This application claims the benefit under Indian Provisional Application No. 201641034689 filed on 10th October 2016 entitled "Process for preparation of amorphous form of sacubitril valsartan tri sodium complex", the content of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention generally relates to stable amorphous form of sacubitril valsartan trisodium complex, processes for their preparation and pharmaceutical composition comprising the same.
The present invention further provides amorphous solid dispersion of sacubitril valsartan trisodium complex, processes for their preparation and pharmaceutical composition comprising the same.
The present invention also provides an improved process for the preparation of sacubitril sodium salt and its use in the preparation of sacubitril valsartan trisodium complex.
BACKGROUND OF THE INVENTION
Sacubitril together with valsartan, known as LCZ696, is a complex comprised of anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1: 1:3:2.5, respectively, and which is represented by a compound of Formula I:
Formula I
Chemically, valsartan is known as (S)-3-methyl-2-(N-{ [2'-(2H-l,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid and sacubitril is known as 4-{ [(2S,4R)-1- (4-biphenylyl) - 5-ethoxy- 4-methyl-5- oxo-2- pentanyl] amino}- 4-oxo-butanoic acid.
A complex comprising valsartan, which is an angiotensin receptor antagonist, and Sacubitril, which is a neprilysin inhibitor, has been approved by US Food and Drug Administration (FDA) under the trade name ENTRESTO® by Novartis for the treatment of heart failure with reduced ejection fraction.
Entresto is a first-in-class medicine (an Angiotensin Receptor Neprilysin Inhibitor, or ARNI) and has a unique mode of action which is thought to reduce the strain on the failing heart. It harnesses the body's natural defenses against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides, while also inhibiting the renin- angiotensin- aldosterone system (RAAS).
U.S. Patent No. 8,877,938 ("the '938 patent") disclosed a complex of trisodium sacubitril valsartan hemipentahydrate in crystalline form and process for preparation thereof. The '938 patent process involves preparation of complex of trisodium sacubitril valsartan hemipentahydrate by dissolving sacubitril free acid and valsartan free acid in acetone, combined the resulting solution with aqueous sodium hydroxide and the obtained solution was evaporated to yield trisodium sacubitril valsartan as a glassy solid. The glassy solid residue is then treated with acetone and sonicated to obtain crystalline trisodium sacubitril valsartan hemipentahydrate. The glassy solid resulted in the '938 patent is not well characterized and does not disclose any polymorphic information. On repetition of the '938 patent process, the present inventors have found that glassy solid of trisodium sacubitril valsartan was obtained as an amorphous form and the same was characterized by XRD pattern.
Chinese patent publication No. 105461647 ("the '647 publication") disclosed crystalline Form A of Sacubitril valsartan trisodium. The '647 publication further disclosed an amorphous Form a, Form β and Form γ of Sacubitril valsartan trisodium and their preparation by dissolving sacubitril and valsartan in a solvent such as ethanol, treating with aqueous sodium base followed by addition of resulting reaction mixture to an anti -solvent to obtain amorphous Form a, Form β and Form γ of sacubitril valsartan trisodium complex. The '647 publication also disclosed another preparation method for preparation of amorphous Form γ of sacubitril valsartan trisodium by dissolving sacubitril, valsartan and aqueous sodium base in ethanol and concentrating the reaction mixture to obtain amorphous Form γ.
PCT Publication No. 2016/125123 ("the Ί23 publication") disclosed amorphous trisodium sacubitril valsartan. The amorphous form has been prepared by different processes by either dissolving trisodium sacubitril valsartan hemipentahydrate in a solvent or in a mixture of solvents followed by isolation or by dissolving sacubitril and valsartan in a solvent followed addition of sodium source, removal of the solvent, optionally treating the resulting reaction mass with mixture of solvents and isolating of amorphous trisodium sacubitril valsartan. The '123 publication also disclosed another preparation method for preparation of amorphous trisodium sacubitril valsartan by dissolving trisodium sacubitril valsartan in a polar solvent, adding the resulting solution to a non-polar solvent and finally isolating amorphous form.
Chinese patent publication Nos. 104860894 ("the '894 publication"), 105348209 (the '209 publication") and 105622535 ("the 535 publication") disclosed a method for the preparation of complex of trisodium sacubitril valsartan by addition of aqueous sodium hydroxide to the reaction mixture containing sacubitril and valsartan.

