FIELD OF THE INVENTION
Present invention provides a process for the preparation of sacubitril of Formula I, pharmaceutical acceptable salts, and solid forms thereof,

Formula I
The present invention further provides stable amorphous form of sacubitril or its pharmaceutically acceptable salts, and process of preparation thereof.
Moreover, present invention provides amorphous solid dispersion of sacubitril or its pharmaceutically acceptable salts; and process of preparation thereof.
BACKGROUND OF THE INVENTION
AHU-377, chemical name (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also known as sacubitril is represented by the Formula I:

Formula I
It is a constituent of a drug for the treatment of hypertension and heart failure. AHU-377 (sacubitril) is disclosed in the patent US 5,217,996 and its process of

preparation is subsequently disclosed in the literature (J. Med. Chem. 1995, 38, 1689-1700).
There are several other patent applications that discloses the preparation of the
advanced intermediate of Formula 3 that is used in the preparation of sacubitril.

Formula 3
US 5,217,996 describes biaryl substituted 4-amino-butyric acid amide derivatives which are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals. US 5,217,996 discloses N-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester as a preferred embodiment. In the preparation of said compound N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester of Formula (i) is hydrogenated in the presence of palladium on charcoal to give N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80 : 20 mixture of diastereomers.


The above said patent applications include PCT applications such as 2017/009784, 2017/033212, 2017/141193, 2008/031567, 2008/083967, 2009/090251, 2011/088797, 2012/025502 and 2014/032627, and Indian patent application number 2647/DEL/2015 that discloses various processes for the preparation of advanced intermediate of Formula 3.
PCT application WO 2008/083967 discloses multistep process for the preparation
of N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-
butenoic acid ethyl ester through an intermediate, (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one. The said intermediate is converted to (S)-5-biphenyl-4-ylmethyl-l-(2,2-dimethylpropionyl)pyrrolidin-2-one followed by methylation, de-protection and ring opening to get (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride which is protected by Boc anhydride to get N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester.
Similarly, WO 2014/032627 and CN 105523964 discloses multistep process for preparation of advanced intermediate of Formula 3 of sacubitril. WO'627 discloses process of preparation of sacubitril by preparing (S)-l-([l,l'-biphenyl]-4-yl)-3-tert-butoxypropan-2-ol and converting it to (R)-l-(l-([l,l'-biphenyll-4-yl)-3-tert-butoxypropan-2-yl)pyrrolidine-2,5-dione followed by de-protection to get (R)-3-([l,r-biphenyll-4-yl)-2-aminopropan-l-ol hydrochloride. The compound so obtained is then reacted with boc anhydride to get N-protected compound which is then oxidized in presence of TEMPO and phosphorous ylide carbethoxyethylidene-triphenylphosphorane to form (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid which is used in preparation of sacubitril.
PCT application WO2017/009784 discloses preparation of sacubitril through an intermediate, ethyl (2R,4S)-5-([1,1 '-biphenyl]-4-yl)-4-amino-2-methylpentanoate of Formula 3 or its acid addition salt wherein said intermediate is prepared by

esterification of (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid or its acid addition salt.
EP 555175 discloses the final step of chemical synthesis leading to sacubitril is represented by the reaction running in accordance with Scheme 1, wherein the advanced intermediate of Formula 3, reacts with succinic anhydride. The reaction results in crude sacubitril in the free carboxylic acid form.
Scheme-1;


H,N

Formula 3

Formula 1

From above disclosures, it can be seen that there are several processes known from the prior published references for the preparation of sacubitril and its pharmaceutical acceptable salts. The preparation of advanced intermediate of Formula 3 and its acid addition salt, is an important reaction step of sacubitril process and the present invention is focussed towards the preparation and purification of the advanced intermediate, wherein said process is simple and economically favourable. Moreover, present invention is also concentrated towards the preparation of a suitable solid form of the sacubitril and its pharmaceutically acceptable salts that increases its solubility in the vehicle and can easily be formulated. Hence, the present invention provides stable amorphous form and/ or solid dispersions of sacubitril or pharmaceutically acceptable salt thereof that possess high solubility and can easily be formulated in a formulation having a desirable release profile.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of advanced intermediate of Formula 3 and its acid addition salt and use of said intermediate in the preparation of sacubitril and/or its pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a process of preparing amorphous form of sacubitril or pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a stable amorphous form of sacubitril or pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a process for the preparation of amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof with atleast one pharmaceutically acceptable carrier.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of advanced intermediate of Formula 3 and its acid addition salt; and use of said intermediate in the preparation of sacubitril and its pharmaceutically acceptable salts thereof.
Accordingly, in one aspect, the present invention provides a process for the preparation of sacubitril or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of suitable acid and ethanol,

