DESC:F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(Section 10, rule 13)

POLYMORPHIC FORMS OF SACUBITRIL-TELMISARTAN (1:1)

Mylan Laboratories Limited,
Plot No. 564/A/22,
Road No. 92, Jubilee Hills,
Hyderabad, 500034
India

The following specification particularly describes the invention and the way it is to be performed.

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is cognate of earlier filed Indian Provisional Patent Application No. IN 202141018214 filed on April 20, 2021 and IN 202141026619 filed on June 15, 2021.

FIELD OF THE INVENTION
The present invention provides polymorphic forms of Sacubitril-Telmisartan and amorphous solid dispersion.

BACKGROUND OF THE INVENTION
Sacubitril, chemically known as 4-[[ -1-(biphenyl-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl] amino]-4-oxobutanoic acid represented in Formula I;

Telmisartan, chemically known as 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimid-azol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid are represented in Formula II.

Sacubitril and its pharmaceutically acceptable salts thereof is known in US 5,217,996.
Telmisartan product is known in the US 5,591,762 and Telmisartan Form A is known in US 6,358,986 B1.
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.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to provide crystalline and amorphous form, amorphous solid dispersion of Sacubitril-Telmisartan and also process for the preparation of the same.

In another aspect, the present invention provides an amorphous form of Sacubitril-Telmisartan (1:1).

In one more aspect, the present invention provides an amorphous solid dispersion of Sacubitril-Telmisartan (1:1).

In another aspect, the present invention provides a process for the preparation of amorphous form of Sacubitril-Telmisartan comprising the steps of:
a) dissolving Sacubitril and Telmisartan in a suitable solvent or mixtures thereof; and
b) removing the solvent to isolate amorphous Sacubitril-Telmisartan.

In one more aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of Sacubitril-Telmisartan comprising the steps of:
a) taking Sacubitril; Telmisartan and a pharmaceutically acceptable excipient in suitable solvent or mixtures thereof; and
b) removing the solvent to isolate amorphous solid dispersion of Sacubitril-Telmisartan

In another aspect, the present invention provides crystalline form I of Sacubitril-Telmisartan.
In one more aspect, the present invention also provides a process for the preparation of crystalline form I of Sacubitril-Telmisartan comprising the steps of:
a) taking Sacubitril-Telmisartan into a suitable solvent or mixtures thereof; and
b) filtering the solvent to isolate crystalline form I of Sacubitril-Telmisartan.

In another aspect, the present invention also provides a process for the preparation of crystalline form I of Sacubitril-Telmisartan comprising the steps of:
a) dissolving Sacubitril-Telmisartan in a first solvent; and
b) optionally seeding with crystalline Form I seeds of Sacubitril-Telmisartan;
c) adding a second solvent; and
d) filtering to isolate crystalline form I of Sacubitril-Telmisartan.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying figures wherein:
FIGURE 1: PXRD pattern of amorphous form of Sacubitril-Telmisartan obtained as per Example 1.
FIGURE 2: PXRD pattern of amorphous form of Sacubitril-Telmisartan obtained as per Example 2.
FIGURE 3: PXRD pattern of amorphous solid dispersion of Sacubitril-Telmisartan obtained as per Example 3.
FIGURE 4: PXRD pattern of amorphous solid dispersion of Sacubitril-Telmisartan obtained as per Example 4.
FIGURE 5: PXRD pattern of amorphous solid dispersion of Sacubitril-Telmisartan obtained as per Example 5.
FIGURE 6: PXRD pattern of crystalline form I of Sacubitril-Telmisartan obtained as per Example 6.
FIGURE 7: PXRD pattern of crystalline form I of Sacubitril-Telmisartan obtained as per Example 7.
FIGURE 8. Modulated DSC plot of Sacubitril-Telmisartan (1:1) Amorphous Form.
FIGURE 9: DSC thermogram of crystalline Sacubitril-Telmisartan (1:1) Form I.
FIGURE 10: TGA/DTA analysis of crystalline Sacubitril-Telmisartan (1:1) Form I.
FIGURE 11: FT-IR spectra of Sacubitril.
FIGURE 12: FT-IR spectra of Telmisartan Form A.
FIGURE 13: FT-IR spectra of amorphous Sacubitril-Telmisartan.
FIGURE 14: FT-IR spectra of crystalline Form I Sacubitril-Telmisartan.

