WO2017009784A1

WO2017009784A1 - Solid state forms of trisodium salt of valsartan/sacubitril complex and sacubitril

Info

Publication number: WO2017009784A1
Application number: PCT/IB2016/054173
Authority: WO
Inventors: Kumar Kamlesh SINGH; Santosh Devidas Diwakar; Shankar Dada JADHAV; Kishorkumar Maneklal Vinchhi; Tirth Harikrishna THAKER
Original assignee: Cadila Healthcare Limited
Priority date: 2015-07-14
Filing date: 2016-07-13
Publication date: 2017-01-19

Abstract

The present invention describes an amorphous form of trisodium salt of valsartan sacubitril complex and a process for the preparation of same comprising: reacting sacubitril sodium and valsartan disodium or sacubitril and valsartan in the presence of a sodium ion source in one or more solvents to obtain a solution; and obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent from the solution or by adding an anti-solvent to the solution. The crystalline form of sacubitril sodium is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 6.3°, 12.0°, 13.8°, 16.5°, 18.3°, 20.0° and 23.8°±0.2° (2θ).

Description

SOLID STATE FORMS OF TRISODIUM SALT OF VALSARTAN/SACUBITRIL

COMPLEX AND SACUBITRIL

FIELD OF THE INVENTION

The field of the invention relates to polymorphic forms and processes for the preparation of compounds containing S-N-valeiyl-N-{[2'-(lH-tetrazole-5-yl)- biphenyl-4-yl]-methyl} -valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropion- ylamino)-2-methylpentanoic acid ethyl ester moieties and cations. In particular, the invention relates to crystalline and amorphous form of compounds and processes for their preparation.

BACKGROUND OF THE INVENTION

Valsartan/sacubitril (brand name Entresto, previously known as LCZ696) is a combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan and sacubitril, in a 1 : 1 mixture by molecule count developed by Novartis. The combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) although the two effects are achieved by two different molecules. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015. Entresto contains 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. The complex is chemically described as Octadecasodiumhexakis(4-{[(l S,3R)-l-([l, -biphenyl]- 4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4oxobutanoate)hexakis(N- pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl)[l,l '-biphenyl]-4-yl]methyl}-L- valinate)-water (1/15). Its empirical formula (hemipentahydrate) is C₄₈H₅₅N608Na3 2.5H₂0. Its molecular mass is 957.99 and its schematic structural formula is

(I)

Tetrahedron Letters Vol. 53 (2012) Pg. 275-276 discloses that LCZ696 is co-crystallized valsartan and sacubitril, in a one-to-one molar ratio. One LCZ696 complex consists of six valsartan anions, six sacubitril anions, 18 sodium cations, and 15 molecules of water, resulting in the molecular formula C₂₈₈H₃3₀N36Nai8O₄8' 15H₂0 and a molecular mass of 5748.03 g/mol. The substance is a white powder consisting of thin hexagonal plates. It is stable in solid form as well as in aqueous (watery) solution with a pH of 5 to 7, and has a melting point of about 138°C.

Tetrahedron Letters Vol. 53 (2012) Pg. 275-276 supplementary data discloses experimental procedure and the structural characterization including x- ray powder diffraction pattern of LCZ696.

U.S. 5,217,996 A discloses biaryl substituted 4-amino-butryic acid amides which includes sacubitril.

U.S. 8,877,938 B2 (the '938 patent) discloses trisodium [3-((l S,3R)-l- biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl)propionate-(S)-3'- methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate which is crystalline form and process for its preparation. The '938 patent also discloses the pharmaceutical composition of trisodium salt of valsartan sacubitril complex. The crystalline form of trisodium salt of valsartan sacubitril complex is designated as "Form-I". WO 2016/051393 A2, WO 2016/029828 Al, WO 2016/037552 Al discloses various crystalline forms of trisodium salt of valsartan sacubitril complex.

WO 2016/037098 Al discloses deuterated sacubitril.

It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favored over another.

The known prior art is described herein to present the invention in a proper technical context. Unless otherwise stated contrary, such disclosure should be construed as such art forms part of a common general knowledge in the field. The present prior art provides trisodium salt of valsartan sacubitril complex as trisodium hemipentahydrate in crystalline form characterized by unit cell parameters and solid states MR data alongwith the x-ray powder diffraction pattern. It has been found that trisodium salt of valsartan sacubitril complex exhibits polymorphism. According to the disclosures in the prior art document, the known solid form of trisodium salt of valsartan sacubitril complex is crystalline form including hemipentahydrate. Therefore, there is a need to provide a solid form, an amorphous form, which is a suitable alternative for the preparation of trisodium salt of valsartan sacubitril complex drug product.

SUMMARY OF THE INVENTION

In one general aspect, there is provided an amorphous form of trisodium salt of valsartan sacubitril complex.

In another general aspect, there is provided a crystalline Form-II of trisodium salt of valsartan sacubitril complex.

In another general aspect, there is provided a crystalline Form-Ill of trisodium salt of valsartan sacubitril complex.

In another general aspect, there is provided a crystalline Form-IV of trisodium salt of valsartan sacubitril complex. In another general aspect, there is provided a crystalline form of sacubitril sodium.

In another general aspect, there is provided a process for the preparation of a trisodium salt of valsartan sacubitril complex, the process comprising reacting a sacubitril sodium and a valsartan disodium or sacubitril and valsartan in the presence of sodium ion source in one or more of solvents to obtain a solution and obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent from the solution or by adding an anti-solvent to the solution.

In another general aspect, there is provided a process for the preparation of sacubitril sodium, the process comprising:

(a) providing a solution of 4-(((2S,4R)-l-([l,l'-biphenyl]-4-yl)-5-ethoxy-4- methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid in one or more solvents to obtain a solution;

(b) adding a sodium source to the solution; and

(c) obtaining sacubitril sodium by the removal of the solvent.

In another general aspect, there is provided a process for the preparation of amorphous valsartan disodium, the process comprising:

(a) providing a solution of valsartan in one or more solvents to obtain the solution;

(b) adding a sodium ion source to the solution; and

(c) obtaining the amorphous valsartan disodium by the removal of the solvent.

