WO2019008604A1

WO2019008604A1 - Novel forms of mu-opioid receptor agonist

Info

Publication number: WO2019008604A1
Application number: PCT/IN2018/050440
Authority: WO
Inventors: Manjinder Singh Phull; Dharmaraj Ramachandra Rao; Geena Malhotra; Sanoj Jose THOPPIL; Sagar Narayan TARATE; Hanmant Nagnath CHAUGULE
Original assignee: Cipla Limited
Priority date: 2017-07-07
Filing date: 2018-07-07
Publication date: 2019-01-10

Abstract

The present invention discloses novel polymorphs of 5-[[[(2S)-2-amino-3-[4- (aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H- imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and its pharmaceutically acceptable salts.

Description

NOVEL FORMS OF MU-OPIOID RECEPTOR AGONIST

Related Applications:

This application is Complete Cognate Application of the Provisional Patent Application No. 201721024013 filed on 7^th July, 2017 and Provisional Patent Application No. 201721036529 filed on 13^th October, 2017.

Technical field of the Invention:

The present invention relates to novel polymorphs of 5-[[[(2S)-2-amino-3-[4- (aminocarbonyl)-2,6-dimethylphenyl]- 1 -oxopropyl] [( 1 S)- 1 -(4-phenyl- 1H- imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and its pharmaceutically acceptable salts.

Background of the Invention:

5 -[ [ [(2 S)-2-amino-3 - [4-(aminocarbonyl)-2, 6-dimethylphenyl] - 1 -oxopropyl] [( 1 S)- l-(4-phenyl-lH-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid is also known as Eluxadoline (I).

(I)

Eluxadoline or its pharmaceutically acceptable salts is a mixed mu opioid receptor (μΟΡν) agonist/delta opioid receptor (50R) antagonist. It is used in adults for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d). Eluxadoline is currently approved in Europe as well as in USA. Eluxadoline is disclosed in WO2005090315. This patent application also discloses process for preparation of Eluxadoline. WO2009009480 describes alpha and beta crystal forms of Eluxadoline and preparation of zwitterion. This patent specifically discloses dihydrochloride salt of Eluxadoline.

WO2017015606 describes amorphous form as well as form I, II, III and IV of Eluxadoline and preparation thereof.

WO2017114446 describes polymorphic forms B and C of Eluxadoline and preparation thereof.

WO2017153471 describes polymorphic forms Gamma and Delta which are actually solvates of Eluxadoline.

It is a well- known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties such as dissolution characteristics, bioavailability patterns, handling properties, solubility, flow characteristics and stability.

Further, different physical forms may have different particle size, hardness and glass transition temperatures.

These physical characteristics are influenced by the conformation and orientation of the molecule in the unit cell which are different for different polymorphic forms. These polymorphic forms exhibit distinct X-ray diffractogram, solid state 13C MR spectrometry, infrared spectrometry. Further, these polymorphic forms may give rise to peculiar thermal behaviour which can be measured by melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC). All these properties can be used to distinguish a particular polymorphic from the other form. Summary of the Invention:

In one aspect, the present invention provides stable amorphous form of Eluxadoline dihydrochloride and process for the preparation of the same.

The stable amorphous forms of Eluxadoline possesses 7.5% to 15% water content.

In another aspect, the present invention provides process for the preparation of stable amorphous form of Eluxadoline base. in a further aspect, the invention provides pharmaceutical compositions comprising stable amorphous form of Eluxadoline base or its dihydrochloride salt and pharmaceutically acceptable carrier, diluent or excipients.

In yet another aspect, the invention provides use of pharmaceutical composition comprising stable amorphous form of Eluxadoline base or its dihydrochloride salt defined hereinabove for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d).

In a further aspect, the present invention provides novel crystalline form E of Eluxadoline and process for preparation thereof.

In a further aspect, the invention provides pharmaceutical compositions comprising crystalline form E of Eluxadoline and pharmaceutically acceptable carrier, diluent or excipients.

