DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION

“AN IMPROVED PROCESS FOR THE PREPARATION OF ARAMCHOL”
2. APPLICANT
NAME : Alkem Laboratories Limited
NATIONALITY : Indian
ADDRESS : ALKEM HOUSE, SENAPATI BAPAT MARG, LOWER PAREL,
MUMBAI – 400013
3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Aramchol. In particular, the present invention relates to a novel intermediate and its use in the preparation of Aramchol. The invention also relates to a process for the preparation of a novel intermediate. Further, the present invention relates to a crystalline form of Aramchol and process for its preparation thereof.

BACKGROUND OF THE INVENTION
Aramchol, having a chemical name 3ß-arachidylamido-7a,12a-dihydroxy-5ß-cholan-24-oic acid is represented as Formula I with structure as follows:

Aramchol is an amide conjugate of arachidic acid and 3-aminocholic acid, effective in reducing liver fat content as well as improving metabolic parameters associated with fatty liver disease. It belongs to a novel family of synthetic Fatty-Acid / Bile-Acid Conjugates (FABACs) and is being developed as a potentially disease modifying treatment for the fatty liver disease and Nonalcoholic steatohepatitis (NASH).

U.S 6,384,024; U.S 6,395,722; and U.S 6,589,946 discloses the process for the preparation of Aramchol wherein amino acid protected bile acid reacted with arachidoyl chloride in the presence of an organic base in an organic solvent and is further hydrolyzed to obtain the Aramchol.

WO 2011079672 (the WO ‘672 patent) discloses the multiple steps for the preparation of Aramchol using the amino bile acid without protection to acid, functional group reacted with arachidoyl chloride in the presence of an organic base in an organic solvent.

WO 2021140480 (the WO’480 patent) discloses the multiple steps for the preparation of Aramchol by reacting protected amino bile acid with an arachidic acid in the presence of a coupling reagent and HOBt/HOAt to form Aramchol. The WO’480 patent also describes the use of an isolated amine intermediate, semisolid compound (VII) is reacted with an acid selected from the group consisting of L-(D)- tartaric acid and L-(+)-Mandelic acid and isolated in form of salt as shown in Scheme 6 (for L-D-tartaric acid).

Then, the isolated tartaric acid salt of amine intermediate purified with suitable solvent leads to control isomer impurity.
The salt formation can be performed using a suitable solvent selected from the group consisting of propanol, methanol, ethanol, ethyl acetate, methyl isobutyl ketone, acetone, isopropyl alcohol and mixture thereof; preferably ethyl acetate or propanol.
The impact of amine intermediate (VII) purification with a salt was studied on different starting materials and summarized in Table 1. Results clearly indicates the necessity and the importance of salt purification procedure to get substantially pure Aramchol by chromatographic purity.

CN106496300 discloses the process which provide the purity of the Aramchol up to 98.00%.
However, the overall yields based on examples provided are poor. This clearly indicates that the procedure is not capable of producing pure Aramchol to meet the ICH Q3A guidelines.

CN 109503693 discloses synthesis of Aramchol using cholic acid and arachidic acid as raw materials. However, amidation reaction between the arachidonic acid chloride and the amino group of an amine intermediate resulting in many side reactions and a decrease in the overall yield and quality of the product.

CN 110981933 discloses multiple steps for the preparation of Aramchol using complex reaction conditions which leads to no improvement in the overall yield.

In view of the above, there is a need for an improved process, which is easy, cost effective and industrially scalable for the preparation of Aramchol.

Therefore, the object of the present invention is to provide a new and improved process for the preparation of Aramchol which is easy, cost effective, results in high yield of pure product and is industrially scalable.

OBJECTIVES OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of Aramchol using a novel intermediate.

Another object of the present invention is to provide an improved process of the preparation of a novel intermediate.

In another object of the present invention is to provide an easy, cost effective and industrially scalable process to achieve pure and high yield of Aramchol.

