Field of the Invention:
The present invention relates to solid state forms of Trisodium (4-{[(lS,3R) biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-P(
yl-N-fPHlH-tetrazol-l-id-S-yDtM'-biphenyn^-y^methylJ-L-valinate) representee following structural formula-1 and process for the preparation thereof.
CH3 0
HT flsC^hfy 9 (I JH
O H T I L. N
.3Na+0 (|7 N'
Formula-1
Background of the Invention:
Trisodium (4-{KlS,3R)-l.([l,l'-biphenyl]^-ylmethyl)-4-ethoxy-3.n«
oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N- {[2'-( 1 H-tetrazol-1 -id-5-yl)[ 1,1 '-bi yl]-4-yl]methyl}-L-valinate) is approved in USA as octadecasodium hexakis-(4-{[(lS ([ljr-biphenyl]-4-ylmethyl>4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)h
(N-pentanoyl-N-f^'-ClH-tetrazol-l-id-S-yDtM'.biphenyn^-yllmethyD-L-valinate^ decahydrate under the brand name of "Entresto" which is represented as below:
CH3 0
fS H3C^Y^O-
^V^l H3C^^YN-,
HC o"kskl O ' ° ITSH
0 H T I L N
,3Na+ .21/2H20 \^
-"6

The above said compound can also be represented as 'Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-yImethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetra2ol-l-id-5-yl)[l,l'-biphenylJ-4-yl]methyl}-L-valinate) hemipenta hydrate", commonly known as "Trisodium Sacubitril Valsartan hemipentahydrate.". 5
Valsartan/sacubitril (brand name Entresto, previously known as (LCZ696) is a
combination drug for use in heart failure developed by Novartis. It consists of the angiotensin
receptor blocker valsartan and the neprilysin inhibitor sacubitril, in a 1:1 mixture by molecule
count. The combination is sometimes described as an "angiotensin receptor-neprilysin
10 inhibitor" (ARNi). It was approved under the FDA's priority review process on July 7, 2015.
Valsartan/sacubitril is used to treat heart failure in people with reduced left
ventricular ejection fraction (LVEF).[3] It is not known whether valsartan/sacubitril is useful
for the treatment of heart failure people with normal LVEF. 15
US8877938B2 disclosed the process for the preparation of Trisodium (4-{[(lS,3R)-l-
([l,l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-
pentanoyl-N^PHlH-tetrazol-l-id-S-yOCl.l'-biphenylJ^-ylJmethyll-L-valinateJheinipenta hydrate and its crystalline form.
20
There is a significant need in the art to develop novel polymorphic forms of the said compound of formula-1 which are stable and having advantageous physical properties such as free flowability, greater stability and greater bioavailability.
25 Brief description of the invention:
The first aspect of the present invention is to provide amorphous form of Trisodium (4-{ [(1 S,3R)-1 -([ 1,1 '-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2'-( 1 H-tetrazol-1 -id-5-yl)[ 1,1 '-biphenyl]-4-yI]methyl} -L-30 valinate) compound of formula-1.
The second aspect of the present invention is to provide a process for the preparation of amorphous form of Trisodium (4-{[(lS,3R)-l-([i,l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-

methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-1-id-5-yl)[l,r-biphenyl]-4-yl]methy]}-L-valinate) compound of formula-1.
The third aspect of the present invention is to provide amorphous solid dispersion 5 comprising Trisodium (4-{[(lS,3R)-l-([l,r-bipheny]]-4-yimethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2'-( 1 H-tetrazol-1 -id-5-y l)[ 1,1 '-biphen yl]-4-yl]methyl}-L-valinate) compound of formula-1 and at least one pharmaceutical Iy acceptable excipient.
10 The fourth aspect of the present invention is to provide process for the preparation of
amorphous solid dispersion comprising Trisodium (4-{[(lS,3R)-l-([l,l,-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 and at least one pharmaceutical^ acceptable excipient.
15
Brief description of the Drawings:
Figure-1: Illustrates the PXRD pattern of amorphous Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentano . yl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate) compound of 20 formula-1 obtained according to example-1.
Figure-2: Illustrates the PXRD pattern of amorphous Trisodium (4-{[(lS,3R)-l-([l,l'-
biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentano
yl-N- {[2'-(l H-tetrazol-1 -id-5-yl)[ 1,1 '-biphenyl]-4-yl]methy 1 }-L-valinate) compound of
formula-1 obtained according to example-2. 25 Figure-3: Illustrates the PXRD pattern of amorphous Trisodium (4-{[(lS,3R)-l-([lJ'-
biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-
pentanoyl-N-{[2'-( 1 H-tetrazol-1 -id-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl}-L-valinate) compound
of formula-1 obtained according to example-3.
Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising Trisodium 30 (4-{[(lS,3R)-l-([l)r-biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-

