WO2019186410A1

WO2019186410A1 - Solid forms of elafibranor and processes thereof

Info

Publication number: WO2019186410A1
Application number: PCT/IB2019/052468
Authority: WO
Inventors: Rohidas Shivaji SULAKE; Rajinder Singh Siyan; Nandu Baban Bhise; Girij Pal Singh
Original assignee: Lupin Ltd
Current assignee: Lupin Ltd
Priority date: 2018-03-27
Filing date: 2019-03-27
Publication date: 2019-10-03
Anticipated expiration: 2020-09-27

Abstract

The present invention relates to solid forms of Elafibranor, processes for preparation thereof, pharmaceutical salts of Elafibranor, their crystalline and amorphous forms and processes for preparation thereof.

Description

SOLID FORMS OF ELAFIBRANOR AND PROCESSES THEREOF

Field of the invention

Background of the invention

Elafibranor is an agonist of the peroxisome proliferator-activated receptor-a and peroxisome proliferator-activated receptor-d. It is a first-in-class drug acting via dual peroxisome proliferator-activated a / d pathways developed to treat, in particular, nonalcoholic steatohepatitis (NASH]; believed to address multiple facets of NASH, including inflammation, insulin sensitivity, lipid/metabolic profile, and liver markers.

This compound belongs to the retrochalcones class of organic compounds. It is chemically described as 2-[2, 6-dimethyl-4-[3-[4-(methylthio] phenyl]-3-oxo-l- propen-l-yl] phenoxy]-2-methylpropanoic acid and structurally represented by formula (I] as given below:

U.S. Patent No. 7, 943, 661 and the family patents describes Elafibranor or an optical isomer, a geometric isomer, a racemate, a tautomer, a salt or mixtures thereof and processes for its preparation. However, this patent does not disclose any polymorphic form of the product obtained by the said process.

U.S. Patent No. 7, 385, 082 and US 8, 765, 992 describes process for preparation of Elafibranor. The PCT publications W02018/060372A1 and W02018/060373A1 describe choline and metformin salt of Elafibranor, respectively.

The PCT publication WO 2018/133705A1 describes different crystal forms of GFT- 505 i.e. Elafibranor.Active pharmaceutical ingredients (APIs] can be prepared in a variety of different forms, for example, chemical derivatives, solvates, hydrates, co crystals, or salts. APIs may also be prepared in different solid forms, in that they may be amorphous, may exist as different crystalline forms, and/or in different solvation or hydration states. One can achieve different set of physicochemical properties by changing a polymorphic form of an API. For instance, solid forms of an API typically have different solubilities such that a thermodynamically more stable solid form is less soluble than a thermodynamically less stable solid form. Solid forms can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color and compressibility; which provide broader scope to a formulation scientist for formulation optimization. Accordingly, variation of the solid state of an API is one of many ways in which to modulate the physical and pharmacological properties thereof.

Active pharmaceutical ingredients often do not exhibit the range of physical properties that makes them directly suitable for formulation development One of the approaches that are used to modify the characteristics of drug substances is to employ a salt form of the substance. The beneficial aspects of using salt forms as active pharmaceutical ingredients are well known, and enable one to modify aqueous solubility, dissolution rate, solution pH, solid form, hygroscopicity, chemical stability, melting point, and even mechanical properties.

Salt formation is a relatively simple and powerful pre-formulation technique that can result in significant improvement of drug’s physicochemical properties. Importantly, different salt forms rarefy change drug’s pharmacological properties.

Moreover introducing counter ions to the drug structure may result in the increased formation of solid forms, hydrates and solvates which ultimately leads to increase in variability of the drug’s pharmaceutical properties providing 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. Accordingly, there is a need in the art to develop new salts of Elafibranor. In light of the potential benefits of different solid forms of APIs and usefulness of Elafibranor there is a need to identify and prepare solid forms of Elafibranor having physicochemical properties that would increase its suitability for desired formulation.

Object of the invention

The present invention describes solid forms, crystalline Form-A and crystalline Form- B of Elafibranor, its processes for preparation thereof and its pharmaceutical composition thereof.

The present invention also relates to salts of Elafibranor, their crystalline and amorphous forms thereof, processes for preparation thereof and its pharmaceutical compositions thereof. The present invention also relates to the use of solid state forms of Elafibranor, for preparing other solid state forms of Elafibranor. The present invention also relates to the use of salts Elafibranor and solid state crystalline and amorphous forms thereof, for preparing other salts or solid state forms of Elafibranor.