In another general aspect, there is provided a process for the preparation of a crystalline Form-II of trisodium salt of valsartan sacubitril complex, the process comprising:

(a) reacting sacubitril and valsartan in the presence of sodium ion source in one or more solvents to obtain a reaction mixture;

(b) concentrating the reaction mixture to obtain a residue;

(c) heating the residue in one or more ester solvents to obtain the solution; and

(d) cooling the solution to obtain the crystalline Form-II of trisodium salt of valsartan sacubitril complex. In another general aspect, there is provided a process for the preparation of a crystalline Form-Ill of trisodium salt of valsartan sacubitril complex, the process comprising:

(a) reacting sacubitril and valsartan in presence of sodium ion source in one or more first solvents to obtain a reaction mixture;

(b) concentrating the reaction mixture to obtain a residue;

(c) heating the residue in one or more ether solvents to obtain the solution; and

(d) cooling the solution to obtain the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex.

In another general aspect, there is provided a process for preparation of crystalline Form-IV of trisodium salt of valsartan sacubitril complex, the process comprising:

(a) providing a solution of sacubitril sodium and valsartan disodium in one or more non-polar solvents; and

(b) obtaining the crystalline Form-IV of trisodium salt of valsartan sacubitril complex by the removal of the solvent.

In another general aspect, there is provided a process for the preparation of sacubitril of Formula (II

(Π)

the process comprising:

(a) reacting a compound of Formula (V),

(IV)

wherein HX is an acid addition salt,

(b) converting the compound of Formula (IV) or its acid addition salt to a compound of Formula (III) or its acid addition salt thereof; and

(III)

wherein HX is an acid addition salt

(c) treating the compound of Formula (III) or its acid addition salt with succinic anhydride in the presence of a base to obtain the sacubitril of Formula (II). In another general aspect, there is provided a pharmaceutical composition comprising amorphous trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-II of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-Ill of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients. In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-IV of trisodium salt of valsartan sacubitnl complex and one or more of pharmaceutically acceptable carrier, diluents and excipients.

In another general aspect, the amorphous trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC.

In another general aspect, the crystalline Form-II of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98%> measured as area percentage by HPLC.

In another general aspect, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98%> measured as area percentage by HPLC.

In another general aspect, the crystalline Form-IV of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98%> measured as area percentage by HPLC.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1: Discloses x-ray powder diffractogram of crystalline Form-I of trisodium salt of valsartan sacubitril complex.

Fig. 2: Discloses differential scanning calorimetry (DSC) of crystalline Form-I of trisodium salt of valsartan sacubitril complex.

Fig. 3: Discloses thermogravimetric analysis (TGA) of crystalline Form-I of trisodium salt of valsartan sacubitril complex.

Fig. 4: Discloses x-ray powder diffractogram of sacubitril sodium.

Fig. 5: Discloses differential scanning calorimetry (DSC) of sacubitril sodium. Fig. 6: Discloses thermogravimetric analysis (TGA) of sacubitril sodium.

Fig. 7: Discloses x-ray powder diffractogram of amorphous valsartan disodium. Fig. 8: Discloses differential scanning calorimetry (DSC) of amorphous valsartan disodium.

Fig. 9: Discloses thermogravimetric analysis (TGA) of amorphous valsartan disodium. Fig. 10: Discloses x-ray powder diffractogram of crystalline Form-II of trisodium salt of valsartan sacubitril complex.

Fig. 11: Discloses differential scanning calorimetry (DSC) of crystalline Form-II of trisodium salt of valsartan sacubitril complex.

Fig. 12: Discloses thermogravimetric analysis (TGA) of crystalline Form-II of trisodium salt of valsartan sacubitril complex.

Fig. 13: Discloses x-ray powder diffractogram of crystalline Form-III of trisodium salt of valsartan sacubitril complex.

Fig. 14: Discloses differential scanning calorimetry (DSC) of crystalline Form-III of trisodium salt of valsartan sacubitril complex.

Fig. 15: Discloses thermogravimetric analysis (TGA) of crystalline Form-III of trisodium salt of valsartan sacubitril complex.

Fig. 16: Discloses x-ray powder diffractogram of crystalline Form-IV of trisodium salt of valsartan sacubitril complex.

Fig. 17: Discloses x-ray powder diffraction pattern of amorphous trisodium salt of valsartan sacubitril complex as per example-14.

Fig. 18: Discloses x-ray powder diffraction pattern of amorphous trisodium salt of valsartan sacubitril complex as per example-15. DETAILED DESCRIPTION OF THE INVENTION

The above objectives of the present invention are achieved by the disclosure and description provided herein after.

The ranges recited herein, if any, for any experimental parameter are not absolute and a reasonable degree of expected experimental, instrumental, technical and/or human error in such measurements should be considered.

As used herein, the term "suspension" may be interchangeable with "slurry" and refers to a heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "general", and "substantially," are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The product obtained by the process of the present invention may be further dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

As used herein, "Particle Size Distribution (PSD)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.

The PSD is measured as the (D₉₀), which is the size, in microns, below which 90% of the particles by volume are found, and the (D₅₀), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D₉₀ or d(0.9) of less than 450 microns means that 90 volume-percent of the particles in a composition have a diameter less than 450 microns.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The term "trisodium salt of valsartan sacubitril complex" herein means trisodium [3-((l S,3R)-l-biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphi

ylmethyl}amino)butyrate]complex of Formula (la).

(la)

The solutions prior to any solid formation may, optionally, be filtered to remove any undissolved solids and/or impurities prior to removal of solvent. In one general aspect, there is provided an amorphous form of trisodium salt of valsartan sacubitril complex.

In general, the amorphous form of trisodium salt of valsartan sacubitril complex is also characterized by x-ray powder diffraction pattern substantially as shown in Fig.18.

In general, the amorphous trisodium salt of valsartan sacubitril complex may be prepared by reacting sacubitril sodium and valsartan disodium in one or more solvents to obtain a solution and the removal of the solvent from the solution or by reacting valsartan and sacubitril in the presence of a sodium ion source.

