The present invention provides the process for the preparation of amorphous
trisodium valsartan: sacubitril and composition comprising said amorphous form.
BACKGROUND OF THE INVENTION
Supramolecular complex of Valsartan: Sacubitril Trisodium also known as
Entresto or LCZ696 is a combination drug consisting of two antihypertensive drugs i.e.
valsartan and sacubitril, in a 1:1 mixture by molecule count developed by Novartis.
Chemically, valsartan is known as (S)-3-methyl-2-(N-{[2'-(2H-1,2,3,4-tetrazol-5-
yl)biphenyl-4-yl]methyl} pentanamido) butanoic acid and sacubitril is known as 4-
{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic
acid.
The formula of the sacubitril valsartan trisodium, as included in the ENTRESTO®
product, is shown below as Formula-I as a single valsartan molecule with a single sacubitril
molecule together with three sodium anions and 2.5 water molecules.
PCT Publication No. WO 2007/056546 describes a dual-acting compound, such
supramolecular complex, comprising: (a) an angiotensin receptor antagonist; (b) a neutral
endopeptidase inhibitor (NEPi); and optionally (c) a pharmaceutically acceptable cation.
3
Several patent applications disclose various solid forms of valsartan sacubitril
trisodium and process of preparation thereof. IN 4528/CHE/2015 discloses process for the
preparation of amorphous form of valsartan sacubitril trisodium salt wherein valsartan and
sacubitril are reacted with sodium source in presence of solvents such as isopropyl acetate,
acetone: heptane, acetone:cyclohexane and the like. The other patent applications that
discloses process for preparing amorphous form of valsartan sacubitril trisodium salt
includes WO 2017/085573, WO 2017/042700, IN 602/CHE/2015, and IN
2655/MUM/2015.
PCT application WO 2016/201238 discloses manufacturing of amorphous
valsartan sacubitril trisodium by reacting valsartan disodium trihydrate and sacubitril
sodium in ethanol or toluene. WO’238, further discloses crystalline forms of valsartan
sacubitril trisodium and process of preparation thereof.
Other patent applications such as IN 2016/41010897, discloses preparation of
valsartan sacubitril trisodium by reacting valsartan and sacubitril with sodium ion source
in presence of mixture of acetone and isopropyl acetate.
Although there are several literature known for preparing amorphous form of
valsartan sacubitril trisodium, however the present invention is focussed towards the
process for the preparation of stable and highly pure amorphous form of valsartan sacubitril
trisodium.
Accordingly, the present invention provides a novel process for the preparation of
amorphous trisodium valsartan: sacubitril.
OBJECT OF THE INVENTION
The main object of the present invention is to develop a novel process for the
preparation of amorphous trisodium valsartan: sacubitril.
Another object of the present invention is to develop a pure amorphous form of
valsartan sacubitril trisodium.
SUMMARY OF THE INVENTION
4
In main aspect, the present invention provides a process for the preparation of
amorphous trisodium valsartan: sacubitril, comprising the steps of:
a) dissolving valsartan and pharmaceutically acceptable salt of sacubitril in one or
more suitable solvent(s) to obtain a solution;
b) adding sodium ion source to the solution; and
c) isolating amorphous trisodium valsartan: sacubitril.
In another aspect, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan, sacubitril sodium and sodium hydroxide,
in acetone to form a mixture;
b) optionally adding second solvent to the mixture; and
c) isolating amorphous trisodium valsartan: sacubitril.
In another aspect, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan in suitable solvent to form a solution and
adding sodium ion source dissolved in a suitable solvent, wherein said sodium source is in
a molar equivalent amount of 2.0-2.5 per mole of valsartan;
b) homogenizing sacubitril sodium in a suitable solvent and adding to solution of
step a) to get a mixture;
c) optionally adding second solvent to the mixture; and
d) isolating amorphous trisodium valsartan: sacubitril.
In another aspect, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan in suitable solvent to form a solution and
adding to a solution of sodium ion source dissolved in a suitable solvent, wherein said
sodium source is in a molar equivalent amount of 2.0-2.5 per mole of valsartan;
b) homogenizing sacubitril sodium in a suitable solvent and adding to solution of
step a) to get a mixture;
c) optionally adding second solvent to the mixture; and
d) isolating amorphous trisodium valsartan: sacubitril.