DETAILED DESCRIPTION OF THE INVENTION
The principal object of the present invention is to provide processes for the preparation of crystalline form I and an amorphous form of Sacubitril-Telmisartan; amorphous solid dispersion of Sacubitril-Telmisartan and process for the preparation of the same.

Instrumentation Details:
Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns of said polymorphs of the present invention were measured on BRUKER D8 Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
MDSC
The glass transition temperature (Tg) was measured on TA Q2000 of TA instruments with modulated DSC software. The sample was heated from 30 to 300ºC at a heating rate of 5.0°C/min with modulation amplitude ±1.0°C, modulation period 60 sec and nitrogen purging at a flow rate of 50ml/min. Standard aluminum pans covered by lids with one pinhole was used.
DSC
DSC was recorded using TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 20°C-300°C purging with nitrogen at a flow rate of 50 ml/min. Standard aluminum pans covered by lids with five pinholes were used.

TGA
TGA was recorded using TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 20°C-300°C purging with nitrogen at a flow rate of 25 ml/min. Standard aluminum pans covered by lids with five pin holes were used.
FT-IR
The FT-IR data was recorded using Perkin Elmer spectrum one instrument in the range of 400-4000 cm-1 by using KBr pellets.
Water Content
Water content for Sacubitril-Telmisartan (1:1) amorphous complex and crystalline Sacubitril-Telmisartan (1:1) Form I were determined on Metrohm Karl-Fisher titrator (Model: 841 titrando) using dehydrated methanol and a 1:1 methanol-DMF mixture. For the determination of water content in sample, 40 ml of dehydrated methanol was placed in the titration vessel and titrated with standardized reagent to get the electrometric end point. 0.25 gram of sample were added, stirred for 1 minute and titrated to the end point with KF reagent. For each determination fresh methanol was used.

In one embodiment, Sacubitril-Telmisartan of the present invention is as shown below is a complex of Sacubitril-Telmisartan (1:1).

The amorphous solid dispersion of Sacubitril-Telmisartan is a complex of Sacubitril-Telmisartan and an excipient (1:1).

The present invention is directed to dual-acting compound where it constituent Sacubitril and Telmisartan molecules are linked via non-covalent bonding, or a supramolecular complex comprising said molecules, also described as mixed salts or cocrystals, depending on the degree of transfer of the proton from the proton donor to the acceptor, linking the two constituent molecules by hydrogen bonding - known examples of such multi-drug, fixed dose combination products being Entresto (valsartan-Sacubitril) and Seglentis (1:1 tramadol hydrochloride-celecoxib complex).
In one embodiment, the present invention provides amorphous form of Sacubitril-Telmisartan.

One embodiment of this invention is a solid phase comprising a 1:1 amorphous complex of Sacubitril and Telmisartan, characterized by a single glass transition in modulated DSC, a distinct halo-like PXRD pattern indicating an amorphous phase and significant shifts in the IR absorption bands compared to the constituent molecules- corresponding to strong hydrogen bonding interactions.

In one embodiment, the amorphous form of Sacubitril-Telmisartan disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG.1 & FIG 2.

In one embodiment, the present invention provides a process for the preparation of amorphous form of Sacubitril-Telmisartan comprising the steps of:
a) dissolving Sacubitril and Telmisartan in a suitable solvent or mixtures thereof; and
b) removing the solvent to isolate amorphous Sacubitril-Telmisartan.

According to the present invention, Sacubitril and Telmisartan are dissolved in a suitable solvent or mixtures thereof. The suitable solvent for dissolving includes, but not limited to polar solvents and non-polar solvents. Polar solvents such as methanol, ethanol, propanol, isopropanol, butanol, trifluroethanol, hexafluro-2-propanol, water, dimethyl sulfoxide and non-polar solvents such as dichloromethane, toluene. Preferably mixture of solvents; more preferably mixture of methanol and dichloromethane. The suitable temperature for dissolving is selected from 20-35°C; preferably 23-27 °C.

