FIELD OF THE INVENTION
The present invention relates to novel crystalline form-IV of 2-n"butyl-4-chloro-5-
hydroxy methyl-l- [[2^-(lH-tetrazol-5"yl) biphenyl-4-yl] methyl] imidazole potassium. It is generically known as Losartan potassium and marketed under brand name 'Cozaar' in US market.
The present invention also relates to the process for the preparation of novel crystalline form-IV of Losartan potassium, which can be depicted as Formula (1).

Formula (1).
BACKGROUND OF THE INVENTION
Losartan potassium is known to inhibit the action of the octapeptide hormone angiotensin II (All) and are useful in the treatment of hypertension. The enzyme renin acts on a blood plasma a 2-globulin, angiotensinogen to produce angiotensin I, which is then converted by angiotensin converting enzyme to AIL The latter substance is a powerfial vasopressor agent, which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog and man. Losartan

potassium inhibit the action of All at its receptors on target cells and thus prevents the increase in blood pressure produced by this hormone receptor interaction. By administering Losartan potassium to a species of mammal with hypertension due to All, the blood pressure is reduced. Losartan potassium is also useful for lowering the cholesterol.
US Patent No. 5,138,069 claims Losartan and its pharmacologically acceptable salts.The said patent also discloses the process for the preparation of Losartan and its potassium salt which comprises, deprotection of trityl group from l-[(2^ (triphenylmethyltetrazol-5-yl)l,l^"biphenyl-4-yl)methyl]-2"butyl-4-chloro-5"hydroxymethyl imidazole with 3.4N hydrochloric acid to get the Losartan. Which is then converted to its potassium sah by treating with potassium hydroxide in isopropanol in the presence of water. WO 95 /17396 disclosed the crystalline forms of Losartan potassium (i.e. form-I and form-II). The said patent also discloses the process for the preparation of form-II, which comprises heating of crystalline form-I of Losartan in a Differential Scanning Colorimetry cell in an open pan at a rate of 10°C/min under nitrogen atmosphere. Crystalline form I and form II were differentiated by x-ray diffraction and by differential scanning calorimetry.
The process for the the preparation of both the crystalline forms (form-I and form-II) of Losartan potassium is disclosed in US patent 5,608,075. These crystalline form-I and form-II are differentiated by x-ray diffraction and by Differential Scanning Colorimetry. Many of the related patents were disclosed the process for the preparation of Losartan and its potassium salt in various methods, but none of these patents were decribed the existence of novel crystalline form of the present invention.

During our laboratory experimentation as a part of process development, novel form of
Losartan potassium was resulted while crystallizing the Losartan and Losartan potassium
in different solvents. Hence, the main aspect of the present invention is to provide novel
crystalline form of Losartan potassium
The main aspect of the present invention is to provide the novel crystalline form of
Losartan potassium which is designated as crystalline form IV and the process for the
preparation thereof
The processes of the present invention is simple, eco-friendly and easily scalable.
SUMMARY OF INVENTION
The present invention relates to the novel crystalline form-IV of Losartan potassium and
the process for the preparation thereof The process for the preparation of novel
crystalline form-IV of Losartan potassium of the present invention, which comprises
treating the Losartan with aqueous potassium hydroxide solution in the presence of a
organic solvent followed by cooling of the reaction solution.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig-1 is a diagram showing the X-ray powder diffraction of novel crystalline form-IV of
Losartan potassium.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel crystalline form-IV of Losartan potassium. The present invention also provides a process for preparing novel crystalline form-IV of Losartan potassium.

by X-ray powder diffraction .The X-ray powder diffraction pattern of novel crystalline form-IV of Losartan potasssium was measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source.The 2-theta values and their intensity percentages of relevant peaks in X-ray powder diffraction patteren of crystalline form-IV of Losartan potassium is shown in the Table-1.