5
In another aspect, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan and sacubitril sodium in a mixture of
alcohol and ethyl acetate to form a solution;
b) adding sodium ion source dissolved in water, wherein said sodium source is in
a molar equivalent amount of 2.0-2.5 per mole of valsartan;
c) distilling the solvents wherein said distillation is either partial distillation to give
a slurry or complete distillation to give a solid mass;
d) adding second solvent to the slurry or solid mass of step c), wherein said second
solvent is selected from cyclohexane, n-hexane, n-heptane and methyl tert-butyl ether; and
e) isolating amorphous trisodium valsartan: sacubitril.
DETAILED DESCRIPTION OF THE INVENTION
Drawings:
Fig. 1 represents the X-Ray Powder Diffraction Pattern of amorphous
trisodium valsartan: sacubitril.
Definitions:
The “suitable solvent” as used in the context of the present invention, is selected
from the group comprising of, but not limited to, 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, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, tpentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,
cyclohexanol, phenol, glycerol, n-pentane, isopentane, neopentane, n-hexane, isohexane,
3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane,
neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-
ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane,
cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, mxylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene,
trifluorotoluene, anisole, 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, diethyl ether, diisopropyl ether, methyl tbutyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane,
dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole,
6
dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-
trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl
methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile,
butanenitrile, water and mixture thereof.
While the invention is susceptible to various modifications and 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
amorphous trisodium valsartan: sacubitril, comprising the steps of:
a) dissolving valsartan and pharmaceutically acceptable salt of sacubitril in
one or more suitable solvent (s) to obtain a solution;
b) adding sodium ion source to the solution; and
c) isolating amorphous trisodium valsartan: sacubitril.
In a preferred embodiment, the suitable solvent used for dissolving valsartan and
pharmaceutically acceptable salt of sacubitril is selected from the group comprising of
tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, isopropyl ether, methyl
tetrahydrofuran, ethanol, methanol, n-propanol, isopropanol, isobutanol, dichloromethane,
carbon tetrachloride, acetone, propyl acetate, propenyl acetate, ethyl acetate, methyl
acetate, acetonitrile, water or mixture thereof.
7
In another embodiment, the second solvent used for purification or precipitation of
amorphous trisodium valsartan: sacubitril is optionally similar to the solvent used for
preparing amorphous valsartan: sacubitril trisodium.
In a preferred embodiment, the second solvent used for purification or precipitation
of amorphous trisodium valsartan: sacubitril is selected from the group comprising of ester,
ethers, alicyclic hydrocarbons, aliphatic hydrocarbons or mixture thereof. More preferably,
the second solvent is selected from the group comprising of cyclohexane, n-heptane,
isopropenyl acetate, acetonitrile, propyl acetate, methyl tert-butyl ether and the like.
In one another embodiment, removal of solvent at any stage of preparation of
amorphous form of trisodium salt of valsartan: sacubitril may include, but not limited to,
solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a
rotational distillation using Büchi® Rotavapor®, flash evaporation, rotational dying,
agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin
film drying, rotary vacuum paddle dryer (RVPD), lyophilization, and the like. In preferred
embodiment, the solvent may be removed under reduced pressures and at a temperature of
less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C,
less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C,
less than about -80°C, or any other suitable temperatures.
In other embodiment, the isolation of amorphous trisodium valsartan: sacubitril is
performed 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 Büchi® Rotavapor®, spray drying, freeze drying, thin film drying,
agitated thin film drying, rotary vacuum paddle dryer (RVPD), filtration, lyophilization and
the like.
In another embodiment of the present invention, there is provided a process for
preparing amorphous trisodium valsartan: sacubitril comprising:
(i) providing a solution of pharmaceutically acceptable salt of sacubitril in a
solvent, preferably wherein the solvent is water miscible, more preferably wherein the
solvent comprises acetone, and wherein the pharmaceutically acceptable salt is selected
8
from, but not limited to, sodium salt, calcium salt, potassium salt, barium salt, or suitable
amine salts,
(ii) adding valsartan and a sodium base, preferably sodium carbonate or sodium
hydroxide, and more preferably in a molar equivalent of about 2.0 to about 3.8 moles of
sodium per mole of valsartan or sacubitril salt, to the sacubitril solution of step (i), and
(iii) isolating the amorphous form, optionally, after adding the valsartan and
sodium base and prior to isolating the amorphous form, the following steps can be carried
out (ii-a) optionally removing the solvent, (ii-b) optionally adding anti-solvent (or second
solvent) to initiate precipitation.
