DESC:“SOLID DISPERSION OF TRISODIUM SACUBITRIL VALSARTAN COMPLEX AND PROCESS FOR THE PREPARATION THEREOF”

FIELD OF INVENTION:
The present invention relates to an amorphous solid dispersion of trisodium Sacubitril valsartan complex with copovidone or colloidal silicon dioxide and process for preparation of amorphous solid dispersion of trisodium Sacubitril valsartan complex with copovidone or colloidal silicon dioxide with high purity and yield.

BACKGROUND OF THE INVENTION
Sacubitril and valsartan brand name Entresto, previously known as (LCZ696) 'is a combination drug for use in heart failure developed by Novartis. It consists of the angiotensin receptor blocker valsartan and the neprilysin inhibitor Sacubitril, in a 1:1 mixture by molecule count. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). It was approved under the FDA's priority review process on July 7, 2015.

(I)

The combination is often described as a dual-acting compounds of angiotensin receptor blockers (ARB) and neutral endopeptidase inhibitors (NEPi). Valsartan is described in U.S. Pat. No. 5,399,578 and Sacubitril in U.S. Pat. No. 5,217,996. U.S. Pat. No. 8,877,938 describes complex of trisodium valsartan-Sacubitril hemipentahydrate in crystalline form.

US'938 also discloses the synthesis for Linked pro-drug of amorphous form of Sacubitril/Valsartan, which is as shown in FIG. 5.
WO2017037596 discloses an amorphous solid dispersion of LCZ696 with one or more pharmaceutically acceptable carrier is a mixture of hydroxypropyl methylcellulose phthalate and silicon dioxide (syloid) by using spray drying technique.

Various polymorphic forms, pseudo polymorphic forms of LCZ696, i.e. crystalline forms in which the cocrystal contains either more molecules or less molecules of water than 2.5 molecules, and amorphous forms of LCZ696 are known, which are described in WO 2016/037552, WO 2016/049663, WO 2016/051393, WO 2016/125123, WO 2016/151525, WO 2016/201238, WO 2017/009784 and WO 2017/012917.
The major disadvantage with the above prior art process is the usage pharmaceutically acceptable carrier caused for unwanted impurities and that leads to low purity of Sacubitril/Valsartan trisodium salt.

Sacubitril and their pharmaceutically acceptable salts, such as Sacubitril monosodium, as well as the amorphous complex of valsartan disodium and Sacubitril monosodium are solid but very hygroscopic substances. These substances become deliquescent and sticky when exposed to air humidity. The polymer constituting the matrix of the solid dispersion of the present invention serves the purpose to protect the active ingredients from moisture. Thus, the present invention also relates to the use of polymers for protecting the active ingredients from moisture-induced chemical and physical (polymorph conversion, recrystallization or amorphization) degradation.

The present invention has many advantages over the prior art processes, which are industrially friendly such as to an amorphous solid dispersion of trisodium Sacubitril valsartan complex with one or more pharmaceutically acceptable carrier selected from a group of copovidone and colloidal silicon dioxide with high yield. Similarly, the present invention involves simple steps which are commonly adopted in industrial scale

Therefore, there is a need for novel an amorphous solid dispersion of trisodium Sacubitril valsartan complex with one or more pharmaceutically acceptable carrier selected from a group of copovidone and colloidal silicon dioxide, there is also a constant need for a low cost and industrial friendly process for preparing the amorphous solid dispersion of trisodium Sacubitril valsartan complex.

OBJECTIVE OF THE INVENTION

An objective of the present invention relates to an amorphous solid dispersion of trisodium Sacubitril valsartan complex with copovidone or colloidal silicon dioxide and process for preparation of amorphous solid dispersion of trisodium Sacubitril valsartan complex with copovidone or colloidal silicon dioxide.

SUMMARY OF THE INVENTION

The present application relates to an amorphous solid dispersion of trisodium Sacubitril valsartan complex with copovidone or colloidal silicon dioxide. The present application also relates to process for preparation of amorphous solid dispersion of trisodium Sacubitril valsartan complex with high purity and yield.