Brief description of the drawing Figure-1: The powder X-ray diffraction (PXRD] pattern of crystalline Form-A of

Elafibranor.

Figure- 2: The differential scanning calorimetry (DSC] thermogram of crystalline

Form-A of Elafibranor.

Figure- 3: The PXRD pattern of crystalline Form-B of Elafibranor.

Figure-4: The DSC thermogram of crystalline Form-B of Elafibranor.

Figure- 5: The PXRD pattern of sodium salt of Elafibranor Figure- 6: The PXRD pattern of potassium salt of Elafibranor

Figure- 7: The PXRD pattern of calcium salt of Elafibranor Figure- 8: The PXRD pattern of piperazine salt of Elafibranor

Description of the invention The present invention describes solid forms of Elafibranor.

In one embodiment, the present invention relates to crystalline Form-A of Elafibranor.

The crystalline Form-A of Elafibranor has substantially the same PXRD (powder X-ray diffraction] pattern, as illustrated in Figure-1.

The crystalline Form-A of Elafibranor is characterized by PXRD having characteristic X-ray diffraction peaks at 9.35, 10.72, 12.24, 14.28,15.83, 16.06, 16.54, 16.92,17.55, 18.41, 18.72,19.25, 20.46, 20.91, 22.34, 22.64, 23.27, 24.08, 24.53,24.98, 25.12, 26.27, 27.74, 28.17, 28.45, 29.27, 29.57, and 32.57 ± 0.2 degree 20.

The crystalline Form-A of Elafibranor is further characterised by differential scanning calorimetry (DSC] thermogram as illustrated in Figure-2. The crystalline Form-A of Elafibranor has characteristic endothermic peak at about 158.98°C with onset at about 155.43°C.

The present invention further relates to a process for the preparation of crystalline Form-A of Elafibranor.

The crystalline Form-A of Elafibranor of the present invention is obtained by providing Elafibranor in a mixture of non-polar and polar solvent or alone in a non polar or a polar solvent to obtain a solution followed by removal of solvent.

The crystalline Form-A is prepared by dissolving Elafibranor in acetonitrile at about 80⁰ C to 85° C, cooling the solution to ambient temperature and isolating Form A. The non-polar solvent is selected from the group of aromatic or aliphatic hydrocarbons and the polar solvent is selected from the group of ester, ketone, ether, alkanol, nitrile, amide, chlorohydrocarbon, water or mixtures thereof.

In another embodiment, the present invention relates to crystalline Form-B of Elafibranor.

The crystalline Form-B of Elafibranor has substantially the same PXRD pattern, as illustrated in Figure- 3.

The crystalline Form-B of Elafibranor is characterized by PXRD having characteristic X-ray diffraction peaks at 7.83, 10.98, 11.16, 12.32, 12.63, 13.48, 15.66, 15.92, 16.25, 16.59, 17.10, 17.24, 17.41, 18.93, 19.94, 20.22, 22.74, 23.44, 23.73, 24.43, 25.14, 25.27,

26.32, 26.59, 27.18, 27.81, 28.33 and 28.61 ± 0.2 degree 20.

The crystalline Form-B is further characterised by differential scanning calorimetry (DSC] thermogram as illustrated in Figure-4.

The crystalline Form-B of Elafibranor has characteristic endothermic peak at about 156.42°C with onset at about 153.96°C.

The present invention is also related to a process for the preparation of crystalline Form-B of Elafibranor.

The Crystalline Form-B of Elafibranor of the present invention is obtained by dissolving Elafibranor in a non-polar or a polar solvent, preferably a polar solvent, followed by removal of solvent from the solution/mixture.

The crystalline Form-B is prepared by dissolving Elafibranor in ethylacetate at about 60⁰ C to 65° C, cooling the solution to ambient temperature and isolating Form B.

