FIELD OF THE INVENTION
The present invention relates to novel crystalline Form of (S)-N- (I-Carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)- biphenyl-4-yl methyl] amine and its process of preparation thereof. The product is also known as Vallarta in therapy and DIOVAN under the trade name. Valsartan may be represented by the following Formula (1).

Formula (1) BACKGROUND OF THE INVENTION
(S)-N- (l-Carboxy-2-methyl-prop-l-yI) -N-pentanoyl-N- [2'-(lH-tetrazol-5-y!)- biphenyl-4-yl methyl] amine (Valsartan) is a non-peptide angiotensin - II antagonist. By inhibiting the action of angiotensin - II on its receptors, this compound prevents in the increase of blood pressure produced by the hormone-receptor interactions and hence used in the treatment of cardiovascular complaints such as hypertension and heart failure.
EP 0443983 / USP 5,399, 578 discloses the process for the preparation of (S)-N- (1-Carboxy-2-methyl-prop-l-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl> biphenyl-4-yI methyl] amine in three different routes.
i) by reacting N-valeryl-N- [(2'-cyanobiphenyl-4-yl) methyI]-(L)-valine
methyl ester with tributyltin azide, further subjecting the resultant compound to flash chromatography and recrystallisation from the ethyl acetate resulted the title compound.

ii) by reacting N-valeryl-N- [{2'-cyanobiphenyl-4-yl) methyl]-(L)-valine benzyl ester with tributyltin azide in xylene at reflux temperature and the resultant benzyl protected valsartan is hydrogenated over palladium carbon in dioxane followed by reaction work up resulted the crude valsartan from ethyl acetate, which on further recrystallisation from diisopropyl ether yielded the pure valsartan. iii) hydrogenating the benzyl protected valsartan over palladium carbon in methanol followed by reaction work up resulted valsartan from ethyl acetate. The said patents also disclose the preparation of different salts of Valsartan, composition and the method of treatment using them.
WO 02/06253 disclosed the preparation, importance and pharmaceutical usages of various inorganic salts and their mixtures such as monopotassium salt, mono sodiumsalt, bis-diemethylammonium salt and like of Valsartan.
The above said patents did not disclose the polymorphic Forms of Valsartan. Our Laboratory experiments with the process disclosed in these patents have not resulted into crystalline forms of Valsartan, these samples are found to be amorphous form (Fig.l) by analysing their X-ray diffractograms.
The latest trend that has, of late, crept into the pharmaceutical industry is the studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. This has especially become very interesting after observing that many antibiotics, antibacterial, tranquillizers etc. exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bioavailability and consequently show much higher activity compared to other polymorphs.

Hence, the objective of the present invention is to prepare a novel polymorphic crystalline
form of (S)-N- (l-Carboxy-2-methyl-prop-l-yI) -N-pentanoyl-N- [2'-(IH-tetrazo!-5-yl)-
biphenyl-4-yl methyl] amine (Valsartan), which is for convenient herein after, referred as
Polymorph Form-I, since no polymorphs have been reported to our knowledge sofar.
Another objective of the present invention is to provide a process for preparation of novel
crystalline polymorph Form-I of Valsartan.
SUMMARY OF THE INVENTION
The present invention is directed to prepare a novel crystalline polymorph Form-I of
Valsartan and also embodies a process for the preparation of novel crystalline polymorph
Form-I of Valsartan, which comprises the dissolution of crude Valsartan in ketone solvents
such as ethyl methyl ketone, methyl isobutyl ketone, methyl isopropyl ketone or diethyl
ketone or mixture thereof and further isolation by adding an aliphatic hydrocarbon solvent
such as petroleum ether, n-hexane, hexane or cyclohexane or mixture thereof at a suitable
temperature to obtain the desired crystalline polymorph Form-I of Valsartan by conventional
methods.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig. 1 is a diagram showing the results of X-ray diffraction of the compound obtained as per
the procedure disclosed in USP '578.
Fig. 2 is a diagram showing the results of X-ray diffraction of the inventive substance.
Fig. 3 is a diagram showing the results of DSC of the inventive substance.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, the present invention provides novel crystalline polymorph Form-I
of Valsartan and a process for the preparation there of.
The Crystalline nature of polymorph Form-I of Valsartan can be characterized by its X-ray
diffractogram and Differential scanning calorimetry thermogram.