In another object of the present invention is to provide a process of preparing Aramchol of Formula I using a novel intermediate of formula VI comprising steps of:
a) reacting compound of Formula VI with Arachidic acid to give compound of formula VII; and
b) hydrolyzing compound of formula VII and isolating solid form of Aramchol of Formula I.

Another object of the present invention is to provide a pharmaceutical composition comprising crystalline form of Aramchol of formula I, wherein the physicochemical stability and the dissolution characteristics of the crystalline form is improved, and wherein crystalline form Aramchol of formula I is rendered more suitable for use in a pharmaceutical composition.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides an improved process for the preparation of Aramchol of formula I. The process of the present invention comprising following steps.
a) reacting compound of formula II with a suitable alcohol in the presence of catalytic amount of an acid in a suitable solvent to give compound of formula III;
b) reacting compound of formula III with methylsulfonyl chloride in the presence of triethylamine and a suitable solvent to give compound of formula IV and in-situ, converting compound of formula IV to compound of formula V using sodium azide in the presence of a suitable solvent;
c) hydrogenation of compound of formula V using a catalyst to obtain amine intermediate which is in-situ stabilized by reacting with an acid to obtain compound of formula VI as acid addition salt; and
d) reacting compound formula VI with arachidic acid chloride prepared using chlorinating agent and triethylamine to give compound of formula VII and hydrolyzing the compound of formula VII in the presence of a base in an aqueous organic solvent to obtain Aramchol of formula I; Optionally, purifying Aramchol of formula I using acid base treatment, crystallization or the like.

In another aspect, there is provided a novel intermediate of formula VI and process for the preparation thereof.

In another aspect, there is provided the use of a novel intermediate of formula VI for the preparation of Aramchol.

In still another aspect, there is provided a pharmaceutical composition comprising crystalline form of Aramchol of formula I or its pharmaceutically acceptable salts, wherein the physicochemical stability and the dissolution characteristics of the crystalline form is improved, and wherein Aramchol of formula I or its pharmaceutically acceptable salts is rendered more suitable for use in a pharmaceutical composition.

BRIEF DESCRIPTION OF DRAWINGS OF THE INVENTION

Fig. 1 illustrates the PXRD pattern of Crystalline Aramchol, obtained by the procedure of Example 4.

DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention.

The present invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In one embodiment, the invention provides an improved process for the preparation of Aramchol of formula I using a novel intermediate comprising following steps.
a) reacting compound of formula II with a suitable alcohol in the presence of catalytic amount of an acid in suitable solvent to give compound of formula III;
b) reacting compound of formula III with methylsulfonyl chloride in the presence of triethylamine and a suitable solvent to give compound of formula IV and in-situ converting compound of formula IV to compound of formula V using sodium azide in the presence of a suitable solvent;
c) hydrogenation of compound of formula V using a catalyst to obtain amine intermediate which is in-situ stabilized by reacting with an acid to obtain compound of formula VI as acid addition salt; and
d) reacting compound formula VI with arachidic acid chloride prepared using chlorinating agent and triethylamine to give compound of formula VII and hydrolyzing the compound of formula VII in the presence of a base in an aqueous organic solvent to obtain Aramchol of formula I; Optionally, purifying Aramchol of formula I using acid base treatment, crystallization or like.

In another embodiment, the process for the preparation of Aramchol of formula I of the present invention is schematically represented in the scheme 1 as given below.
Scheme 1:
Step (a):

Step (b):

Step (c):

Step (d):

The inventors of the present invention, after extensive experimentation have surprisingly found that the in-situ stabilization of an amine intermediate using an acid in step c) of the process of the present invention, reduced the formation of greater amount of undesired impurities, which are difficult to eliminate with simple solvent purifications. Ultimately, the in-situ stabilization of an amine intermediate using an acid in step c) of the process of the present invention helped to obtain a highly pure Aramchol of formula I. Additionally, the present invention provides the process for the preparation of Aramchol of formula 1 with a smaller number of process steps with an improved yield of the final product.

