WO2017085573A1

WO2017085573A1 - Amorphous sacubitril-valsartan complex and process for preparation thereof

Info

Publication number: WO2017085573A1
Application number: PCT/IB2016/055857
Authority: WO
Inventors: Rohit Chhagan KULKARNI; Gaurav Amrut PATIL; Uday Tanaji CHAVAN; Arjun Nishikant Vinchurkar; Suryabhan Prabhakar Dange; Shailendra Gopal PATHAK; Radhakrishna Bhikaji SHIVDAVKAR; Dhananjai Shrivastava; Girij Pal Singh
Original assignee: Lupin Limited
Priority date: 2015-11-20
Filing date: 2016-09-30
Publication date: 2017-05-26

Abstract

The present invention relates to amorphous sacubitril-valsartan complex and its solid dispersion. The invention also relates to process for the preparation of sacubitril-valsartan complex and its solid dispersion.

Description

AMORPHOUS SACUBITRIL- VALSARTAN COMPLEX AND PROCESS FOR

PREPARATION THEREOF

Field of the invention

The present invention relates to amorphous sacubitril-valsartan complex and its hydrates. The present invention also relates to amorphous solid dispersion of sacubitril-valsartan complex and a process for preparation of the same.

Background of the invention

Sacubitril is chemically known as 4-{ [(25,4R)-l-(4-biphenylyl)-5-ethoxy-4-methyl-5- oxo-2-pentanyl] amino }-4-oxobutanoic acid, which is a neprilysin inhibitor. Valsartan is chemically known as (5)-3-methyl-2-(N-{ [2'-(2H-l,2,3,4-tetrazol-5-yl)biphenyl-4- yl] methyl }pentanamido)butanoic acid, which is Angiotensin II Receptor Blocker (ARBs). The supramolecular complex of sacubitril and valsartan is known in the US 8,877,938 patent. The patent discloses the supramolecular complex in form of trisodium sacubitril- valsartan hemipentahydrate. The supramolecular complex is a neprilysin inhibitor and angiotensin II receptor blocker combination shown to reduce the risk of death and hospitalization in patients with chronic heart failure. It is a first-in-class combination of the angiotensin II receptor blocker, valsartan and the neprilysin (NEP) inhibitor, sacubitril.

Said supramolecular complex is an aggregate which is comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1 : 1 :3:2.5, respectively. The supramolecular complex is chemically described as Octadecasodiumhexakis(4- { [( 1 S,3R)- 1 -( [ 1 , 1 '-biphenyl] -4-ylmethyl)-4-ethoxy-3-methyl- 4-oxobutyl] amino } -4oxobutanoate)hexakis(N-pentanoyl-N- { [2'-(lH-tetrazol- 1 -id-5- yl)[l,l '-biphenyl]-4-yl] methyl }-L-valinate) - water (1/15). Its empirical formula of the supramolecular complex is C4gH55N₆0gNa₃ 2.5 H2O and structurally represented in formula- 1 as given below:

Formula- 1

U.S. Patent No. 8,877,938 also discloses a process for preparation of said supramolecular complex.

Polymorphism is a known phenomenon among pharmaceutical substances. A single compound may exist in a variety of solid forms having distinct physical properties like melting point, solubility, chemical reactivity, etc. This variation in solid forms may be significant and may also appreciably influence pharmaceutical properties such as dissolution rate, bioavailability, stability and other properties. Because solid forms may vary in their physical properties, regulatory authorities require that efforts shall be made to identify all possible solid forms, e.g., crystalline, amorphous, solvated, etc., of new pharmaceutical substances.

The existence and possible number of solid forms for a given compound cannot be predicted, and there are no "standard" procedures that may be used to prepare solid forms of a substance. However, the discovery of new solid forms, hydrates or solvates of an active pharmaceutical ingredient provides broader scope to a formulation scientist for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have an amorphous form of drugs with high purity to meet the needs of regulatory requirements and also highly reproducible processes for their preparation.

Demonstrating the physical stability of amorphous formulations is therefore one of the key regulatory demands. Preventing the amorphous phase to crystallize has all to do with prevention of crystallization nuclei to be formed. The most commonly used methodology is that of the solid dispersion.

