DESC:FIELD OF THE INVENTION

The present invention is directed to solid state forms of salts of Sacubitril of formula-I and process for the preparation thereof.

Formula-I

BACKGROUND OF THE INVENTION

Sacubitril is a neprilysin inhibitor, inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, an enzyme involved in degradation of natriuretic peptides. Combination of Sacubitril and Valsaran is marketed as EntrestoTM by Novartis. It is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Sacubitril is chemically known as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester and is represented by compound of formula I.

Formula-I
US5217996A discloses process for the preparation of Sacubitril and as provided in Example 1 it is isolated as sodium salt having melting point 159°-160°C.

J. Med. Chem., 38, 1689-1700 (1995) discloses process for the preparation of Sacubitril and its sodium salt.

Patent applications WO2016029828A1, WO2016074651A1, WO2017003483A1, CN105693543A, CN105884644A, CN106065006A, CN 107188817 A disclose calcium salt of Sacubitril and solid state forms thereof.

Patent applications WO2016201238, WO2017009784 (Indian Family equivalent-IN2655/MUM/2015), WO2016074651, WO2017097275, WO2017154017, WO2017191620, WO 2018078592, CN106977417A and CN 107188820 A disclose sodium salt of Sacubitril and solid state forms thereof.

Drugs in pharmaceutical compositions can be prepared in a variety of different forms. Such drugs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such drugs can also be prepared to have different physical forms. For example, the drugs may be amorphous or may have different crystalline polymorphs, perhaps existing in different solvation or hydration states. By varying the form of a drug, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the solvation state of a drug is one of many ways in which to modulate the physical properties thereof.

Present inventors have unexpectedly discovered solid state form of sodium and calcium salts of Sacubitril and process for preparing the same.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to novel crystalline form AL of sodium salt of Sacubitril.

In another aspect, the present invention relates to process for the preparation of crystalline form AL of Sacubitril sodium comprising steps of:
i) obtaining a solution of Sacubitril in a suitable solvent(s);
ii) adding sodium ion source;
iii) optionally adding suitable anti-solvent; and
iv) isolating crystalline form AL of Sacubitril sodium.

In further aspect, the present invention relates to process for the preparation of amorphous form of Sacubitril calcium comprising steps of:
(i) obtaining a solution of Sacubitril in a suitable solvent(s) or water or mixture thereof;
(ii) adding sodium ion source;
(iii) adding aqueous solution of calcium ion source in the reaction mixture obtained in step (ii);
(iv) optionally adding suitable anti-solvent; and
(v) isolating amorphous form of Sacubitril calcium.

In one embodiment, the present invention relates to use of crystalline form AL of sodium salt of Sacubitril in preparation of Sacubitril; Valsartan complex.

In another embodiment, the present invention relates to use of amorphous form of calcium salt of Sacubitril in preparation of Sacubitril; Valsartan complex.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of a PXRD pattern of crystalline form AL of sodium salt of Sacubitril.
Figure 2 is an illustration of a PXRD pattern of crystalline form AL of sodium salt of Sacubitril.
Figure 3 is an illustration of a PXRD pattern of amorphous form of calcium salt of Sacubitril.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

In one embodiment, the present invention relates to novel crystalline form AL of sodium salt of Sacubitril characterized by a powder X-ray diffraction pattern having characteristic 2T values (±0.2° 2T) at 5.2?, 8.8?, 10.5?, 20.7? ± 0.2? 2T.

In another embodiment, the present invention relates to novel crystalline form AL of sodium salt of Sacubitril characterized by a powder X-ray diffraction pattern comprising 2T values (±0.2? 2T) selected from the group consisting of : 3.4?, 5.2?, 8.8?, 10.5?, 10.9?, 11.6?, 12.3?, 12.5?, 13.5?, 14.7?, 15.8?, 16.9?, 17.1?, 17.5?, 18.6?, 19.4?, 19.8?, 20.3?, 20.7?, 21.5?, 21.9?, 23.8?, 24.7?, 25.2?, 26.7?, 27.2?, 27.6?, 28.4?, 29.2?, 29.7?, 30.2?, 31.0?, 31.4?, 32.0?, 32.5?, 33.7?, 35.5?, 35.9?, 36.0?, 37.4?, 38.7? ± 0.2? 2T.

In still another embodiment, the present invention relates to novel crystalline form AL of sodium salt of Sacubitril characterized by a powder X-ray diffraction pattern illustrated by figure-1 or figure-2. The novel crystalline form AL of sodium salt of Sacubitril according to the present invention is either in anhydrous form or in the solvated form.