In one another embodiment, the process comprises the steps of:
(i) providing a solution of valsartan in a solvent (preferably wherein the solvent is
water miscible and more preferably wherein the solvent comprises acetone),
(ii) adding aqueous or alcoholic solution of sodium base (preferably sodium
carbonate or sodium hydroxide, and more preferably in a molar equivalent of about 2.0 to
about 3.8 moles of sodium per mole of valsartan or pharmaceutically acceptable salt of
sacubitril), to the valsartan solution
(iii) adding pharmaceutically acceptable salt of sacubitril to above solution, (iii-a)
optionally removing the solvent, (iii-b) optionally adding anti-solvent (second solvent), (iv)
isolating the amorphous form.
In another embodiment, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan, sacubitril sodium and sodium hydroxide,
in acetone to form a mixture;
b) optionally adding second solvent to the mixture; and
c) isolating amorphous trisodium valsartan: sacubitril.
In another embodiment, the second solvent used for precipitating amorphous form
of valsartan sacubitril trisodium is selected from the group comprising of ether such as
methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether; hydrocarbon
solvent selected from cyclohexane, n-hexane, n-heptane; or mixture thereof. Preferably, the
second solvent is selected from cyclohexane, n-heptane, methyl tert-butyl ether or mixture
thereof.
9
In another embodiment, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan, sacubitril sodium and sodium hydroxide,
in a solvent system comprising ethyl acetate and alcohol to form a mixture;
b) optionally removing the solvent from the mixture;
c) optionally adding second solvent to the mixture, wherein said second solvent is
selected from cyclohexane, n-hexane, n-heptane and methyl tert-butyl ether; and
d) isolating amorphous trisodium valsartan: sacubitril.
In a specific embodiment, the present invention provides a process for preparing
an amorphous trisodium valsartan: sacubitril comprising the steps of:
a) homogenizing a mixture of valsartan and sacubitril sodium in a mixture of
alcohol and ethyl acetate to form a solution;
b) adding sodium ion source dissolved in water, wherein said sodium source is in
a molar equivalent amount of 2.0-2.5 per mole of valsartan;
c) distilling the solvents wherein said distillation is either partial distillation to give
a slurry or complete distillation to give a solid mass;
d) adding second solvent to the slurry or solid mass of step c), wherein said second
solvent is selected from cyclohexane, n-hexane, n-heptane and methyl tert-butyl ether; and
e) isolating amorphous trisodium valsartan: sacubitril.
In another embodiment, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising:
a) homogenizing a mixture of valsartan in suitable solvent to form a solution and
adding sodium ion source dissolved in a suitable solvent, wherein said sodium source is in
a molar equivalent amount of 2.0-2.5 per mole of valsartan;
b) homogenizing sacubitril sodium in a suitable solvent and adding to solution of
step a) to get a mixture;
c) optionally adding second solvent to the mixture; and
d) isolating amorphous trisodium valsartan: sacubitril.
In another embodiment, the present invention provides a process for preparing an
amorphous trisodium valsartan: sacubitril comprising:
10
a) homogenizing a mixture of valsartan in suitable solvent to form a solution and
adding to a solution of sodium ion source dissolved in a suitable solvent, wherein said
sodium source is in a molar equivalent amount of 2.0-2.5 per mole of valsartan;
b) homogenizing sacubitril sodium in a suitable solvent and adding to solution of
step a) to get a mixture;
c) optionally adding second solvent to the mixture; and
d) isolating amorphous trisodium valsartan: sacubitril.
In one more embodiment, the sacubitril pharmaceutically acceptable salt as used in the
context of the present invention is selected from, but not limited to, sodium salt, calcium
salt, potassium salt, barium salt, or suitable amine salts.
In one embodiment, the present invention provides a process for the preparation of
amorphous trisodium valsartan: sacubitril, comprising the steps of:
a) dissolving valsartan disodium and sacubitril free base in one or more
suitable solvent (s) to obtain a solution;
b) adding sodium ion source to the solution; and
c) isolating amorphous trisodium valsartan: sacubitril.