Formula VI

Formula VII.

b) purifying the compound of Formula VII in one or more aprotic solvent at a temperature of about 30-100°C; and
c) isolating the compound of Formula VII and converting to sacubitril or its pharmaceutically acceptable salts.
In another aspect, the present invention provides a process for the preparation of sacubitril or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of thionyl chloride and ethanol,



HCIH2N

Formula VI Formula VII
b) purifying the compound of Formula VII with heptane at a temperature of about 30-50°C to get a wet mass;
c) adding nitrile solvent to the wet mass and heating at 65-90°C;
d) cooling and filtering to get pure compound of Formula VII; and

e) optionally drying the compound of Formula VII and converting to sacubitril and its sodium salt.
In another aspect, the present invention provides stable amorphous form of sacubitril or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable after exposure to 40°C/75% RH for a period of six months or 25°C /60% RH, for a period of at least 12 months and contains less than about 0.5% (wt/wt) total impurities.
In another aspect, the present invention provides a process for the preparation of amorphous form of sacubitril or pharmaceutically acceptable salt thereof, comprising the steps of;
a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof; in one or more suitable solvent; and
b) isolating the amorphous form of sacubitril or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides an amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof in
a suitable solvent;
b) adding a solution of atleast one pharmaceutically acceptable carrier in a suitable solvent to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to step a); and
c) isolating to get amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Drawings:
Fig. 1 represents the XRPD graph of amorphous solid dispersion of sacubitril
sodium prepared as per the process mentioned in Example 9.
Definitions:
The terms "amorphous form of sacubitril or pharmaceutically acceptable salt thereof indicate that the sacubitril or pharmaceutically acceptable salt thereof is present in substantially amorphous state and is substantially free from crystalline form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Substantially pure amorphous" denotes that atleast 90%, preferably atleast 95%, more preferably atleast 99% of the apabetalone or a salt thereof is amorphous. In other words, "substantially free from crystalline form" preferably means that the amorphous form does not contain detectable amounts, of crystalline portions of sacubitril or a pharmaceutically acceptable salt thereof e.g. measurable upon X-ray powder diffraction analysis and/or differential scanning calorimetry, and preferably the crystalline form is less than about 5% w/w of the amorphous form.
"Solid dispersion" as used herein refers to the dispersion of one or more active ingredients in an inert polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Solid dispersion consists of

two or more components, generally a polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve. A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a polymer or carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the polymer dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles. Further, the term "solid dispersion" as used in the context of the present invention, denotes a state where most of the sacubitril or pharmaceutically acceptable salt thereof, preferably 90%, 95% or all of the sacubitril or pharmaceutically acceptable salt thereof of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer/ carrier matrix. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "suitable solvent" as used in the context of the present invention is selected from protic and aprotic solvents such as group comprising of, but not limited to, alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl

ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.
The term "aprotic solvent" used in context of the present invention is selected from, but not limited to, the group comprising of hexane, heptane, cyclohexane, acetonitrile, propionitrile, butanenitrile, anisole, toluene, ethylacetate, butylacetate, propylacetate, dichloromethane, trichloromethane, 1,4-dioxane, carbon tetrachloride, tetrahydrofuran, pentane, methyl-tetrahydrofuran, acetone, methyl ethyl ketone, methyl t-butyl ketone, and the like.
The terms "pharmaceutically acceptable salt" as used in the context of the present invention refers to inorganic salts that includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, organic amine salts such as primary, secondary and tertiary amine salts selected from, but not limited to, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxy ethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine, dicyclohexyl amine, piperdine, morpholine, triethyl amine, isopropyl amine, methyl ethyl amine, dimethyl amino pyridine, pyridine, piperazine, tromethamine and the like.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
In one embodiment, the present invention provides a process for the preparation of sacubitril or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of suitable acid and ethanol,

Formula VI

Formula VIT.

b) purifying the compound of Formula VII in one or more aprotic solvent at a temperature of about 30-100°C; and
c) isolating the compound of Formula VII and converting to sacubitril or its pharmaceutically acceptable salts.
In another embodiment, the intermediate of Formula VII is isolated by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, filtration, distillation, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilisation and the like.
Moreover, drying at any stage of the process may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
In another embodiment, the sacubitril or its pharmaceutically acceptable salt is isolated by method selected from lyophilisation, filtration, evaporation under vacuum, centrifugation, or by any of the known conventional methods.