Amorphous form and solid dispersion of amorphous form have better stability, higher solubility and better handling during large scale production that can be exploited by pharmaceutical scientists.

For these reasons, there is a need for amorphous sacubitril-valsartan complex, especially amorphous solid dispersion of sacubitril-valsartan complex.

Object of the invention

It is an object of the present invention to provide amorphous sacubitril-valsartan complex and its hydrates.

It is another object of the present invention to provide amorphous solid dispersion of sacubitril-valsartan complex.

It is another object of the present invention to provide process for preparation of amorphous sacubitril-valsartan complex.

It is another object of the present invention to provide process for preparation of amorphous solid dispersion of sacubitril-valsartan complex. It is another object of the present invention to provide process for preparation of stable amorphous solid dispersion of sacubitril-valsartan complex from amorphous sacubitril- valsartan complex. In another general aspect, there is provided a pharmaceutical composition that includes amorphous sacubitril-valsartan complex or amorphous solid dispersion of sacubitril- valsartan complex and one or more pharmaceutically acceptable carriers or diluents.

Brief description of the drawing

Figure- 1 : The PXRD pattern of amorphous sacubitril-valsartan complex according to present invention

Figure-2: The PXRD pattern of amorphous solid dispersion of sacubitril-valsartan complex according to present invention. Description of the invention

Accordingly, the present invention relates to amorphous sacubitril-valsartan complex and also relates to amorphous solid dispersion of sacubitril-valsartan complex, suitable for pharmaceutical preparations and having greater stability. As used herein, the term "sacubitril-valsartan complex" means trisodium (4-{ [(25,4R)-l- (4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoate)((5)-3- memyl-2-(N-{ [2'-(2H-l,2,3,4-tetrazol-l-id-5-yl)biphenyl-4-yl]memyl}pentanamido) butanoate) or sacubitril-valsartan trisodium. As used herein, the term "amorphous" refers to a non-crystalline solid. An amorphous pharmaceutical solid is one in which the constituent molecules are not ordered or organized with respect to one another, but are arranged in a more or less random fashion. An amorphous pharmaceutical lacks long-range intermolecular order although it may have local correlations between molecules.

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient sacubitril-valsartan complex dispersed among at least one other component, for example a polymer or silicon dioxide.

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 "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 pharmaceutical use.

In an embodiment, the present invention relates to amorphous sacubitril-valsartan complex.

In another embodiment, the present invention also relates to amorphous solid dispersion of sacubitril-valsartan complex.

In another embodiment, the present invention relates to stable amorphous solid dispersion of sacubitril-valsartan complex. In another embodiment, the present invention also relates to stabilize the amorphous sacubitril-valsartan complex by preparation of its solid dispersion.

In another embodiment, the present invention also relates to provide process for preparation of stable amorphous solid dispersion of sacubitril-valsartan complex from amorphous sacubitril-valsartan complex. In another embodiment, the amorphous solid dispersion of sacubitril-valsartan complex of the present invention having the moisture content less than 8%.

In another embodiment, the amorphous solid dispersion of sacubitril-valsartan complex having a purity by HPLC of greater than about 98%.

In another embodiment, the amorphous solid dispersion of sacubitril-valsartan complex having a purity by HPLC of >98%. In particular, the purity by HPLC of >99%, more particularly, the purity HPLC of >99.5%, most particularly, the purity HPLC of >99.8%.

In another embodiment, the amorphous solid dispersion of sacubitril-valsartan complex is substantially free from residual solvents. The term "substantially free" means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%.

In another embodiment, the amorphous solid dispersion of sacubitril-valsartan complex is stable and does not convert to any other form after various stability stations as per pharmacopoeial requirement.

In another embodiment, the present invention is directed to amorphous sacubitril- valsartan complex characterized by powder X-ray diffraction (PXRD).

In another embodiment, the present invention provides the amorphous sacubitril-valsartan complex characterized by a PXRD pattern, substantially as illustrated by Figure- 1.

In another embodiment, the present invention is directed to amorphous solid dispersion of sacubitril-valsartan complex characterized by powder X-ray diffraction (PXRD).