The non-polar solvent is selected from the group of aromatic or aliphatic hydrocarbons and the polar solvent is selected from the group of ester, ketone, ether, alkanol, nitrile, amide, chlorohydrocarbon and water or mixtures thereof. The term‘non-polar solvent’ includes a group of aromatic hydrocarbon such as toluene, xylene, ethyl benzene and the like, aliphatic hydrocarbon such as n-hexane, n-heptane, n-pentane, cyclohexane, methyl cyclohexane and the like, or mixtures thereof. The term‘polar solvent’ incudes a group of esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; ketones such as acetone, methyl isobutyl ketone (MIBK], butanone and the like; ethers such as methyl tert-butyl ether (MTBE], dioxane, tetrahydrofuran, diisopropyl ether, and the like; alkanol such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, pentanol and the like; amides such as dimethyl formamide, N-methylpyrrolidone and the like; nitriles such as acetonitrile and the like; chlorohydrocarbon such as dichloromethane, chloro benzene and the like; and water; or combinations thereof. In yet another embodiment of the present invention relates to amorphous and amorphous solid dispersion of Elafibranor and processes for preparation thereof. The isolation of solid forms of Elafibranor of the present invention is done by techniques such as decantation, filtration by gravity or suction, centrifugation, or slow solvent evaporation or any other suitable technique known in the art and optionally the isolated solid is washed with a solvent, such as an anti-solvent or the solvent, to reduce the amount of entrained impurities. The processes for preparation of solid forms of the present invention as described herein above is not limited, but also includes other already established techniques and procedures in the art and known variations in the techniques and procedures which can be readily developed by a person skilled in the art by reading the present invention. Elafibranor used in the present invention is purchased from commercial sources or prepared from processes known in the art.

In yet another embodiment the process for preparation of Elafibranor comprises of reacting ethyl 2- (4-formyl- 2, 6-dimethylphenoxy]-2-methylpropanoate and 4- methylthiolacetophenone to afford (E]-2-(2,6-dimethyl-4-(3-(4- (methylthio]phenyl]-3-oxoprop-l-en-l-yl]phenoxy]-2-methylpropanoate; followed by reaction of (E]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3-oxoprop-l-en-l- yl]phenoxy]-2-methylpropanoate with a base as per Example-5 to afford Elafibranor.

The present invention also provides salts of Elafibranor with alkali metals, alkaline earth metals, organic amines, ammonia and the like, wherein the salts of Elafibranor can be in crystalline and amorphous forms and processes for preparation thereof.

An embodiment of the present invention is ammonium salt of Elafibranor.

The ammonium salt of Elafibranor is characterized by powder X-ray diffraction (PXRD], differential scanning calorimetry (DSC], Infra-red spectroscopy (IR), 1H NMR and the like.

The present invention also provides a process for preparation of ammonium salt of Elafibranor.

The ammonium salt of Elafibranor is prepared by contacting Elafibranor, with aqueous ammonia solution in a suitable solvent at ambient temperature or optionally heating to about 30 °C to about 60 °C, preferably to about 40 °C to about 50 °C followed by isolation of the ammonium salt of Elafibranor by a suitable technique.

The suitable solvents include but are not limited to alcohol such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, 1-pentanol and the like, ketone such as acetone, methyl ethyl ketone and the like, ether such as tetrahydrofuran, dioxane and the like, chlorinated hydrocarbon such as dichloromethane and the like, ester such as ethyl acetate, isopropyl acetate and the like, nitrile such as acetonitrile and the like, amide such as dimethyl formamide, water or combinations thereof in a suitable proportion.

Suitable techniques for isolation include but are not limited to precipitation, anti- solvent precipitation and solvent removal such as slow evaporation, decantation, filtration by gravity or suction or centrifugation, using a rotational distillation device such as a Buchi® Rotavapor® and the like or any other suitable technique known in the art Example 8 illustrates the preparation of ammonium salt of Elafibranor.

Another embodiment of the present invention is alkali metal salts of Elafibranor.

In yet another embodiment of the present invention the alkali metal salt of Elafibranor is sodium salt of Elafibranor and potassium salt of Elafibranor. The alkali metals salts of Elafibranor is characterized by powder X-ray diffraction (PXRD], differential scanning calorimetry (DSC], Infra-red spectroscopy (IR], ⁱff NMR and the like.

The sodium salt of Elafibranor is characterized by a PXRD pattern, substantially as illustrated by Figure- 5 and the potassium salt of Elafibranor is characterized by a PXRD pattern, substantially as illustrated by Figure-6.

The present invention also provides processes for preparation of the alkali metal salts of Elafibranor.

The alkali metal salts of Elafibranor is prepared by contacting Elafibranor or its alkyl ester derivative with an alkali metal hydroxide, optionally as a solution in water or an alcoholic solvent such as methanol, ethanol and the like, in a suitable solvent at ambient temperature or optionally heating to about 30°C to about 60°C, preferably to about 40 °C to about 50°C, followed by isolation of the alkali metal salts of Elafibranor by using a suitable technique.

