FIELD OF THE INVENTION
The present invention relates to a solid form of trisodium valsartan sacubitril complex and process of preparation thereof.
The present invention further relates to the amorphous trisodium valsartan sacubitril complex and process of preparation thereof. The present invention further provides a pharmaceutical composition comprising said amorphous trisodium valsartan sacubitril complex along with atleast one pharmaceutical acceptable excipient.
BACKGROUND OF THE INVENTION
Trisodium valsartan: sacubitril complex 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. 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 reduced formula of the sacubitril valsartan complex, 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.
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US 8,877,938 discloses a crystalline form of supramolecular complex of trisodium valsartan sacubitril hemipentahydrate and process of preparation thereof.
US 2016/0324821 A1 discloses a process for the preparation of trisodium valsartan sacubitril hemipentahydrate and crystalline form thereof.
There are several patent applications that discloses various solid forms of trisodium valsartan sacubitril complex and process of preparation thereof. IN 4528/CHE/2015 discloses a process of preparation of amorphous form of trisodium valsartan sacubitril complex. The other patent applications disclosing process for the preparation of amorphous form of valsartan sacubitril trisodium complex includes WO 2017/085573, IN 602/CHE/2015, IN 201641010897, IN 2655/MUM/2015 and CN 106518709. PCT application WO 2017/085573 further discloses amorphous solid dispersion of sacubitril valsaran complex and process of preparation thereof.
PCT application WO 2016/201238 discloses manufacturing of amorphous hydrated complex by reacting valsartan disodium trihydrate and sacubitril sodium in ethanol or toluene/n-heptane. It further discloses crystalline trisodium valsartan: sacubitril form II prepared by suspending amorphous trisodium salt of valsartan: sacubitril in t-butyl methyl ether or toluene. The PCT application WO 2017/042700 discloses
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various solid forms comprising valsartan and sacubitril wherein said solid forms includes crystalline and amorphous forms and process of their preparation.
IN 2647/DEL/2015 discloses a manufacturing process for preparing crystalline trisodium valsartan sacubitril complex by reacting sacubitril t-butyl amine salt with valsartan in presence of NaOH in acetone.
It is observed that the trisodium valsartan sacubitril complex is generally prepared by combining valsartan and sacubitril in presence of external sodium ion source. There are several methods known in prior published references for the synthesis of solid forms of trisodium valsartan sacubitril complex, however the present invention is concentrated towards the development of a method for synthesizing stable and highly pure amorphous form of trisodium valsartan sacubitril complex that possesses good pharmacokinetic properties. The present invention provides a novel process for the preparation of amorphous form of trisodium complex comprising valsartan and sacubitril without the involvement of external sodium ion source.
OBJECT OF THE INVENTION
The main object of the present invention is to develop a novel process for the preparation of amorphous form of trisodium valsartan sacubitril complex.
Another object of the present invention is to prepare a composition comprising amorphous form of trisodium valsartan sacubitril complex along with atleast one pharmaceutical acceptable excipients.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:
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a) dissolving valsartan disodium and sacubitril sodium in a solvent system comprising of one or more organic solvent to obtain a solution at 40-90oC;
b) cooling the solution to room temperature;
c) isolating a solid mass from the solution;
d) optionally adding second solvent to the solid mass followed by isolation of solid; and
e) drying the solid mass obtained from step c) or solid obtained from step d) to get amorphous trisodium valsartan sacubitril complex.
In another aspect, the present invention further provides a process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:
a) dissolving valsartan disodium and sacubitril sodium in ethyl acetate optionally in presence of an alcohol to obtain a solution at 60-90oC;
b) cooling the solution to room temperature;
c) distilling and isolating a solid mass;
d) adding a second solvent selected from ether or hydrocarbon or mixture thereof, to the solid mass;
e) isolating and drying to get amorphous trisodium valsartan sacubitril complex.
In one another aspect, the present invention provides a composition comprising a pharmaceutically effective amount of the amorphous form of trisodium valsartan sacubitril complex in combination with a pharmaceutically acceptable excipients wherein said composition is free of binder.
DETAILED DESCRIPTION OF THE INVENTION
Drawings:
Fig. 1 represents the X-Ray Powder Diffraction Pattern of amorphous form of trisodium valsartan sacubitril complex.
