatographic results are considered to be equivalent by the one skilled in the art. Further, by "substantially the same results" it can be meant to refer that the compared chromatographic results share a similarity of more than 80%, preferably more than 90%, even more preferably more than 95%, and yet even more preferably more than 99%.
Preferably, the chromatographic separation comprises HPLC or GC and as such the steps (b) to (d) of the method above comprise:
(b) carrying out HPLC or GC on said reference sample to determine the relative retention time of said reference marker compared to said olmesartan or olmesartan medoxomil;
(c) carrying out HPLC or GC on said test sample;
(d) comparing relative retention times determined in steps (b) and (c); wherein if there is observed a relative retention time in step (c) substantially the same as the relative retention time of said reference marker compared to said olmesartan or olmesartan medoxomil, preferably olmesartan, free base, in step (b), then a compound of Formula (I), is present in said test sample.

Alternatively, the chromatographic separation can comprise TLC and as such the steps (b) to (d) of the method above comprise:
(b) carrying out TLC on said reference sample to determine the relative component position on a chromatographic support of said reference marker compared to said olmesartan;
(c) carrying out TLC on said test sample;
(d) comparing the relative component positions determined in steps (b) and (c); wherein if there is observed on said chromatographic support a relative component position in step (c) substantially the same as the relative component position of said reference marker compared to olmesartan or olmesartan medoxomil preferably olmesartan, free base, in step (b), then a compound of Formula (I), is present in said test sample.
In another general aspect, there is provided a method for quantifying the amount of compound (I), in a test sample comprising olmesartan or olmesartan medoxomil, the method comprising:
(a) providing a test sample of olmesartan, , preferably olmesartan free base or olmesartan medoxomil, containing an unknown concentration of a compound of Formula (I);
(b) subjecting said test sample to chromatographic separation;
(c) obtaining a chromatographic quantitative measurement for a compound of Formula (I), in said test sample; and
(d) calculating the amount of a compound of Formula (I), in said test sample based on the measurement of step (c) and also chromatographic quantitative measurement for a compound of Formula (I), obtained from at least one reference sample having a known concentration of a compound of Formula (I).
The embodiments of the above quantification method further includes, the following steps are carried out:
(a) providing a test sample of olmesartan or olmesartan medoxomil, containing an unknown concentration of a compound of Formula (I);
(b) providing at least one reference sample having a known concentration of a compound of Formula (I);
(c) subjecting said test sample and said reference sample to chromatographic separation;

(d) obtaining chromatographic quantitative measurements for a compound of Formula (I), in said test sample and said reference sample; and
(e) calculating the amount of a compound of Formula (I), in said test sample from the measurements of step (d).
More precisely, the following steps are typically carried out in the steps (b) to (e) of the above general aspect of the quantification method according to the present invention:
(b) providing at least one reference sample having a known concentration of a compound of Formula (I),
(c) subjecting said test sample and said reference sample to HPLC or GC;
(d) measuring the area or height of peaks obtained for a compound of Formula (I), in said test sample and said reference sample; and
(e) calculating the concentration of a compound of Formula (I), in said test sample from the measurements of step (d).
Alternatively, in a second embodiment of the quantification method, the following steps are carried out:
(a) providing a test sample of olmesartan, preferably olmesartan free base, containing an unknown concentration of a compound of Formula (I),
(b) subjecting said test sample to chromatographic separation;
(c) obtaining chromatographic quantitative measurement for a compound of Formula (I), in said test sample; and
(d) calculating the concentration of a compound of Formula (I), in said test sample based on the measurement of step (c) and also a calibration curve that is representative of chromatographic quantitative measurement for a compound of Formula (I), obtained from more than one reference sample each having a respectively defined concentration of a compound of Formula (I).
Typically, the calibration curve referred to above is obtained with at least two reference samples, preferably with at least five or six reference samples, and the concentration of a compound of Formula (I), is then calculated by reference to the thus obtained calibration curve.

The chromatographic quantitative measurements of the quantitative methods of the invention is preferably carried out by
(a) subjecting said test sample and said at least one reference sample to HPLC or GC, and
(b) measuring the area or height of peaks obtained for a compound of Formula (I), in said test sample and said at least one reference sample. The method is preferably an HPLC method, and more preferably the HPLC method comprises the following features: the column is a Inertsil C8-3 (250mm x 4.6 mm, 5μm), at 40°C; the diluent is a premix the water and acetonitrile in the ratio of 20:80, wherein the buffer solution is prepared by dissolving 0.68 g of potassium dihydrogen phosphate and 1.0 mL of triethylamine in 500 mL of water, then adjusting the pH to 2.6±0.05 with 10% orthophosphoric acid; the detector wavelength is 220 nm wavelength; the flow rate is 1.0 mL per minute.
In further embodiments there is provided a method for ensuring the purity of a test sample comprising olmesartan, the method carrying out a quantification method substantially as hereinbefore described so as to ensure that olmesartan, particularly olmesartan medoxomil, as present in said test sample has less than 0.15%, preferably less than 0.10%, as measured by HPLC of a compound of Formula (I).
In further embodiments there is provided a compound olmesartan, particularly olmesartan medoxomil, having equal to or less than 0.20%, particularly having equal to or less than 0.15%, more particularly equal to or less than 0.10%, as measured by HPLC of a compound of Formula (I),