In another general aspect, firstly the solution of valsartan disodium is prepared by reacting valsartan with 2 moles of sodium ion source. The solution of sacubitril sodium may be added to the solution of valsartan disodium. Alternatively the solution of sacubitril sodium is prepared by reacting sacubitril with 1 mole of sodium ion source. The solution of valsartan disodium may be added to the solution of sacubitril sodium.

In another general aspect, the solution of sacubitril and valsartan may be prepared by dissolving sacubitril and valsartan in one or more solvents in the presence of sodium ion source. The sodium ion source may be added to the solution to obtain a solution of trisodium salt of valsartan sacubitril complex. The sodium ion source may be added to the solution in solid form or in form of its aqueous solution.

In general, the trisodium salt of valsartan sacubitril complex obtained may be further isolated and redissolved in one or more solvents.

In general, the solvents for preparation of the solution comprises one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from toluene, methyl enedi chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N-methylpyrrolidone, water, or mixture thereof. In particular, methanol, ethanol, acetone, methylene dichloride or mixture thereof may be used.

In general, the solvent is removed by one or more techniques selected from rotational distillation device (e.g. Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization) to obtain the amorphous form of trisodium salt of valsartan sacubitril complex.

In general, the solution, suspension or slurry comprising trisodium salt of valsartan sacubitril complex may be spray-dried to get the amorphous form.

In general, the solution of trisodium salt of valsartan sacubitril complex may be evaporated using a rotational distillation device such as a Buchi rotavapor to obtain the amorphous form. In general, the obtained amorphous trisodium salt of valsartan sacubitril after removal of the solvent may be isolated by adding one or more anti-solvent.

In general, the anti-solvent comprises one or more of hydrocarbons selected from n-hexane, n-heptane, and cyclohexane; ethers selected from diethyl ether, diisopropyl ether, methyltertbutyl ether, and 1,4-dioxane.

In another general aspect, the sacubitril sodium used for the preparation of trisodium salt of valsartan sacubitril complex may be crystalline.

In another general aspect, there is provided a crystalline form of sacubitril sodium.

In general, the crystalline form of sacubitril sodium is characterized by x- ray powder diffraction pattern having characteristic peaks expressed in terms of 2- theta at about 6.3°, 12.0°, 13.8°, 16.5°, 18.3°, 20.0° and 23.8°±0.2° (2Θ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 4.

In general, the crystalline form of sacubitril sodium is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 5 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 6.

(a) providing a solution of 4-(((2S,4R)-l-([l, l'-biphenyl]-4-yl)-5-ethoxy-4- methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid in one or more solvents to obtain a solution;

(b) adding a sodium source to the solution; and

(c) obtaining sacubitril sodium by the removal of the solvent.

In general, the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; and N- methylpyrrolidone or mixture thereof. In particular, the solvent acetone may be used. In general, the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.

In general, the solvent from the solution of sacubitril sodium may be removed by one or more techniques selected from filtration, decantation, centrifugation, and evaporation to obtain crystalline sacubitril sodium.

In another general aspect, there is also provided a process for the preparation of an amorphous form of sacubitril sodium.

In general, the solvent from the solution of sacubitril sodium may be removed by one or more techniques selected from rotational distillation device (e.g. Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization) to obtain amorphous form of sacubitril sodium.

In general, the valsartan disodium used for the preparation of trisodium salt of valsartan sacubitril complex may be amorphous.

In general, the amorphous form of valsartan disodium is characterized by x-ray powder diffraction pattern substantially as same as shown in Fig. 7.

In general, the amorphous form of valsartan disodium is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 8 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 9.

(b) adding a sodium source to the solution; and

(c) obtaining the amorphous valsartan disodium by the removal of the solvent.

In general, the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N- methylpyrrolidone, water or mixture thereof. In particular, the solvent acetone may be used.

In general, the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.

In general, the solvent from the solution of valsartan disodium may be removed by one or more techniques selected from filtration, decantation, centrifugation, and evaporation to obtain amorphous valsartan disodium.

In another general aspect, there is provided a process for the preparation of a trisodium salt of valsartan sacubitril complex, the process comprising reacting sacubitril sodium and valsartan disodium in one or more of solvents to obtain the solution and obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent.

In general, the solvents comprises one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from toluene, methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; and N- methylpyrrolidone, water or mixture thereof.

In another general aspect, there is provided a crystalline Form-I of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.2°, 5.3°, 12.5°, 17.0°, and 19.4°±0.2° (2Θ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 1.

In general, the crystalline Form-I of trisodium salt of valsartan sacubitril complex is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 2 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 3.

In another general aspect, there is provided a crystalline Form-II of trisodium salt of valsartan sacubitril complex. In general, the crystalline Form-II of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 4.9°, 9.8°, 12.5° and 14.7°±0.2° (2Θ) and x-ray powder diffraction pattern substantially as shown in Fig. 10.

In general, the crystalline Form-II of trisodium salt of valsartan sacubitril complex is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 1 1 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 12.

(a) reacting valsartan and sacubitril in the presence of a sodium ion source in one or more solvents to obtain a reaction mixture;

(b) concentrating the reaction mixture to obtain a residue;

(d) cooling the solution to obtain crystalline Form-II of trisodium salt of valsartan sacubitril complex.

In general, the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylene dichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N-methyl pyrrolidone, water or mixture thereof. In particular, the solvent methanol, ethanol, acetone, methylene dichloride may be used.

In general, the ester solvents in step (c) comprise one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate. In particular, isopropyl acetate may be used. In general, the heating in step (c) comprises temperature from about 40°C to reflux temperature of solvent and cooling in step (d) comprises from about 0°C to about 35°C.

In general, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 5.0°, 9.7°, 12.4°, 14.8°, 16.8° and 22.6°±0.2° (2Θ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 13.

In general, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 14 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 15.

In another general aspect, there is provided a process for the preparation of a crystalline Form-Ill of trisodium salt of valsartan sacubitril complex, the process comprising:

(a) reacting sacubitril and valsartan in the presence of sodium ion source in one or more first solvents to obtain a reaction mixture;

(b) concentrating the reaction mixture to obtain a residue;

(d) cooling the solution to obtain crystalline Form-Ill of trisodium salt of valsartan sacubitril complex.