The novel crystalline form-IV of Losartan potassium of present invention is having the X-ray powder diffractogram patteren substabtially as depicted in Figure (1). The novel crystalline form-IV of 2-n-butyl-4-chloro-5-hydroxy methyl-l-[[2^-(lH-tetrazol"5-yl) biphenyl-4-yl] methyl] imidazole potassium (Losartan potassium) of the present invention is prepared by the process, which comprises,
a) Suspention of 2-n-butyl-4-chloro-l- [(2^-(lH tetrazole-5-yl)"biphenyl-4-yl] methyl]-lH-imidazole-5-methanol (Losartan) in organic solvents Hke CI -C5 straight or branched chain nitrile solvents such as acetonitrile or propionitrile, preferably acetonitrile or ester solvents such as methyl acetate, ethyl acetate preferably ethyl acetate.
b) adjusting the pH of the solution of step (a) to 8.5-9.0 with aqueous potassium hydroxide solution.
c) stirring the solution of step (b) at 25-30°C for 0.5-5 hours.
d) filtering the solution of step (c) through hyflow bed.
e) cooling the filtrate fi-om step (d) to a temperature of-10 to lO'^C.
f) maintaining the solution of step (e) at -10 to 10° C for 0.5 to 5 hrs.
g) filtering the separated solid fi*om step (f) by conventional methods.
h) drying the resulting compound fi-omstep (g) at 30-70 °C for 3-10 hours to get the
desired novel crystalline form-IV of Losartan potassium. The pH values of the solution of above said step (b) are varied fi-om 7.0 to 12, preferably 8.0 to 9.0

If the drying temparature of the solid as mentioned in step (h) was increased to 80-90°C and maintaining the drying process upto the constant weight, then we can get amorphous form of Losartan Potassium, which was already claimed in our prior application 72/MAS/2003.
In another ambodiment of the present invention the process for the preparation of novel crystalline form-IV of Losartan potassium from crystalline form-I of Losartan potassium, which comprises;
a) dissolving the crystalline form -I of 2-n-butyl-4-chloro-5-hydroxy methyl-1- [[2^-(IH- tetrazol-5-yl) biphenyl-4-yl] methyl] imidazole potassium (Losartan potassium) in an aqueous solution of organic solvents like C1-C5 straight or branched chain nitrile solvents such as acetonitrile or propionitrile, preferably acetonitrile or ester solvents such as methyl acetate, ethyl acetate preferably ethyl acetate.
b) stirring the solution of step (a) at 25-30^C for 0.5-5 hours.
c) filtering the solution of step (b) through hyflow bed.
d) cooling the filtrate from step(c) to a temperature of-10 to 10° C.
e) maintaining the solution of step (d) at -10 to 10° C for 0.5 to 5 hrs.
f) fihering the separated solid from step (e) by conventional methods.
g) drying the resulting compound from step (f) at 30-70 °C for 3-10 hours to get the
desired novel crystalline form-IV of Losartan potassium.
The novel crystalline form-IV of Losartan potassium of the present invention is having moisture content varying from 7.0 to 13.0% by KF method usually the moisture content of the substance is having around 10.0 % by KF method.

The moisture content of crystalline form-IV of Losartan potassium of the present
invention was measured on Mettler dI-35 instrument using Karl-Fisher reagent.
The present inventive substance is thermally stable; hence it may be well suited for
pharmaceutical formulations.
Hence, the present invention is directed to provide novel crystalline form-IV of Losartan
potassium. The process for the preparation of present invention is simple, eco-friendly
and commercially viable.
Reference examples: Preparation of Losartan.
l-[(2^(Triphenylmethyhetrazol-5-yl)biphenyl-4-yl)methyl]-2-butyl]-4-chloro-5-hydroxy
methyl imidazole (500 grams) was added in acetonitrile (1500 ml) and hydrochloric acid (120 ml) and stirred at 20-25°C till the reaction was substantially completes. Then the reaction mass pH adjusted to around 8.5 with caustic lye. And charged water (6.0 lit) to the reaction mass and filtered the separated by product by conventional methods. Then the fihrate heated to 40-45 °C followed by adjusted the pH to around 5.0 with hydrochloric acid and maintained for around 30-45 minutes. Cooled the solution to 25-30°C and maintained for around 30-45 minutes. Filtered the separated solid compound and washed with water foUwed by dried at a temperature of 70-80*^C under reduces pressure to get constant weight of Losartan (Weight: 300gramsM.R: 178-185°C).
Example: 01
Preparation of Novel crystalline form-IV of Losartan potassium.
Losartan (50 grams) was taken in acetonitrile (400 ml) and pH is adjusted to 8.0-8.5with
aqueous potassium hydroxide solution (8.0 grams potassium hydroxide in 20 ml of water) and strried to get the clear solution, then the reaction solution is filtered through h5^ow