In another embodiment, the present invention provides a process for the preparation of sacubitril or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of thionyl chloride and ethanol,

Formula VT

Formula VII

b) purifying the compound of Formula VII with heptane at a temperature of about 30-50°C to get a wet mass;
c) adding nitrile solvent to the wet mass and heating at 65-90°C;
d) cooling and filtering to get pure compound of Formula VII; and
e) optionally drying the compound of Formula VII and converting to sacubitril and its sodium salt.
In another embodiment, the ethanol used for the reaction in step a) is used in the range of IV to 12V of the starting material and the reaction is carried out at a temperature in the range of 35-80°C. In another preferred embodiment, the ethanol is distilled out either fully or partially before purifying the compound of Formula VII with heptane.
In another embodiment, the present invention provides stable amorphous form of sacubitril or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable after exposure to 40°C/75% RH for a period of six months or 25°C /60% RH, for a period of at least 12 months and contains less than about 0.5% (wt/wt) total impurities.

In another embodiment, the present invention provides a process for the preparation of amorphous form of sacubitril or pharmaceutically acceptable salt thereof, comprising the steps of;
a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof; in one or more suitable solvent; and
b) isolating the amorphous form of sacubitril or pharmaceutically acceptable salt thereof.
In another embodiment, solution of sacubitril or pharmaceutically acceptable salt thereof may be combined with the anti-solvent at a suitable temperature and for sufficient time to obtain amorphous product.
In another embodiment, the present invention provides an amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof in
a suitable solvent;
b) adding a solution of atleast one pharmaceutically acceptable carrier in a suitable solvent to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, comprising the steps of:

a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to step a); and
c) isolating to get amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof.
The present invention provides a solid dispersion of sacubitril or pharmaceutically acceptable salt thereof suitable for powder handling and downstream processes. A solid dispersion of sacubitril or pharmaceutically acceptable salt thereof of the present application was found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In the present invention, the solid dispersion technology is used for dispersing sacubitril or pharmaceutically acceptable salt thereof, monomolecularly in a solid state into an inert carrier. The technology specifically includes a solvent process, a fusion process, and a mixed-grinding process.
In another embodiment, the sacubitril and the pharmaceutically acceptable carriers may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein comprises amorphous or crystalline sacubitril or pharmaceutically acceptable salt, and the carrier present in weight ratios ranging from about 1:99 to about 99:1. Preferably, the ratio is about 50:50. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable carrier.
In further embodiment, the sacubitril salt such as sacubitril sodium as obtained by the process of the present invention is characterized by purity of about 99.5% and above.

In an embodiment, the present application provides amorphous form and amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.
In another embodiment, the amorphous form or solid dispersion of sacubitril or its pharmaceutically acceptable salt prepared as per the process of the present invention are used to form a complex with valsartan or its pharmaceutical acceptable salts to get valsartan-sacubitril complex or pharmaceutical acceptable salts thereof.
In another embodiment, the amorphous form or solid dispersion of sacubitril or its pharmaceutically acceptable salt prepared as per the process of the present invention are used to form a composition comprising above said sacubitril or its salt along with valsartan or its pharmaceutically acceptable salt either in a single layer or in separate layers.
In one another embodiment, the present invention provides a process for the preparation of a premix of sacubitril or its pharmaceutically acceptable salt, comprising the steps of:
a) adding sacubitril or its pharmaceutically acceptable salt to atleast one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of sacubitril or its pharmaceutically acceptable salt either by removal of solvent from solution of step b) or by isolating the solid mass of step a).
In another embodiment, a solution of sacubitril or pharmaceutically acceptable salt thereof used to prepare amorphous solid dispersion/ premix/ amorphous form of sacubitril or its pharmaceutically acceptable salt, may be prepared by