In an embodiment, the present invention provides a novel intermediate of formula VI as represented follows.

In another embodiment, the present invention provides the use of a novel intermediate represented by compound of formula VI for the preparation of Aramchol of formula I.

In an embodiment, the step (a) can be carried out in the presence of catalytic amount of an acid which is selected from the group consisting of sulfuric acid, hydrochloric acid, p-tolylsulfonic acid and acetic chloride.

In an embodiment, the step (a) can be carried out in the presence of an alcohol, wherein the alcohol is selected from the group consisting of methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol and isobutyl alcohol.

In an embodiment, the suitable solvent used in step (a) is an aqueous and an organic solvent, wherein the organic solvent is selected from the group consisting of an alcoholic solvent, an ester solvent, ketone solvent and mixtures thereof. In another embodiment, the solvent used in step (a) is selected from the group consisting of water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol (IPA), tert-butyl alcohol, n-butyl alcohol, methylene dichloride (MDC), dimethylformamide (DMF), tetrahydrofuran, 1,4-dioxane, and mixtures thereof. Preferably, the suitable solvent is a mixture of alcohol and water.

In an embodiment, the reaction of step (a) is carried out at a temperature range of about 60?C to 65?C.

In another embodiment, the suitable solvent used for the preparation of compound of formula IV in step (b) is selected from the group consisting of tetrahydrofuran, methylene dichloride (MDC), water, methanol, and pyridine and mixtures thereof.

In an embodiment, the suitable solvent used for the preparation of compound of formula V in step (b) is selected from the group consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and N, N'-dimethylpropyleneurea (DMPU), N-Methyl-2-pyrrolidone (NMP), acetone, acetonitrile, methylene dichloride (MDC), tetrahydrofuran and mixtures thereof. Preferably, the suitable solvent is dimethyl sulfoxide.

In another embodiment, the reaction for the preparation of compound of formula V in step (b) can be carried out at a temperature range of about 90 ?C to 95?C.

In an embodiment, the hydrogenation of azido intermediate represented by formula IV in step (c) is carried out using a catalyst. In an embodiment, the catalyst is selected from the group consisting of platinum, nickel, palladium on carbon, rhodium, and ruthenium. Preferably, the catalyst is palladium on carbon (Pd/C).

In another embodiment, the acid to prepare the compound of formula VI which is isolated as acid addition salt is selected from Benzoic acid, hydrochloric acid and salicylic acid.

In an embodiment, the suitable solvent used to prepare a novel intermediate of formula VI in step (c) is an organic solvent selected from the group consisting of an alcoholic solvent, an ester solvent, ketone solvent and mixtures thereof. In another embodiment, the solvent is selected from the group consisting of methanol, ethanol, n-butanol, tert-butyl alcohol, ethyl acetate, acetonitrile, methyl ethyl ketone, acetone, methylene dichloride (MDC), dimethylformamide (DMF), tetrahydrofuran, toluene, dimethyl sulfoxide (DMSO), cyclohexane, n-hexane and mixtures thereof.

In another embodiment, the present invention provides a novel intermediate of formula VI as represented follows.

In an embodiment, the suitable solvent used for the preparation of compound formula VII in step (d) is selected from an organic solvent. In an embodiment, the organic solvent is selected from the group consisting of an alcoholic solvent, an ester solvent ketone solvent and mixtures thereof. In an embodiment, the suitable solvent is selected from the group consisting of toluene, ethanol, acetonitrile, isopropyl alcohol (IPA), tert-butyl alcohol, n-butanol, methylene dichloride (MDC), dimethylformamide (DMF), tetrahydrofuran and mixtures thereof. Preferably, the solvent is methylene dichloride (MDC).

In an embodiment, hydrolysis of compound of formula VII in step (d) is carried out using an inorganic base. In an embodiment, hydrolysis of compound of formula VII is carried out using sodium hydroxide or potassium hydroxide. Preferably, hydrolysis of compound of formula VII is carried out using potassium hydroxide.