In aspect of the present invention is to provide amorphous solid dispersion of Sacubitril valsartan trisodium complex with copovidone or colloidal silicon dioxide

In another aspect of the present invention is to provide a process for the preparation of solid dispersion of trisodium Sacubitril valsartan complex, comprising the steps of:
a) providing trisodium Sacubitril valsartan complex solution in a solvent;
b) adding colloidal silicon dioxide to step-a);
c) removing the solvent; and
d) isolating amorphous solid dispersion of Sacubitril valsartan complex.

In another aspect of the present invention is to provide a process for the preparation of solid dispersion of trisodium Sacubitril valsartan complex, comprising the steps of:
a) providing trisodium Sacubitril valsartan complex solution in a solvent;
b) adding copovidone to step-a);
c) removing the solvent; and
d) isolating amorphous solid dispersion of Sacubitril valsartan complex

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig 1: X-ray powder diffraction (PXRD) of solid dispersion of trisodium Sacubitril valsartan complex with 20% colloidal silicon dioxide prepared according to Example-2

Fig 2: X-ray powder diffraction (PXRD) of solid dispersion of trisodium Sacubitril valsartan complex with 30% colloidal silicon dioxide prepared according to Example-3.

Fig 3: X-ray powder diffraction (PXRD) of solid dispersion of trisodium Sacubitril valsartan complex with 20% copovidone prepared according to Example-9.

DETAILED DESCRIPTION OF THE INVENTION

The present application relates to an amorphous solid dispersion of trisodium Sacubitril valsartan complex with copovidone or colloidal silicon dioxide. The present application also relates to process for preparation of amorphous solid dispersion of trisodium Sacubitril valsartan complex with high purity and yield.

In aspect of the present invention is to provide amorphous solid dispersion of Sacubitril valsartan trisodium complex with copovidone or colloidal silicon dioxide.

In another aspect of the present invention is to provide a process for the preparation of solid dispersion of trisodium Sacubitril valsartan complex, comprising the steps of:
a) providing trisodium Sacubitril valsartan complex solution in a solvent;
b) adding colloidal silicon dioxide solution to step-a);
c) removing the solvent; and
d) isolating amorphous solid dispersion of Sacubitril valsartan complex.

The step a) of providing a solution or suspension of Sacubitril valsartan complex in a suitable solvent at a suitable temperature of at about 25°C. to about reflux. The suitable solvent includes, but are not limited to ketones, alcohols, amides, sulfoxides, ethers and mixtures thereof. The ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol, butanol and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, ethyl acetate, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixtures thereof; preferably the suitable solvent is acetone or Methanol or ethanol.

Step b) of the aforementioned process an amorphous solid dispersion of Sacubitril valsartan trisodium complex with Colloidal silicon dioxide, where in the weight ration of Sacubitril valsartan trisodium complex and Colloidal silicon dioxide for the solid dispersion is about 10 to 50%, preferably 20%.

In another aspect of the present invention is to provide a method of preparing a solid dispersion
In order to form a solution of step b), the contents may be stirred for sufficient period of time at a suitable temperature of at about 25°C. to about reflux. Typically, the contents were stirred for about 10 min to about 2 hrs at a temperature of 25-35° C.

Step c) of the aforementioned process involves removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution to obtain amorphous form as a solid or semi-solid. Evaporation can be achieved by a co-distillation, lyophilisation or freeze-drying technique, rotational drying, spray drying, fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably, the solvent may be removed completely by co-distillation under vacuum at a temperature of about 25° C. to about 60°C.

If the resultant compound is a semi-solid compound obtained in Step d) then it may be further treated with a suitable solvent at a temperature of about 15°C. to about 50°C. to obtain substantially a solid compound. Preferably, the addition of suitable solvent is carried out at a temperature of 15-35°C. The suitable solvent includes, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. Aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like, water and mixture thereof.
The isolation of amorphous form of Sacubitril valsartan trisodium complex may be carried out by any conventional techniques known in the art for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about 0° C. to about 30° C., preferably at about 10° C. to about 25°C.