PCT Publication No. 2017/009784 ("the 784 publication") disclosed an amorphous form of trisodium salt of valsartan sacubitril complex and its preparation method by treating sacubitril sodium salt and valsartan disodium or sacubitril and valsartan in the presence of a sodium ion source in one or more solvents followed by removal of solvent. However, this patent publication neither disclosed the impurities formed nor disclosed the control of impurities.

PCT Publication No. 2017/012917 ("the 917 publication") disclosed an amorphous powder comprising a 1: 1 stoichiometric mixture of the trisodium salts of Valsartan and Sacubitril and having a water content of at maximum 4% by weight and its preparation method by dissolving crystalline trisodium sacubitril valsartan hemipentahydrate in water or in a mixture of water and a water miscible solvent followed by freeze drying or spray drying the resulting solution to obtain amorphous form The '917 publication also disclosed another preparation method for preparation of amorphous trisodium sacubitril valsartan by addition of sodium hydroxide to the reaction mixture containing sacubitril and valsartan followed by freeze drying or spray drying the resulting solution to obtain amorphous compound.

PCT Publication No. 2017/037596 ("the 596 publication") disclosed an amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier and further disclosed a preparation method of amorphous form of trisodium sacubitril valsartan by dissolving trisodium sacubitril valsartan complex in methanol or in a mixture of methanol and acetone followed by evaporation of the solvent by rotavapor.

PCT Publication No. 2017/037591 ("the '591 publication") disclosed a process for the preparation of amorphous form of sacubitril valsartan sodium complex by reacting sacubitril with valsartan in a solvent followed addition of sodium source, removal of the solvent, treating with an organic solvent and removing the solvent and then finally isolating the amorphous form of sacubitril valsartan sodium complex. The '591 publication further disclosed that the amorphous form of Sacubitril Valsartan sodium salt obtained from this process is stable at 25 + 2°C/30 + 5% RH.

Chinese patent publication No. 106316973 ("the '973 publication") disclosed amorphous trisodium sacubitril valsartan and its process.

PCT Publication No. 2017/042700 ("the '700 publication") disclosed an amorphous solid salt form comprising valsartan and sacubitril and its preparation method by treating valsartan and sacubitril with a source of cation in a solvent.

Chinese patent publication No. 106518709 ("the '709 publication") disclosed a process for the preparation of amorphous Sacubitril/Valsartan sodium by addition of sodium source to the reaction mixture containing sacubitril and valsartan followed by freeze drying or spray drying the resulting solution to obtain amorphous compound.

PCT Publication No. 2017036420 ("the '420 publication") disclosed an amorphous solid dispersion of sacubitril valsartan complex with one or more pharmaceutically acceptable carrier.

PCT Publication No. 2017/085573 ("the 573 publication") disclosed an amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier and further disclosed amorphous sacubitril-valsartan complex and its preparation method by addition of sodium hydroxide to the reaction mixture containing sacubitril and valsartan followed by removal of solvent.

PCT Publication No. 2017/154017 ("the '017 publication") disclosed various methods for the preparation of amorphous form of trisodium salt of valsartan sacubitril by dissolving sacubitril sodium salt and valsartan disodium salts in aq methanol followed by removal of solvent or by addition of sodium hydroxide to the reaction mixture containing sacubitril and valsartan. The '017 publication also disclosed another preparation method for the preparation of amorphous form of trisodium salt of valsartan sacubitril by dissolving trisodium sacubitril valsartan complex in a solvent or in a mixture of solvents followed by removal of the solvent to obtain amorphous compound. However, this patent publication neither disclosed the impurities formed nor disclosed the control of impurities. The '017 publication disclosed amorphous solid dispersion of sacubitril valsartan complex with one or more pharmaceutically acceptable carrier.