In another embodiment, the present invention provides the amorphous solid dispersion of sacubitril-valsartan complex characterized by a PXRD pattern, substantially as illustrated by Figure-2. In yet another embodiment, the present invention is directed to process for the preparation of amorphous sacubitril-valsartan complex.

Amorphous sacubitril-valsartan complex is prepared from the pharmaceutical substances sacubitril and valsartan or salts thereof.

Amorphous sacubitril-valsartan complex of the present invention is obtained by

(i) Dissolving sacubitril or its salt and valsartan or its salt in a solvent to form a solution;

(ii) Adding a base to solution of step (i); and

(iii) Evaporating the solution of step (ii) to obtain the amorphous sacubitril-valsartan complex.

The suitable solvent of the present invention is selected from the group of esters preferably ethyl acetate, isopropyl acetate, butyl acetate etc.; ketones preferably acetone, methyl isobutyl ketone (MIBK), butanone etc.; ethers preferably methyl tert-butyl ether (MTBE), dioxane, tetrahydrofuran, diisopropyl ether, etc.; alcohols preferably, methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, pentanol etc.; amides preferably dimethyl formamide, N-methylpyrrolidone etc.; nitriles preferably acetonitrile, propionitrile etc.; chlorohydrocarbons preferably dichloromethane and dichloroethane etc.; water and mixture thereof.

The base used in the present invention is selected from the group of inorganic base and organic base. The inorganic base is selected from the group of alkali metal and alkaline earth metal hydroxide, carbonate and bicarbonate, preferably sodium hydroxide.

The organic base is selected from the group of alkali metal alkoxide, preferably sodium methoxide.

Suitable technique for evaporating the solution includes concentration, filtration, various evaporation techniques like spray drying, fluidized bed spray drying, agitated thin film drying, freeze drying (lyophilization), flash evaporation, distillation, vacuum distillation and the like, or any other suitable technique known in the art.

The amorphous sacubitril-valsartan complex of the present invention is used to prepare stable amorphous solid dispersion of sacubitril-valsartan complex.

The amorphous sacubitril-valsartan complex of the present invention can be used as neprilysin inhibitor and angiotensin II receptor blocker combination indicated to reduce the risk of death and hospitalization in patients with chronic heart failure.

The amorphous sacubitril-valsartan complex of the present invention can be used to prepare pharmaceutical composition for the treatment of heart failure with reduced ejection fraction. Such pharmaceutical composition can be prepared by the methods known in the literature.

In yet another embodiment, the present invention is directed to amorphous solid dispersion of sacubitril-valsartan complex.

In yet another embodiment, amorphous solid dispersion of sacubitril-valsartan complex is prepared from sacubitril-valsartan complex and one or more pharmaceutically acceptable excipients.

Amorphous solid dispersion of sacubitril-valsartan complex of the present invention is obtained by

(i) Dissolving sacubitril-valsartan complex in a solvent to form a solution;

(ii) Adding an excipient to solution of step (i); and

(iii) Evaporating the solution of step (ii) to obtain the amorphous solid dispersion of sacubitril-valsartan complex. The amorphous solid dispersion of sacubitril-valsartan complex of the present invention is also obtained by (i) Dissolving sacubitril or its salt and valsartan or its salt in a solvent to form a solution;

(ii) Adding a base to solution of step (i);

(iii) Adding an excipient to solution of step (ii); and

(iv) Evaporating the solution of step (iii) to obtain the amorphous solid dispersion of sacubitril-valsartan complex.

The excipient used in the present invention is selected from the group of silica compound and polymeric compound. The silica compound is selected from silicon dioxide, aerosil® R-972, aerosil® 200 and syloid® 244FP. The polymeric compound is selected from methacrylic acid copolymers, polyvinylpyrrolidone, 4-vinylpyrrolidone-vinyl acetate copolymer (copovidone), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hypromellose phthalate and hydroxypropylmethyl cellulose acetate succinate. The preferred excipient is colloidal silicon dioxide.

In some embodiments, the ratio of the amount of weight of sacubitril-valsartan complex within the solid dispersion to the amount by weight of the polymer or colloidal silicon dioxide therein is from about 10: 1 to about 1 :10. The composition of sacubitril-valsartan complex with polymer or colloidal silicon dioxide may be prepared by using about 10: 1 to about 1 : 10 polymer or colloidal silicon dioxide with respect to sacubitril-valsartan complex.