In yet another embodiment, the present invention relates to process for the preparations of crystalline form AL of Sacubitril sodium comprising steps of:
i) obtaining a solution of Sacubitril in a suitable solvent(s);
ii) adding sodium ion source;
iii) optionally adding suitable anti-solvent; and
iv) isolating crystalline form AL of Sacubitril sodium.

In another embodiment, the solvent used in step (i) is selected from butyl acetate, methyl acetate, ethyl acetate, iso-propyl acetate, THF, dichloromethane, water or mixtures thereof; preferably the use of isopropyl acetate. The solution obtained in step (i) is carried out either 25 + 5oC temperature or by heating the reaction mass of step (i). Further sodium ion source is added and stirred at 20 to 50° C. The process may optionally employ anti-solvent. The solid obtained is filtered and dried to yield the crystalline form AL of sodium salt of Sacubitril. The form thus obtained is stable and has better flow property and hence has advantageous property for further formulation either alone or for the preparation of co-crystal with Valsartan.

In one embodiment, the present invention relates to use of crystalline form AL of sodium salt of Sacubitril in preparation of Sacubitril; Valsartan complex.

In one embodiment, the present invention relates to crystalline form of calcium salt of Sacubitril characterized by a powder X-ray diffraction pattern comprising 2T values (±0.2? 2T) selected from the group consisting of : 3.2?, 6.4?, 7.4?, 7.8?, 8.3?, 9.2?, 9.6?, 10.3?, 11.3?, 11.4?, 11.9?, 12.8?, 14.8?, 15.5?, 16.0?, 16.6?, 16.8?, 17.6?, 18.6?, 19.5?, 20.7?, 21.3?, 22.5?, 22.8?, 23.4?, 25.0?, 25.4?, 26.1?, 27.1?, 27.2?, 28.0?, 29.0?, 29.8?, 32.0?, 34.1?, 35.0?, 35.8?, 37.7?, 39.5? ± 0.2? 2T.

In another embodiment, the present invention relates to amorphous form of calcium salt of Sacubitril characterized by a powder X-ray diffraction pattern illustrated by Figure-3.

In further embodiment, the present invention relates to process for the preparation of amorphous form of Sacubitril calcium comprising steps of:
(i) obtaining a solution of Sacubitril in a suitable solvent(s) or water or mixture thereof;
(ii) adding sodium ion source;
(iii) adding aqueous solution of calcium ion source in the reaction mixture obtained in step (ii);
(iv) optionally adding suitable anti-solvent; and
(v) isolating amorphous form of Sacubitril calcium.

In an embodiment, the solvent used in step (i) is selected from butyl acetate, methyl acetate, ethyl acetate, iso-propyl acetate, THF, dichloromethane, water or mixtures thereof; preferably the use of isopropyl acetate. The solution obtained in step (i) is carried out either at 25 + 5oC temperature or by heating the reaction mass of step (i). Further sodium ion source is added and stirred at 20 to 50° C. To the reaction mixture of step ii) aqueous solution of calcium ion source was added and stirred at 20 to 50° C. The process may optionally employ anti-solvent. The solid obtained was filtered and dried to yield the amorphous form calcium salt of Sacubitril. The form thus obtained is stable and has better flow property and hence has advantages property for further formulation either alone or for the preparation of co-crystal with Valsartan.

In one embodiment, the present invention relates to use of amorphous form of calcium salt of Sacubitril in preparation of Sacubitril; Valsartan complex.

In another aspect, the present invention provides pharmaceutical compositions comprising Sacubitril; Valsartan complex.

Further the present invention provides a process of preparing a pharmaceutical composition of Sacubitril; Valsartan complex which process comprises the step of mixing Sacubitril; Valsartan complex substantially as hereinbefore described together with a pharmaceutically acceptable carrier. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.

Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol. The said polymers/agents are used to facilitate the presence of propylene glycol solvate of Sacubitril; Valsartan complex.

The term "isolation" as used herein includes using but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization, milling or freeze drying techniques.

The term “sodium ion source” as used herein refers to an inorganic or organic salt, oxide, alcoholate, hydride of hydroxide of sodium. The term “sodium source” further refers to sodium hydroxide, sodium bicarbonate, sodium 2-ethyl hexanoate, sodium octanoate, sodium formate, sodium acetate, sodium propionate, sodium butyrate, sodium valerate, sodium caproate, sodium oxalate, sodium lactate, sodium malate, sodium citrate, sodium benzoate, sodium succinate and the like.