Accordingly, the present invention further provides a pharmaceutical composition comprising an effective amount of olmesartan medoxomil, substantially free from dimer impurity, together with a pharmaceutically acceptable carrier, diluent or excipient thereof.

the process comprising: treating olmesartan medoxomil having the structural Formula (II):

with olmesartan acid having structural Formula (III)
The term "effective amount" as used herein means an amount of olmesartan medoxomil, which is capable of providing an anticonvulsive, antipyretic and/or analgesic therapeutic effect. By "pharmaceutically acceptable composition" is meant that the carrier, diluent or excipient must be compatible with olmesartan and not be deleterious to a recipient thereof. In another general aspect, the invention provides a process for preparing 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy)carbonyl)-2-propyl-lH-imidazol-4-yl)propan-2-yl l-((2,-(2H-tetrazol-5-yl)bipheny!-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-lH-imidazole-5-carboxylate i.e. dimer Impurity (compound of Forrnula I)


in presence of atleast one suitable organic solvent and obtaining compound of Formula (I).
The embodiments of the process further includes addition of water to the reaction mixture obtained in suitable organic solvent and heating. The compound (I) may be obtained by removal of solvent followed by purification of compound (I).
In general, the suitable organic solvent comprises one or more methanol, ethanol, isopropanol, n-butanol, tert-butyl alcohol, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, toluene, xylene, ethyl benzene, dioxane, diethyl ether, acetone. More particularly, the solvent may be ethyl acetate.
The reaction mixture is particularly heated around the reflux temperature preferably around 50-8O°C more preferably around 60-70°C even more preferably around 65-70°C.
Water may be optionally added to the reaction mixture to form a suspension comprising compound of Formula (I) and then filtering the suspension.
The compound (I) may be obtained by concentrating under vacuum and then optionally purified by performing recrystallization from acetonitrile.
In still another embodiment, the invention provides a process for analyzing the purity of a composition containing olmesartan medoxomil, comprising monitoring the amount of compound (I), present in a sample of the composition.
The composition of the invention above preferably comprises up to 99%, more preferably up to 99.5%, even more preferably up to 99.8%, and yet even more preferably up to 99.95% by

weight of olmesartan medoxomil, based on the combined weight of compound of Formula (I), and olmesartan medoxomil.
Also, the invention provides a composition comprising compound of Formula I, a carrier, and up to 99%, preferably up to 99.95%, by weight of olmesartan, based on the combined weight of compound of Formula (IV), and olmesartan medoxomil.
Preferably, the compositions of the invention as hereinabove described are pharmaceutical compositions and the carrier is a pharmaceutically acceptable carrier.
Olmesartan medoxomil can exist in solvated, as well as unsolvated forms, including hydrated forms, i.e. olmesartan can contain in its structure stoichiometric amounts of solvent in the case of solvates, or of water in the case of hydrates. It is to be understood that the invention encompasses all such solvated, as well as unsolvated, forms. The preparation of solvates and hydrates depends on the solvent or mixture of solvents used and the crystallization conditions that can be determined by the skilled person.
The following examples further illustrate embodiments of the invention but, of course, should not be construed as in any way limiting its scope.
GENERAL EXPERIMENTAL CONDITIONS
HPLC method:
Equipment : Shimadzu LC2010C HPLC system equipped with a dual wavelength
UV-VIS detector or equivalent.
Column : Inertsil C8-3 (250mm x 4.6 mm, 5μm).Part no: 5020-01901, make-
GL Sciences Inc.
Flow rate : 1.0 mL / minute
Column oven temp : 40°C
Wavelength : UV at 220 nm
Injection volume : 10 μL
Run time : 65 minutes
Diluent : Premix the water and acetonitrile in the ratio of 20: 80 v/v.