In further embodiment, the present invention provides amorphous trisodium valsartan:
sacubitril prepared as per the process of the present invention is characterized by particle
size distribution wherein, d90 is between 0.1µm to 200µm.
In a preferred embodiment, the amorphous trisodium valsartan: sacubitril prepared
as per the process of the present invention is characterized by particle size distribution
wherein, d90 is between 2.0 µm to 150µm.
In further embodiment, the present invention provides amorphous trisodium
valsartan: sacubitril, which is substantially free of crystalline form.
In an embodiment, the present invention provides a substantially pure amorphous
trisodium valsartan: sacubitril, wherein said amorphous form comprises of less than about
5% w/w of crystalline form.
11
Further, the present invention has the advantage of providing an amorphous form
of valsartan sacubitril trosodium salt that has high stability and has purity of 99.0% and
above.
In another embodiment, present invention provides a stable Amorphous form of
Sacubitril / Valsartan sodium salt having water content less than about 8% w/w; wherein
said amorphous form is stable for atleast six months at 40oC and 75% RH, and wherein
said amorphous form of Sacubitril / Valsartan sodium salt is prepared as per the process of
the present invention.
In a preferred embodiment, present invention provides a stable Amorphous form
of Sacubitril / Valsartan sodium salt having water content less than about 3% w/w; wherein
said amorphous form is stable for atleast six months at 40oC and 75% RH.
In another embodiment, the amorphous trisodium valsartan: sacubitril obtained as
per the process of the present invention may be isolated as anhydrous form or as a hydrate.
In another embodiment, the present invention is directed towards a pharmaceutical
composition comprising a pharmaceutically effective amount of the amorphous trisodium
valsartan: sacubitril in combination with pharmaceutically acceptable excipients, wherein
said amorphous form of trisodium valsartan: sacubitril is prepared as per the process of the
present invention.
In another embodiment, the present invention is directed towards a pharmaceutical
composition comprising a pharmaceutically effective amount of the amorphous trisodium
valsartan: sacubitril in combination with pharmaceutically acceptable excipients, wherein
said amorphous form of trisodium valsartan: sacubitril is prepared as per the process of the
present invention, and wherein said composition is free of binder.
Certain specific aspects and embodiments of the present application will be
explained in details with reference of the following examples, which are provided only for
purposes of illustration and should not able constructed as limited the scope of the
application in any manner.
12
EXAMPLES
Example 1: Preparation of amorphous form of trisodium valsartan: sacubitril.
To 20 vol of ethyl acetate was added 50.0 g of valsartan, 45.2 g of sacubitril sodium and
heated to 78-80°C to get clear solution under continuous stirring for 60 min, cooled the
solution to room temperature and added 2.1 equivalents of aqueous solution of sodium
hydroxide. Stirred the solution at 55°C and distilled the ethyl acetate under reduced
pressure at 50-55°C. Cooled the solid so obtained to 25-30°C and added n-heptane at 25-
30°C followed by stirring for 10-15 min at 25-30°C. Filtered the solid to get amorphous
form of trisodium valsartan: sacubitril (Yield: 96%, Purity: 99.9% by HPLC).
Example 2: Preparation of amorphous form of trisodium valsartan: sacubitril.
Charged 10 ml of 1:1 of ethanol: ethyl acetate to 0.45g of sacubitril sodium, 0.5g of
valsartan and heated to 45-50°C under continuous stirring for 30 min. Added 2.1 equivalent
of ethanolic solution of sodium hydroxide to the above solution and slowly cooled the
solution to room temperature. Distilled out the solvents under reduced pressure at 45-50°C
to get amorphous form of trisodium valsartan: sacubitril (Yield: 90%, Purity: 99.8% by
HPLC).
Example 3: Preparation of amorphous form of trisodium valsartan: sacubitril.
Charged 10 vol of acetone to 0.45g of sacubitril sodium, 0.5g of valsartan and stirred at
room temperature for 1hr. Slowly added aqueous solution of sodium hydroxide at room
temperature, and then distilled out the solvents under reduced pressure at 50°C to get
amorphous form of trisodium valsartan: sacubitril (Yield: 91%, Purity: 99.6% by HPLC)
Example 4: Preparation of amorphous form of trisodium valsartan: sacubitril.