oxobutanoate)-(N-pentanoyl-N-{[2-(lH-tetrazol-l-id-5-yl)[l3r-bipheny]]-4-yl]methyl}-L-valinate) compound of formula-1 and PVP-K-30.
Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising Trisodium
(4-{[(lS,3R)-l-([l,l'-biphenyi]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-
5 oxobutanoate^-pentanoyl-N-I^HlH-tetrazol-l-id-S-yOtlJ'-biphenylJ^-yOmethylJ-L-valinate) compound of formula-1 and HPMC.
FJgHI^niustrates.^^
(^{[(lS^RJ-l-aM'-biphenylJ^-ylmethylH-ethoxy^-methyl-^oxobutylJamino}^-
oxobutanoate)-CN-pentanoyl-N-{[2HlH-tetrazol-l-id-5-yt)[l,r-biphenylj-4-yI]methyl}-L-10 valinate) compound of formula-] and HPMCAS.
Figure-7: Illustrates the PXRD pattern of amorphous solid dispersion comprising Trisodium
(4-{[(lS]3R)-l-C[l,l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-
oxobutanoateJ-CN-pentanoyl-N-iPHlH-tetrazol-l-id-S-yOtU'-biphenylJ^-y^methylJ-L-valinate) compound of formula-1 and HPC.
15
Detailed description of the Invention:
The "suitable solvent" used in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl
20 ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro
15 solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanoi, ethane-l,2-diol, propane-1,2-diol, alkyl ethers of ethylene
10 glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl

ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopiopyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether. ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether and the like; "polar solvents" such as 5 water; formic acid, acetic acid or mixtures thereof.
The first aspect of the present invention is to provide amorphous form of Trisodmrn (4-{[(lS,3R)-l^[lJ^biphenyl]-4-ylrnethyl)-4-ethoxy-3-methyl-4-oxobutyl]arnino}-4-
oxobutanoat^-CN-pentanoyl-N-tPHlH-tetrazol-l-id-S-yOtU-.biphenyO^-ylJrnethylJ-L-0 valinate) compound of formula-1.
The second aspect of the present invention is to provide a process for the preparation of amorphous form of Trisodmrn (4-{[(lS,3R)-l.([l5r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetra2ol-l-id-5-5 yl)[l,l'-biphenyl]^.yl]methyl}.L-valinate) compound of formula-1, comprising of:
a) Dissolving the Trisodium (4-{[(lS,3R)-l.ai,r-biphcnyl]-4.ylmethyl)^ethoxy-3. methyl-4-oxobutyI]amino}-4-oxobutanoate)-(N-pentanoyI-N-{[2'-(lH-tetra2ol-l-id-5-yl)[l5l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 in a suitable solvent or mixture of solvents,
b) optionally filtering the reaction mixture,
c) removing the solvent from the reaction mixture to provide amorphous form of compound of formula-1.
Wherein, in step-a) the suitable solvent can be selected from but not limited to chloro solvents, ketone solvents, C2-C6 alcohol solvents, ester solvents, nitrile solvents, ether solvents or their mixtures; and the dissolution of compound of formula-1 in a suitable solvent or mixture of solvents can be carried out at 25-30X or by heating the reaction mixture to a temperature ranging from 30°C to reflux temperature of the solvents employed;
In step-c) suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a

Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any 5 other suitable techniques.
The solvent may be removed at temperatures ranging from 25°C to !00°C optionally
under reduced pressures.
The preferred embodiment of the present invention provides a process for the 10 preparation of amorphous form of Trisodium (4-{[(lS33R)-l-([l,l'-biphenyl]-4-yImethyl)-4-ethoxy-3 -methyl-4-oxobutyl]amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2'-(l H-tetrazol-1 -id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1, comprising of:
a) Dissolving the Trisodium (4-{[(lS,3R)-l-([l,l'-biphehyl]-4-ylmethyl)-4-ethoxy-3-
methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N- {[2'-( 1 H-tetrazol-1 -id-5-
15 yl)[U'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 in methanol,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to provide amorphous form of compound of formula-1.
20 The preferred embodiment of the present invention provides a process for the
preparation of amorphous form of Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N- {[2'-(l H-tetrazol-1 -id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-I, comprising of:
a) Dissolving the Trisodium (4-{[(lS)3R)-l-([ljr-biphenyl]-4-ylmethyl)-4-ethoxy-3-
25 methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(l H-tetrazol- l-id-5-
ylXU'-biphenylH-ylJmethylJ-L-valinate) compound of formula-1 in a mixture of dichloromethane and methanol,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to provide amorphous form of compound of 30 formula-1.