Next, the solvent is removed from the above resulting Sacubitril-Telmisartan solution to isolate amorphous Sacubitril-Telmisartan. The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by distillation, evaporation, spray drying, lyophilization, freeze drying or by agitated thin film drier.

In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of Sacubitril-Telmisartan.
In one embodiment, the pharmaceutical excipient for the solid dispersion of Sacubitril-Telmisartan may include diluents, lubricants, binders, glidants, stabilizers, surface active agents, anti-adherents, opacifiers, solvents, colorants, lubricants, pigments, anti-foam agents, and polishing agents. In some embodiments, microcrystalline cellulose, polysorbate, mannitol, and hydroxypropyl alkylcellulose, hydroxypropyl alkylcellulose acetate succinate, hydroxypropyl alkylcellulose acetate succinate L-type M-type and H-type grades are found to be particularly useful excipients. Within the context of the present invention, the excipient or combinations of excipients may be included in the formulation.
In another embodiments, the preferable pharmaceutical excipients for the amorphous solid dispersion of Sacubitril-Telmisartan is ethyl cellulose, Plasdone S-630 and Povidone-K30.
In one embodiment, the amorphous solid dispersion of Sacubitril-Telmisartan and ethyl cellulose disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG.3.
In one embodiment, the amorphous solid dispersion of Sacubitril-Telmisartan and Plasdone S-630 disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG.4.
In one embodiment, the amorphous solid dispersion of Sacubitril-Telmisartan and Povidone-K30 disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG 5.
In one more embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of Sacubitril-Telmisartan (1:1).
In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of Sacubitril-Telmisartan comprising the steps of:
a) taking Sacubitril; Telmisartan and a pharmaceutically acceptable excipient in suitable solvent or mixtures thereof; and
b) removing the solvent to isolate amorphous solid dispersion of Sacubitril-Telmisartan