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Accordingly, in main embodiment, the present invention provides a process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:
a) dissolving valsartan disodium and sacubitril sodium in a solvent system comprising of one or more organic solvent to obtain a solution at 40-90oC;
b) cooling the solution to room temperature;
c) isolating a solid mass from the solution;
d) optionally adding second solvent to the solid mass followed by isolation of solid; and
e) drying the solid mass obtained from step c) or solid obtained from step d) to get amorphous trisodium valsartan sacubitril complex.
In other embodiment, the solvent system used for dissolving valsartan disodium and sacubitril sodium in step a) comprises of one or more organic solvent selected from, but not limited to, the group comprising of ethers, alcohols, esters, ketones, nitriles, alicyclic hydrocarbons, aliphatic hydrocarbons, halogenated solvent, or mixture thereof.
In a preferred embodiment, the solvent system used for dissolving valsartan disodium and sacubitril sodium in step a) comprises of one or more organic solvent selected from, but not limited to, the group comprising of tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, methyl tetrahydrofuran, ethanol, methanol, isopropanol, isobutanol, cyclohexane, n-heptane, dichloromethane, carbon tetrachloride, acetone, propyl acetate, propenyl acetate, ethyl acetate, methyl acetate, isopropenyl acetate, acetonitrile or mixture thereof. More preferably the solvent is selected from esters such as propyl acetate, propenyl acetate, methanol, ethanol, ethyl acetate and mixture thereof.
In another embodiment, the second solvent used for further purification of amorphous form of valsartan-sacubitril complex (the solid mass) obtained from step c) is selected from the group comprising of, but not limited to, ester, ethers, alicyclic hydrocarbons, aliphatic hydrocarbons or mixture thereof. Preferably, the second
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solvent is selected from the group comprising of tetrahydrofuran, cyclohexane, n-heptane, isopropenyl acetate, acetonitrile, propyl acetate, isopropyl acetate, ethyl acetate, methyl tert-butyl ether and mixture thereof.
In one another embodiment, isolation of solid mass in step c) or solid in step e) may be performed by a method selected from, but not limited to, filtration under reduced pressure at a temperature range of 45-60oC, concentration, filtration, distillation, distillation under vacuum, spray drying, fluidized bed spray drying, agitated thin film drying, flash evaporation and freeze drying (lyophilization).
In further embodiment, the solid obtained after treatment with second solvent in step d) above, is optionally treated with third solvent at a temperature of 60-100oC wherein said third solvent may be same or different from the second solvent. The said third solvent is selected from, but not limited to, the group comprising of tetrahydrofuran, cyclohexane, n-heptane, isopropenyl acetate, acetonitrile, propyl acetate, isopropyl acetate, ethyl acetate, methyl tert-butyl ether and the like. After treatment with third solvent, the solid so obtained is isolated by a method selected from, but not limited to, filtration under reduced pressure at a temperature range of 45-60oC, concentration, filtration, distillation, distillation under vacuum, spray drying, fluidized bed spray drying, agitated thin film drying, flash evaporation and freeze drying (lyophilization).
In another embodiment, the present invention provides a process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:
a) dissolving valsartan disodium and sacubitril sodium in ethyl acetate optionally in presence of an alcohol to obtain a solution at 60-90oC;
b) cooling the solution to room temperature;
c) distilling and isolating a solid mass;
d) adding a second solvent selected from ether or hydrocarbon or mixture thereof, to the solid mass;
e) isolating and drying to get amorphous trisodium valsartan sacubitril complex.
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In another embodiment, the alcohol used in combination with ethyl acetate to dissolve valsartan disodium and sacubitril sodium in step a) is selected, without limitation from the group comprising of ethanol, methanol, isopropanol, butanol and t-butanol. Preferably the alcohol solvent used is methanol and ethanol.
In another embodiment, the second solvent used in step d) 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.
In one another embodiment, the isolation of amorphous trisodium valsartan sacubitril complex in step e) may be performed by a method selected from, but not limited to, filtration under reduced pressure at a temperature range of 45-60oC, concentration, filtration, distillation, distillation under vacuum, spray drying, fluidized bed spray drying, agitated thin film drying, flash evaporation and freeze drying (lyophilization).
In one another embodiment, the present invention provides an alternate process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:
a) dissolving valsartan disodium and sacubitril sodium in an alcohol to obtain a solution at 60-90oC;
b) adding a second solvent selected from hydrocarbon;
c) distilling the solvent to get a solid; and
d) drying the solid to get amorphous trisodium valsartan sacubitril complex.