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of Imodium (^{[(lS^^-l-^lJ'-biphenyO^-ylmethylH-
ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-CN-pentanoyl-N-{[2'-(lH-tetra2ol-1-id-S-yOtU'-biphenylJ^-ylJmethylJ-L-valinate) compound of formula-1, comprising of: 5 a) Dissolving the Trisodium (^{[(lS^^-l-ftlJ'-biphenylJ-^ylmethyO^-ethoxy-S-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-
yl)[lJ'-biphenyll-4-yl]rnethyl}-L-valinate) compound of fnrmu!a-Uin methanol,
b) filtering the reaction mixture,
c) spray drying the filtrate obtained in step-b) to provide amorphous form of compound of 10 formula-1.
The third aspect of the present invention is to provide amorphous solid dispersion comprising Trisodium (4-{ [(1 S,3R)-1 -([ 1,1 '-biphenyl]-4-ylmethyl)-4-ethoxy-3 -methyl-4-
oxobutyl]amino}-4-oxobutanoate>(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,r-biphen 15 yl]-4-yl]methyl}-L-valinate) compound of formula-1 and at least one pharmaceutical^ acceptable excipient.
Wherein, the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol,
20 polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose
25 (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate,
30 magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xvlitol, lactitol. sorbitol. mannitol maltitnl mnltnco TcPTmnca

fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, p., y-cyclodextrins, sulfobutylether 5 beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate 'sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
0 The fourth aspect of the present invention is to provide process for the preparation of
amorphous solid dispersion comprising Trisodium (4-{[(lS,3R)-!-([l,l'-biphenyl]-4-
ylmethyl)-4-ethoxy-3-methyI-4-oxobutyl]amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2'-( 1H-
tetra20l-l-id-5-yl)[l,l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 and at
least one pharmaceutical^ acceptable excipient. The said process comprising of:
5 a) Dissolving the Trisodium (4-{[(lS53R)-l-([l,l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-
methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-
yl)[l3l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 and at least one
excipient in a suitable solvent or mixture of solvents at a suitable temperature,
b) removing the solvent from the reaction mixture to provide amorphous solid dispersion
) comprising Trisodium (4-{[(lS)3R)-l-([l,l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-
oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 and an excipient. . Wherein, in step-a) the suitable excipient is same as defined in the third aspect of the present invention;
> the suitable solvent is same as defined in step-a) of the second aspect of the present
invention; the suitable temperature ranges from 0°C to reflux temperature of the solvent used;
After dissolving the compound of formula-1 and excipient in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove
1 color and/or to clarify the solution;

In step-b) the suitable techniques which may be used for the removal of solvent from the reaction mixture are same as defined in step-c) of the second aspect of the present invention;
The solvent may be removed at temperatures ranging from 25°C to I00°C optionally 5 under reduced pressures.
In the present invention, the ratio of the amount of weight of Trisodium (4-{[(lS,3R)-l-ftU'-biphenylJ^-ylmethylJ^-ethoxy-S-methyl^-oxobutylJaminol^-oxobutanoateJ-CN-pentanoyl-N-IPHlH-tetrazol-l-id-S-yDfU'-biphenylJ^-yllmethylJ-L-valinate) compound 10 of formula-1 within the solid dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1:0.05 to about 1:5.
The preferred embodiment of the present invention provides a process for the
preparation of amorphous solid dispersion of Trisodium (4-{[(lS,3R)-l-([l,l'-biphenyrj-4-
15 ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-
tetrazol-l-id-S-ylJtlJ'-biphenylJ^-ylJmethylJ-L-valinate) compound of formula-1 in
combination with polyvinyl pyrrolidine (PVP K-30), comprising of:
a) Dissolving the compound of formula-1 and PVP K-30 in a mixture of
dichloromethane and methanol at 25-30°C,
20 b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) distilling off the solvent from the filtrate to provide amorphous solid dispersion of compound of formula-1 in combination with polyvinyl pyrrolidine (PVP K-30).
25 The another preferred embodiment of the present invention provides a process for the
preparation of amorphous solid dispersion of Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-
ylmethyO^-ethoxy-S-methyl^-oxobutylJaminoJ^-oxobutanoateJ-CN-pentanoyl-N-ip'-flH-tetrazoI-l-id-5-yl)[l,l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 in combination with HPMC, comprising of:
30 a) Dissolving the compound of formula-1 and HPMC in a mixture of dichloromethane
and methanol at 25-3 0°C,