The term “calcium ion source” as used herein refers to an inorganic or organic salt, oxide, alcoholate, hydride of hydroxide of calcium. The term “calcium source” further refers to calcium acetate, calcium chloride, calcium carbonate, calcium oxalate, calcium lactate, calcium malate, calcium citrate, calcium phosphate, calcium chloride dihydrate and the like.

The term suitable “solvent” and “anti-solvent” as used herein includes but not limited to water, esters and mixtures thereof.

Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.

To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermograms, thermal gravimetric analyzers thermograms, melting point information, polarized light microscopy, hotstage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.

EXAMPLES
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.

Example-1: Preparation of crystalline form AL of Sacubitril sodium
To a solution of (2S,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride (10 g) in MDC (80 ml) succinic anhydride (3.5 g) was added at about 30-35° C. Triethylamine (4.3 g) was added to reaction mass and the reaction mass was stirred at about 30-35° C for 1 to 3 hours. After completion of reaction, water (90 ml) was charged into reaction mass and organic layer was separated and solvent was distilled under vacuum. Isopropyl acetate (140 ml) was charged into residue and sodium acetate (2.3 g) was added and reaction mass was stirred at about 30-35° C for 3 to 6 hours. The obtained sodium salt was filtered and washed with isopropyl acetate (20 ml). Wet material was dried at 50-60ºC for 6-9 hr to obtain crystalline form AL of Sacubitril sodium (9.8 g). PXRD is illustrated by Figure-1.

Example-2: Preparation of crystalline form AL of Sacubitril sodium
To a solution of (2S,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride (10 g) in MDC (80 ml) succinic anhydride (3.5 g) was added at about 30-35° C. Triethylamine (4.3 g) was added to reaction mass and the reaction mass was stirred at about 30-35° C for 1 to 3 hours. After completion of reaction, water (90 ml) was charged into reaction mass and organic layer was separated and solvent was distilled under vacuum. Isopropyl acetate (140 ml) was charged into residue and sodium acetate (2.3 g) was added and reaction mass was stirred at about 30-35° C for 3 to 6 hours. The obtained sodium salt was filtered and washed with isopropyl acetate (20 ml). Wet material was dried at 40-50ºC for 8-10 hr to obtain crystalline form AL of Sacubitril sodium (9.7 g). PXRD is illustrated by figure-2.

Example-3: Preparation of crystalline form AL of Sacubitril sodium
To a solution of (2S,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride (10 g) in MDC (80 ml) succinic anhydride (3.5 g) was added at about 30-35° C. Triethylamine (4.3 g) was added to reaction mass and the reaction mass was stirred at about 30-35° C for 1 to 3 hours. After completion of reaction, water (90 ml) was charged into reaction mass and organic layer was separated and solvent was distilled under vacuum. Isopropyl acetate (140 ml) was charged into residue and sodium hydroxide was added and reaction mass was stirred at about 30-35° C for 3 to 6 hours. The obtained sodium salt was filtered and washed with isopropyl acetate (20 ml). Wet material was dried at 60-70ºC for 6-9 hr to obtain crystalline form AL of Sacubitril sodium (9.8 g).

Example-4: Preparation of crystalline form AL of Sacubitril sodium
To the solution of Sacubitril (10 g, oil) in Isopropyl acetate (140 ml), sodium acetate (2.3 g) charged and reaction mass was stirred at about 30-35° C for 3 to 6 hours. The obtained sodium salt was filtered and washed with isopropyl acetate (20 ml). Wet material was dried at 50-60ºC for 6-9 hr to obtain crystalline form AL of Sacubitril sodium (9.8 g).

Example-5: Preparation of amorphous form of Sacubitril calcium
To a solution of (2S,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride (10 g) in MDC (80 ml) succinic anhydride (3.5 g) was added at about 30-35° C. Triethylamine (4.3 g) was added at 5-10°C and reaction mass was stirred at 30-35° C till completion of the reaction. After completion of reaction, water (90 ml) was charged into reaction mass and organic layer was separated and solvent was distilled under vacuum. Isopropyl acetate (80 ml) was charged into residue and sodium hydroxide (1.8 g) was added and reaction mass was stirred for 1 to 3 hours. Water (140 ml) was added to reaction mass and layers were separated. Isopropyl acetate (20 ml) was charged into aqueous layer and the reaction mass was stirred for 30 minutes to 2 hr. Layers were separated. To aqueous layer water (20 ml) was added followed by addition of solution of calcium chloride (1.8 g in 100 ml water) and reaction mass was stirred at 25 + 5oC temperature for 2-4 hours. The obtained calcium salt was filtered and washed with water (200 ml). Wet material was dried at 60-70ºC for 12-15 hr under vacuum to obtain amorphous form of Sacubitril calcium (9.8 g). PXRD is illustrated by figure-3.