In another embodiment, the alcohol solvent used to dissolve valsartan disodium and sacubitril sodium in step a) is selected from methanol, ethanol, isopropyl alcohol, butanol, iso-butanol, tert-butanol and the like.
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The second solvent, added to the solution of valsartan disodium and sacubitril sodium in alcohol, is selected from the hydrocarbon solvent such as cyclohexane, heptane, hexane or mixture thereof.
In a preferred embodiment, the valsartan disodium used for the preparation of amorphous form of trisodium valsartan-sacubitril complex may be obtained from any commercial source or can be prepared by any known method, wherein said valsartan disodium is either crystalline or amorphous in nature.
In another preferred embodiment, the sacubitril sodium used for the preparation of amorphous form of trisodium valsartan-sacubitril complex may be obtained from any commercial source or can be prepared by any known method, wherein said sacubitril sodium is either crystalline or amorphous in nature.
In further embodiment, the present invention provides amorphous trisodium valsartan sacubitril complex characterized by particle size distribution wherein, d90 is between 0.1μm to 200μm.
In a preferred embodiment, the amorphous trisodium valsartan sacubitril complex is characterized by particle size distribution wherein, d90 is between 2.0 μm to 150μm.
In further embodiment, the present invention provides an amorphous trisodium valsartan sacubitril complex which is substantially free of crystalline form.
In a preferred embodiment, the present invention provides an amorphous trisodium valsartan sacubitril complex which is substantially free of crystalline form as depicted from Fig. 1.
Further, the present invention has the advantage of providing an amorphous form of trisodium valsartan sacubitril complex that has purity of 99.0% and above.
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In another embodiment, the amorphous trisodium valsartan sacubitril complex obtained as per the process of the present invention may be isolated as anhydrous form or a hydrate form.
In a preferred embodiment, the present invention provides an amorphous form of trisodium valsartan sacubitril complex having moisture content below 15% w/w.
In another embodiment, the present invention is directed towards a pharmaceutical composition comprising a pharmaceutically effective amount of the amorphous form of trisodium valsartan sacubitril complex in combination with a pharmaceutically acceptable excipients.
In another embodiment, the present invention is directed toward a pharmaceutical composition comprising a pharmaceutically effective amount of the amorphous form of trisodium valsartan sacubitril complex in combination with a pharmaceutically acceptable excipients wherein said composition is free of binder.
In another embodiment, the present invention is directed toward a pharmaceutical composition comprising a pharmaceutically effective amount of the amorphous form of trisodium valsartan sacubitril complex in combination with a pharmaceutically acceptable excipients wherein said composition contains more than 32% of diluents.
In a preferred embodiment, the present invention provides a composition comprising amorphous trisodium valsartan sacubitril complex along with a pharmaceutical acceptable excipient wherein said amorphous trisodium valsartan sacubitril complex is prepared as per the process of the present invention and wherein said composition is free of binder.
In another preferred embodiment, the pharmaceutical acceptable excipient is selected from, but not limited to, the group comprising of suitable film forming polymers selected from the group comprising cellulose derivatives, e.g., methyl
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cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and ethyl cellulose; vinyl polymers, e.g., polyvinylpyrrolidones; acrylic polymers; and mixtures thereof. Alternatively, commercially available coating compositions comprising film forming polymers marketed under various trade names, e.g., Opadry®, may be used for coating along with other pharmaceutically acceptable excipients such as magnesium stearate.
The pharmaceutically acceptable excipients of the present invention may include filler, disintegrant, lubricant, diluent, plasticizer, pH adjusting agent, pigment, opacifier, surfactant, glidant, and/or any combinations thereof. Some of the excipients may have two or more functions at the same time.
Suitable fillers/ diluents include, without limitation, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose (e.g., cellulose MK GR), mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, and combinations thereof. When present, a filler may be employed in an amount ranging from about 10% to about 80%, preferably from about 20% to about 70% by weight of the tablet (prior to any optional film coating).
Suitable lubricants include, without limitation, zinc stearate, magnesium stearate, aluminum or calcium silicate, stearic acid, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the tablet (prior to any optional film coating).