According to the present invention, Sacubitril; Telmisartan and a pharmaceutically acceptable excipient are dissolved in a suitable solvent or mixtures thereof. The suitable solvent for dissolving includes, but not limited to polar solvents and non-polar solvents. Polar protic solvents such as methanol, ethanol, trifluroethanol, hexafluro-2-propanol, propanol, isopropanol, butanol, water, dimethyl sulfoxide and non-polar solvents such as dichloromethane, toluene, preferably mixture of solvents; more preferably mixture of methanol and dichloromethane. The suitable temperature for dissolving is selected from 20-35°C; preferably 23-27 °C.
In one embodiment, the pharmaceutical excipient may include diluents, lubricants, binders, glidants, stabilizers, surface active agents, anti-adherents, opacifiers, solvents, colorants, lubricants, pigments, anti-foam agents, and polishing agents. In some embodiments, microcrystalline cellulose, polysorbate, mannitol, and hydroxypropyl alkylcellulose, hydroxypropyl alkylcellulose acetate succinate, hydroxypropyl alkylcellulose acetate succinate L-type, M-type and H-type grades are found to be particularly useful excipients. Within the context of the present invention, the excipient or combinations of excipients may be included in the formulation.
Examples of useful pharmaceutical excipients within the context of the present invention include starches, lactose, mannitol (for example, Pearlitol™ SD200), cellulose and cellulose derivatives, and confectioner's sugar. Different forms of lactose may be useful in the context of the present invention, for example, lactose monohydrate, lactose DT (direct tableting), and lactose anhydrous. Different forms of starches may be used in the context of the present invention, for example, maize starch, potato starch, rice starch, wheat starch, pre-gelatinized starch, starch 1500, starch 1500 LM grade, and fully pre-gelatinized starch. Examples of suitable cellulose compounds for use in the context of the present invention include crystalline celluloses, such as Ceolus™ KG-801, and a variety of Avicel™ celluloses (for example, PH-101, PH-102, PH-301, PH-302, PH-F20, PHI-12, PH-114, and PH-112). Powdered celluloses may be used as well. Other useful cellulose derivatives include hydroxypropylcellulose (HPC examples include Klucel ™ LF and Klucel™ EXF), low-substituted hydroxypropylcelluloses (L-HPCS examples include LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30, LH-32 and LH-33), hydroxypropyl alkyl cellulose (also called hypromellose or HPMC, HPMC-AS (hydroxypropyl alkylcellulose acetate succinate including L-type M-type and H-type grades) one example is Methocel™). Other suitable binders/disintegrants include polyvinylpyrrolidones (also called povidone; examples include PVP-K25, PVP-K29, PVP-K30, and PVP-K90), copovidone (for example, Plasdone™ S-630). Other suitable excipients include powdered acacia, gelatin, guar gum, sodium starch glycolate, colloidal silicon dioxide, carbomers (for example, Carbopol™), alkylcelluloses, polymethacrylates, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, and crospovidones (for example, cross-linked povidone, Kollidon™ CL Polyplasdone™ XL, XI- I 0, and INF- 10). Further examples of suitable excipients include sorbitan esters (for example, Span™), polyhydroxyethylenically-treated sorbitan esters (for example, Tween™), aliphatic alcohols and polyethylene glycol (PEG) ethers, phenol and PEG ethers, quaternary ammonium salts (e.g., cetyltrimethylammonium bromide), amine salts (for example, octadecylamine Hydrochloride), stearates (for example, glyceryl monostearates, polyoxyethylene monostearates, ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sodium stearate, potassium stearate, ammonium stearate, calcium stearate, sodium stearate, triethenolamine stearate, zinc stearate, and magnesium stearate), sodium lauryl sulfate, magnesium lauryl sulfate, calcium and sodium soaps, sodium dioctylsulfosuccinate, sodium dodecylbenzenesulfonate, palmitic acid, talc, carnauba wax, silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and combinations thereof. Phospholipids (e.g., diacylphosphatidylglycerols, diaceylphosphatidylcholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as soybean lecithin and egg yolk) may also be used. Examples of suitable pigments include titanium oxide, silicon dioxide, iron oxides, zinc oxide, and combinations thereof. Suitable plasticizers include, as examples, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, polyethylene glycol 6000, stearic acid, propylene glycol, triacetin, and triethyl citrate. Suitable basic inorganic salts of sodium, potassium, magnesium, and calcium (e.g., sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, potassium hydrogen carbonate, potassium hydroxide, heavy magnesium carbonate, magnesium, [Mg6Al(OH)16·CO3·4H2O], aluminum hydroxide-magnesium, and [2.5MgO·Al2O3·H2O] may be include in the formulation as well.
Many of the excipients listed above can act in a multitude of functional roles (e.g., starches can act both as a disintegrates and a binder depending on the formulation) to dictate the final properties of the desired product. One of skill in the art will readily recognize these various functional aspects of each excipient and be able to incorporate, without undue experimentation, an excipient, or combinations of excipients to achieve the desired final product.
In another embodiment, ethyl cellulose, Plasdone S-630 and Povidone-K30 have been found to particularly useful excipients for preparing an amorphous solid dispersion of Sacubitril and Telmisartan.
Next, the solvent is removed from the above resulting Sacubitril-Telmisartan solution to isolate amorphous Sacubitril-Telmisartan solid dispersion. The solvent removal of the above embodiment may carried out according to the methods well known in the art, for example, by distillation, evaporation, spray drying, lyophilization, freeze drying or by agitated thin film drier.
In one more embodiment, the present invention provides crystalline form I of Sacubitril-Telmisartan.
Yet another embodiment of this invention is a 1:1 crystalline complex of Sacubitril and Telmisartan designated as Form I, characterized by a single melting endotherm in DSC and a crystalline PXRD pattern, both distinct from either of the constituent molecules and significant shifts in the IR absorption bands compared to the constituent molecules-corresponding to strong hydrogen bonding interactions, and containing water in the range of 1.5% to 2.5% indicating that it is a hydrate, preferably a monohydrate.
In one embodiment, the crystalline form I of Sacubitril-Telmisartan disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG.6 & FIG.7.
Within the context of the present invention, the crystalline form I of Sacubitril-Telmisartan disclosed herein may be characterized by PXRD spectrum having peaks 4.50, 16.53, 20.09, 24.32, 24.74 ±0.2° 2?.
In one embodiment of the present invention, the crystalline form I of Sacubitril-Telmisartan disclosed herein may be further characterized by PXRD spectrum having peaks 4.50, 12.78, 16.53, 18.95, 20.09, 20.97, 24.32, 24.74, 25.71 ±0.2° 2?.
In one more embodiment, the present invention also provides a process for the preparation of crystalline form I of Sacubitril-Telmisartan comprising the steps of:
a) taking Sacubitril-Telmisartan into a suitable solvent or mixtures thereof; and
b) filtering the solvent to isolate crystalline form I of Sacubitril-Telmisartan.
Within the context of the present invention, the Sacubitril-Telmisartan is taken into suitable solvent or mixtures thereof. The Sacubitril-Telmisartan of this embodiment may in an amorphous form and may further dissolved or suspended in suitable solvent or mixtures thereof. The suitable solvent for the dissolution or suspension is selected from organic solvents, but not limited to non-polar solvents such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, cylcopentyl methyl ether, toluene, xylene or mixtures thereof. The reaction is maintained at 0 °C to reflux temperature, preferably at room temperature. The reaction mixture is stirred for 30 min to-24 hrs; preferably 1-5 hrs; more preferably 2-3 hrs.
Next, the solvent is removed by filtering from the above resulting Sacubitril-Telmisartan mixture to isolate the solid of Sacubitril-Telmisartan. The solid may be further processed by drying to obtain crystalline form I of Sacubitril-Telmisartan.
In one more embodiment, the present invention also a provides a process for the preparation of crystalline form I of Sacubitril-Telmisartan comprising the steps of:
a) dissolving Sacubitril-Telmisartan into a first solvent or mixtures thereof; and
b) optionally seeding with crystalline Form I seeds of Sacubitril-Telmisartan;
c) adding a second solvent; and
d) filtering the solvent to isolate crystalline form I of Sacubitril-Telmisartan.