dissolving sacubitril or pharmaceutically acceptable salt thereof in a suitable solvent or by taking the reaction mixture containing sacubitril or pharmaceutically acceptable salt thereof directly.
In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion may include, but not limited to, an inorganic oxide such as Si02, Ti02, Zn02, ZnO, AI2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, and cross-linked styrene divinyl benzene or any other carrier at any aspect of present application. In an embodiment, atleast one pharmaceutically acceptable carrier may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxy ethyl cellulose, Soluplus® (polyvinyl caprolactam-poly vinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar carriers, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin,

dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other carrier at any aspect of present application. The use of mixtures of more than one of the pharmaceutical carrier to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining sacubitril or pharmaceutically acceptable salt thereof with a suitable non-polymeric carrier by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
Amorphous form or solid dispersion or premix of sacubitril or its pharmaceutically acceptable salt, may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In another embodiment, the present invention provides amorphous form of sacubitril or pharmaceutically acceptable salt thereof, solid dispersion comprising sacubitril or pharmaceutically acceptable salt thereof, wherein said sacubitril or pharmaceutically acceptable salt thereof is having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

In another embodiment, the amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, is characterized by particle size distribution of less than about 300um, preferably less than about 200um and most preferably about lOOum.
In another embodiment, the amorphous form of sacubitril or pharmaceutically acceptable salt thereof, is characterized by particle size distribution wherein, ds>o is between O.lum to 200 um, specifically ds>o is between 2.0 um to 150um.
The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
EXAMPLES EXAMPLE 1; Preparation of ethyl (2R.4SV5-([l.l'-biphenvll-4-vn-4-amino-2-methylpentanoate hydrochloride (Formula VII)
Process 1: Charged lOO.Og of (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-
butoxycarbonyl)amino]-2-methyl pentanoic acid of Formula VI in ethanol (3.0 V)
and added 46.5 g of thionyl chloride at 25°C. Heated the reaction mas at a
temperature of 60-75°C for 2-4h. After completion of reaction, completely
distilled out the ethanol and added 500.0ml of n-heptane at 35-40°C and distilled
out the n-heptane completely. Repeated the process by adding 500.0ml of n-
heptane at 35-40°C and then distilled the n-heptane completely. Again added
500.0ml of n-heptane and filtered the solid so obtained followed by washing with
n-heptane. To the wet material so obtained was charged acetonitrile and heated to
75-80°C followed by cooling at room temperature and filtration. Washed the wet
material so obtained with acetonitrile to get pure and wet material of ethyl
(2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride
which is proceeded as such in next step without drying.

Process 2: Charged lOO.Og of (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methyl pentanoic acid of Formula VI in ethanol (3.0 V) and added 46.5 g of thionyl chloride at 25°C. Heated the reaction mas at a temperature of 60-75°C for 2-4h. After completion of reaction, partially distilled out the ethanol (1-2V) and added 500ml of n-heptane. Distilled out solvents completely at 35-40°C. Again added n-Heptane (500.0 ml) at 35-40°C followed by distillation. Again added 500.0ml of n-heptane and filtered the solid so obtained followed by washing with n-heptane. To the wet material so obtained was charged acetonitrile and heated to 75-80°C followed by cooling at room temperature and filtration. Washed the wet material so obtained with acetonitrile to get pure and wet material of ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride which is proceeded as such in next step without drying.
EXAMPLE 2; Preparation of Sacubitril (Formula I)
Charged ethyl (2R,4S)-5 -([1,1 '-biphenyl] -4-yl)-4-amino-2-methylpentanoate hydrochloride of Formula VII in methylene dichloride and cooled the solution to 0-10°C. Added succinic anhydride and triethyl amine and stirred the reaction mass at 5-10°C till completion of reaction. After completion of reaction, quenched the reaction mas with IN hydrochloric acid. Distilled the solvents to get sacubitril crude compound.
EXAMPLE 3; Preparation of Sacubitril sodium salt
Charged sacubitril of Formula I in ethanol (4.5 V) and added sodium hydroxide ethanolic solution at room temperature. Stirred the reaction mass for 1 hr at room temperature. After completion of reaction, distilled off the ethanol to get crude mass. Purified the crude mass in ethanol and n-heptane. Filtered the solid so obtained and charged acetone (7V) followed by stirring for 60-90 min. Filtered the product and added acetone again and stirred for 60-90 min at RT. Filtered the product and washed with acetone. Dried the crystals at 60-65°C to get pure sacubitril sodium.