In general, the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N- methylpyrrolidone, water or mixture thereof. In particular, the solvent acetone may be used. In general, the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.

In general, the ether solvents in step (c) comprise one or more of diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and tetrahydrofuran. In particular, the solvent methyl tert-butyl ether may be used.

In general, the heating in step (c) comprises temperature from about 40°C to reflux temperature of solvent and cooling in step (d) comprises from about 0°C to about 35°C.

In another general aspect, there is provided crystalline Form-IV of trisodium salt of valsartan sacubitril complex.

In general, the crystalline Form-IV of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 3.0°, 6.0°, 7.0°, 11.7°, 12.5°, 16.2°, 18.1° and 19.6°±0.2° (2Θ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 16.

In another general aspect, there is provided a process for the preparation of crystalline Form-IV of trisodium salt of valsartan sacubitril complex, the process comprising:

In general, the non-polar solvent comprises one or more of hexane, heptane, cyclohexane, toluene, xylene, ethylbenzene, diisopropyl ether, diethyl ether, and methyl tert-butyl ether. In particular, cyclohexane may be used.

In general, the solvent from the solution of trisodium salt of valsartan sacubitril complex may be removed by one or more techniques selected from filtration, decantation, centrifugation and evaporation to obtain crystalline Form- IV of trisodium salt of valsartan sacubitril complex.

In another general aspect, there is provided a process for the preparation of sacubitril of Formula (II),

(V)

with an acid in the presence of one or more solvents to obtain a compound of Formula (IV) or its acid addition salt thereof;

(IV)

wherein HX is an acid addition salt,

(b) converting the compound of Formula (IV) or its acid addition salt to a compound of Formula (III) or its acid addition salt thereof;

(III)

wherein HX is an acid addition salt, (c) treating the compound of Formula (III) or its acid addition salt with succinic anhydride in presence of a base to obtain the sacubitril of Formula (II).

In another general aspect, the sacubitril of Formula (II) prepared by the process of the present invention is further converted to trisodium salt of valsartan sacubitril complex by one or more process as disclosed herein above.

In general, the staring compound of Formula (V) may be prepared by the known methods disclosed in WO 2008/031567 Al or J. Med. Chem. Vol. 38 Pg. 1689-1700 (1995) which are incorporated herein as reference.

In general, the compound of Formula (V) is treated with an acid selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and triflouroacetic acid. In particular, hydrochloric acid may be used.

In general, the reaction of compound of Formula (V) with an acid may be performed in one or more solvents selected from methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, methylene di chloride, ethylene di chloride, chloroform, and carbon tetrachloride. In particular, methanol, ethanol or methylene dichloride may be used.

The reaction may be performed at an ambient temperature from about 0°C to 25°C. In particular, the reaction is performed at 0°C to 10°C.

In general, the compound of Formula (IV) is a hydrochloride salt.

The compound of Formula (IV) as hydrochloride salt is further treated with a chlorinating agent selected from thionyl chloride or oxalyl chloride in the presence of ethanol solvent to obtain the compound of Formula (III) or its acid addition salt.

In general, the compound of Formula (III) is a hydrochloride salt.

In another general aspect, the compound of Formula (III) as hydrochloride salt is further reacted with succinic anhydride in presence of a base selected from one or more of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, piperidine, morpholine, and DBU. In particular, triethylamine may be used. The reaction may be performed in presence of solvent selected from one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and methylene dichloride. In particular, the solvent is acetonitrile.

In general, the compound sacubitril of Formula (II) obtained may be converted to pharmaceutically acceptable salts.

In general, the compound sacubitril of Formula (II) obtained may be converted to trisodium salt of valsartan sacubitril complex by the methods as disclosed herein above.

In another general aspect, there is provided a pharmaceutical composition comprising an amorphous trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-Ill of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-IV of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.

In another general aspect, the amorphous trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by UPLC.

In particular, the amorphous trisodium salt of valsartan sacubitril complex has purity of more than 99%, preferably more than 99.5%, more preferably 99.8% measured as area percentage by UPLC. In another general aspect, the crystalline Form-II of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC. In particular, the crystalline Form-II of trisodium salt of valsartan sacubitril complex compound has purity of more than 99%, preferably more than 99.5%, more preferably 99.8% measured as area percentage by HPLC.

In another general aspect, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC. In particular, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex compound has purity of more than 99%), preferably more than 99.5%, more preferably 99.8% measured as area percentage by HPLC.

In another general aspect, the crystalline Form-IV of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC. In particular, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex compound has purity of more than 99%), preferably more than 99.5%, more preferably 99.8% measured as area percentage by HPLC.

In general, the trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 μτη, 50% particles having particle size (D50) less than 100 μιη and 10% particles having particle size (D10) less than 50 μτη.

In general, the trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 100 μτη, 50% particles having particle size (D50) less than 50 μιη and 10% particles having particle size (D10) less than 25 μτη.

In general, the amorphous trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 μτη, 50% particles having particle size (D50) less than 100 μτη and 10% particles having particle size (D10) less than 50 μτη. In general, the crystalline Form-II of trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 μπι, 50% particles having particle size (D50) less than 100 μιη and 10% particles having particle size (D10) less than 50 μιη.

In general, the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 μπι, 50% particles having particle size (D50) less than 100 μιη and 10% particles having particle size (D10) less than 50 μιη.

In general, the crystalline Form-IV of trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 μπι, 50% particles having particle size (D50) less than 100 μιη and 10% particles having particle size (D10) less than 50 μιη.

In further aspect, the trisodium salt of valsartan sacubitril complex may be micronized to achieve the better particle size distribution in order to make suitable Formulation.

In general, the starting compound ethyl (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- amino-2-methylpentanoate hydrochloride for the preparation of sacubitril and thereby trisodium salt of valsartan sacubitril complex may be prepared by the process disclosed hereinafter in the examples.