Within the context of the present invention, the Sacubitril-Telmisartan is dissolved into suitable first solvent and optionally seeded with Form I seeds and further added a second solvent and maintained the reaction for completion. After completion of the reaction, the reaction mass was filtered to isolate crystalline Form I of Sacubitril-Telmisartan. The suitable first and second solvents are selected from organic solvents. The first solvent is selected from alcoholic solvents such as methanol, ethanol, propanol, isopropanol; halogenated solvents selected from dichloromethane, trifluroethanol, trichloro ethanol, and hexafluroisopropanol. The second solvents selected from non-polar solvents such heptane, diethyl ether, isopropyl ether, cylcopentyl methyl ether; preferably; the suitable first solvent is dichloromethane and the second solvent is heptane.
The reaction is maintained at 0 °C to reflux temperature, preferably at room temperature. The reaction mixture is stirred for 30 min to-24 hrs; preferably 1-5 hrs; more preferably 2-3 hrs.
The Sacubitril-Telmisartan of this embodiment may in an amorphous form and may further dissolved or suspended in suitable solvent or mixtures thereof.
Next, the solvent is removed by filtering from the above resulting Sacubitril-Telmisartan mixture to isolate the solid of Sacubitril-Telmisartan. The solid may be further processed by drying to obtain crystalline form I of Sacubitril-Telmisartan.

DSC studies:
MDSC analysis (Figure 8) of the Sacubitril-Telmisartan (1:1) amorphous complex shows a single glass transition at Tg = 62.95°C, which indicates that it is a single, unique phase.
Similarly, DSC overlay (Figure 9) of crystalline Sacubitril-Telmisartan (1:1) Form I shows one endothermic peak at about 88°C. The later events seen in the thermogram of crystalline Sacubitril-Telmisartan (1:1) Form I may be attributed to the recrystallization of Telmisartan Form A.