Suitable disintegrants include, without limitation, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone or kollidon XL), croscarmellose sodium, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone),
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crosslinked CMC (Ac-Di-Sol), carboxymethyl starch-Na (primojel and explotab). A disintegrant is employed in an amount of 0.01 to 15%, such as of 0.05 to 12%, such as at least 0.1 to 10%, by weight of the tablet, said percentage of weight being defined prior to any optional film coating. In particular, the disintegrant is crospovidone.
Suitable glidants include, without limitation, zinc stearate, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the tablet (prior to any optional film coating).
The surfactants include but are not limited to anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. Further, the amount of surfactant present in the dosages form of valsartan and sacubitril, or salt thereof ranges from about 0.1% to about 5% by total weight of the composition.
Suitable pH adjusting agents are selected form the group comprising meglumine, Na2HPO4, Mg(OH)2, sodium hydroxide, carbonates, potassium citrate, sodium citrate and other pharmaceutically acceptable alkalizing salts.
Suitable plasticizers are selected from the group comprising triethylcitrate, dibutyl sebacate, acetylated triacetin, tributylcitrate, glycerlotributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, or mixtures thereof.
Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, or mixtures thereof.
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Suitable colorants include natural colorants i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, ferrosoferric oxide, alizarin, indigo, rutin, quercetin, and the like. Synthetic colorants may also be used, which is typically an FD&C or D&C dye, e.g., an approved dye selected from the so-called ‘coal-tar’ dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a ‘lake’ thereof, i.e. an aluminum or calcium salt thereof. Particularly preferred colorants are food colorants in the ‘GRAS’ (Generally Regarded as Safe) category.
Certain specific aspects and embodiments of the present application will be explained in greater detail 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.
EXAMPLES
Preparation of amorphous form of trisodium valsartan sacubitril complex.
Experiment 1:
To 20 vol of ethyl acetate was added 50.0 g of valsartan disodium, 45.2 g of sacubitril sodium and heated to 78-80°C to get cleared solution under continuous stirring for 60 min. Slowly cooled the solution to 55°C and distilled the ethyl acetate under reduced pressure at 50-55°C, degassed for 30-40 min at 50-55°C. Cooled the solid so obtained to 25-30°C and added MTBE / n-Heptane / cyclohexane at 25-30°C stirred for 10-15 min at 25-30°C. Filtered the solid to get 80.0g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 2:
Charged 20V of ethyl acetate and 2.5V of ethanol (2.5V) to 100.0 g of valsartan disodium crystalline (having moisture content of 13.72%) and 78.4 g (on dry basis) of sacubitril sodium (having moisture content of 0.27%), and heated to 78-80°C for 60 min. Filtered the reaction mass and distilled under reduced pressure. Cooled to
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25-30°C and added n-Heptane (10.0V) at RT, stirred for 60-90min, filtered the product and washed with 1V of n-Heptane. Dried under vacuum at 60-700C to get 160.0g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 3:
Charged 20V of ethyl acetate and ethanol (2.5V) to RBF and added 50.0 g of amorphous valsartan disodium (having moisture content of 2.65%) and (44.0 g ) of sacubitril sodium (having moisture content of 0.55%), and heated to 78-80°C for 60 min. Filtered the reaction mass and distilled under reduced pressure followed by cooling to 25-30°C. Added n-Heptane (10.0V) at room temperature and then stirred for 60-90min and filtered the product followed by washing with 1V of n-Heptane. Dried under vacuum at 60-700C to get 86g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 4:
To 10 vol of tetrahydrofuran to autoclave was added 0.45g of sacubitril sodium, 0.5g of valsartan disodium and charged 5kg nitrogen pressure. Stirred the solution under heating at 65-70°C for 30 min. Slowly cooled to the reaction solution to room temperature followed by filtering and washing with 2ml of tetrahydrofuran. Dried at 35-40°C to get 0.78g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 5:
Charged 10 ml of 50% of ethanol: ethyl acetate to 0.45g of sacubitril sodium, 0.5g of valsartan sodium and heated to 45-50°C under continuous stirring for 30 min. Slowly cooled the solution to room temperature, and then distilled out the solvents under reduced pressure at 45-50°C to get 0.80g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 6:
Charged 10 vol 50% of tetrahydrofuran: methyl tert-butyl ether to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and heated to 70-75°C under
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continuous stirring for 1hr. Slowly cooled the solution to room temperature, and then distilled out the solvents under reduced pressure at 50°C to get 0.75g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 7:
Charged 10 vol of 50% of ethyl acetate: cyclohexane to 0.45g of sacubitril sodium, 0.5g of valsartan sodium and heated under continuous stirring at 70-75°C for 1hr. Cooled the solution to room temperature followed by filtration of solid so obtained. Dried the solid at 40-45°C to get 0.70g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 8:
Charged 10 vol of 50% of ethanol: isopropyl ether followed by 0.45g of sacubitril sodium, 0.5g of valsartan disodium to round bottom flask. Stirred and heated the solution to 60-65°C for 1hr. Slowly cooled the solution to room temperature, and then distilled out the solvents under reduced pressure at 50°C to get 0.73g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 9:
Charged 10 vol of methyl acetate to autoclave, and added 0.45g of sacubitril sodium, 0.5g of valsartan disodium, followed by purging 5kg nitrogen pressure. Stirred and heated the solution at 65-70°C for 30 min. Slowly cooled the solution to room temperature, filtered the solid so obtained and washed with 2ml of isopropyl alcohol. Dried the solid so obtained at 35-40° to get 0.75g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 10:
Charged 10 vol of isopropyl alcohol to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and stirred and heated at 60-65°C for 1hr. Slowly cooled to room temperature, distilled out the solvent under reduced pressure at 50°C to get 0.75g of amorphous form of trisodium valsartan sacubitril complex.
