DESC:“CRYSTALLINE FORM OF TRISODIUM SACUBITRIL VALSARTAN HYDRATE AND A PROCESS FOR PREPARATION THEREOF”

FIELD OF INVENTION:

The present invention relates to a novel crystalline form of a trisodium Sacubitril valsartan hydrate, which have been designated by us Form P. Particularly, present invention relates to a process for the preparation of crystalline form P of a trisodium Sacubitril valsartan.

BACKGROUND OF INVENTION:

The trisodium hemipenta hydrate cocrystal complex of Sacubitril Valsartan in 1:1 molar ratio, is a combination drug, marketed under the trade name ENTRESTO® by Novartis. Sacubitril valsartan is also known as LCZ696. Chemically complex of Sacubitril Valsartan Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl] amino}-4-oxobutanoate) hexakis (N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl) [1,1´ -biphenyl]-4-yl] methyl}-L-valinate)-water (1/15) and has the following structural formula

Formula I

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.

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 Sacubitril valsartan hemipentahydrate crystalline form. which is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at 4.45, 5.52, 5.57, 9.94, 12.82, 15.66, 17.01, 17.12, 17.2, 18.32, 18.46, 19.76, 21.53, 21.72, 23.27,24.88, 25.3, 27.4, 27.88, 28.04 and 30.2 degrees of two-theta and hemipentahydrate can be further characterized by water content 4.67 at 179oC.

The crystalline hemipentahydrate is further characterized by an infrared absorption spectrum comprising peak 3061, 2930, 1612, 1523, 1461, 1427, 1287, 1195, 1108, 1153, 1041, 1011, 997, 866, 850, 822, 808, 735, 715, 669, 643, 631, 618, 602, 557, 522, 453, 410 and 328

US 10,689,352 B2 describes complex of trisodium Sacubitril valsartan crystalline from II and its process comprises combining trisodium Sacubitril valsartan with aromatic solvent, preferably toluene or methyl benzoate.

US 9957240 of Crystal pharmatech describes Crystalline Form I, II and III of trisodium Sacubitril valsartan hydrate.

US10857132B2 discloses a stable amorphous form of Sacubitril valsartan trisodium complex with fluid bed drying or freeze-drying technique.

WO 2016/051393 A1 discloses a formulation comprising a unit dosage of crystalline Form IV of trisodium salt of Sacubitril valsartan complex hydrate and one or more excipients.

WO 2017/009784 A1 discloses composition comprising an amorphous trisodium salt of Sacubitril valsartan complex and composition comprising crystalline Form II or Form IV of trisodium salt of Sacubitril valsartan complex.

WO 2017/037596 A1 discloses an amorphous solid dispersion of Sacubitril valsartan complex with one or more carrier.

WO 2016125123 discloses amorphous trisodium Sacubitril valsartan.

Though one crystalline form of the supramolecular complex comprising valsartan and AHU-377 has been reported to exist as a trisodium hemipentahydrate form in U.S. Pat. No. 8,877,938 B2 (the “patent form”), in the present invention describes new crystalline form of the supramolecular complex comprising trisodium Sacubitril valsartan hydrate.
The new crystalline polymorph of the present invention is a hydrate form and could contain up to 5 to 7% water. The invention also provides processes for their particular stable polymorphs with superior pharmacological activities suitable for formulation, and convenient methods to prepare them remain a great need.

In continuation of our studies on the synthesis of new crystalline forms of trisodium Sacubitril valsartan hydrate, we have discovered that new crystalline form herein designated as Form P can be isolated from ecological friendly solvents and has a good thermal stability combined with good solubility characteristics.

SUMMARY OF INVENTION:

The present invention relates to a new crystalline of trisodium Sacubitril valsartan hydrate designated as Form P. The present invention also relates to process for the preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate with high purity and yield.

One aspect of the present invention is to provide crystalline Form P of trisodium Sacubitril valsartan hydrate, which is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 4.17, 4.91, 12.52, 16.91, 20.10 ± 0.2 degrees of two-theta.