TGA analysis:
TGA analysis of crystalline Sacubitril-Telmisartan (1:1) Form I (Figure 10) shows about 2.5% weight loss at around 80°C, which is matching with the water content determined by Karl Fischer titration (Table 1).
Water content:
The Sacubitril-Telmisartan (1:1) amorphous form and crystalline Sacubitril-Telmisartan (1:1) Form I were analyzed for water content by Karl-Fischer (KF) titration. The results are summarized in Table 1.
KF analysis of Sacubitril-Telmisartan (1:1) amorphous form shows the water content is around 1% whereas in crystalline Sacubitril-Telmisartan (1:1) Form I the water content is in the range of 1.5% to 2.5% which indicates that crystalline Sacubitril-Telmisartan (1:1) Form I is a hydrate and preferably, a monohydrate.
Table 1. Comparison of water content of Sacubitril-Telmisartan (1:1) amorphous form and crystalline Sacubitril-Telmisartan (1:1) Form I.
Table 1
Polymorph of Sacubitril-Telmisartan (1:1) Complex Water content (%)
Form I 1.66
Form I 2.34
Form I 1.74
Amorphous form 1.05
Amorphous form 1.0
Amorphous form 1.16

FTIR spectra:
Comparison of the FTIR spectra of Sacubitril crystalline form (Figure 11), Telmisartan Form A (Figure 12), Sacubitril-Telmisartan (1:1) Amorphous form (Figure 13) and Sacubitril-Telmisartan Form I (Figure 14) reveals significant shifts in the wavenumbers for Sacubitril-Telmisartan (1:1) amorphous form and Sacubitril-Telmisartan (1:1) Form I corresponding to O-H, C=O stretching vibrations in Telmisartan and N-H, C=O (ester) and C=O (amide) stretching vibrations in Sacubitril compared to that of native APIs (Refer Table 2).
Table 2. The characteristic FT-IR data for Sacubitril crystalline form, Telmisartan form A, Sacubitril-Telmisartan Amorphous Form and Sacubitril-Telmisartan Form I.
Table 2
S.No Functional Group Stretch Frequencies in cm-1
Sacubitril (A) Telmisartan (B) 1: 1 Sacubitril-Telmisartan
Amorphous form Form I
1. O-H (Bacid) -- 3431 3411 3503
2. N-H (Aamide) 3319 -- -- 3261
3. C-H (A/Baliphatic) 2979 2929 2967 2929
4. C=O (Aester) 1729 -- 1724 1724
5. C=O (Bacid) 1698 1697 1668 1646
6. C=O (Aamide) 1643 -- 1599 1599

Based on the observations from FT-IR data, coupled with the unique thermal behavior of these two phases (amorphous form and Form I) and their distinct PXRD patterns further confirms the Sacubitril-Telmisartan (1:1) amorphous form and crystalline Sacubitril-Telmisartan (1:1) Form I are novel complexes. From water content data, the crystalline Sacubitril-Telmisartan (1:1) Form I is a hydrate, preferably a monohydrate.
Stability:
In yet another embodiment, the physical and chemical stability of Sacubitril-Telmisartan (1:1) amorphous form was determined by storing the samples at 5±3°C and 25°C and 60% relative humidity (RH) conditions for 9 months and the samples were analyzed by PXRD and HPLC Purity. The results are shown in below Table 3A. The Sacubitril-Telmisartan (1:1) amorphous form was found to be physically and chemically stable at 5±3°C and 25°C and 60% relative humidity (RH) conditions upto nine months.
Table 3A- Summary of Sacubitril-Telmisartan amorphous form stability study.
Period Sacubitril-Telmisartan amorphous form
PXRD HPLC purity
at 5±3°C
Initial Amorphous 99.70
1 month Stable NA
2 months Stable 99.54
3 months Stable 99.71
6 months Stable 99.60
9 months Stable 99.60
at 25°C/60% RH
Initial Amorphous 99.70
1 month Stable NA
2 months Stable 99.50
3 months Stable 99.66
6 months Stable 99.52
9 months Stable 99.49