Suitable techniques for isolation include but are not limited to precipitation, anti solvent precipitation and solvent removal such as slow evaporation, decantation, filtration by gravity or suction or centrifugation, using a rotational distillation device such as a Buchi® Rotavapor® and the like or any other suitable technique known in the art

Example-9 and example- 10 illustrate a method for the preparation of sodium salt and potassium salt of Elafibranor, respectively.

Yet another embodiment of the present invention is alkaline earth metal salts of Elafibranor.

In yet another embodiment of the present invention the alkaline earth metal salt of Elafibranor is calcium salt of Elafibranor. The alkaline earth metal salts of Elafibranor is characterized by powder X-ray diffraction (PXRD], differential scanning calorimetry (DSC], Infra-red spectroscopy (IR), Ή NMR and the like.

The calcium salt of Elafibranor is characterized by a PXRD pattern, substantially as illustrated by Figure-7. The present invention also provides processes for preparation of the alkaline metal salts of Elafibranor.

The alkaline earth metal salts of Elafibranor is prepared by contacting Elafibranor with alkali metal hydroxide, optionally as a solution in water or alcoholic solvent such as methanol, ethanol and the like, in a suitable solvent at ambient temperature and heating to about 30 °C to about 60 °C, preferably to about 40 °C to about 50 °C, followed by addition of basic alkaline earth metal salt such as hydroxide, carbonate, oxide, acetate and the like and isolation of the alkali metal salt of Elafibranor by using a suitable technique.

Suitable techniques for isolation include but are not limited to precipitation, anti- solvent precipitation and solvent removal such as slow evaporation, decantation, filtration by gravity or suction or centrifugation, using a rotational distillation device such as a Buchi® Rotavapor® and the like or any other suitable technique known in the art

Example 11 illustrates a method for preparation of calcium salt of Elafibranor. Yet another embodiment of the present invention is directed to organic amine salts of Elafibranor.

Examples of useful amines which form amine salt of Elafibranor include, but are not limited to, amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tert-butylamine, dibutylamine, ethanolamine, ethylenediamine, meglumine, Tris(hydroxymethyl]aminomethane, metformin, tetramethyl quaternary ammonium, tetraethyl quaternary ammonium or choline and the like, cycloalkylamine such as piperazine, piperidine and the like and aryl amine such as aniline, benzidine, 2-naphthylamine and the like.

In yet another embodiment of the present invention the organic amine salt is dimethylamine, diethylamine and piperazine salt of Elafibranor.

The organic amine salts of Elafibranor is characterized by powder X-ray diffraction (PXRD], differential scanning calorimetry (DSC], Infra-red spectroscopy (IR), ⁱff NMR and the like.

The piperazine salt of Elafibranor is characterized by a PXRD pattern, substantially as illustrated by Figure-8.

The present invention also provides a process for preparation of the organic amine salt of Elafibranor. The organic amine salt of Elafibranor is prepared by contacting Elafibranor with an organic amine or the corresponding buffer at ambient temperature in a suitable solvent and optionally heating to about 30 °C to about 60 °C, preferably to about 40 °C to about 50 °C, followed by isolation of organic amine salt of Elafibranor by a suitable technique.

Example 12, Example 13, Example 14 and Example 15 illustrate method for the preparation of dimethylamine, diethylamine, piperazine and piperazine bis- Elafibranor salt of Elafibranor, respectively.

In other embodiment, the present invention also provides a pharmaceutical composition comprising solid forms of Elafibranor of the present invention along with one or more pharmaceutically acceptable carriers, excipients, or diluents.

The solid forms of Elafibranor of the present invention are used as agonist of the peroxisome proliferator-activated receptor-a and peroxisome proliferator-activated receptor-d.

The solid forms of Elafibranor of the present invention are used in preparing pharmaceutical compositions for prevention or treatment of nonalcoholic steatohepatitis (NASH] Such pharmaceutical compositions are prepared by the methods known in the literature.

The present invention is further illustrated with the following non-limiting examples.