In another aspect of the present invention is to provide a process for the preparation of solid dispersion of trisodium Sacubitril valsartan complex, comprising the steps of:
a) providing trisodium Sacubitril valsartan complex solution in a solvent;
b) adding copovidone to step-a);
c) removing the solvent; and
d) isolating amorphous solid dispersion of Sacubitril valsartan complex

The step a) of providing a solution or suspension of Sacubitril valsartan complex in a suitable solvent at a suitable temperature of at about 25°C. to about reflux. The suitable solvent includes, but are not limited to ketones, alcohols, amides, sulfoxides, ethers and mixtures thereof. The ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol, butanol and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, ethyl acetate, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixtures thereof; preferably the suitable solvent is acetone or methanol or ethanol.

Step b) of the aforementioned process an amorphous solid dispersion of Sacubitril valsartan trisodium complex with copovidone, where in the weight ration of Sacubitril valsartan trisodium complex and copovidone for the solid dispersion is about 10 to 50%, preferably 20%.

In another aspect of the present invention is to provide a method of preparing a solid dispersion
In order to form a solution of step b), the contents may be stirred for sufficient period of time at a suitable temperature of at about 25°C. to about reflux. Typically, the contents were stirred for about 10 min to about 2 hrs at a temperature of 25-35°C.

Step c) of the aforementioned process involves removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution to obtain amorphous form as a solid or semi-solid. Evaporation can be achieved by a co-distillation, lyophilisation or freeze-drying technique, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably, the solvent may be removed completely by co-distillation under vacuum at a temperature of about 25°C to about 60°C.

If the resultant compound is a semi-solid compound obtained in Step d) then it may be further treated with a suitable solvent at a temperature of about 15°C to about 50°C. to obtain substantially a solid compound. Preferably, the addition of suitable solvent is carried out at a temperature of 15-35°C. The suitable solvent includes, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. Aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like, water and mixture thereof.

The isolation of amorphous form of Sacubitril valsartan trisodium complex may be carried out by any conventional techniques known in the art for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about 0° C. to about 30° C., preferably at about 10° C. to about 25°C.

The pure amorphous Sacubitril valsartan trisodium complex of the present invention have a superior polymorphic purity is evident from perfect a single broad diffraction peak (halo) in XRPD. The amorphous of the present invention may have a chemical purity by High Performance Liquid Chromatography (HPLC) of greater than about 96.0% or greater than about 98.0% or greater than about 99.0% or greater than about 99.8%.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example-1: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex with 50% colloidal silicon dioxide.
To a mixture of 100 gm of 50% colloidal silicon dioxide and 200 mL of Ethanol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Ethanol) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white coloured final product was isolated by distilled the solvent completely under vacuum and isolated in n-heptane.
Weight of the product = 195 gm.

Example-2: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex with 20% colloidal silicon dioxide.
To a mixture of 25 gm of 20% colloidal silicon dioxide and 50 mL of Ethanol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Ethanol) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white colored final product was isolated by distilled the solvent completely under vacuum and isolated in n-heptane.
Weight of the product = 115 gm.
Purity: 99.8%

Example -3: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex with 30% colloidal silicon dioxide.
To a mixture of 42 gm of 30% colloidal silicon dioxide and 80 mL of Ethanol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Ethanol) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white colored final product was isolated by distilled the solvent completely under vacuum and isolated in n-heptane.
Weight of the product = 115 gm.
Purity: 99.7%
Example -4: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex colloidal silicon dioxide.
To a mixture of 100 gm of colloidal silicon dioxide and 200 mL of Ethanol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Ethanol) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white colored final product was isolated by distilled the solvent completely under vacuum and isolated in cyclohexane.
Weight of the product = 195 gm.
Purity: 99.99%