The suitable solvent of the present invention is selected from the group of esters preferably ethyl acetate, isopropyl acetate, butyl acetate etc.; ketones preferably acetone, methyl isobutyl ketone (MIBK), butanone etc.; ethers preferably methyl tert-butyl ether (MTBE), dioxane, tetrahydrofuran, diisopropyl ether, etc.; alcohols preferably, methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, pentanol etc.; amides preferably dimethyl formamide, N-methylpyrrolidone etc.; nitriles preferably acetonitrile, propionitrile etc.; chlorohydrocarbons preferably dichloromethane, dichloroethane etc.; water and mixture thereof. The preferred solvent is selected from alcohol, water and mixture thereof. The base used in the present invention is selected from the group of inorganic base and organic base. The inorganic base is selected from the group of alkali metal and alkaline earth metal hydroxide, carbonate and bicarbonate, preferably sodium hydroxide. The organic base is selected from the group of alkali metal alkoxide, preferably sodium methoxide.

The pharmaceutically active agents, sacubitril and valsartan or salts thereof used in the present invention are purchased from commercial sources or prepared from processes known in the art or by a novel process.

In another embodiment, the present invention also provides a pharmaceutical composition comprising amorphous solid dispersion of sacubitril-valsartan complex along with one or more pharmaceutically acceptable carriers or diluents.

The amorphous solid dispersion of sacubitril-valsartan complex of the present invention can be used as neprilysin inhibitor and angiotensin II receptor blocker combination indicated to reduce the risk of death and hospitalization in patients with chronic heart failure.

The amorphous solid dispersion of sacubitril-valsartan complex of the present invention can be used to prepare pharmaceutical composition for the treatment of heart failure with reduced ejection fraction. Such pharmaceutical composition can be prepared by the methods known in the literature.

The present invention is further illustrated with the following non-limiting examples. Example-1: Preparation of amorphous sacubitril- valsartan complex

To a mixture of 10.0 gm of sacubitril calcium and 100 mL of isopropyl acetate was added 23 mL 2N HC1 at 25 °C. The reaction mixture was stirred for 30-45 min and the layers were separated. The organic layer was washed with water (20 mL X 3) and the solvent was distilled off under vacuum to obtain an oily residue. To the oily residue was added 50 mL isopropanol, 9.8 gm valsartan and 10 mL of 25-30% aqueous sodium hydroxide. The reaction mixture was stirred for 2 hours to obtain a clear solution. The solvent was distilled off under vacuum and stripped with isopropanol (30 mL X 3) to yield 17 gm of white solid.

Example-2: Preparation of amorphous solid dispersion of sacubitril-valsartan complex.

To a mixture of 100 gm of colloidal silicon dioxide and 200 mL of water, aqueous solution of sacubitril-valsartan complex (dissolved 100 gm sacubitril-valsartan trisodium in 500 mL water) was added at 25 °C. 100 mL of water was added to the reaction mixture and stirred for 30 minutes. The off-white colored final product was isolated by spray drying of reaction mixture (Inlet temperature of spray dryer was set at 110 - 130°C and outlet temperature of spray dryer was set at 70 - 95 °C). Weight of the product = 172 gm. Example-3: Preparation of amorphous solid dispersion of sacubitril-valsartan complex.

To a mixture of 100 gm of sacubitril calcium and 1000 mL of isopropyl acetate was added 200 mL 2N HC1 at 25 °C to adjust pH 1-1.5. The reaction mixture was stirred for 10-15 minutes and the layers were separated. 99.0 gm of valsartan was added to the organic layer and then aqueous solution of sodium hydroxide (dissolved 27.5 gm sodium hydroxide in 500 mL water) was added. The reaction mixture was stirred for 15-30 minutes and the layers were separated. 53 gm of colloidal silicon dioxide was added to aqueous layer at 25°C and the reaction mixture was stirred for 30 minutes. The off-white colored final product was isolated by spray drying of reaction mixture (Inlet temperature of spray dryer was set at 110 - 140°C and outlet temperature of spray dryer was set at 70 - 95°C). Weight of the product = 180 gm. Example-4: Preparation of amorphous solid dispersion of sacubitril-valsartan complex.