b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) distilling off the solvent from the filtrate to provide amorphous solid dispersion of compound of formula-1 in combination with HPMC.
5
The another preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl)-4-
ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetra2ol-l-id-5-yl)[l,I'.biphenyl]-4-yl]methyl}-L-vaIinate) compound of formula-1 in 0 combination with HPMC-AS, comprising of:
a) Dissolving the compound of formula-1 and HPMC-AS in a mixture of dichloromethane and methanol at 25-30°C,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
5 d) distilling off the solvent from the filtrate to provide amorphous solid dispersion of
compound of formula-1 in combination with HPMC-AS.
The another preferred embodiment of the present invention provides a process for the
preparation of amorphous solid dispersion of Trisodium (4-{[(IS,3R)-l-(p,l'-biphenyl]-4-
) ylmethyI)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-
tetrazol-l-id-5-yl)[l,l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 in
combination with HPC, comprising of:
a) Dissolving the compound of formula-1 and HPC in a mixture of dichloromethane and methanol at 25-30°C,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) distilling off the solvent from the filtrate to provide amorphous solid dispersion of compound of formula-1 in combination with HPC.
The Trisodium (4-{[(lS,3R)-l-([l,l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-inethyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(] H-tetrazoM -id-5-yl)[l, 1'-

biphenyl]-4-yljmethyl}-L-valmate) compound of formula-1 utilized as starting material in the present invention can be prepared by any of the known processes.
The solid state forms of compound of formula-1 of the present invention are useful 5 for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-1 is present in the composition in particular polymorphic form mentioned.
In a further aspect, the solid state forms of compound of formula-1 of the present ) invention can be micronized to achieve the desired better particle size distribution in order to make suitable formulation.
P-XRD Method of Analysis:
PXRD analysis of compound of formula-1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of amorphous form of Trisodium (4-{[(lS,3R)-l-([l,r-
biphenyI]-4-y]methyl)-4-ethoxy-3-methyI-4-oxobutyl]amino}-4-oxobutanoate)-(N-
pentanoyI-N-{[2'-(lH-tetrazol-l-id-5-yI)Il,r-biPhenyl]-4-ylImethyI}-L-valinate) compound of formula-1:
A mixture of Trisodium (4-{[(IS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1 (10 gms) and methanol (300 ml) were stirred for 10 minutes at 25-30°C to get a clear solution. Filtered the resulting

solution and distilled off the solvent completely from the filtrate under reduced pressure and dried to get the title compound. Yield: 7.6 gms.
The PXRD pattern of the obtained compound is shown in figure-1. 5
ExampIe-2: Preparation of amorphous form of Imodium (4-{|(lS,3R)-l-([l,l'.
biphenyl]-4-ylmethyI)-4-ethoxy-3-methyl.4-oxobutyl]amino}-4-oxobutanoate)-(N-
pentanoyl-N-{[2'-(lH-tetra2ol-l-id-5-y!)[l,r-biphenyl|-4-yl|methyl}-L-valinate) compound of formula-1:
10 . A mixture of Trisodium (4-{[(lS,3R>l-([l,l'-biphenyl]^-ylmeihyl)-4-ethoxy-3-
methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetra2ol-l-id-5-yl)[l,l'-biphenyI]-4-yI]methyl}-L-valinate) compound of formula-1 (0.5 gms), methanol (10 ml) and dichloromethane (10 ml) were stirred for 10 minutes at 25-30°C to get a clear solution. Filtered the resulting solution and distilled off the solvent completely from the
15 filtrate under reduced pressure and then dried the material to get the title compound. Yield: 0.4 gms.
The PXRD pattern of the obtained compound is shown in figure-2.
ExampIe-3: Preparation of amorphous form of Trisodium (4-{[(iS,3R)-l-([l,1'->0 biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-rN-
pentanoyI-N-{[2'-(lH-tetrazoI-l-id-5-yl)[l,l'-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1:
A mixture of Trisodium (4-{[(lS,3R)-l-([l1l'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-'■5 yl)[l,l'-biphenyl]-4-yl]methyI}-L-vaIinate) compound of formula-1 (5 gms) and methanol (100 ml) were stirred for 15 min at 25-30°C to get a clear solution. Filtered the resulting solution at 25-30°C and the obtained clear solution was spray dried under following conditions.
Inlet temperature: 60°C
0 Feed rate: 10 ml/min