Example- 1: Preparation of (E)-3-(4-hydroxy-3, 5-dimethylphenyl)-l-(4-

(methylthio)phenyl)prop-2-en-l-one

To a saturated ethanolic HC1 solution, 3, 5-dimethyl-4-hydroxy benzaldehyde (58.0 g, 0.386 mol] and 4-methylthiolacetophenone (70.6 g, 0.42 mol] were added. The reaction mixture was stirred till starting material disappears on thin layer chromatography (TLC] Thereafter the reaction mixture was concentrated under reduced pressure, diluted with methanol (200 mL], stirred and then filtered. The wet solid obtained was dried under vacuum to give (E]-3-(4-hydroxy-3, 5- dimethylphenyl]-l-(4-(methylthio] phenyl]prop-2-en-l-one (106.0 g]

Example-2 Preparation of ethyl (E)-2-(2, 6-dimethyl-4-(3-(4-(methylthio) phenyl)-3- oxoprop-l-en-l-yl)phenoxy)-2-methylpropanoate

To a solution of (E]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3-oxoprop-l-en-l- yl]phenoxy]-2-methylpropanoate (50.0 g, 0.167 mol] in acetonitrile (750 mL], potassium carbonate (46.25 g, 0.335 mol] and ethylbromoisobutyrate (49.03 g, 0.251 mol] were added. The reaction mixture was stirred at 85 °C for 48 hrs, cooled to ambient temperature and then filtered. The filtrate was diluted with ethyl acetate (500 mL] and washed with water (500 mL] The organic layer was separated and concentrated under reduced pressure. The residue obtained was stirred in isopropanol (200 mL] and the precipitated solid was filtered and dried under reduced pressure to give ethyl (E]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3-oxoprop- l-en-l-yl]phenoxy]-2-methylpropanoate (59.4 g]. Example- 3:

Preparation of Ethyl 2-(4-formyl-2, 6-dimethylphenoxy)-2-methylpropanoate

To a solution of 4-hydroxy-3, 5-dimethylbenzaldehyde (5.0 g, 0.033 mol] in methyl isobutyl ketone (100 mL], CS2CO3 (21.69 g, 0.066 mol] and ethyl bromoisobutyrate (12.99 g, 0.066 mol] were added. Reaction mixture was stirred at 95 °C for 48 h.

Reaction mixture was cooled to ambient temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was dissolved in ethylacetate (100 mL] and then washed with water (100 mL] The ethyl acetate layer was concentrated under reduced pressure. Residue obtained (8.3 g, crude] was used in the next step without purification.

Example-4:

Preparation of Ethyl (£')-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3- oxoprop-l-en-l-yl]phenoxy]-2-methylpropanoate

To a saturated HC1 solution in ethanol, ethyl 2-(4-formyl-2,6-dimethylphenoxy]-2- methylpropanoate (8.3 g, crude] and 4-methylthiolacetophenone (5.5 g, 0.331 mol] were added. Stirring was continued till starting material disappears on TLC. The reaction mixture was concentrated under reduced pressure followed by addition of isopropanol (100 mL] Thereafter the reaction mixture was stirred and the solid obtained was filtered and dried under vacuum to give ethyl (£]- 2-(2, 6-dimethyl-4-(3- (4- (methyl thio] phenyl]-3-oxoprop-l-en-l-yl] phenoxy]-2-methylpropanoate (8.6 g)·

Example- 5:

Preparation of Elafibranor

To a stirred solution of (£]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3-oxoprop- l-en-l-yl]phenoxy]-2-methylpropanoate (5.0 g, 0.012 mol] in a mixture of methanol and tetrahydrofuran (2:1; 45 mL] was added sodium hydroxide (1.45 g, 0.036 mol] dissolved in water (5 mL] and stirring was continued for 6 hrs at ambient temperature. The organic solvent was removed under reduced pressure and the reaction mixture was diluted with water (50 mL] The reaction mixture was acidified and then extracted with dichloromethane (2 X 30 mL] Dichloromethane was removed under reduced pressure to give residue which was stirred in methanol (50 mL] The solid obtained was filtered and dried to give (£]- 2-(2, 6-dimethyl-4-(3-(4- (methylthio] phenyl]-3-oxoprop-l-en-l-yl] phenoxy]-2-methylpropanoic acid (4.3 g)·

Example-6:

Preparation of Elafibranor crystalline Form-A (£]- 2-(2, 6-dimethyl-4-(3-(4-(methylthio] phenyl]-3-oxoprop-l-en-l-yl]phenoxy]-2- methylpropanoic acid (1.0 g, 0.010 mol] was dissolved in acetonitrile (40 mL] at 85 °C. The reaction mixture was cooled to ambient temperature and the precipitated solid was filtered and then dried under vacuum to give Elafibranor crystalline Form- A (0.71 g] as yellow solid. Example- 7:

Preparation of Elafibranor crystalline Form-B

(£]-2-(2, 6-dimethyl-4-(3-(4-(methylthio] phenyl]-3-oxoprop-l-en-l-yl] phenoxy]- 2-methylpropanoic acid (4.0 g, 0.010 mol; prepared as per Example-5] was dissolved in ethyl acetate (40 mL] at 65 °C to 70°C. It was cooled to ambient temperature; the solid obtained was filtered and then dried under vacuum to give Elafibranor crystalline Form-B (3.8 g] as yellow solid.

Example-8: Preparation of ammonium salt of Elafibranor

To a stirred solution of Elafibranor (2.0 g, 0.0051mol] in THF (20 mL], aq. ammonia solution (3.53 mL, 15 M] was added at ambient temperature. Reaction mixture was stirred for 22 Hrs at ambient temperature. Reaction mixture was concentrated and then triturated with isopropanol (20 mL] Solid obtained was filtered, washed with isopropanol and then dried to give 1.6 g of ammonium (E]-2-(2,6-dimethyl-4-(3-(4- (methylthio]phenyl]-3-oxoprop-l-en-l-yl]phenoxy]-2-methylpropanoate

Example-9: Preparation of sodium salt of Elafibranor

To a stirred solution of ethyl (E]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3- oxoprop-l-en-l-yl]phenoxy]-2-methylpropanoate (2.0 g, 0.0048 mol] in a mixture of methanol and tetrahydrofuran (2:1; 18 mL] was added sodium hydroxide(0.58 g, 0.0145 mol] solution in water (2 mL] and stirring was continued for 6 Hrs at ambient temperature. Organic solvents were removed under reduced pressure. Water (15 mL] was added to the residue and stirred. Solid obtained was filtered, washed with acetone and dried to give 1.6 g of sodium salt of Elafibranor.

Example-10: Preparation of potassium salt of Elafibranor

To a stirred solution of ethyl (E]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3- oxoprop-l-en-l-yl]phenoxy]-2-methylpropanoate (2.0 g, 0.0048 mol] in a mixture of methanol and tetrahydrofuran (2:1; 18 mL] was added potassium hydroxide (0.54 g, 0.0096 mol] solution in water (2 mL] and stirring was continued for 20 Hrs atambient temperature. Organic solvents were removed under reduced pressure. Water (15 mL] was added to the residue and extracted with 2-butanone. Organic solvent was removed under reduced pressure and the residue was triturated with acetone (10 mL] Solid obtained was filtered, washed with acetone and dried to give 1.1 g of potassium salt of Elafibranor.

Example- 11: Preparation of calcium salt of Elafibranor

To a stirred solution of Elafibranor (2.0 g, 0.0051 mol] in methanol (15mL], sodium hydroxide solution (0.22 g in 5 mL water] was added followed by addition of calcium acetate (0.549 g, 0.0031 mmol] at ambient temperature and stirred for 2 Hrs. The reaction mass was cooled and filtered. Solid material was dried under vacuum to give 1.5 g of calcium salt of Elafibranor. Example-12: Preparation of dimethyl ammonium salt of Elafibranor

To a stirred solution of Elafibranor (2.0 g, 0.0051 mol] in tetrahydrofuran (20 mL], dimethylamine (5.2 mL, 2 M] was added at ambient temperature. Reaction mixture was stirred for 23 Hrs at ambient temperature. Reaction mixture was concentrated under reduced pressure to give 2.1 g of dimethyl ammonium salt of Elafibranor.

Example-13: Preparation of diethyl ammonium salt of Elafibranor

To a stirred solution of Elafibranor (2.0 g, 0.0052 mol] in tetrahydrofuran (20 mL], diethyl amine (0.38 g, 0.0052 mol] was added at ambient temperature. Reaction mixture was stirred for 2 Hrs at 50 °C and then concentrated under reduced pressure to give 2.3 g of diethyl ammonium salt of Elafibranor.

Example-14: Preparation of piperazine salt of Elafibranor

To a stirred solution of Elafibranor (2.0 g, 0.0052 mol] in tetrahydrofuran (20 mL], Piperazine (0.44 g, 0.0052 mol] solution in THF (5 mL] was added at 5 °C. Reaction mixture was stirred for 5 Hrs at 30 °C and then filtered. Obtained solid was dried under reduced pressure to give 1.7 g of Piperazine salt of Elafibranor.