bed . Taken the filtrate into round bottom flask stirred for 1 hr followed by cooling given to 0-5°C for 3 hours. Then the separated solid was filtered under reduced pressure and dried at a temperature of 60-65°c for 5 hrs to get the desired novel crystalline form IV of Losartan potassium (Weight: 77 grams)
Example: 02
Losartan (20 grams) was taken in ethyl acetate (160 ml) and heated to 70-75°C. Then
pH is adjusted to 7.5 with aqueous potassium hydroxide solution (3.2 grams potassium hydroxide in 6.0 ml of water) and strried for 60 minutes at 70-75°C to get the clear solution Then the reaction solution is filtered through hyflow bed and the fihrate charged into round bottom flask, and cooled to 30-35°C. The solution further cooled to 0-5 °C and stirred for 3 hours at 0-5°C and then the separated solid filtered under vacuum and dried at a temperature of 60-65°C for 5 hrs resulted the novel form of Losartan potassium (Weight: 15 grams).
Example: 03
Losartan potassium crystalline form-I (10 grams) was taken in ethyl acetate (120 ml)
and heated to 70-75°C then water is added upto clear dissolution and strried for 20 minutes at 70-75'^C . Then the reaction solution is filtered through hyflow bed and fihrate charged into round bottom flask. Then the filtrate stirred at 0-5° for 1 hour. Then the separated solid filtered under reduced pressure and dried at a temperature of 60-65°C for 5 hrs resuhed the novel crystalline form of Losartan potassium (Weight: 7.0grams).

DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig-1 is characteristic X-ray powder diffraction pattern of novel crystalline form-IV of
Losartan Potassium.
Vertical axis: Intensity (CPS); Horizontal axis: 2 theta (degrees). It shows a plain halo
with no peaks, which is characteristic of the novel nature of product.
Vertical axis: Heat flow (W/g); Horizontal axis: Temperature (°C).

We claim:
1) A novel crystalline form-IV of 2-n~butyl-4"Chloro-5-hydroxy methyl-1- [[2^-(lH-
tetrazole-S-yl) biphenyl-4-yi] methyl] imidazole potassium. (Losartan potassium).
2) The novel crystalline form-IV of 2-n"butyl"4-chloro-5-hydroxy methyM- [[2^-(lH-tetra2ole-5-yl)biphenyl-4-yl]methyl]imidazolepotassium (Losartan potassium).which is characterized by powder X-ray diffractogram in accordance with figure (1).
3) The novel crystalline form-IV of Losartan potassium of claim 1, which is having moisture content varying from 7.0-13.0 % by KF method.
4) A process for the preparation of novel crystalline form-IV of 2-butyl-4-chloro-5-hydroxymethyl-1- [[2^-(lH-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazole potassium (Losartan potassium), which comprises ;
a) suspention of 2-n-butyl-4*chloro-l- [(2^-(lH tetrazole-5-yl)-biphenyl-4-yl] methyl]-lH-imidazole-5-methanol (Losartan) in an organic solvent like CI -C5 straight or branched chain nitrile solvents such as acetonitrile or propionitrile, preferably acetonitrile or ester solvents such as methyl acetate, ethyl acetate preferably ethyl acetate.

b) adjusting the pH of the solution of step (a) to 8.5-9.0 with aqueous potassium
hydroxide solution.
c) stirring the solution of step (b) at 25-30°C for 0.5-5 hours.
d) filtering the solution of step (c) through hyflow bed.
e) cooling the filtrate fi-om step (d) to a temperature of-10 to 10° C.
f) maintaining the solution of step (e) at -10 to 10° C for 0.5 to 5 hrs,
g) fihering the separated solid fi"om step (f) by conventional methods.
h) drying the resulting compound fi'om step (g) at 30-70 °C for 3-10 hours to get the desired novel crystalline form-IV of Losartan potassium,
5) A process for the preparation of novel crystalline form-IV of 2-butyl-4-chloro-5-
hydroxy methyl-1- [[2^-(lH-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazole
potassium (Losartan potassium), fi-om crystalline form-I of Losrtan potassium.
6) Novel crystalline form-IV of Losartan potassium and the process for the preparation
thereof which is substantially as here in described and exemplified.