In an embodiment, the suitable solvent used for the hydrolysis of compound of formula VII in step (d) is selected from an aqueous and organic solvents selected from the group consisting of an alcoholic solvent, an ester solvent ketone solvent and mixtures thereof. In an embodiment, the suitable solvent is selected from the group consisting of water, toluene, ethanol, acetonitrile, isopropyl alcohol, tert-butyl alcohol, n-butanol, methylene dichloride (MDC), dimethylformamide (DMF), tetrahydrofuran and mixtures thereof.

In another embodiment, the final product Aramchol of formula I is isolated using a suitable solvent selected from the group consisting of methyl tert-butyl ether (MTBE), methanol, ethanol, n-butanol, tert-butyl alcohol, ethyl acetate, acetonitrile, methyl ethyl ketone, Acetone, methylene dichloride, dimethylformamide (DMF), tetrahydrofuran, toluene, dimethyl sulfoxide (DMSO), cyclohexane, n-hexane and mixtures thereof. Preferably, the final product Aramchol of formula I is isolated using methyl tert-butyl ether (MTBE) and acetone.

As used herein, the term “crystalline” refers to a material that contains a specific compound, which may be hydrated and/or solvated, and has sufficient crystal content to exhibit a discernible diffraction pattern by XRPD or other diffraction techniques.

In another embodiment, the invention provides a crystalline form of Aramchol of formula I with an improved physicochemical stability and dissolution characteristics.

In another embodiment, the invention provides a crystalline form of Aramchol of formula I with an improved physicochemical stability and dissolution characteristics.

In yet another preferred embodiment, provided herein is a crystalline form of Aramchol having an x-ray powder diffraction pattern (XRPD) comprising peaks with two-theta positions of about 5.2±0.2?, 7.9±0.2?, 15.5±0.2? and 20.6±0.2? as depicted in FIG.1.

The crystalline form as provided herein may be characterized by using a number of methods known to a person of skilled in the art, including X-ray powder diffraction (XRPD), microscopy (e.g Scanning Electron Microscopy (SEM), thermal analysis (e.g Differential Scanning Calorimetry (DSC)), thermal gravimetric analysis (TGA), and hot-state microscopy and spectroscopy (e.g infrared, Raman, solid-state nuclear magnetic resonance). The purity of the crystalline form provided herein may be may be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS).

In another embodiment, there is provided a crystalline form of Aramchol having a particle size distribution having D(10) of about 10 µm or less, D(50) of about 25 µm or less and D(90) of about 100 µm or less. The particle size and size distribution may be determined by conventional methods, such as laser light scattering technique.

In another embodiment, the invention provides an amorphous form of Aramchol of formula I with an improved physicochemical stability and dissolution characteristics.

In an embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of Aramchol of the formula I prepared using the process of the present invention and pharmaceutically acceptable excipients.

In another embodiment, the compositions containing Aramchol are useful in reducing cholesterol levels in the blood or treating fatty liver, or for the treatment of NonAlcoholic SteatoHepatitis (NASH) or any disease that its treatment may benefit from modulating cholesterol or lipid balance.

The pharmaceutical composition of the present invention provided herein may be in the form selected from the tablets, pills, capsules, pellets, granules, powders, lozenges, sachets, cachets, patches, elixirs, suspensions, dispersions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

The pharmaceutically acceptable excipients may be selected from, but not limited to, disintegrants, lubricants, diluents, binders, preservatives, suspending agents, sweetening agents, lubricants/glidants, colouring agents, flavoring agents, surfactants.

The workability of the present invention has been exemplified below based on some non-limiting illustrations. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1: Preparation of compound of formula III
A compound of formula II (10 g,1 mole eq.) was reacted with methanol (25 ml) in presence of a catalytic amount of sulfuric acid (0.5 g,0.2 mole eq.) at temperature range 60-65?C. The compound of formula III was isolated by addition of process water (5 ml), followed by filtration, and drying. Dry wt: 9 g.