The embodiments of the present invention are further described using specific examples herein after. The examples are provided for better understanding of certain embodiments of the invention and not, in any way, to limit the scope thereof. Plausible modifications and equivalents apparent to those skilled in the art using the teachings of the present description and the general art in the field of the invention shall also form the part of this specification and are intended to be included within the scope of it.

EXAMPLES

Example-1: Preparation of ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2- methylpentanoate hydrochloride

In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 50 g (130.38 mmol) (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- ((tert-butoxycarbonyl)amino)-2-methylpentanoic acid and 150 mL ethanol were added and cooled to 0-5°C. 17.06 g (143.41 mmol) thionyl chloride was added and the reaction mixture was stirred for 5 hours at 25-35°C. The reaction mixture was concentrated at 50-55°C under vacuum. 650 mL diisopropyl ether was added at 25-35°C and stirred for 1 hour. The white solid compound obtained was filtered and washed with diisopropyl ether. The wet-cake was dried at 50-55°C under vacuum for 4 hours to obtain 41.69 g (91.5%) titled compound having 99.10% purity and 158-159°C melting point.

Example-2: Preparation of (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4- methyl- ntanoic acid hydrochloride

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 12 g (31.29 mmol) (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- ((tert-butoxycarbonyl)amino)-2-methylpentanoic acid and 120 mL methylene dichloride were added and cooled to 0-5°C. HC1 gas was purged into the reaction mixture for 5 hours at 0-5°C. The reaction was monitored by HPLC. After the completion of the reaction, 120 mL methylene dichloride was added and stirred for 10 mins at 0-5°C. The product obtained was filtered and washed with methylene dichloride. The wet-cake was dried at 50-55°C under vacuum for 5 hours to obtain 9.59 g (96%) titled compound having 99.92%) purity. Example-3: Preparation of ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2- meth lpentanoate hydrochloride

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 9 g (28.139 mmol) (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- amino-2-methylpentanoic acid hydrochloride obtained in example-2 and 45 mL ethanol were added and cooled to 0-5°C. 3.06 mL (42.20 mmol) thionyl chloride was added and the reaction mixture was stirred for 10 min. The reaction mixture was heated to 50-55°C for 2 hours. The reaction was monitored by HPLC. After the completion of the reaction, ethanol was distilled at 50-55°C under vacuum. 72 mL diisopropyl ether was added at 35-40°C and stirred for 1 hour. The white solid compound obtained was filtered and washed with diisopropyl ether. The wet-cake was dried at 50-55°C under vacuum for 5 hours to obtain 9.31 g (95.19%) titled compound having 99.82% purity.

Example-4: Preparation of 4-(((2S,4R)-l-([l,l'-biphenyl]-4-yl)-5-ethoxy-4- methyl -5-oxopentan-2-yl)amino)-4-oxobutanoic acid

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 5 g (14.37 mmol) ethyl (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- amino-2-methylpentanoate hydrochloride prepared in example- 1, 25 mL methylene dichloride and 2.909 g (28.745 mmol) triethylamine were added and stirred for 10 min. 2.157 g (21.559 mmol) succinic anhydride was added to the reaction mixture and stirred for 2 hours at 25-35°C and cooled to 5-10°C. 1 N hydrochloric acid was added to adjust the pH 1.5-2.5 and stirred for 15 min. The separated aqueous layer was extracted with 15 mL methylene di chloride. The combined organic layer was washed with water to adjust the pH 5-6. The separated methylene dichloride layer was concentrated to dryness at 40°C under vacuum. The residue was degassed for 2 hours under vacuum at 40°C to obtain 5.89 g (99.83%) titled compound as colourless oil having 99.09% purity.

Example-5: Preparation of 4-(((2S,4R)-l-([l,l'-biphenyl]-4-yl)-5-ethoxy-4- methy -5-oxopentan-2-yl)amino)-4-oxobutanoic acid

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 7 g (20.12 mmol) ethyl (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- amino-2-methylpentanoate hydrochloride prepared in example-3, 35 mL acetonitrile and 2.52 g (25.15 mmol) succinic anhydride was added and cooled to 0-5°C. 8.5 mL triethylamine solution in 7 mL acetonitrile was added to the reaction mixture and stirred for 1 hour at 0-5°C. The reaction was monitored by HPLC. After the completion of the reaction, 1 N hydrochloric acid was added to adjust the pH 3-3.5 and stirred for 15 min. 70 mL methylene dichloride was added at 25-30°C and stirred for 15 min. The separated aqueous layer was extracted with 28 mL methylene dichloride. The combined organic layer was washed with water. The separated methylene dichloride layer was concentrated to dryness at 50-55°C under vacuum. The residue was degassed for 5 hours under vacuum at 40-45°C to obtain 8.16 g (98.73%) titled compound as colourless oil having 99.76%) purity. Reference Example-6: Preparation of trisodium salt of valsartan sacubitril complex as per WO 2007/056546 Al as in example-2

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.945 g (2.296 mmol) 4-(((2S,4R)-l-([l,l'-biphenyl]-4- yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, 30 mL acetone and 1 g (2.296 mmol) valsartan were added at 25-35°C. 0.276 g (69 mmol in 0.8 mL water) aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 1 hour at 25-35°C. The reaction mixture was concentrated at 30°C under vacuum. 15 mL isopropyl acetate (15.87 mmol) was added and the reaction mixture was concentrated to half the volume at 30°C. 15 mL isopropyl acetate (15.87 mmol) was again added and the reaction mixture was concentrated to half the volume at 30°C. The suspension was stirred for 1 hour at 20-25°C and white solid was obtained. The product was filtered and washed with isopropyl acetate. The wet-cake was dried at 30-35°C under vacuum for 4 hours to obtain 1.982 g (90.13%) trisodium salt of valsartan sacubitril complex having 99.42% purity. The compound was characterized as crystalline trisodium hemipentahydrate (Form -I).