Example-6: Preparation of amorphous form of Sacubitril calcium
To the solution of Sacubitril sodium (10 g) in water (20 ml), aqueous solution of calcium chloride (1.8 g in 100 ml water) was charged and obtained reaction mass was stirred at 25 + 5oC temperature for 2-4 hours. The obtained calcium salt was filtered and washed with water (200 ml). Wet material was dried at 60-70ºC for 12-15 hr under vacuum to obtain amorphous form of Sacubitril calcium (9.9 g).

Example-7: Preparation of amorphous form of Sacubitril calcium
To a solution of (2S,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride (100 g) in MDC (750 ml), succinic anhydride (35.96 g) was added followed by addition of triethylamine (43.63 g) and the reaction mass was stirred at about 30-35° C for 1 to 3 hours. After completion of reaction, water (500 ml) was charged into reaction mass and organic layer was separated and solvent was distilled under vacuum. Isopropyl acetate (800 ml) and Water (500 ml) was charged into residue and sodium bicarbonate solution (26.6 g in 500 ml water) was added and reaction mass was stirred at about 30-35° C for 1 to 3 hours. After completion of reaction, aqueous layer was separated. Charge isopropyl acetate (10 ml) into the aqueous layer followed by addition of calcium chloride solution (23.24 g calcium chloride dihydrate in 500 ml water) at about 30-35° C and stir for about 5 to 7 hours. The obtained calcium salt was filtered and washed with isopropyl acetate (200 ml) and water (500 ml). Wet material was dried under vacuum to obtain amorphous form of Sacubitril calcium (110 g).

Dated this 26th November 2018

,CLAIMS:We Claim:

1. Crystalline Form AL of Sacubitril sodium characterized by following PXRD diffraction pattern peaks having two theta at 5.2?, 8.8?, 10.5?, 20.7? ± 0.2? 2T.

2. The crystalline Form AL of Sacubitril sodium as claimed in claim 1 which is further characterized by following PXRD diffraction pattern peaks having two theta at 5.2?, 8.8?, 10.5?, 12.3?, 14.7?, 15.8?, 16.9?, 17.5?, 19.4?, 19.8?, 20.3?, 20.7?, 21.5?, 21.9?, 26.7? ± 0.2? 2T.

3. A process for preparation of crystalline Form AL of Sacubitril sodium comprising the steps of:
(i) obtaining a solution of Sacubitril in a suitable solvent(s);
(ii) adding sodium ion source;
(iii) optionally adding suitable anti-solvent; and
(iv) isolating crystalline form AL of Sacubitril sodium.

4. A process for preparation of amorphous form of Sacubitril calcium comprising the steps of:
(i) obtaining a solution of Sacubitril in a suitable solvent(s) or water or mixture thereof;
(ii) adding sodium ion source;
(iii) adding aqueous solution of calcium ion source in the reaction mixture obtained in step (ii);
(iv) optionally adding suitable anti-solvent; and
(v) isolating amorphous form of Sacubitril calcium.

5. The process as claimed in step (i) of claim 3 or step (i) of claim 4 wherein suitable solvent(s) selected from ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, water or mixture thereof.

6. The process as claimed in step (ii) of claim 3 or step (ii) of claim 4 wherein sodium ion source is selected from sodium hydroxide, sodium bicarbonate, sodium 2-ethyl hexanoate, sodium octanoate, sodium formate, sodium acetate, sodium propionate, sodium butyrate, sodium valerate, sodium caproate, sodium oxalate, sodium lactate, sodium malate, sodium citrate, sodium benzoate and sodium succinate.

7. The process as claimed in step (iii) of claim 4 wherein calcium ion source is selected from oxide, alcoholate, hydride of hydroxide of calcium, calcium acetate, calcium chloride, calcium carbonate, calcium oxalate, calcium lactate, calcium malate, calcium citrate, calcium phosphate, calcium chloride dihydrate.

8. The process as claimed in step (iii) of claim 3 or step (iv) of claim 4 wherein suitable anti-solvent selected from ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, water or mixture thereof.

9. The process as claimed in step (iv) of claim 3 or step (v) of claim 4 wherein isolation techniques selected from distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization, milling and freeze drying.

Dated this 26th November 2018