In yet another embodiment, the physical and chemical stability of crystalline Sacubitril-Telmisartan (1:1) Form I was determined by storing the samples at 5±3°C and 25°C and 60% relative humidity (RH) conditions for 3 months and the samples were analyzed by PXRD and HPLC Purity. The results are shown in below Table 3B. The crystalline Sacubitril-Telmisartan (1:1) Form I was found to be physically and chemically stable at 5±3°C and 25°C and 60% relative humidity (RH) conditions upto three months.
Table 3B- Summary of Sacubitril-Telmisartan Form I stability study.
Period Sacubitril-Telmisartan Form I
PXRD HPLC purity
at 5±3°C
Initial Form I 99.87
1 month Stable 99.65
2 months Stable 99.66
3 months Stable 99.66
at 25°C/60% RH
Initial Form I 99.87
1 month Stable 99.64
2 months Stable 99.64
3 months Stable 99.62

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Examples:
Example 1: Amorphous Sacubitril-Telmisartan (1:1):
4 g of Sacubitril and 5g of Telmisartan were dissolved in a mixture of 15 mL of methanol and 60 mL of dichloromethane at 25±2°C. The resulting clear solution was filtered through hyflo. The hyflo bed washed with the mixture of 2 mL methanol and 8mL dichloromethane and subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 5ml/min and inlet temperature at 65 °C to yield amorphous form of Sacubitril-Telmisartan (1:1). Yield: 6.2 g

Example 2: Amorphous Sacubitril-Telmisartan (1:1):
Dissolve 0.08 g of Sacubitril and 0.1 g of Telmisartan were dissolved in a mixture of 0.4 mL of methanol and 1.6 mL of dichloromethane at 25±2°C. The resulting clear solution was distilled completely under vacuum in laboratory rotary evaporator to yield amorphous form of Sacubitril-Telmisartan (1:1). Yield: 0.15 g

Example 3: Amorphous solid dispersion of Sacubitril-Telmisartan (1:1):
0.08 g of Sacubitril, 0.1 g of Telmisartan and 0.18 g of ethyl cellulose were dissolved in a mixture of 0.4 mL of methanol and 1.6 mL of dichloromethane at 25±2°C. The resulting clear solution was distilled completely under vacuum in laboratory rotary evaporator to yield 1:1 (w/w) amorphous solid dispersion of Sacubitril-Telmisartan with ethyl cellulose. Yield: 0.25 g

Example 4: Amorphous solid dispersion of Sacubitril-Telmisartan (1:1):
0.08 g of Sacubitril, 0.1 g of Telmisartan and 0.18 g of Plasdone S-630 were dissolved in a mixture of 0.4 mL of methanol and 1.6 mL of dichloromethane at 25±2°C. The resulting clear solution was distilled completely under vacuum in laboratory rotary evaporator to yield 1:1 (w/w) amorphous solid dispersion of Sacubitril-Telmisartan with Plasdone S-630. Yield: 0.25 g

Example 5: Amorphous solid dispersion of Sacubitril-Telmisartan (1:1):
0.08 g of Sacubitril, 0.1g of Telmisartan and 0.18 g of PVP K30 were dissolved in a mixture of 0.6 mL of methanol and 2.4 mL of dichloromethane at 25±2°C. The resulting clear solution was distilled completely under vacuum in laboratory rotary evaporator to yield 1:1 (w/w) amorphous solid dispersion of Sacubitril-Telmisartan with PVP K30. Yield: 0.13 g

Example 6: Crystalline Form I of Sacubitril-Telmisartan (1:1):
10 g of Amorphous form of Sacubitril-Telmisartan was dissolved in 140 mL of toluene at 25±2°C. The resulting clear solution was maintained under stirring for 2h at 25±2°C. The product obtained was filtered, washed with 40 mL of toluene and suck-dried for 30min. The wet product was further dried under vacuum at 55±2°C for 15h to yield novel crystalline Sacubitril-Telmisartan (1:1) Form I. Yield: 9.6 g