PCT Publication No. 2017/097275 ("the '275 publication") disclosed the preparation of sacubitril sodium salt by conversion of crude sacubitril free acid to the crystalline amines salts, neutralizing the sacubitril amine salts with acid and isolating crystalline sacubitril free acid from an organic solvent. Finally, the crystalline sacubitril free acid thus formed is further converted to its sacubitril sodium salt. According to this publication, the conversion of crude sacubitril free acid to the crystalline amine salts leads to removal of impurities which were formed during the synthesis of sacubitril free acid, especially the lactone impurity. This process requires additional steps such as formation of sacubitril amine salt, conversion of the sacubitril amine salt to pure crystalline sacubitril free acid, isolation of the crystalline sacubitril free acid and its conversion to sacubitril sodium, which are tedious, labour intensive and time consuming thereby not viable for commercial scale operations.

Several other polymorphic forms of complex of sacubitril valsartan have been reported in the art such as:

Chinese patent publication No. 105037289 ("the '289 publication") disclosed crystalline Form Π of a complex of sacubitril valsartan.

PCT Publication No. 2016/037552 ("the '552 publication") disclosed crystalline sacubitril vaisartan sodium hydrate such as sacubitril valsartan 3Na-2.5H20, sacubitril valsartan 3Na-3.1H20, sacubitril valsartan 18Na- 18.5H20, sacubitril valsartan 3Na- 2.9H20 & sacubitril valsartan 18Na- 17.5H20, sacubitril valsartan 3Na- 6.5H20 & sacubitril valsartan 3Na- 3.0H2O.

PCT Publication No. 2016/049663 ("the '663 publication") disclosed crystalline trisodium sacubitril-valsartan hydrate Form I, Form Π & Form ΙΠ.

PCT Publication No. 2016/051393 ("the '393 publication") disclosed crystalline trisodium sacubitril valsartan hydrate Form Γ .

PCT Publication No. 2016/151525 ("the '525 publication") disclosed crystalline Form I of sacubitril valsartan 3Na- 3.5H20.

PCT Publication No. 2016/201238 ("the '238 publication") disclosed crystalline form Π of trisodium valsartan: sacubitril and amorphous trisodium valsartan : sacubitril.

PCT Publication No. 2017/009784 ("the 784 publication") disclosed crystalline Form-Π, Form ΙΠ and Form- IV of trisodium salt of valsartan sacubitril complex.

IN Application No. 3835/DEL/2015 ("the 3835" application) disclosed crystalline trisodium s acubitril - val s artan hemipentahydr ate .

IN Application No. 4304/DEL/2015 ("the 4304" application) disclosed crystalline trisodium s acubitril - val s artan hemipentahydr ate .

PCT Publication No. 2017/097085 ("the 085 publication") disclosed crystalline trisodium sacubitril-valsartan hydrate Form Π.

The amorphous form of sacubitril valsartan trisodium complex disclosed is highly unstable as it was indicated to store below at room temperature at about 25-35% RH. Storage of drug products at low temperatures and low RH atmosphere are always additional burden to the cost of the product. The amorphous form of sacubitril valsartan trisodium complex prepared by the present invention is stable even at accelerated conditions and is away from the difficulties associated with the prior art methods.

The present invention provides a stable amorphous form of sacubitril valsartan trisodium complex, wherein the stable amorphous sacubitril valsartan trisodium complex does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for up to about six months. The present invention further provides an amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier.

Further, the prior-art processes for the preparation of amorphous form of sacubitril valsartan trisodium complex involves reaction of sacubitril free acid, valsartan free acid and a suitable sodium source in a solvent. However, the sacubitril free acid obtained from the known chemical processes may contaminated with impurities, which are carry forward into sacubitril valsartan trisodium complex, if untreated at the free acid stage itself. These impurities once formed in the final sacubitril valsartan trisodium complex are difficult to remove as additional purifications at final stage may disturb the linkage between the sacubitril, valsartan and trisodium Therefore compromising the purity of the final sacubitril-valsartan complex; thus in order to improve the purity of the final sacubitril-valsartan complex it is necessary to remove these impurities from sacubitril free acid before forming the complex without compromising the yield.

In view of the drawbacks of the reported processes, the present inventors have developed improved processes for the preparation of sacubitril valsartan trisodium complex, particularly in an amorphous form which allows the final product to be produced in a higher yield and purity which is very practical for scale-up production, especially in terms of operating efficiency.