Charged 5 vol of acetone to 0.45g of sacubitril sodium, and added a mixture of 0.5g of
valsartan and 2.0 equivalent of sodium hydroxide in 5 vol of acetone, and stirred under
heating at 60-65°C for 1hr. After completion of reaction, cooled the solution and distilled
the solvent under reduced pressure at 50-55°C. Charged 10 vol of propyl acetate, heated
under continuous stirring at 100°C. Cooled the solution to RT and then distilled the solvent
at 50°C to get amorphous form of trisodium valsartan: sacubitril (Yield: 94%, Purity:
99.9% by HPLC)
Example 5: Preparation of amorphous form of trisodium valsartan: sacubitril.
13
Prepared a solution of 2.0 g valsartan in 20 V of ethyl acetate: ethanol (1:1) mixture. Added
aqueous solution of 2.2 equivalent of sodium hydroxide under heating at 60oC. Charged
2.0g of sacubitril sodium dissolved in ethanol and heated at 60-65°C for 1hr, distilled the
solvents under reduced pressure at 50-55°C. Charged 10 vol of acetonitrile and heated to
70-75°C. Cooled the solution under stirring at RT, and then filtered the solid so obtained.
Dried the solid at 40-45°C to get amorphous form of trisodium valsartan: sacubitril (Yield:
97%, Purity: 99.9% by HPLC)
Example 6: Preparation of amorphous form of trisodium valsartan: sacubitril.
Sacubitril hemicalcium salt (5.0 g) was suspended in acetone (200 ml) at room temperature
and added 1.0 equivalent of HCl under stirring at room temperature for 1 hr. Added 3.5
equivalent of sodium hydroxide to the acetone solution followed by addition of 4.9g of
valsartan, heated to 40 °C and agitated for 60 min. The solvent was evaporated to dryness.
100 ml of n-heptane was added to the residue and the solvent was evaporated to dryness.
The wet product was suspended in n-heptane (60ml) and agitated at 20-25 °C for 30 min.
The suspension was again filtered over a Buchner funnel. The product was washed with nheptane (30ml) and dried at 25 °C under reduced pressure to get amorphous form of
trisodium valsartan: sacubitril (Yield: 89%, Purity: 99.5% by HPLC).
Example 7: Preparation of amorphous form of trisodium valsartan: sacubitril.
Prepared a solution of 2.0 g of valsartan in 20 V of methanol: water (1:1). Added aqueous
solution of 2.2 equivalent of sodium hydroxide under heating at 60oC. Charged 2.0g of
sacubitril sodium and stirred at 25-30°C for 1hr. Distilled the solvents under reduced
pressure at 50-55°C to get amorphous form of trisodium valsartan: sacubitril (Yield: 89%,
Purity: 95% by HPLC).
Example 8: Preparation of amorphous form of trisodium valsartan: sacubitril.
Added methyl tert-butyl ether to valsartan and sacubitril sodium followed by addition of
aqueous solution of sodium hydroxide at room temperature. Heated the reaction at 50oC
for 1 h. After completion of reaction, cooled the reaction to room temperature. Filtered and
washed with methyl tert-butyl ether and dried the solid so obtained to get amorphous form
of trisodium valsartan: sacubitril (Yield: 92%, Purity: 97% by HPLC).
Example 9: Preparation of amorphous form of trisodium valsartan: sacubitril.
14
Added ethanol (2.5 V) and ethylacetate (20V) to 48g of valsartan and 40.0g of sacubitril
sodium followed by addition of aqueous solution of sodium hydroxide (2.1 eq) under
stirring at room temperature. Heated the reaction at 78-70oC for 1 h. After completion of
reaction, filtered the reaction mass and distilled under reduced pressure. Cooled to room
temperature and added n-heptane (10V) at room temperature. Stirred the mixture so
obtained at room temperature for 1h and filtered the solids. Washed the solid with nheptane and dried the solid to get amorphous form of trisodium valsartan: sacubitril (Yield:
96%, Purity: 99.5% by HPLC)
Example 10: Preparation of amorphous form of trisodium valsartan: sacubitril.
Added 20V of ethylacetate 20V to 50g of valsartan disodium and 44.0g of sacubitril
dissolved in 2.5V of ethanol followed by addition of aqueous solution of sodium hydroxide
(1.1 eq) under stirring at room temperature. Heated the reaction at 78-70oC for 1 h. After
completion of reaction, filtered the reaction mass and distilled under reduced pressure.