The X-ray powder diffraction pattern of crystalline polymorph Form-I of Valsartan was measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source. The Crystalline polymorph Form-I of Valsartan has X-ray powder diffraction pattern essentially as shown in the Table-1. The X-ray powder diffraction pattern is expressed in the terms of the 29 (in degrees), and percentage intensity (in %). Tsble-1:

The present invention of crystalline polymorph Form-I of Valsartan is characterized by its X-ray powder diffraction as depicted in Figure (2).
The present invention also provides Differential Scanning Calorimetry thermogram of crystalline polymorph Form-I of Valsartan. The Differential Scanning Calorimetry thermogram exhibits a significant endo peak at around 90.24 ° C and as depicted in

Another embodiment of the present invention is to provide the process for preparation of novel crystalline polymorph Form-I of Valsartan, which comprises;
a) dissolving Valsartan (obtained as per reference example) in ketone solvents such as ethyl methyl ketone, methyl isobutyl ketone, methyl isopropyl ketone or diethyl ketone or mixture thereof, preferably methyl isobutyl ketone at reflux temperature;
b) adding the aliphatic hydrocarbon solvent as an anti solvent such as petroleum ether, n-hexane, hexane or cyclohexane or mixture thereof, preferably hexane;
c) cooling the reaction mass of step (b) to a temperature of 25-35°C;
d) stirring the mass of step (c) till the solid mass crystallizes;
e) isolating the solid mass obtained in step (d) by conventional methods;
f) drying the compound of step (e) at a temperature of 40° - 90° C, preferably 60° - 70°C to afford the crystalline polymorph Form-I of Valsartan.
Thus, the present invention provides a novel crystalline polymorph Form-lof
Valsartan. In general crystalline solids are preferred over amorphous solids for
pharmaceutical applications.
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 construed
to limit the scope of the invention.
Reference example:
Preparation of (S)-N- (l-carboxy-2-methyl-prop-l-yl) -N-pentanoyl-N- [2'-(lH-
tetrazol-5-yl)- biphenyl-4-yl methyl] amine (Valsartan):
N-Valeryl-N- [(2'-cyanobiphenyl-4-yl) methyl ]-(L)-valine methyl ester (51.5 kg, 0.126
moles), tributyl tin chloride (61.9 kg, 0.190 moles), sodium azide (16.5 kg, 0.253
moles) were added to xylene (258 lit) and stirred for 1-2 hours at a temperature of

25-35 C then heated the mass to reflux and stirred till the reaction substantially completes. Cool the mass to 25-35°C and 10% sodium hydroxide solution (250 lit.) was added and further stirred for 24-30 hours. The aqueous layer was separated from the resulting biphasic solution and washed with toluene (52 X 2 lit.). The pH of the aqueous layer was adjusted towards neutral with acetic acid (115 lit.) and washed with chloroform (52 X 2 lit.). The pH of the aqueous layer was further lowered with acetic acid (20 lit.) and extracted the compound into dichloromethane (220 x 1 + 110 x 1). The combined organic layer was successively washed with water, 5% sodium chloride solution and dried over anhydrous sodium sulphate. The solvent from the reaction solution was completely distilled off and triturated the resulting oily mass with hexane to yield the crude Valsartan, which was recrystallised in dichloromethane followed by ethyl acetate to afford sufficient pure Valsartan, which is having an amorphous pattern by its X-ray diffractogram (Yield: 8.8 kgs). Preparation of Crystalline Polymorph Form-I of Valsartan: Valsartan (25.0 grams, 0.0578 moles, prepared as per reference example) was dissolved in Methyl isobutyl Ketone (50.0ml) at a temperature of 60-65°C and the mixture was further heated to a temperature of 80-85°C. Hexane (60.0 ml) was slowly added at a temperature of 80-85 °C followed by Methyl isobutyl Ketone (10.0 ml) and cooled the mass to a temperature of 25-35°C and left overnight to crystallize the solid mass. The isolated crystalline solid mass was filtered, washed with hexane (10.0ml) and dried at 50-70°C to a constant weight to obtain 23.0 g of the desired crystalline polymorph Form-I of Valsartan.