X-ray powder diffraction (FIG.1)

DSC (FIG.2)

TGA (FIG.3)

Sodium content: 7.38% by IC

Moisture content: 6.58%

Example-7: Preparation of sacubitril sodium

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.5 g (1.215 mmol) 4-(((2S,4R)-l-([l, l'-biphenyl]-4-yl)-5- ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, 3.5 mL acetone and 20% 0.32 mL (0.607 mmol) sodium carbonate solution were stirred for 2 hours at 25-35°C. The reaction mixture was concentrated to dryness at 40°C under vacuum and the residue was degassed for 1 hour at 40°C. 6 mL isopropyl acetate was added to the residue and stirred overnight at 25-35°C. The white solid obtained was filtered and washed with isopropyl acetate. The product was dried at 50-55°C under vacuum for 4 hour to obtain 0.425 g (80.95%) sacubitril sodium having 99.44%) purity. The compound was characterized as crystalline monosodium salt having 1.7% water loss by TGA.

X-ray powder diffraction (FIG.4)

DSC (FIG.5)

TGA (FIG.6)

Example-8: Preparation of valsartan disodium

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 2 g (4.592 mmol) valsartan, 10 mL acetone and 0.367 g (9.175 mmol) sodium hydroxide solution in 1.6 mL water were stirred for 5 hours at 25-35°C. The reaction mixture was concentrated to dryness at 40°C under vacuum and the residue was degassed for 1 hour at 40°C. 10 mL methyl tert-butyl ether was added and stirred for 2 hours at 25-35°C. The white solid obtained was filtered and washed with methyl tert-butyl ether. The product was dried at 30- 35°C under vacuum for 4 hours to obtain 2.2 g (91.66%) valsartan disodium having 99.07% purity. The compound was characterized as amorphous powder with disodium salt. Sodium content: 9.13% by IC.

X-ray powder diffraction (FIG.7)

DSC (FIG.8),

TGA (FIG.9). Example-9: Preparation of crystalline Form-II of trisodium salt of valsartan sacubitril complex

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.472 g (1.147 mmol) 4-(((2S,4R)-l-([l, l'-biphenyl]-4- yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid in 7 mL acetone, 0.5 g (1.148 mmol) valsartan and 8 mL acetone were added at 25-35°C. 0.138 g (3.444 mmol in 0.4 mL water) aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 1 hour at 25-35°C. The reaction mixture was concentrated at 40°C under vacuum and degassed for 2 hours. 7.5 mL isopropyl acetate was added and the reaction mixture was heated to reflux temperature and stirred for 15 min. The reaction mixture was cooled to 25-35°C and stirred overnight. The white solid obtained was filtered and washed with isopropyl acetate. The wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 1 g (90.83%) trisodium salt of valsartan sacubitril complex having 99.92%) purity with onset at 114.85°C and melting endotherm at 127.23°C in DSC. The compound was characterized as crystalline trisodium hemipentahydrate.

X-ray powder diffraction (FIG.10)

DSC (FIG.11)

TGA (FIG.12)

Sodium content: 7.38% by IC.

Moisture content: 6.12%

Example-10: Preparation of crystalline Form-Ill of trisodium salt of valsartan sacubitril complex

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.5 g (1.215 mmol) 4-(((2S,4R)-l-([l, l^*-biphenyl]-4-yl)-5- ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid in 7 mL acetone, 0.529 g (1.215 mmol) valsartan and 9 mL acetone were added at 25-35°C. 0.145 g (3.645 mmol in 0.42 mL water) aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 2 hour at 25-35°C. The reaction mixture was concentrated at 30-35°C under vacuum and degassed for 1 hour. 7.5 mL methyl tert-butyl ether was added and the reaction mixture was heated to reflux temperature and stirred for 30 min. The reaction mixture was cooled to 25-35°C and stirred for 30 min. The white solid obtained was filtered and washed with methyl tert-butyl ether. The wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 0.95 g (81.54%) crystalline trisodium salt of valsartan sacubitril complex having with onset at 109.48°C and melting endotherm at 133.20°C in DSC. The compound was characterized as crystalline trisodium hemipentahydrate.

X-ray powder diffraction (FIG.13)

DSC (FIG.14)

TGA (FIG.15)

Sodium content: 7.09% by IC.

Moisture content: 6.06%

Example-11: Preparation of crystalline Form-IV of trisodium salt of valsartan sacubitril complex

In a 150 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.25 g (0.576 mmol) sodium 4-(((2S,4R)-l-([l, l'- biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoate and lmL cyclohexane were added at 25-35°C and stirred. 0.3 g (0.576 mmol) valsartan disodium and 1.5 mL cyclohexane were added and the reaction mixture was stirred at 25-35°C for 1 hour. The product obtained was filtered and washed with cyclohexane. The wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 0.47 g (85.29%) crystalline Form-IV of trisodium salt of valsartan sacubitril complex having 98.96%) purity and moisture content of 5.12%. X-ray powder diffraction (FIG.16). Example-12: Preparation of crystalline Form of trisodium salt of valsartan sacubitril complex

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.5 g (1.215 mmol) 4-(((2S,4R)-l-([l, l^*-biphenyl]-4-yl)-5- ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid in 7 mL acetone, 0.529 g (1.215 mmol) valsartan and 9 mL acetone were added at 25-35°C. 0.145 g (3.645 mmol in 0.42 mL water) aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 2 hour at 25-35°C. The reaction mixture was concentrated at 30-35°C under vacuum and degassed for 1 hour. 7.5 mL diisopropyl ether was added and the reaction mixture was heated to reflux temperature and stirred for 30 min. The reaction mixture was cooled to 25-35°C and stirred for 30 min. The white solid obtained was filtered and washed with diisopropyl ether. The wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 1.01 g (86.69%) crystalline trisodium salt of valsartan sacubitril complex having 99.47% purity.

Example- 13: Preparation of Preparation of trisodium salt of valsartan sacubitril complex Form-I

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.5 g (0.953 mmol) valsartan disodium, 15 mL acetone, 0.4 mL water and 0.413 g (0.953 mmol) sacubitril sodium were added at 25-35°C. The reaction mixture was heated to reflux temperature and stirred for 1 hour. The reaction mixture was concentrated under vacuum at 30-35°C and the residue was degassed in presence of 2.5 mL acetone. 10 mL acetone was added and heated to reflux temperature and stirred for 30 min. The reaction mixture was cooled to 25- 35°C and stirred for 30 min. The white solid produced was obtained. The product was filtered and washed with acetone. The wet-cake was dried at 30-35°C under vacuum for 6 hours to obtain 0.538 g (59.12%) trisodium salt of valsartan sacubitril complex having 99.09% purity with onset at 138.70°C and melting endotherm at 146.81°C. The compound was characterized as crystalline trisodium hemipentahydrate (Form -I).