100 gm sacubitril-valsartan complex was dissolved in 1400 mL isopropanol at 50-60°C and then cooled at 25°C to 30°C temperature. Aerosil R972 was added to the reaction mixture and stir for 10 to 20 minutes. The final product was isolated by spray drying of reaction mixture (Inlet temperature of spray dryer was set at 90 - 140°C and outlet temperature of spray dryer was set at 55 - 90°C). Weight of the product = 150 gm.

Claims

1. Amorphous solid dispersion of sacubitril-valsartan complex.

2. The amorphous solid dispersion of sacubitril-valsartan complex comprising amorphous sacubitril-valsartan complex and one or more pharmaceutically acceptable excipient.

3. The amorphous solid dispersion of sacubitril-valsartan complex of claim 2, wherein the excipient is selected from silica compounds and polymeric compounds.

4. The amorphous solid dispersion of sacubitril-valsartan complex of claim 3, wherein the silica compound is selected from silicon dioxide, syloid® 244FP, aerosil® 200 and aerosil® R-972.

5. The amorphous solid dispersion of sacubitril-valsartan complex of claim 3, wherein the polymeric compound is selected from methacrylic acid copolymers, polyvinylpyrrolidone, 4-vinylpyrrolidone-vinyl acetate copolymer (copovidone), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hypromellose phthalate and hydroxypropylmethyl cellulose acetate succinate.

6. The amorphous solid dispersion of sacubitril-valsartan complex according to claims 1 to 2, having HPLC purity of greater than about 99.0%.

7. Amorphous sacubitril-valsartan complex.

8. A process for the preparation of amorphous solid dispersion of sacubitril-valsartan complex comprising:

(i) Dissolving sacubitril-valsartan complex in a solvent to form a solution;

(ii) Adding an excipient to solution of step (i); and

(iii) Evaporating the solution of step (ii) to obtain the amorphous solid dispersion of sacubitril-valsartan complex.

9. A process for the preparation of amorphous solid dispersion of sacubitril-valsartan complex comprising:

(ii) Adding a base to solution of step (i);

(iii) Adding an excipient to solution of step (ii); and (iv) Evaporating the solution of step (iii) to obtain the amorphous solid dispersion of sacubitril-valsartan complex.

The process according to claims 8 and 9, wherein the solvent comprising one or more of ester, ketone, ether, alcohol, amide, nitrile, chlorohydrocarbon and water or mixtures thereof.

The process according to claim 9, wherein the base is inorganic base or organic base.

The process according to claim 11, wherein the inorganic base is selected from alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates. The process according to claim 12, wherein the inorganic base is sodium hydroxide.

The process according to claim 11 , wherein the organic base is sodium methoxide. The process according to claims 8 and 9, wherein evaporating the solution comprising one or more of concentration, filtration, distillation, distillation under vacuum, spray drying, fluidized bed spray drying, agitated thin film drying, flash evaporation and freeze drying (lyophilization).

A pharmaceutical composition comprising amorphous solid dispersion of sacubitril-valsartan complex together with one or more pharmaceutically acceptable carriers, excipients or diluents.

A process for the preparation of amorphous sacubitril-valsartan complex comprising:

(ii) Adding a base to solution of step (i); and

(iii) Evaporating the solution of step (ii) to obtain the amorphous sacubitril- valsartan complex.

The process according to claim 17, wherein the solvent comprising one or more of ester, ketone, ether, alcohol, amide, nitrile, chlorohydrocarbon and water or mixtures thereof.

The process according to claim 17, wherein the base is inorganic base or organic base. The process according to claim 19, wherein the inorganic base is selected from alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates. The process according to claim 20, wherein the inorganic base is sodium hydroxide.

The process according to claim 19, wherein the organic base is sodium methoxide. The process according to claim 17, wherein evaporating the solution comprising one or more of concentration, filtration, distillation, distillation under vacuum, spray drying, fluidized bed spray drying, agitated thin film drying, flash evaporation and freeze drying (lyophilization).