The present invention provides an improved processes for preparation of sacubitril valsartan trisodium complex by removing the impurities formed during the synthesis of sacubitril by formation of sacubitril as its sodium salt and subsequent purifications, if any, prior to use in the formation of sacubitril valsartan trisodium complex, which makes the process simple, environmental-friendly, economical, industrially feasible and scalable.

SUMMARY OF THE INVENTION

The present invention encompasses a stable amorphous form of sacubitril valsartan trisodium complex with high product yield and quality, processes for their preparation, a pharmaceutical composition comprising the same and amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier and its preparation method. The present invention further provides an improved process for the preparation of sacubitril sodium salt and its use in the preparation of sacubitril valsartan trisodium complex.

In accordance with one embodiment, the present invention provides a stable amorphous form of sacubitril valsartan trisodium complex.

In accordance with one embodiment, the present invention provides a stable amorphous form of sacubitril valsartan trisodium complex, wherein the amorphous sacubitril valsartan trisodium complex does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about three months or more.

In accordance with another embodiment, the present invention provides processes for the preparation of amorphous form of sacubitril valsartan trisodium complex.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of sacubitril valsartan trisodium complex, comprising:

a) providing a solution or suspension of valsartan sodium and sacubitril sodium salt in a suitable solvent (S I),
b) removing the solvent from the step a) reaction mass,
c) optionally adding a suitable solvent (S2) to the step b); and
d) isolating the amorphous form
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of sacubitril valsartan trisodium complex, comprising:
a) providing a solution or suspension of valsartan sodium and sacubitril sodium salt in a suitable solvent (S I),

b) removing the solvent from the step a) reaction mass,

c) optionally adding a suitable solvent (S2) to the step b); and

d) isolating the amorphous form; wherein the suitable solvent (SI) is selected from the group consisting of ketones, alcohols, amides, sulfoxides, ethers and mixtures thereof; and the suitable solvent (S2) is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of sacubitril valsartan trisodium complex, comprising:

a) providing a solution or suspension of trisodium sacubitril valsartan complex in a suitable solvent (S I),
b) removing the solvent from the step a) reaction mass,
c) optionally adding a suitable solvent (S2) to the step b); and
d) isolating the amorphous form
In accordance with another embodiment, the present invention provides amorphous solid dispersion of sacubitril valsartan trisodium complex.
In accordance with another embodiment, the present invention provides amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier comprises one or more of a povidone, copovidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids.
In accordance with another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier, which comprising:
a) providing a solution or suspension of valsartan sodium, sacubitril sodium salt and one or more pharmaceutically acceptable carrier in a suitable solvent (S3) or mixture of solvents; and
b) isolating the amorphous solid dispersion; wherein the pharmaceutically acceptable carrier comprises one or more of a povidone, copovidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids; and wherein the suitable solvent (S3) is selected from the group consisting of water, alcohols and ketones and the like and mixtures thereof.
In accordance with another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of sacubitril valsartan trisodium complex with one or more pharmaceutically acceptable carrier, which comprising:
a) providing a solution or suspension of sacubitril valsartan trisodium complex and one or more pharmaceutically acceptable carrier in a suitable solvent (S3) or mixture of solvents; and
b) isolating the amorphous solid dispersion; wherein the pharmaceutically acceptable carrier comprises one or more of a povidone, copovidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids .

WE CLAIM:

Claim 1: A stable amorphous form of sacubitril valsartan trisodium complex, wherein the amorphous sacubitril valsartan trisodium complex does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about three months or more.
Claim 2: A process for preparation of stable amorphous form of sacubitril valsartan trisodium complex, comprising:
a) providing a solution or suspension of valsartan sodium and sacubitril sodium salt in a suitable solvent (S I),
b) removing the solvent from the step a) reaction mass,
c) optionally adding a suitable solvent (S2) to the step b); and
d) isolating the amorphous form
Claim 3: The process of claim 2, wherein the suitable solvent (S I) is selected from ketones, alcohols, amides, sulfoxides, ethers and mixtures thereof.
Claim 4: The process of claim 3, wherein the suitable solvent is selected from the group consisting of acetone, methylisobutylketone, methylethylketone, methanol, ethanol, propanol, isopropanol, butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethyl sulfoxide, diethyl sulfoxide, trahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof.
Claim 5: The process of claim 2, wherein the removal of the solvent involves one or more of techniques selected from complete evaporation of the solvent by distillation, by rotational drying by a Buchi Rotavapor, spray drying, fluid bed drying or freeze-drying technique.
Claim 6: The process of claim 2, wherein the suitable solvent (S2) is selected from water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and mixtures thereof.
Claim 7: The process of claim 6, wherein the suitable solvent is selected from the group consisting of water, tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, hexane, heptane, propane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and mixtures thereof.
Claim 8: The process of claim 2, wherein the suitable solvent (SI) is acetone or ethanol and the suitable solvent (S2) is cyclohexane or heptane.
Claim 9: A process for the preparation of stable amorphous form of sacubitril valsartan trisodium complex, comprising:
a) providing a solution or suspension of trisodium sacubitril valsartan complex in a suitable solvent (S I),
b) removing the solvent from the step a) reaction mass,
c) optionally adding a suitable solvent (S2) to the step b); and
d) isolating the amorphous form
Claim 10: The process of claim 9, wherein the suitable solvent is selected from the group consisting of acetone, methylisobutylketone, methylethylketone, methanol, ethanol, propanol, isopropanol, butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethyl sulfoxide, diethyl sulfoxide, trahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof.
Claim 11: The process of claim 9, wherein the removal of the solvent involves one or more of techniques selected from complete evaporation of the solvent by distillation, by rotational drying by a Buchi Rotavapor, spray drying, fluid bed drying or freeze-drying technique.
Claim 12: The process of claim 9, wherein the suitable solvent is selected from the group consisting of water, tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, hexane, heptane, propane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and mixtures thereof.
Claim 13: An amorphous solid dispersion of sacubitril valsartan trisodium complex and a pharmaceutically acceptable carrier, wherein the carrier is selected from the group comprising: povidone, copovidone, (2-hydroxy propyl)-P-cyclodextrin, lactose, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

Claim 14: A process for the preparation of amorphous solid dispersion of sacubitril valsartan trisodium complex, comprising:
a) providing a solution or suspension of valsartan sodium, sacubitril sodium salt and one or more pharmaceutically acceptable carrier in a suitable solvent (S3) or mixture of solvents; or
b) providing a solution or suspension of sacubitril valsartan trisodium complex in one or more pharmaceutically acceptable carrier in a suitable solvent (S3) or mixture of solvents, and
c) isolating the amorphous solid dispersion from either step a) or step b); wherein the pharmaceutically acceptable carrier is selected from the group comprising: povidone, copovidone, (2-hydroxy propyl)-P-cyclodextrin, lactose, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.
Claim 15: The process of claim 14, wherein the suitable solvent (S3) is selected from the group consisting of water; alcohols selected from methanol, ethanol, isopropanol; ketones selected from acetone, methylisobutylketone, methylethylketone; and mixtures thereof.

Claim 16: The process of claim 14, wherein the isolation is carried out by complete evaporation of the solvent, concentrating the solution or cooling the solvent to precipitation.

Claim 17: The process of claim 16, wherein the isolation is carried out by complete evaporation of the solvent, which involves one or more of techniques selected from complete evaporation of the solvent by distillation, by rotational drying by a Buchi Rotavapor, spray drying, fluid bed drying or freeze-drying technique.

Claim 18: An amorphous solid dispersion of sacubitril valsartan trisodium complex with hydroxypropyl methylcellulose.

Claim 19: An amorphous solid dispersion of sacubitril valsartan trisodium complex with hydroxypropyl methylcellulose, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figures 6.

Claim 20: An amorphous solid dispersion of sacubitril valsartan trisodium complex with hydroxypropyl methylcellulose, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figures 7.

Claim 21: An amorphous solid dispersion of sacubitril valsartan trisodium complex with hydroxypropyl cellulose.