Example -5: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex colloidal silicon dioxide.
To a mixture of 100 gm of colloidal silicon dioxide and 200 mL of Ethanol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Ethanol) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white colored final product was isolated by distilled the solvent completely under vacuum and isolated in a mixture of cyclohexane& n-heptane.
Weight of the product = 195 gm.
Purity: 99.6%

Example-6: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex colloidal silicon dioxide.
To a mixture of 100 gm of colloidal silicon dioxide and 200 mL of Isopropyl alcohol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Isopropyl alcohol) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white coloured final product was isolated by distilled the solvent completely under vacuum and isolated in a mixture of cyclohexane& n-heptane.
Weight of the product = 195 gm.

Example-7: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex colloidal silicon dioxide.
To a mixture of 100 gm of colloidal silicon dioxide and 200 mL of Methanol, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Methanol-Ethyl aceate) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white colored final product was isolated by distilled the solvent completely under vacuum and isolated in a mixture of cyclohexane& n-heptane.
Weight of the product = 195 gm.

Example -8: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex colloidal silicon dioxide.
To a mixture of 100 gm of colloidal silicon dioxide and 200 mL of Acetone, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL Acetone) was added at 25°C to the reaction mixture and stirred for 30 minutes. The off-white coloured final product was isolated by distilled the solvent completely under vacuum and isolated in a mixture of cyclohexane& n-heptane.
Weight of the product = 195 gm

Example -9: Preparation of Amorphous Solid Dispersions of Sacubitril Valsartan Trisodium Complex with 20% copovidine.
To a mixture of 100 gm of 20% copovidine and 200 mL of ethyl acetate, Sacubitril-valsartan complex (dissolved 100 gm Sacubitril-valsartan trisodium in 300 mL ethyl acetate) was added at 25°C to the reaction mixture and stirred for 30 minutes. The final product was isolated by distilled the solvent completely under vacuum and isolated in a mixture of cyclohexane& n-heptane.
Weight of the product = 245 gm.
Purity: 99.8%

,CLAIMS:WE CLAIM:

1. An amorphous solid dispersion of Sacubitril valsartan trisodium complex with copovidone or colloidal silicon dioxide.

2. A process for the preparation of solid dispersion of trisodium Sacubitril valsartan, comprising the steps of:
a) providing trisodium Sacubitril valsartan complex solution in a solvent at 25°C;
b) adding colloidal silicon dioxide to step-a);
c) removing the solvent; and
d) isolating amorphous solid dispersion of Sacubitril valsartan complex.

3. The process as claimed in claim 2, wherein step a) the solvent is selected from acetone, methanol, ethanol, propanol, isopropanol, butanol and mixtures thereof; wherein step d) the solvent is selected from hexane, heptane, propane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane, water and mixture thereof.

4. The process as claimed in claim 2, wherein step b) the weight ration of Sacubitril valsartan trisodium complex and copovidone for the solid dispersion is about 10 to 50%, preferably 20%.

5. A process for the preparation of solid dispersion of trisodium Sacubitril valsartan complex, comprising the steps of:
a) providing trisodium Sacubitril valsartan complex solution in a solvent at 25°C;
b) adding copovidone to step-a);
c) removing the solvent; and
d) isolating amorphous solid dispersion of Sacubitril valsartan complex.

6. The process as claimed in claim 4, wherein step a) the solvent is selected from ethyl acetate; wherein step d) the solvent is selected from hexane, heptane, propane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane, water and mixture thereof.
7. The process as claimed in claim 5, wherein step b) the weight ration of Sacubitril valsartan trisodium complex and Colloidal silicon dioxide for the solid dispersion is about 10 to 50%.

8. An amorphous solid dispersion of Sacubitril valsartan trisodium complex with copovidone or colloidal silicon dioxide have a chemical purity greater than about 99.0% or greater than about 99.8%.