Example-15: Preparation of piperazine bis-Elafibranor salt of Elafibranor

To a stirred solution of Elafibranor (2.0 g, 0.0052 mol] in tetrahydrofuran (20 mL], Piperazine (0.228 g, 0.0026 mol] solution in tetrahydrofuran (5 mL] was added at 5 °C. Reaction mixture was stirred for 5 Hrs at 55 °C. Reaction mixture was cooled to ambient temperature and then filtered. Obtained solid was dried under reduced pressure to give 1.6 g of Piperazine bis Elafibranor salt

Claims

1. A crystalline Form-A of Elafibranor characterized by a powder X-Ray diffraction diffractogram pattern havingpeaks at 10.72, 14.28, 16.54 and 24.08 ± 0.2 degrees 2 0 and a differential scanning calorimetry thermogram having characteristic endothermic peak at about 158.98°C with onset at about

155.43°C.

2. The crystalline Form-A of Elafibranor of claim 1 characterized by powder X- Ray diffraction diffractogram pattern having peaks at 10.72, 14.28, 16.54 and 24.08 ± 0.2 degrees 2 0 and having any 1-5 additional peaks selected from

12.24, 15.83, 17.55, 20.46 and 26.27 ± 0.2 degrees 2 0 and a differential scanning calorimetry thermogram substantially as depicted in Figure-2.

3. The crystalline Form-A of Elafibranor of claim 1 characterized by a powder X- Ray diffraction pattern substantially as depicted in Figure- 1.

4. The crystalline Form-A of Elafibranor of claim 1, wherein the powder X-Ray diffraction diffractogram comprises peaks, in terms of degrees 2 0, at 9.35, 10.72, 12.24, 14.28,15.83, 16.06, 16.54, 16.92,17.55, 18.41, 18.72,19.25, 20.46, 20.91, 22.34, 22.64, 23.27, 24.08, 24.53,24.98, 25.12, 26.27, 27.74, 28.17,

28.45, 29.27, 29.57, and 32.57 ± 0.2 degrees 2 0.

5. A process for preparing crystalline Form-A of Elafibranor as defined in claims 1, comprising the steps:

(a] dissolving Elafibranor in acetonitrile at about 80°C to 85°C,

(b] cooling the solution to ambient temperature and

(c] isolating crystalline Form A of Elafibranor.

6. A crystalline Form-B of Elafibranor characterized by a powder X-Ray diffraction diffractogram pattern havingpeaks at 13.48, 17.24, 22.74 and 23.44 ± 0.2 degrees 2 Q and a differential scanning calorimetry thermogram having characteristic endothermic peak at about 156.42°C with onset at about 153.96°C. 7. The crystalline Form-B of Elafibranor of claim 6 characterized by a powder X-

Ray diffraction diffractogram pattern having peaks at 13.48, 17.24, 22.74 and 23.44 ± 0.2 degrees 2 0 and also having any 1-5 additional peaks selected from 7.83, 12.32, 16.25, 26.32 and 28.33 ± 0.2 degrees 2 0 and a differential scanning calorimetry thermogram substantially as depicted in Figure-4.

8. The crystalline Form-B of Elafibranor of claim 6, characterized by a powder X- Ray diffraction pattern substantially as depicted in Figure- 3.

9. The crystalline Form-B of Elafibranor of claim 6, wherein the powder X-Ray diffraction diffractogram comprises peaks, in terms of degrees 20, at 7.83,

10.98, 11.16, 12.32, 12.63, 13.48, 15.66, 15.92, 16.25, 16.59, 17.10, 17.24, 17.41, 18.93, 19.94, 20.22, 22.74, 23.44, 23.73, 24.43, 25.14, 25.27, 26.32, 26.59, 27.18, 27.81, 28.33 and 28.61 ± 0.2 degree 20. 10. A process for preparing crystalline Form-B of Elafibranor as defined in claims

6, comprising the steps:

(a] dissolving Elafibranor in ethylacetate at about 60°C to 65°C,

(b] cooling the solution to ambient temperature and

(c] isolating crystalline Form B of Elafibranor.

11. An sodium salt of Elafibranor.

12. An potassium salt of Elafibranor.

13. An calcium salt of Elafibranor.

14. An piperazine salt of Elafibranor