Example 2: Preparation of compound of formula V
Part-A: The reaction of compound of formula III (10 g,1 mole eq.) was performed with methane sulfonyl chloride (3 g,1.1 mole eq.) in presence of triethylamine (6 g,2.5 mole eq.) in methylene dichloride (40 ml). The reaction was quenched with water; organic layer was separated, and methylene dichloride was distilled off, followed by stripping with isopropyl acetate (4 ml) to remove traces of methylene dichloride and to obtain the compound of formula IV.

Part-B: The reaction of compound the of formula IV was performed with sodium azide (1.85 g, 1.2 mole eq.) in dimethyl sulfoxide (25 ml) at temperature range 90-95?C. The product was isolated by adding of water, followed by filtration and drying to obtain the compound of formula V. Dry wt:6.5-7.5 g.

Example 3: Preparation of compound of formula VI
Hydrogenation of stage-2 of compound of formula V (10 g, 1 mole eq.) was performed in the presence of 10% palladium on carbon (Pd/C) (1g,10 % w/w) in methanol (100 ml) and isolated the compound of formula VI with the addition of benzoic acid (2.73 g, 1 mole eq.), filtration, followed by drying. Dry wt:8.5 to 9.5 g.

Example 4: Preparation of compound of formula I
Part-A: Arachidic acid (5.17 g, 0.90 mole eq.) reacted with thionyl chloride (2.4 g,1.1 mole eq.) in the presence of methylene dichloride (40 ml) to get arachidoyl chloride. Reaction of arachidoyl chloride with compound of formula VI (10 g, 1 mole eq.) was performed in presence of triethylamine (5.5 g, 3 mole eq.) in methylene dichloride (40 ml) to form the ester intermediate of formula VII.
Part-B: The ester intermediate of formula VII was hydrolyzed with aqueous potassium hydroxide (2.35 g) in acetonitrile (20 ml) to obtain Aramchol of formula I. The Aramchol of formula I was isolated as a crystalline solid from the reaction mixture by methyl tert-butyl ether (30 ml) and acetone (30 ml), filtration, and drying. Dry wt: 10 g Yield: 77.50%; Purity: 99.2; The crystalline solid obtained has a an XRPD pattern as depicted in Figure 1.

Dated this the 10th day of October, 2022

Mr. Thirupathi Bendram
AVP & Head - IPR
Alkem Laboratories Limited

We Claim:
1. An improved process for the preparation of Aramchol of formula I comprising the steps of:
a) reacting compound of formula II with an alcohol in the presence of catalytic amount of an acid and a suitable solvent to give compound of formula III;
b) reacting compound of formula III with methylsulfonyl chloride in the presence of triethylamine and a suitable solvent to give compound of formula IV and in-situ converting compound of formula IV to compound of formula V using sodium azide in the presence of a suitable solvent;
c) hydrogenation of compound of formula V using a catalyst to obtain amine intermediate which is in-situ stabilized by reacting with an acid to obtain compound of formula VI as acid addition salt;
d) reacting compound formula VI with arachidic acid to give compound of formula VII and hydrolyzing the compound of formula VII in the presence of a base in an aqueous organic solvent to obtain Aramchol of formula I; optionally, purifying Aramchol of formula I using acid base treatment or crystallization.

2. The process as claimed in claim 1, wherein the alcohol is selected from the group consisting of methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol and isobutyl alcohol.

3. The process as claimed in claim 1, wherein the acid in step (a) is selected from the group consisting of sulfuric acid, hydrochloric acid, p-tolylsulfonic acid and acetic chloride.

4. The process as claimed in claim 1, wherein the suitable solvent is selected from the group consisting of water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol (IPA), tert-butyl alcohol, n-butyl alcohol, dimethylformamide (DMF), tetrahydrofuran, 1,4-dioxane, methylene dichloride (MDC), methanol, methyl tert-butyl ether (MTBE), pyridine, dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-Methyl-2-pyrrolidone, n-butanol, methyl ethyl ketone, cyclohexane, n-hexane and mixtures thereof.
5. The process as claimed in claims 1, wherein the hydrogenation of azido intermediate of formula IV in step (c) is carried out using a catalyst selected from platinum, nickel, palladium on carbon, rhodium, and ruthenium.