Another aspect of the present invention is to provide a process for the preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 4.17, 4.91, 12.52, 16.91, 20.10 ± 0.2 degrees of two-theta, comprising the steps of:

a) providing a solution or suspension of valsartan and Sacubitril in a solvent;
b) treating the product obtained in step-a) with sodium hydroxide solution; and
c) isolating the crystalline Form P of trisodium Sacubitril valsartan hydrate.

wherein the solvent selected from ester, ketone, alcohol such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and isopropyl acetate, acetone, methanol, ethanol, isopropanol or mixture thereof.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig 1: X-ray powder diffraction (PXRD) of crystalline Form P of trisodium Sacubitril valsartan hydrate.

Fig 2: Infrared spectroscopy (IR) of crystalline Form P of trisodium Sacubitril valsartan hydrate.

DETAILED DESCRIPTION OF INVENTION:

The present invention relates to a new crystalline Form P of trisodium Sacubitril valsartan hydrate. The present invention also relates to process for the preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate with high purity and yield.

One embodiment of the present invention is to provide new crystalline Form P of trisodium Sacubitril valsartan hydrate, which is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 4.17, 4.91, 12.52, 16.91, 20.10 ± 0.2 degrees of two-theta.

The new polymorph Form P displays a sharp peak at 4.17, 12.52 and a very strong peak at 4.17 Its powder XRD spectrum is reproduced in FIG I displays addition characteristic 2? (± 0.2) values of 4.91, 16.91, 20.10.

According to the embodiment of the present invention is further characterised by its X-Ray powder diffraction pattern having additional peaks at about 4.17, 4.91, 5.99, 8.34, 9.08, 10.24, 12.52, 13.33, 13.97, 15.33, 16.01, 16.91, 17.64, 19.34, 20.10, 20.84, 22.57, 24.24, 26.34, 27.10, 29.18. 30.59 ± 0.2 degrees of two-theta.

The crystalline Form P of the present invention is further characterized by the PXRD pattern as illustrated in Figure-1.

The crystalline Form P is further characterized by an infrared absorption spectrum comprising peaks at about 3401.33, 3114.09, 3009.06, 2958.95, 2355.74, 1712.75, 1690.25, 1638.75, 1599.57, 1497.81, 1487.93, 1480.81, 1435.51, 1403.05, 1315.03 1296.23, 1266.89, 1213.19, 1176.33, 1150.02, 1085.64, 1045.47, 1010.08, 923.9, 763.88, 742.29, 698.79, 560.13 cm-1. The crystalline Form P of the present invention is further characterized by the Infrared spectroscopy (IR spectroscopy) as illustrated in Figure-2.

According to present invention, Form P can be further characterized by water content within the range of 5 to 8 %, preferably 5-7 %.

Another embodiment of the present invention is to provide a process for the preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 4.17, 4.91, 12.52, 16.91, 20.10 ± 0.2 degrees of two-theta, comprising the steps of;

a) providing a solution or suspension of valsartan and Sacubitril in a solvent;
b) treating the product obtained in step-a) with sodium hydroxide solution; and
c) isolating the crystalline Form P of trisodium Sacubitril valsartan hydrate.

According to an embodiment of the present invention, wherein the solvent selected from ester, ketone, alcohol such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and isopropyl acetate, acetone, methanol, ethanol, isopropanol or mixture thereof.

In an embodiment of the present invention provides, a solution of Sacubitril and valsartan in ester solvent, followed by treated with sodium hydroxide solution (NaOH in alcohol solvent) at below 10°C for 1-5 hrs, preferably at 0-5°C for 1-2 hrs to get supramolecular complex of trisodium Sacubitril valsartan hydrate, which is isolation from organic solvent at 40-45°C to get highly pure crystalline Form P of trisodium Sacubitril valsartan hydrate.

According to an embodiment of the present invention, wherein the alcohol solvent is methanol, ethanol, propanol, butanol and isopropyl alcohol.

According to an embodiment of the present invention, wherein the organic solvent is ethyl acetate, hexane, heptane, acetone, dichloromethane, dimethylformamide and Dimethyl sulfoxide.