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Experiment 11:
Charged 10 vol of acetone to 0.45g of sacubitril sodium, 0.5g of valsartan sodium, and stirred under heating at 60-65°C for 1hr. Distilled the solvent under reduced pressure at 50-55°C. Charged 10 vol of isopropenyl acetate to the solid mass so obtained and heated to 100°C. Cooled the solution to room temperature under continuous stirring. Distilled the solvents at 50°C to get amorphous form of trisodium valsartan sacubitril complex.
Experiment 12:
Charged 10 vol acetone to 0.45g of sacubitril sodium, 0.5g of valsartan disodium, and stirred under heating at 60-65°C for 1hr, distilled the solvent under reduced pressure at 50-55°C. Charged 10 vol of propyl acetate, heated at 100oC under continuous stirring followed by cooling the solution to room temperature and then distilled the solvent at 50°C to get 0.70g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 13:
Charged 10 vol of acetone to 0.45g of sacubitril sodium, 0.5g of valsartan disodium, and heated at 60-65°C for 1hr. Distilled the solvent under reduced pressure at 50-55°C. Charged 10 vol of acetonitrile and heated to 70-75°C. Cooled the solution under stirring at room temperature, and then filtered the solid so obtained. Dried the solid at 40-45°C to get 0.70g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 14:
Charged 10 vol 20% methanol: carbon tetrachloride to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and stirred at 0-5°C for 1hr. Distilled out the solvent under reduced pressure at 50°C to get 0.75g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 15:
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Charged 10 vol of 50% 1,4-dioxane: methyl tert-butyl ether to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and stirred the solution at 60-65°C for 1hr. Distilled the solvents under reduced pressure at 50-55°C to get 0.75g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 16:
Charged 10 vol of 50% ethanol: methyl tert-butyl ether to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and heated under continuous stirring at 60-65°C for 1hr. Distilled the solvents under reduced pressure at 50-55°C to get 0.75g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 17:
Charged 10 vol of isobutanol to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and stirred under heating at 60-65°C for 1hr. Distilled the solvents under reduced pressure at 50-55°C to get amorphous form of trisodium valsartan sacubitril complex.
Experiment 18: Charged 10 vol of 60% of dichloromethane: isopropyl ether to 0.45g of sacubitril sodium, 0.5g of valsartan disodium and stirred at 50-55°C for 1hr. Distilled the solvents under reduced pressure at 50-55°C to get amorphous form trisodium valsartan sacubitril complex.
Experiment 19:
Charged 4V of ethanol to 0.45g of sacubitril sodium, 0.5g of valsartan disodium, and stirred under heating at 75-80°C for 30 min. Added 4V of cyclohexane and stirred for 1hr at 75-80°C. Slowly cooled the solution to room temperature. Distilled under reduced pressure at 50-55°C to get amorphous form of trisodium valsartan sacubitril complex.