Claim 22: An amorphous solid dispersion of sacubitril valsartan trisodium complex with hydroxypropyl cellulose, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 8.

Claim 23: An amorphous solid dispersion of sacubitril valsartan trisodium complex with copovidone.

Claim 24: An amorphous solid dispersion of sacubitril valsartan trisodium complex with copovidone, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 10.

Claim 25: An amorphous solid dispersion of sacubitril valsartan trisodium complex with povidone.

Claim 26: An amorphous solid dispersion of sacubitril valsartan trisodium complex with povidone, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 11.

Claim 27: A process for preparation of sacubitril sodium salt of formula Π,

Formula II

comprising:

a) reacting a compound of formula ΙΠ with a suitable halogen source in presence of ethanol and a suitable non-polar solvent to obtain a compound of formula IV or its acid addition salt thereof;

Formula III Formula IV

b) treating the compound of formula IV or its acid addition salt with succinic anhydride in presence of a ba

Formula V

c) treating the sacubitril of formula V with a suitable sodium source to obtain sacubitril sodium of formula Π.

Claim 28: The process of claim 27, wherein the suitable halogen source is selected from the group consisting of thionyl chloride, oxalyl chloride, phosgene or acetyl chloride.

Claim 29: The process of claim 27, wherein the suitable non-polar solvent is selected from the group consisting of cyclohexane, heptane, hexane, dichloromethane, toluene; and mixtures thereof.

Claim 30: The process of claim 27, wherein the step a) reaction is carried out with thionyl chloride in presence of ethanol and cyclohexane.

Claim 31: The process of claim 27, wherein the step a) reaction is carried out at a temperature of about 35°C to about 55°C.

Claim 32: The process of claim 27, wherein base is selected from the group consisting of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, piperidine, morpholine or DBU.

Claim 33: The process of claim 27, wherein the base is added in a lot wise manner.

Claim 34: The process of claim 27, wherein the addition of base is carried out at a temperature of below 10°C.

Claim 35: The process of claim 27, wherein the step b) is carried out in a solvent selected from the group consisting of dichloromethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran.

Claim 36: The process of claim 27, wherein the sodium source is selected from the group consisting of sodium carbonate, sodium bicarbonate or sodium 2-ethyl hexanoate.

Claim 37: A process for the purification of sacubitril sodium of Formula Π, comprising: i) dissolving sacubitril sodium salt of Formula Π in one or more solvents,
ii) optionally adding an antisolvent to the step i) reaction mixture or vice -versa, and iii) isolating the pure sacubitril sodium salt of Formula Π.
Claim 38: The process of claim 37, wherein the one or more solvents are selected from ketones, esters, halogenated hydrocarbons and mixtures thereof.
Claim 39: The process of claim 38, wherein the one or more solvents are selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, dichloromethane, dichloroethane, chloroform and mixtures thereof.
Claim 40: The process of claim 37, wherein the step i) is carried out at a temperature of about 40°C to about 75 °C.
Claim 41: The process of claim 37, further comprises adding an antisolvent to the step a) solution.
Claim 42: The process of claim 41, wherein the antisolvent is selected from the group consisting of toluene, xylene, n-hexane, n-heptane, cyclohexane, cycloheptane,
tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof.
Claim 43: The process of claim 37, wherein the solvent of step i) is methyl ethyl ketone and the anti solvent is n-heptane.
Claim 44: The process of claim 37, wherein the antisolvent is added at a temperature in between 15 to 35°C.
Claim 45: The process of claim 37, wherein the isolation is carried out by cooling of the reaction mass to below about 30°C and filtration.
Claim 46: Sacubitril sodium of Formula Π having less than 0.1% of one or more of desethyl sacubitril impurity of Formula B, lactam impurity of Formula C and succinamide impurity of Formula D as measured by HPLC.
Claim 47: Sacubitril valsartan trisodium complex having less than 0.1% of one or more of desethyl sacubitril impurity of Formula B, lactam impurity of Formula C and succinamide impurity of Formula D as measured by HPLC.
Claim 48: A pharmaceutical composition comprising amorphous form of sacubitril valsartan trisodium complex prepared according to claims 1-47 and at least one pharmaceutically acceptable excipient.