Preparation of buffer:
Weigh about 0.68 gm potassium dihydrogen orthophosphate into a 1000 mL volumetric flask. Add about 500 mL water and sonicate to dissolve. Add 1.0 mL of triethylamine and mix. Make up the volume with water. Adjust the pH 2.6 ± 0.05 with controlled addition of dilute (10 %) orthophosphoric acid. Filter through 0.2 μm membrane filter paper.
Gradient composition:

Time (in minute) % Buffer % Acetonitrile
0.01 60 40
5 60 40
40 20 80
50 20 80
51 60 40
65 60 40

Component -RRTs
Olmesartan acid 0.34
Olmesartan ethyl ester 0.75
Olmesartan Medoxomil 1.00
N-Alkylated Impurity 1.56
Trityl alcohol 2.44
Olmesartan ester dimer 2.5
OL-IV 3.67
Example 1: Preparation of dimer impurity (i. e. compound of Formula I)
Equimolar quantities of Olmesartan Medoxomil (28.9 g, 0.051 moles) and Olmesartan Acid (27 g 0.0603 moles) in solvent ethyl acetate (600 ml) in the presence of water (115 ml) refluxed for 3.0 days to afford 15-25% of this impurity on HPLC Chart paper. The resulting mass is concentrated under vacuum and residue is fractionally recrystallized from acetonitrile. Resultimg mother liquor affords about 30% of impurity which was eluted through column chromatography in 80:20 (EthylAcetate: Hexane).
Analytical Data:
Mass: 987.3 [M]+, 986.5 [986.5 [M-l]+
1H-NMR (400MHz) DMSO d6 : 7.63-7.50 (8H, m, ArH), 7.51-7.57 (4H, dd, ArH), 6.92-
6.82 (2H, d, J= 8 Hz, ArH), 6.84-6.82 (2H, d, J=8.0 Hz, ArH), 5.54 (2H, s, -NCH2), 5.42(2H,
s, -NCH2), 5.07 (2H, s, -OCH2), 2.61-2.58 (2H, t, -CH2), 2.57-2.54 (2H, t, -CH2), 2.07

(3H,s, -CH3), 1.91 (6H, s, O-ipr CH3), 1.67-1.52 (4H, m, -CH2), 1.46 (6H, s, O-ipr CH3), 0.90-0.79 (6H, m, -CH3)
The product was observed at RRT 2.5 on HPLC and identified by LCMS having M/Z: 987. Thus it was assumed to be the ester of olmesartan acid and olmesartan Medoxomil by the molecular mass.
Example-2: Preparation of ethyl-4-(1-hydroxy-l-methylethyl)-2-propyl-l-[[2'-[2-
(triphenvlmethyl]-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxvlate of
Formula (IIP
100 g of ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V), 172.4 g of potassium carbonate and 700 ml of acetone were stirred at 25 °C. 258.4 g of N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV) and 100 ml of N,N-dirnethylformamide were added to the reaction mixture and heated to 60°C for 20 hours. After completion reaction was monitored by TLC & acetone was distilled and the residue was titurated with 200 ml of acetone and stirred for 30 minutes. The reaction mixture was cooled and the product was filtered and washed with acetone. The wet-cake was suspended in 800 ml of water and stirred for 1 hour. The product was filtered and washed with water. The product was dried in a hot air oven at 50°C to 55°C for 15 hours to obtain 214 g (83%) of ethyl-4-(l-hydroxy-l-methylethyl)2-propyl-l-[[2,-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl] imidazole-5-carboxylate of Formula (III).
Example-3: Preparation of Trityl Olmesartan Medoxomil of Formula (ID
100 g of ethyl-4-(l-hydroxy-l-methylethyl)2-propyl-l-[[2'-[2-(triphenylmethyl) -2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III), 15.65 g of potassium hydroxide and 1 L of acetone were stirred at 25°C for 4 hours. After the completion of reaction, the reaction mass was filtered through a hyflow bed and washed with acetone to obtain Reaction Mass-A. In another round bottom flask, 500 ml acetone, 19.7 g of potassium carbonate and 5.78 g of potassium iodide were taken. 26.0 g of 4-chloromethyl-5-methyl-2-oxo-1, 3-dioxolene was added at 25°C to obtain Reaction Mass-B. The reaction mass B was

heated at 35°C to 40°C and reaction mass -A was added during 2-3 hours and maintained for 6 hours. The reaction was cooled to 25°C and filtered. The filtrate was distilled under vacuum till thick mass was obtained. The residue was treated with 200 ml ethyl acetate and stirred at 45°C. The reaction mixture was cooled and stirred. The product was filtered and washed with ethyl acetate. The wet-cake was further purified in ethyl acetate followed by washing with methanol to obtain 80 g (80%) of trityl olmesartan medoxomil (II).
Example-4: Preparation of olmesartan medoxomil (I)
400 ml of aqueous acetic acid obtained by mixing 412.5 ml acetic acid in 137.5 ml of water and 100 g of trityl olmesartan medoxomil were heated to 35°C to 40°C for 3 hours. After completion, the reaction mass was cooled and treated with 150 ml of water. The reaction mass was further cooled to 0°C to 5°C and stirred for 1 hour. The reaction mass was filtered and washed with aqueous acetic acid. The filtrate was extracted with methylene dichloride. The separated aqueous layer was further washed with methylene dichloride. Combined organic layer was treated with sodium bicarbonate solution and allowed to settle. The methylene dichloride layer was filtered and distilled under vacuum at 50°C to get a residue. The residue was treated with 300 ml of ethyl acetate at 35°C and cooled to 0°C to 5°C. The isolated product was filtered and washed with 100 ml of ethyl acetate. The product was dried in hot air oven at 50°C to 55°C for 8 hours to obtain 56g (81%) of olmesartan medoxomil. HPLC Purity: 99.9% (Dimer Impurity < 0.10%)
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.