Nitrogen pressure: 2.0 kg
The obtained solid was collected from the spray dryer and dried at 40-45°C under vacuum to get the title compound. Yield: 3.2 gms 5 The PXRD pattern of the obtained compound is shown in figure-3.
Example-4: Preparation of amorphous solid dispersion comprising Trisodium (4-{[(lS,3R)-l-([l,r-biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyI]amino}-4-
oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,r-biphenyl]-4-yl]methyl}-10 L-valinate) and polyvinyl pyrroIidine-K-30: (1:1)
A mixture of Trisodium (^{[(lS^^-l-a^'-biphenylJ-^ylmethyO^-ethoxy^-methyl^-oxobutylJaminoJ^-oxobutanoateXN-pentanoyl-N-l^'-fl H-tetrazol-1 -id-5-yl)[UM>iphenyl]-4-yl]memyl}-L-valinate) compound of formula-1 (0.5 gms), polyvinyl pyrrolidine-K-30 (0.5 gms), methanol (20 ml) and dichloromethane (20 ml) were stirred for 15 10 minutes at 25-30°C to get a clear solution. Filtered the resulting solution and distilled off the solvent completely from the filtrate under reduced pressure and then dried the material to get the title compound. Yield: 0.8 gms.
The PXRD pattern of the obtained compound is shown in figure-4. 20
Example-5: Preparation of amorphous solid dispersion comprising Trisodium (4-
{[(lS,3R)-l-([l,r-biphenyI]-4-ylmethyI)-4-ethoxy-3-methyl-4-oxoburyl]amino}-4-
oxobutanoate)-(N.pentanoyl-N-{[2'.(lH-tetraZol-l.id-5-yl)[l,r-biphenyl]-4-yl]niethyl}. L-valinate) and hydroxypropyl methylcellulose (HPMC): (1:1)
25 A mixture of Trisodium (4-{KlS)3R)-l-([l>r-biphenyi].4.ylrnethylH.ethoxy.3.
methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl) [U'-bipheny^-ylJmethylJ^-valinate) compound of formula-1 (0.5 gms), hydroxypropyl methylcellulose (0.5 gms), methanol (20 ml) and dichloromethane (20 ml) were stirred for 10 minutes at 25-30°C to get a clear solution. Filtered the resulting solution and distilled off the JO solvent completely from the filtrate under reduced pressure and then dried the material to get the title compound.

Yield: 0.6 gms.
The PXRD pattern of the obtained compound is shown in figure-5.
Example-6: Preparation of amorphous solid dispersion comprising Trisodium (4-{[(lS,3R)-l-([l,r.biphenyl]-4-ylmethyl)-4-ethoxy-3-methy!-4-oxobutyl]amino}-4-.
oxobutanoate)-(N-Pentanoyl-N-{[2'-(lH-tetrazoM-id-5-y.)[l,r-biPhenyl].4-yl]methyl}-L-valinate) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS): (1:1)
A mixture of Trisodium (^{[(lS^RM-CtlJLbiphenyll^-ylmethylH-ethoxy-S-methyl-4-oxobutyI]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2'-(lH-tetra2ol-l-id-5-yl) [l,l'-biPhenyl]-4-yl]methyl}-L-valinate) compound of formula-1 (0.5 gms), hydroxypropyl methylcellulose acetate succinate (0.5 gms), methanol (20 ml) and dichloromethane (20 ml) were stirred for 10 minutes at 25-30°C to get a clear solution. Filtered the resulting solution and distilled off the solvent completely from the filtrate under reduced pressure and then dried the material to get the title compound. Yield: 0.8 gms.
The PXRD pattern of the obtained compound is shown in figure-6.
Example-7: Preparation of amorphous solid dispersion comprising Trisodium (4-{[(lS,3R)-l.([l,l'-biPhenyl]-4-yImethyIH-ethoxy-3-methyl-4-oxobutyl]amino}-4-
oxobutanoateJ-fN-pentanoyl-N-l^'-dH-tetrazol-l-id-S-yOH.l'-biphenylJ^yllmethyl}-L-valinate) and hydroxypropyl cellulose (HPC); (1:1)
A mixture of Trisodium (4-{[(lS)3R)-l-([l)r-biPhenyl]-4-ylmethyl)-4-ethoxy-3- . methyl-4-oxobutyl]amino}-4-oxobutanoate).(N-pentanoyl-N-{[2HlH-tetrazol-l-id-5-yl) [lsr-biPhenyl]-4-yl]methyl}-L-valinate) compound of formula-1 (0.5 gms), hydroxyl propylcellulose (0.5 gms), methanol (20 ml) and dichloromethane (20 ml) were stirred for 10 minutes at 25-30°C to get a clear solution. Filtered the resulting solution and distilled off the solvent completely from the filtrate under reduced pressure and then dried the material to get the title comPound. Yield; 0.6 gms. The PXRD pattern of the obtained compound is shown in figure-7