X-ray powder diffraction is similar to FIG.1.

DSC is similar to FIG.2

TGA is similar to FIG.3

Sodium content: 8.11% by IC.

Moisture content: 6.83%

Example-14: Preparation of amorphous trisodium salt of valsartan sacubitril complex

In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.5 g (0.953 mmol) valsartan disodium, 15 mL acetone, 0.4 mL water and 0.413 g (0.953 mmol) sacubitril sodium were added at 25-35°C. The reaction mixture was heated to reflux temperature and stirred for 1 hour. The reaction mixture was concentrated under vacuum at 30-35°C and the residue was degassed in presence of 2.5 mL acetone. 10 mL acetone was added and heated to reflux temperature and stirred for 30 min to obtain clear solution. The reaction mixture spray dried in JISL Mini spray drier LSD-48 with feed pump running at 30-35 rpm, inlet temperature 50-55°C, out let temperature 45-50°C, aspiration rate 1200-1300 rpm, hot air supply 1.8-2.2 Kg/cm² and vacuum for conveying the dry product 80 mm (of Hg). The product collected from cyclone was found to be amorphous by XRD; and was further dried to obtain the amorphous form of trisodium salt of valsartan sacubitril complex (Fig.17).

Example- 15: Preparation of amorphous trisodium salt of valsartan sacubitril complex

In a 150 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 2 g (4.86 mmol) 4-(((2S,4R)-l-([l,l '-biphenyl]-4-yl)-5- ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, 2.117 g (4.86 mmol) valsartan, 30 mL methanol, 0.583 g (14.58 mmol) NaOH solution in 1.7 mL water were added at 25-35°C. The reaction mixture was stirred for 1 hour and concentrated under vacuum at 40°C and the residue was degassed. 30 mL methyl tert-butyl ether was added and concentrated under vacuum at 40°C. The residue was degassed. 10 mL cyclohexane was added and stirred at 30-35°C for 1 hour. The product was filtered and washed with cyclohexane. The product was dried at 30-35°C for 5 hours under vacuum to obtain 4.1 g (93.18%) amorphous trisodium salt of valsartan sacubitril complex as confirmed by XRPD (Fig.18) having 99.2% purity. The obtained compound was sieved and micronized to achieve (D90) < 100 μιη.

Example-16: Preparation of amorphous trisodium salt of valsartan sacubitril complex

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 6.26 g (14.38 mmol) valsartan, 5.91 g (14.38 mmol) sacubitril and 88.8 mL methanol were added at 25-35°C. The reaction mixture was cooled to 15-20°C and 1.725 g aqueous sodium hydroxide solution was added. The reaction mixture was stirred at 25-35°C for 1 hour. Methanol was distilled at 50-55°C under vacuum and the residue was degassed. 88.8 mL methyl tert-butyl ether was added at 40-45°C and stirred for 10 min. The reaction mixture was distilled to remove methyl tert-butyl ether at 50-55°C under vacuum to obtain white solid. The solid was degassed at 40-45°C for 30 min. 29.6 mL cyclohexane was added at 35-40°C and stirred for 1 hour. The product was filtered and washed with cyclohexane. The wet-cake was dried at 35°C under vacuum for 5 hours to obtain 12.38 g (94.23%) trisodium salt of valsartan sacubitril complex having 99.76% purity (Sacubitril= 46.87 %w/w, Valsartan= 52.07%w/w). The compound was confirmed as amorphous form having x-ray powder diffraction as in Fig.18. Example-17: Preparation of amorphous trisodium salt of valsartan sacubitril complex by spray drying

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 5 g crystalline trisodium hemipentahydrate Form-I prepared in reference example-6, 35 mL methanol and 25 mL methylene dichloride were added. The reaction mixture was stirred for 30 min and filtered. The filtrate was spray dried by keeping aspirator 70%, inlet temperature at 70°C, pump flow 12%, Q-flow 45-50, N₂ pressure at 2.5-3 kg/cm², Oxygen pressure 1.1 kg/cm². The temperature was allowed to reach 25-35°C and the obtained compound was under nitrogen atmosphere. The amorphous solid 2.9 g (58%) with purity 98.9% (Sacubitril- 43.1% + Valsartan- 55.83%) was obtained.

Example- 18: Preparation of amorphous sacubitril sodium by spray drying

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 5 g sacubitril prepared in example-5, 35 mL acetone and 20%) sodium carbonate solution were added and stirred for 2 hours. The reaction mixture concentrated to dryness at 45-50°C under vacuum. 30 mL methanol was added and degassed to obtain clear solution. The solution was filtered and washed with methanol. The filtrate was spray dried by keeping aspirator 70%, inlet temperature at 85°C, pump flow 7%, Q-flow 45-50, N₂ pressure at 2.5-3 kg/cm², Oxygen pressure 1.1 kg/cm². The temperature was allowed to reach 25-35°C and the obtained compound was under nitrogen atmosphere. The amorphous solid 3.0 g (60%)) with purity 99.5% was obtained. Example-19: Preparation of amorphous valsartan disodium by spray drying

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 5 g valsartan disodium prepared in example 8 and 50 mL methanol were stirred for 30 min to obtain a solution. The solution was filtered and washed with methanol. The filtrate was spray dried by keeping aspirator 70%, inlet temperature at 85°C, pump flow 7%, Q-flow 45-50, N₂ pressure at 2.5-3 kg/cm², Oxygen pressure 1.1 kg/cm². The temperature was allowed to reach 25- 35°C and the obtained compound was under nitrogen atmosphere. The amorphous solid 3.0 g (59.8%) was obtained.