DETAILED DESCRIPTION OF THE ACCOMPAINYING DRAWINGS:
Fig: I is characteristic X-ray powder diffraction pattern of the compound obtained as
per the procedure mentioned in USP '578.
Vertical axis: Intensity (CPS); Horizontal axis; 20 (degrees).
It shows a plain halo with no peaks, which is a characteristic nature of the amorphous
form.
Fig: 2 is characteristic X-ray powder diffraction pattern of the novel crystalline
polymorph Form-1 of Valsartan.
Vertical axis: Intensity (CPS); Horizontal axis: 29 (degrees).
The significant 26 values (in degrees) obtained are 5.415, 9.891, 10.726, 13.145,
14.213,14.894,17.52, 21.09 and 22.1.
Fig: 3 is characteristic Differential Scanning Calorimetric Thermogram of novel
crystalline polymorph of Form-1 of Valsartan.
Vertical axis: Temperature (in ° C); Horizontal axis: Signal (in mV).
The Differential Scanning Calorimetric Thermogram exhibits a significant endo peak at
about 90.24 ° C.
We Claim:
1. A Novel crystalline polymorph Form-1 of (S)-N- (l-carboxy-2-methyl-prop-l-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)- biphenyl-4-yl methyl] amine (Valsartan).
2. The crystalline polymorph Form-1 of Valsartan of claim 1 having X-ray powder diffraction pattern with peaks at 26 values of 5.415, 9.891, 10.726, 13.145, 14.213,14.894,17.52,21.09 and 22.1 degrees.

3. The crystalline polymorph Form-1 of Valsartan of claim 2 having an X-ray powder diffraction pattern as depicted in Figure (2).
4. The crystalline polymorph Form-1 of Valsartan of claim 1 having differential scanning calorimetry thermogram which exhibits a characteristic endo peak at about 90.24 ° C.
5. The crystalline polymorph Form-1 of Valsartan of claim 4 having a differential scanning calorimetry thermogram substantially as depicted in Figure (3).
6. A process for preparation of crystalline polymorph Form-1 of (S)-N- (1-Carboxy-2-methyl-prop-l-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)- biphenyl-4-yl methyl] amine (Valsartan), which comprises;
a. dissolving crude Valsartan in ketone solvents such as ethyl methyl
ketone, methyl isobutyl ketone, methyl isopropyl ketone or diethyl
ketone or mixture thereof, preferably methyl isobutyl ketone at reflux
temperature;
b. adding the aliphatic hydrocarbon solvent as an anti solvent such as
petroleum ether, n-hexane, hexane or cyclohexane or mixture thereof,
preferably hexane;
c. cooling the reaction mass of step (b) to a temperature of 25-35 C;
d. stirring the mass of step (c) till the solid mass crystallizes;
e. isolation of solid mass obtained in step (d) by conventional methods;
f. drying the compound of step (e) at a temperature of 40° - 90 C,
preferably 60° - 70°C to afford the crystalline polymorph Form-I of
Valsartan.
7. A process according to claim 6 of step (a) where in the ketone solvent is methyl
isobutyl ketone.

8. A process according to claim 6 of step (b) where in the aliphatic hydrocarbon
solvent is hexane.
9. The process for the preparation of novel crystalline polymorph Form-I of
Valsartan as exemplified herein.