Cooled to room temperature and added n-heptane (10V) at room temperature. Stirred the
mixture so obtained at room temperature for 1h and filtered the solids. Washed the solid
with n-heptane and dried the solid to get amorphous form of trisodium valsartan: sacubitril
(Yield: 96%, Purity: 99.5% by HPLC)

WE CLAIM

1. A process for the preparation of amorphous trisodium valsartan: sacubitril, comprising
the steps of:
a) dissolving valsartan and pharmaceutically acceptable salt of sacubitril in one or
more suitable solvent (s) to obtain a solution;
b) adding sodium ion source to the solution; and
c) isolating amorphous trisodium valsartan: sacubitril.
2. The process as claimed in claim 1, wherein said process comprises the steps of:
a) homogenizing a mixture of valsartan, sacubitril sodium and sodium hydroxide
in a solvent system comprising ethyl acetate and alcohol to form a mixture;
b) optionally removing the solvent from the mixture;
c) optionally adding second solvent to the mixture, wherein said second solvent is
selected from cyclohexane, n-hexane, n-heptane and methyl tert-butyl ether; and
d) isolating amorphous trisodium valsartan: sacubitril.
3. The process as claimed in claim 2, wherein said process comprises the steps of:
a) homogenizing a mixture of valsartan and sacubitril sodium in a mixture of ethyl
acetate and alcohol to form a solution;
b) adding sodium ion source dissolved in water, wherein said sodium source is in
a molar equivalent amount of 2.0-2.5 per mole of valsartan;
c) distilling the solvents wherein said distillation is either partial distillation to give
a slurry or complete distillation to give a solid mass;
d) adding second solvent to the slurry or solid mass of step c), wherein said second
solvent is selected from cyclohexane, n-hexane, n-heptane and methyl tert-butyl ether; and
e) isolating amorphous trisodium valsartan: sacubitril.
4. The process as claimed in claim 1, wherein said process comprises the steps of:
a) homogenizing a mixture of valsartan in suitable solvent to form a solution and
adding sodium ion source dissolved in a suitable solvent, wherein said sodium source is in
a molar equivalent amount of 2.0-2.5 per mole of valsartan;
b) homogenizing sacubitril sodium in a suitable solvent and adding to the solution
of step a) to get a mixture;
c) optionally adding second solvent to the mixture; and
d) isolating amorphous trisodium valsartan: sacubitril.
16
5. The process as claimed in claim 1, wherein said process comprises the steps of:
a) homogenizing a mixture of valsartan in suitable solvent to form a solution and
adding to a solution of sodium ion source dissolved in a suitable solvent, wherein said
sodium source is in a molar equivalent amount of 2.0-2.5 per mole of valsartan;
b) homogenizing sacubitril sodium in a suitable solvent and adding to the solution
of step a) to get a mixture;
c) optionally adding second solvent to the mixture; and
d) isolating amorphous trisodium valsartan: sacubitril.
6. A process for preparing an amorphous trisodium valsartan: sacubitril comprising the
steps of:
a) homogenizing a mixture of valsartan, sacubitril sodium and sodium hydroxide,
in acetone to form a mixture;
b) optionally adding second solvent to the mixture; and
c) isolating amorphous trisodium valsartan: sacubitril.
7. The process as claimed in claim 6, wherein said second solvent is selected from methyl
tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, cyclohexane, nhexane, n-heptane, or mixture thereof.
8. The process as claimed in claim 1, wherein said amorphous trisodium valsartan:
sacubitril is characterized by one or more of the following:
a) having purity of greater than equal to 99.0%,
b) having less than about 5% w/w of crystalline form,
c) having water content less than about 3% w/w, and
d) having stability for atleast six months at 40oC and 75% RH and can be
formulated easily for administering to patients.
9. A pharmaceutical composition comprising a pharmaceutically effective amount of the
amorphous trisodium valsartan: sacubitril prepared as per the process claimed in claim 1,
along with atleast one pharmaceutically acceptable excipients, wherein said composition is
free of binder.
17
10. A process for the preparation of amorphous trisodium valsartan: sacubitril, comprising
the steps of:
a) dissolving valsartan disodium and sacubitril free base in one or more
suitable solvent (s) to obtain a solution;
b) adding sodium ion source to the solution; and
c) isolating amorphous trisodium valsartan: sacubitril.