While the present invention has been described in terms of its specific embodiments, certain modification and equivalents will be apartment to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

WE CLAIM:

1. An amorphous form of trisodium salt of valsartan sacubitril complex.

2. A process for the preparation of trisodium salt of valsartan sacubitril complex, the process comprising:

(a) reacting sacubitril sodium and valsartan disodium or sacubitril and valsartan in the presence of a sodium ion source in one or more solvents to obtain a solution; and

(b) obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent from the solution or by adding an anti-solvent to the solution.

3. The process according to claim 2, wherein the trisodium salt of valsartan sacubitril complex is amorphous.

4. The process according to claim 2, wherein the solvent comprises one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from toluene, methylene dichloride, acetonitrile, dimethyl formamide, dimethyl sulfoxide; N-methylpyrrolidone, water, or mixture thereof.

5. The process according to claim 2, wherein the solvent is removed by one or more techniques selected from rotational distillation device (e.g. Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization).

6. The process according to claim 2, wherein the anti-solvent comprises one or more of hydrocarbons selected from n-hexane, n-heptane, and cyclohexane; and ethers selected from diethyl ether, diisopropyl ether, methyltertbutyl ether, and 1,4-dioxane.

7. A crystalline form of sacubitril sodium, characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 6.3°, 12.0°, 13.8°, 16.5°, 18.3°, 20.0° and 23.8°±0.2° (2Θ).

8. A process for the preparation of crystalline sacubitril sodium according to claim 7, the process comprising:

(b) adding a sodium ion source to the solution; and

(c) obtaining the sacubitril sodium by the removal of the solvent.

9. The process according to claim 8, wherein the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethyl formamide, dimethyl sulfoxide; and N-methylpyrrolidone or mixture thereof.

10. The process according to claim 8, wherein the sodium ion source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2- ethyl hexanoate.

1 1. The process according to claim 8, wherein wherein the solvent is removed by one or more techniques selected from filtration, decantation, centrifugation, and evaporation.

12. A crystalline Form-II of trisodium salt of valsartan sacubitril complex characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4. Γ, 4.9°, 9.8°, 12.5° and 14.7°±0.2° (2Θ).

13. A process for the preparation of a crystalline Form-II of trisodium salt of valsartan sacubitril complex, the process comprising:

(b) concentrating the reaction mixture to obtain a residue;

(c) heating the residue in one or more ester solvents to obtain the solution; and (d) cooling the solution to obtain crystalline Form-II of trisodium salt of valsartan sacubitril complex.

14. The process according to claim 13, wherein the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethyl formamide, dimethyl sulfoxide; N-methylpyrrolidone, water, or mixture thereof.

15. The process according to claim 13, wherein the sodium ion source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2- ethyl hexanoate.

16. The process according to claim 13, wherein the ester solvent comprises one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate.

17. A crystalline Form-Ill of trisodium salt of valsartan sacubitril complex characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 5.0°, 9.7°, 12.4°, 14.8°, 16.8° and 22.6°±0.2° (2Θ).

18. A process for the preparation of a crystalline Form-Ill of trisodium salt of valsartan sacubitril complex, the process comprising:

(b) concentrating the reaction mixture to obtain a residue;

19. The process according to claim 18, wherein the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethyl formamide, dimethyl sulfoxide; N-methylpyrrolidone, water, or mixture thereof.

20. The process according to claim 18, wherein the sodium ion source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2- ethyl hexanoate.

21. The process according to claim 18, wherein the ether solvents comprises one or more of diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and tetrahydrofuran.

22. A crystalline Form-IV of trisodium salt of valsartan ion sacubitril complex characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 3.0°, 6.0°, 7.0°, 1 1.7°, 12.5°, 16.2°, 18. Γ and 19.6°±0.2° (2Θ).

23. A process for the preparation of a crystalline Form-IV of trisodium salt of valsartan sacubitril complex, the process comprising:

24. The process according to claim 23, wherein the non-polar solvent comprises one or more of hexane, heptane, cyclohexane, toluene, xylene, ethylbenzene, diisopropyl ether, diethyl ether, and methyl tert-butyl ether.

25. A process for the pre aration of sacubitril of Formula (II),

(Π)

the process comprising: (a) reacting a compound of Formula (V),

(V)

(IV)

wherein HX is an acid addition salt,

(III)

wherein HX is an acid addition salt,

(c) treating the compound of Formula (III) or its acid addition salt with succinic anhydride in the presence of a base to obtain the sacubitril of Formula (II).

26. The process according to claim 25, wherein the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and triflouroacetic acid.

27. The process according to claim 25, wherein the acid addition salt of compound (III) or compound (IV) is a hydrochloride salt.

28. The process according to claim 25, wherein the base is selected from diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, piperidine, morpholine, and DBU.

29. The process according to claim 25, further comprises converting sacubitril of Formula (II) to trisodium salt of valsartan sacubitril complex.

30. The process for the preparation of trisodium salt of valsartan sacubitril complex according to claim 29, comprising preparing the preparing the hydrochloride salt of compound (IV) or preparing the hydrochloride salt of compound (III).

31. A pharmaceutical composition comprising an amorphous trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.

32. A pharmaceutical composition comprising crystalline trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients wherein the crystalline trisodium salt of valsartan sacubitril complex is:

(a) Form-II characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 4.9°, 9.8°,

12.5° and 14.7°±0.2° (2Θ); or

(b) Form-II characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 5.0°, 9.7°, 12.4°, 14.8°, 16.8° and 22.6°±0.2° (2Θ); or

(c) Form-IV characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 3.0°, 6.0°, 7.0°, 11.7°, 12.5°, 16.2°, 18. Γ and 19.6°±0.2° (2Θ).

33. The pharmaceutical composition according to claim 31, wherein the amorphous trisodium salt of valsartan sacubitril complex has purity of more than 99% by HPLC.

34. The pharmaceutical composition according to claim 32, wherein the crystalline trisodium salt of valsartan sacubitnl complex has purity of more than 99% by HPLC.

35. The pharmaceutical composition according to claim 31, wherein the amorphous the amorphous trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 μιτι, 50% particles having particle size (D50) less than 100 μιη and 10% particles having particle size (D10) less than 50 μιη.