Example-4; Preparation of amorphous form of sacubitril sodium
Charged sacubitril of Formula I in ethanol (4.5 V) and added sodium hydroxide ethanolic solution at room temperature. Stirred the reaction mass for 1 hr at room temperature. After completion of reaction, distilled off the ethanol and added ethanol to the crude compound so obtained. Stirred the solution at room temperature and filtered the solids so obtained to get amorphous form of sacubitril sodium.
Example-5; Preparation of amorphous form of sacubitril sodium
Sacubitril sodium (1.5gm) was dissolved in 24.5 ml of methanol, concentrated to 10 ml on a rotary evaporator and to this solution were added 50 ml of cyclohexane. The formed precipitate was filtered and dried on a rotary evaporator (50° C. 100 mbar, 24 h) to obtain amorphous form of sacubitril sodium.
Example-6; Preparation of amorphous form of sacubitril hemicalcium
Sacubitril hemicalcium (10 gm) was dissolved in methyl isobutyl ketone (60 ml). The solution is subjected to vacuum drying at about 45°C. for 12 hours to give amorphous sacubitril hemicalcium salt.
Example-7; Preparation of solid dispersion of sacubitril with PVP K-90
A mixture of sacubitril (0.4 g) and PVP K-90 (0.6 g) was dissolved in ethanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.
Example-8; Preparation of solid dispersion of sacubitril with HPC (Hydroxypropyl cellulose)
A mixture of sacubitril (1.2 g) and HPC (1.2 g) was dissolved in methanol (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title

compound.
Example-9; Preparation of solid dispersion of sacubitril sodium with HPC (Hydroxypropyl cellulose)
A mixture of sacubitril sodium (1.5 g) and HPC (1.0 g) was dissolved in methanol (50 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.
Example 10; Preparation of premix of sacubitril sodium with more than one pharmaceutically acceptable carrier
A universal mixer was charged with sacubitril sodium (30 g), hydroxypropylmethylcellulose (140 g), low-substituted hydroxypropylcellulose (85 g) and the charge is mixed at 110°C for 1-2 hours to provide a premix.

WE CLAIM

1. A process for the preparation of sacubitril or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of suitable acid and ethanol,



HCI.H2N

Formula VI

Formula VII

b) purifying the compound of Formula VII in one or more aprotic solvent at a temperature of about 30-100°C; and
c) isolating the compound of Formula VII and converting to sacubitril or its pharmaceutically acceptable salts.
2. The process as claimed in claim 1, wherein said process further comprises the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of thionyl chloride and ethanol,

Formula VI

Formula VII.

b) purifying the compound of Formula VII with heptane at a temperature of about 30-50°C to get a wet mass;
c) adding nitrile solvent to the wet mass and heating at 65-90°C;
d) cooling and filtering to get pure compound of Formula VII; and
e) optionally drying the compound of Formula VII and converting to sacubitril and its sodium salt.

3. Stable amorphous form of sacubitril or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable after exposure to 40°C/75% RH for a period of six months or 25°C /60% RH, for a period of at least 12 months.
4. A process for the preparation of amorphous form of sacubitril or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein said process comprising the steps of;

a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof; in one or more suitable solvent; and
b) isolating the amorphous form of sacubitril or pharmaceutically acceptable salt thereof.

5. The amorphous form of sacubitril or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein said amorphous form is having less than 5% of crystallinity as per X-ray diffraction analysis.
6. Amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.
7. A process for the preparation of amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof as claimed in claim 6, wherein said proess comprising the steps of:
a) providing a solution of sacubitril or pharmaceutically acceptable salt thereof in a suitable solvent;

b) adding atleast one pharmaceutically acceptable carrier to step a); and
c) isolating to get amorphous solid dispersion of sacubitril or pharmaceutically acceptable salt thereof.

8. Composition comprising amorphous form of sacubitril or its pharmaceutically acceptable salt as claimed in claim 3, wherein said composition further comprises of valsartan or pharmaceutically acceptable salt thereof.
9. Composition comprising solid dispersion of sacubitril or its pharmaceutically acceptable salt as claimed in claim 6, wherein said composition further comprises of valsartan or pharmaceutically acceptable salt thereof.
10. The composition as claimed in claims 8 and 9, wherein said sacubitril or its
salt and valsartan or its salt are present either in monolayer or separate layers.