Example 7: Crystalline Form I of Sacubitril-Telmisartan (1:1):
20 g of amorphous form of Sacubitril-Telmisartan was suspended in 400 mL of isopropyl ether at 25±2°C and stir the reaction mass at 25±2°C for 2 h. The product obtained was filtered, washed with 80 mL of isopropyl ether and suck-dried for 30 min. The wet product was further dried under vacuum at 55±2°C for 15h to yield novel crystalline Sacubitril-Telmisartan (1:1) Form I. Yield: 19.2 g

Example 8: Crystalline Form I of Sacubitril-Telmisartan (1:1):
100 mg of Sacubitril-Telmisartan amorphous form was dissolved in 1 mL xylene at 25±2°C. Stir the reaction mass at 25±2°C for 2 h. The product obtained was filtered and suck-dried for 30 minutes to yield novel crystalline Sacubitril-Telmisartan Form I. Yield: 80 mg.
Example 9: Crystalline Form I of Sacubitril-Telmisartan (1:1):
50 g of Sacubitril-Telmisartan amorphous form was dissolved in 150 mL of dichloromethane at 25±2°C and cooled to 2±2°C, then added 2.5g of Sacubitril-Telmisartan Form I seeds and added 1L of n-heptane at 2±2°C for 40 minutes. The reaction mass was maintained under stirring at 2±2°C for 17 h, filtered, washed with 100 mL of chilled heptane and dried under vacuum at 50 °C for 48h. The resulting solid was identified as novel crystalline Sacubitril-Telmisartan Form I. Yield: 48.8 g.
,CLAIMS:1. A crystalline form I of Sacubitril-Telmisartan having PXRD peaks 4.50, 16.53, 20.09, 24.32 and 24.74 ±0.2° 2?.

2. A crystalline form I of Sacubitril-Telmisartan characterized by PXRD pattern substantially as depicted in FIG.6.

3. A process for the preparation of crystalline form I of Sacubitril-Telmisartan comprising the steps of:
a) taking Sacubitril-Telmisartan into a suitable solvent or mixtures thereof; and
b) filtering the solvent to isolate crystalline form I of Sacubitril-Telmisartan.

4. The process as claimed in claim 3, wherein the suitable solvent is selected from diethyl ether, isopropyl ether, methyl tertiary butyl ether, cylcopentyl methyl ether, toluene and xylene.

5. A process for the preparation of crystalline form I of Sacubitril-Telmisartan comprising the steps of:
a) dissolving Sacubitril-Telmisartan into a first solvent or mixtures thereof; and
b) optionally seeding with crystalline Form I seeds of Sacubitril-Telmisartan;
c) adding a second solvent; and
d) filtering the solvent to isolate crystalline form I of Sacubitril-Telmisartan.

6. The process as claimed in claim 5, wherein the first solvent is selected from methanol, ethanol, propanol, isopropanol; dichloromethane, trifluroethanol and hexafluro-2-propanol; second solvent is selected from heptane, diethyl ether, isopropyl ether and cylcopentyl methyl ether.

7. An amorphous form of Sacubitril-Telmisartan and its solid dispersion.

8. An amorphous form of Sacubitril-Telmisartan characterized by PXRD pattern substantially as depicted in FIG.1

9. A process for the preparation of amorphous form of Sacubitril-Telmisartan comprising the steps of:
a) dissolving Sacubitril and Telmisartan in a suitable solvent or mixtures thereof; and
b) removing the solvent to isolate amorphous Sacubitril-Telmisartan.

10. A process for the preparation of an amorphous solid dispersion of Sacubitril-Telmisartan comprising the steps of:
a) taking Sacubitril; Telmisartan and a pharmaceutically acceptable excipient in suitable solvent or mixtures thereof; and
b) removing the solvent to isolate amorphous solid dispersion of Sacubitril-Telmisartan.

11. The process as claimed in claim 9 & 10, wherein solvent is selected from polar and non-polar solvents or mixtures thereof.

12. The process as claimed in claim 11, wherein the polar solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, trifluroethanol, hexafluro-2-propanol, water, dimethyl sulfoxide; non-polar solvent selected from dichloromethane and toluene.