Experiment 20:
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Charged 10 V of acetone to 0.45g of sacubitril sodium, 0.5g of valsartan disodium, and added NaOH solution (0.137g of NaOH in 1ml of DM water) under stirring followed by distillation under reduced pressure at 50-55°C. Added 10V of isopropyl acetate and distilled under reduced pressure at 40°C. Charged 10V of isopropenyl acetate and stirred at 85-90°C. Cooled slowly to room temperature and filtered the solid so obtained. Dried the solid at 30-35°C to get 0.85g of amorphous form of trisodium valsartan sacubitril complex.
Experiment 21:
Charged 5.0 g of valsartan free acid and 4.72g of sacubitril free acid in 50 ml of acetone at room temperature. Added aqueous sodium hydroxide solution (1.37 g sodium hydroxide in 4.0 ml DM water) slowly at room temperature. Stirred for 1.0h at room temperature. Distilled under reduced pressure at 50-55°C to get 8.8g of amorphous form of trisodium valsartan sacubitril complex.
Preparation of pharmaceutical composition comprising amorphous form of trisodium valsartan and sacubitril complex:
Ingredients
% (w/w)
Active ingredient (prepared as per Experiment 1)
50.00
Microcrystalline cellulose
37.50
Croscarmellose sodium
8.75
Colloidal silicon dioxide
2.50
Magnesium stearate
1.25
Procedure
1. The pre-sifted active ingredient, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide were blended in a suitable blender.
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2. The dry mixed ingredients of step 1 were lubricated with magnesium stearate to form a blend.
3. The blend obtained in step 2 was passed through roller compactor to obtain compact mass/ribbons which were then milled and passed through appropriate sieve to obtain granules.
4. The granules obtained in step 3 were compressed to obtain tablet which can be further film coated using Opadry.

WE CLAIM
1. A process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:
a) dissolving valsartan disodium and sacubitril sodium in a solvent system comprising of one or more organic solvent to obtain a solution at 40-90oC;
b) cooling the solution to room temperature;
c) isolating a solid mass from the solution;
d) optionally adding second solvent to the solid mass followed by isolation of solid; and
e) drying the solid mass obtained from step c) or solid obtained from step d) to get amorphous trisodium valsartan sacubitril complex.
2. The process as claimed in claim 1, wherein said solvent system used in step a) comprises of one or more organic solvent selected from tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, methyl tetrahydrofuran, ethanol, methanol, isopropanol, isobutanol, cyclohexane, n-heptane, dichloromethane, carbon tetrachloride, acetone, propyl acetate, propenyl acetate, ethyl acetate, methyl acetate, isopropenyl acetate, acetonitrile or mixture thereof.
3. The process as claimed in claim 1, wherein said second solvent used in step d) is selected from tetrahydrofuran, cyclohexane, n-heptane, isopropenyl acetate, acetonitrile, propyl acetate, isopropyl acetate, ethyl acetate, methyl tert-butyl ether and mixture thereof.
4. The process as claimed in claim 1, wherein said isolation of solid mass in step c) or solid in step d) is performed by a method selected from filtration under reduced pressure at a temperature range of 45-60oC, concentration, filtration, distillation, distillation under vacuum, spray drying, fluidized bed spray drying, agitated thin film drying, flash evaporation and freeze drying (lyophilization).
5. A process for the preparation of amorphous trisodium valsartan sacubitril complex, comprising the steps of:

a) dissolving valsartan disodium and sacubitril sodium in ethyl acetate optionally in presence of an alcohol to obtain a solution at 60-90oC;
b) cooling the solution to room temperature;
c) distilling and isolating a solid mass;
d) adding a second solvent selected from ether or hydrocarbon or mixture thereof, to the solid mass;
e) isolating and drying to get amorphous trisodium valsartan sacubitril complex.
6. The process as claimed in claim 5, wherein said alcohol is selected from ethanol, methanol, isopropanol, butanol and t-butanol.
7. The process as claimed in claim 5, wherein said second solvent used in step d) is selected from methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether; hydrocarbon solvent selected from cyclohexane, n-hexane, n-heptane, and mixture thereof.
8. The process as claimed in claim 1 and 5, wherein said amorphous form of trisodium valsartan sacubitril complex is substantially free from crystalline form and is represented as in Fig. 1.
9. A composition comprising a pharmaceutically effective amount of the amorphous form of trisodium valsartan sacubitril complex prepared as per the process claimed in claim 1 or 5 in combination with a pharmaceutically acceptable excipient, wherein said composition is free of binder.
10. The composition as claimed in claim 9, wherein said composition contains more than 32% of diluents.