We claim:
1. A compound 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy)carbonyl)-2-propyl-1H-imidazol-4-yl)propan-2-yl-1 -((2'-(2H-tetrazol-5-yl)-biphenyl-4-yl)methyl-4-(2-hydroxypropan-2-yl)-2-propyl-lH-imidazole-5-carboxylate i.e. dimer impurity of Formula (I)

2. Use of compound of Formula (I), as a reference marker to detect the presence of compound (I), in a sample comprising olmesartan, and/or as a reference standard to quantify the amount of compound (I) in a sample comprising olmesartan, and/or as a reference standard to ensure the purity of a sample comprising olmesartan, so as to ensure that olmesartan, particularly olmesartan free base or olrnesartan medoxomil, as present in said sample has less than 0.15%, as measured by HPLC of a compound of Formula (I).
3. A method of use of compound of Formula (I), as a reference standard to detect the presence of compound (I), in a sample comprising olmesartan, and/or as a reference standard to quantify the amount of compound (I) in a sample comprising olmesartan, and/or as a reference standard to ensure the purity of a sample comprising olmesartan, so as to ensure that olmesartan, particularly olmesartan free base or olmesartan medoxomil, as present in said sample has less than 0.15%, as measured by HPLC of a compound of Formula (I).
4. A method for determining the presence of a compound (I), in a test sample comprising olmesartan, particularly olmesartan free base or olmesartan medoxomil, the method comprising:
(a) providing a reference sample comprising (i) olmesartan, or olmesartan medoxomil, and (ii) a reference marker which is a compound of Formula (I);

(b) carrying out chromatographic separation on said reference sample to obtain a reference chromatographic result of said reference marker relative to said olmesartan or olmesartan mixomil;
(c) carrying out chromatographic separation on said test sample to obtain a test chromatographic result;
(d) comparing the chromatographic results obtained in steps (b) and (c); wherein if the test chromatographic result is substantially the same as the reference chromatographic result for said reference marker, then a compound of Formula (I), is present in said test sample.
5. A method for quantifying the amount of compound (I), in a test sample comprising
olmesartan or olmesartan medoxomil, the method comprising:
(a) providing a test sample of olmesartan, , preferably olmesartan free base or olmesartan medoxomil, containing an unknown concentration of a compound of Formula (I);
(b) subjecting said test sample to chromatographic separation;
(c) obtaining a chromatographic quantitative measurement for a compound of Formula (I), in safest sample; and
(d) calating the amount of a compound of Formula (I), in said test sample based on the inurement of step (c) and also chromatographic quantitative measurement for a compound of Formula (I), obtained from at least one reference sample having a known concentration of a compound of Formula (I).

6. A method for ensuring the purity of a test sample comprising olmesartan, the method carrying out a quantification method substantially as hereinbefore described so as to ensure that olmesartan, particularly olmesartan medoxomil, as present in said test sample has less than 0.15% as measured by HPLC of a compound of Formula (I).
7. A compound olmesartan, particularly olmesartan medoxomil having equal to or less than 0.20% as measured by HPLC of a compound of Formula (I).
8. A pharmaceutical composition comprising an effective amount of olmesartan medoxomil, substantially free from dimer impurity, together with a pharmaceutically acceptable carrier, diluent or excipient thereof.
9. A process for preparing 2-(l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-5-(((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy)carbonyl)-2-propyl-lH-imidazol-4-yl)propan-2-yl l-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-lH-imizole-5-carboxylate i.e. dimer Impurity (compound of Formula I)



with olmesartan acid having structural Formula (III)

the process comprising: treating olmesartan medoxomil having the structural Formula (II):
in presence of atleast one suitable organic solvent and obtaining compound of Formula
(I).
10. The process according to claim 9, wherein the suitable organic solvent comprises one or more methanol, ethanol, isopropanol, n-butanol, tert-butyl alcohol, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, toluene, xylene, ethyl benzene, dioxane, diethyl ether, acetone.