Comparison of Form P and hemipentahydrate of U.S. Pat. No. 8,877,938

The X-Ray diffraction and IR peaks of Form P and hemipentahydrate are summarized in the following table.

Comparison of XRD

Present invention (Form P)- 2? values
US 8877938 -Sacubitril valsartan trisodium hemipentahydrate-2? values
4.17 -
- 4.45
4.91 -
- 5.52
- 5.57
5.99 -
8.34 -
9.08 -
- 9.94
10.24 -
12.52 -
- 12.82
13.33 -
13.97 -
15.33 -
- 15.66
16.01 -
16.91 -
- 17.01
- 17.12
- 17.2
17.64 -
- 18.32
- 18.46
18.78 -
19.34 -
- 19.76
20.10 -
20.84 -
- 21.53
- 21.72
22.57 -
23.27
24.24 -
- 24.88
- 25.3
26.34 -
27.1 -
- 27.4
- 27.88
- 28.04
29.18 -
30.2
30.59 -

Comparison of IR

Present invention (IR) US 8877938 -Sacubitril valsartan trisodium hemipentahydrate (IR)
3400.98 -
3114.05 -
3058.6 3061
3010.44 --
2958.42 -
- 2930
1868.57 -
1712.99 -
1691.44 -
1638.92 -
1618.43 -
- 1612
1599.33 -
- 1523
1498.54 -
1487.7 -
1480.72 -
1459.6 1461
1435.77 -
- 1427
1403.7 -
1333.3 -
- 1287
1266.73 -
1195
1176.62 -
1108
1149.3 1153
1085.77 -
1045.35 1041
1010.09 1011
997
921.1 -
- 866
- 850
- 822
- 808
762.98 -
751.9 -
742.32 -
- 735
- 715
709.12 -
698.57 -
680.29 -
- 669
- 643
- 631
- 618
- 602
560.83 557
- 522
- 453
- 410
- 328

Comparison of TGA:

Test Present invention (Form P) US 8877938 B2
TGA 6-7 4.67

The difference between crystalline Sacubitril valsartan trisodium hemipentahydrate which is disclosed in US 8877938 and Form P of the present invention can be clearly seen when the X-Ray diffraction and IR peaks of the corresponding Forms are compared. Moreover, Form P of the present invention has 2? peak values are at 4.17, 4.91, 12.52, 16.91, 20.10 ±0.2°? which are not present in crystalline Sacubitril valsartan trisodium hemipentahydrate.

Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form) and are well known in the pharmaceutical art to affect, for example, the solubility, stability, followability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

Crystalline Form-P of trisodium Sacubitril valsartan hydrate produced by the process of the present invention is different from Sacubitril valsartan trisodium hemipentahydrate.

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

Example

Examplep-1:

Preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate

Ethyl acetate, Sacubitril calcium (100g), purified water were added into RB Flask and followed by dropwise addition of aqueous HCl solution to the mixture at 25-30°C. The obtained reaction mixture was stirred for 10 minutes and separate the layers. Take product layer, washed with purified water and extracted with ethyl acetate, again washed with purified water at 25-30°C. Further addition of valsartan (100g) into reaction mass, stirred for 10 minutes at 25-30°C.
The resultant reaction mass was filtered and cooled to 0-10°C. Slowly addition of sodium hydroxide solution (NaOH in methanol) to the reaction mass at 0-5°C for 1-2 hours and raised to 30-40°C, stirred for 60 minutes and then distilled out the ethyl acetate solvent under vacuum at below 45°C and cooled to room temperature. The obtained solid was filtered and washed with ethyl acetate then dried to get pure crystalline Form P of trisodium Sacubitril valsartan hydrate (wt.: ~250-300 g).
Purity: 99.98% by HPLC