6. The process as claimed in claims 1, wherein an acid to obtain the compound of formula VI as acid addition salt is selected from benzoic acid, hydrochloric acid and salicylic acid.

7. The process as claimed in claims 1, wherein the hydrolysis of compound of formula VII in step (d) is carried out using an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate.

8. An intermediate of formula VI:

9. The process as claimed in claim 1, wherein the obtained crystalline form of compound of formula I is characterized by XRPD pattern having characteristic peaks at about 5.2±0.2?, 7.9±0.2?, 15.5±0.2? and 20.6±0.2? as depicted in Figure 1.

10. A pharmaceutical composition comprising crystalline form of Aramchol of formula I as claimed in claim 1 and pharmaceutically acceptable excipients.

Dated this the 10th day of October, 2022

Mr. Thirupathi Bendram
AVP & Head - IPR
Alkem Laboratories Limited
,CLAIMS:We Claim:
1. An improved process for the preparation of Aramchol of formula I comprising the steps of:
a) reacting compound of formula II with an alcohol in the presence of catalytic amount of an acid and a suitable solvent to give compound of formula III;
b) reacting compound of formula III with methylsulfonyl chloride in the presence of triethylamine and a suitable solvent to give compound of formula IV and in-situ converting compound of formula IV to compound of formula V using sodium azide in the presence of a suitable solvent;
c) hydrogenation of compound of formula V using a catalyst to obtain amine intermediate which is in-situ stabilized by reacting with an acid to obtain compound of formula VI as acid addition salt;
d) reacting compound formula VI with arachidic acid to give compound of formula VII and hydrolyzing the compound of formula VII in the presence of a base in an aqueous organic solvent to obtain Aramchol of formula I; optionally, purifying Aramchol of formula I using acid base treatment or crystallization.

2. The process as claimed in claim 1, wherein the alcohol is selected from the group consisting of methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol and isobutyl alcohol.

3. The process as claimed in claim 1, wherein the acid in step (a) is selected from the group consisting of sulfuric acid, hydrochloric acid, p-tolylsulfonic acid and acetic chloride.

4. The process as claimed in claim 1, wherein the suitable solvent is selected from the group consisting of water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol (IPA), tert-butyl alcohol, n-butyl alcohol, dimethylformamide (DMF), tetrahydrofuran, 1,4-dioxane, methylene dichloride (MDC), methanol, methyl tert-butyl ether (MTBE), pyridine, dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-Methyl-2-pyrrolidone, n-butanol, methyl ethyl ketone, cyclohexane, n-hexane and mixtures thereof.
5. The process as claimed in claims 1, wherein the hydrogenation of azido intermediate of formula IV in step (c) is carried out using a catalyst selected from platinum, nickel, palladium on carbon, rhodium, and ruthenium.

6. The process as claimed in claims 1, wherein an acid to obtain the compound of formula VI as acid addition salt is selected from benzoic acid, hydrochloric acid and salicylic acid.

7. The process as claimed in claims 1, wherein the hydrolysis of compound of formula VII in step (d) is carried out using an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate.

8. An intermediate of formula VI:

9. The process as claimed in claim 1, wherein the obtained crystalline form of compound of formula I is characterized by XRPD pattern having characteristic peaks at about 5.2±0.2?, 7.9±0.2?, 15.5±0.2? and 20.6±0.2? as depicted in Figure 1.

10. A pharmaceutical composition comprising crystalline form of Aramchol of formula I as claimed in claim 1 and pharmaceutically acceptable excipients.

Dated this the 10th day of October, 2022

Mr. Thirupathi Bendram
AVP & Head - IPR
Alkem Laboratories Limited