Example -2
Preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate

Acetone, of Sacubitril calcium (100g), purified water were added into RB Flask and followed by dropwise addition of aqueous HCl solution to the mixture at 25-30°C. The obtained reaction mixture was stirred for 10 minutes and separate the layers. Take product layer, washed with purified water and extracted with acetone, again washed with purified water at 25-30°C. Further addition of valsartan (100g) into reaction mass, stirred for 10 minutes at 25-30°C.
The resultant reaction mass was filtered and cooled to 0-10°C. Slowly addition of sodium hydroxide solution (NaOH in ethanol) to the reaction mass at 0-5°C for 1-2 hours and raised to 30-40°C, stirred for 60 minutes and then distilled out the acetone solvent under vacuum at below 45°C and cooled to room temperature. The obtained solid was filtered and washed with acetone then dried to get pure crystalline Form P of trisodium Sacubitril valsartan hydrate (wt.: ~250-300 g).

Purity: 99.96% by HPLC

Example -3
Preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate

Mixture of ethyl acetate /isopropanol, Sacubitril calcium (100g), purified water were added into RB Flask and Followed by dropwise addition of aqueous HCl solution to the mixture at 25-30°C. The obtained reaction mixture was stirred for 10 minutes and separate the layers. Take product layer, washed with purified water and extracted with ethyl acetate, again washed with purified water at 25-30°C. Further addition of valsartan (100g) into reaction mass, stirred for 10 minutes at 25-30°C.
The resultant reaction mass was filtered and cooled to 0-10°C. Slowly addition of sodium hydroxide solution (NaOH in methanol) to the reaction mass at 0-5°C for 1-2 hours and raised to 30-40°C, stirred for 60 minutes and then distilled out the ethyl acetate solvent under vacuum at below 45°C and cooled to room temperature. The obtained solid was filtered and washed with ethyl acetate then dried to get pure crystalline Form P of trisodium Sacubitril valsartan hydrate (wt.: ~250-300 g).

Purity: 99.97% by HPLC
,CLAIMS:WE CLAIM:

1. A crystalline Form P of trisodium Sacubitril valsartan hydrate, which is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 4.17, 4.91, 12.52, 16.91, 20.10 ± 0.2 degrees of two-theta.

2. The crystalline Form P of trisodium Sacubitril valsartan hydrate as claimed in claim 1, which is characterised by its X-Ray powder diffraction pattern having additional peaks at about 4.17, 4.91, 5.99, 8.34, 9.08, 10.24, 12.52, 13.33, 13.97, 15.33, 16.01, 16.91, 17.64, 19.34, 20.10, 20.84, 22.57, 24.24, 26.34, 27.10, 29.18. 30.59 ± 0.2 degrees of two-theta.

3. The crystalline Form P of trisodium Sacubitril valsartan hydrate as claimed in claim 1, which is characterized by an infrared absorption spectrum comprising peaks at about 3401.33, 3114.09, 3009.06, 2958.95, 2355.74, 1712.75, 1690.25, 1638.75, 1599.57, 1497.81, 1487.93, 1480.81, 1435.51, 1403.05, 1315.03 1296.23, 1266.89, 1213.19, 1176.33, 1150.02, 1085.64, 1045.47, 1010.08, 923.9, 763.88, 742.29, 698.79, 560.13 cm-1.

4. The crystalline Form P of trisodium Sacubitril valsartan hydrate as claimed in claim 1, having water content within the range of 5 to 8 %, preferably 5-7 %.

5. A process for the preparation of crystalline Form P of trisodium Sacubitril valsartan hydrate, comprising the steps of:

a) providing a solution or suspension of valsartan and Sacubitril in a solvent;
b) treating the product obtained in step-a) with sodium hydroxide solution; and
c) isolating the crystalline Form P of trisodium Sacubitril valsartan hydrate.

6. The process as claimed in claim 5, wherein step a) the solvent is selected from ester, ketone, alcohol such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and isopropyl acetate, acetone, methanol, ethanol, isopropanol or mixture thereof.

7. The process as claimed in claim 5, wherein the alcohol solvent is methanol, ethanol, propanol, butanol and isopropyl alcohol.

8. The process as claimed in claim 5, wherein the organic solvent is ethyl acetate, hexane, heptane, acetone, dichloromethane, dimethylformamide and Dimethyl sulfoxide.