In yet another aspect, the invention provides use of pharmaceutical composition comprising crystalline form E of Eluxadoline defined hereinabove for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d). Brief Description of accompanying drawings:

Figure 1 is an X-ray powder diffractogram (XRD) of amorphous Eluxadoline dihydrochloride.

Figure 2 is an X-ray powder diffractogram (XRD) of amorphous Eluxadoline base. Figure 3 is an X-ray powder diffractogram (XRD) of crystalline form E of Eluxadoline.

Figure 4 is an Infrared diffractogram (IR) of crystalline form E of Eluxadoline. Detailed Description of the Invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

Accordingly, in one embodiment, the present invention provides amorphous form of Eluxadoline dihydrochloride. Amorphous form of Eluxadoline dihydrochloride of the present invention is characterized by its powder X-ray diffraction pattern. The XRPD of the amorphous Eluxadoline dihydrochloride was measured on a Rigaku Miniflex II X-ray powder diffractometer using a Cu K_a radiation source, and is characterized by its XRPD pattern substantially as depicted in Figure 1.

In another embodiment, the invention provides process for preparation of an amorphous form of Eluxadoline dihydrochloride. The amorphous form of Eluxadoline dihydrochloride can be prepared from Eluxadoline free base which may be in any polymorphic form, obtained by the processes known in the art.

The process for preparation of amorphous Eluxadoline dihydrochloride involves following steps:

a) dissolving protected Eluxadoline base compound (II)

Compound (II) in a suitable solvent;

b) adding hydrochloric acid or passing hydrogen chloride gas through the reaction mass followed by stirring the reaction mass for 25 to 35 hrs; and c) isolating the product formed and drying the obtained product at 40 to 50°C to yield amorphous Eluxadoline dihydrochloride.

The protected Eluxadoline as referred above is compound (II), i.e., the protected Eluxadoline is tert-butoxycarbonyl group (Boc) protected Eluxadoline.

The suitable solvent used to dissolve the compound (II) is selected from the group consisting of but not limited to hydrocarbons, esters, ethers, alcohols, organic acids, ketones, nitriles, water and mixtures thereof.

Drying of the product is carried out for 25 to 35 hours, preferably 15 to 17 hours. The water content in the amorphous Eluxadoline dihydrochloride is between 7.5% (w/w) to 15%) (w/w) by Karl Fischer method.

The product may be dried in a spray dryer, lyophilser or fluid bed dryer or by any other conventional manner.

In another embodiment, the invention provides alternate process for preparation of amorphous Eluxadoline dihydrochloride. The process involves following steps: a) dissolving Eluxadoline base in a suitable solvent; b) dissolving hydrochloric acid in a suitable solvent;

c) Mixing the solutions containing eluxadoline and hydrochloric acid; and d) isolating the product formed and drying the obtained product at 40 to 50°C.

The suitable solvent used to dissolve the Eluxadoline base and hydrochloric acid is selected from the group consisting of but not limited to hydrocarbons, esters, ethers, alcohols, organic acids, ketones, nitriles, water and mixtures thereof. The solvent is preferably selected from the group consisting of ethyl acetate, acetone, THF, water and mixture thereof.

Drying of the product is carried out for 25 to 35 hours. The water content in the amorphous Eluxadoline dihydrochloride is between 7.5 %(w/w) to 15%(w/w) by Karl Fischer method.

In another embodiment, the invention provides, a process for preparation of stable amorphous form of Eluxadoline base.

The XRPD of the amorphous Eluxadoline base was measured on a Rigaku Miniflex II X-ray powder diffractometer using a Cu K_a radiation source, and is characterized by its XRPD pattern substantially as depicted in Figure 2.

The process for preparation of stable amorphous Eluxadoline base involves following steps:

a) dissolving Eluxadoline base in a suitable solvent; and

b) isolating the product formed and drying the obtained product at 40 to 50°C. The suitable solvent used to dissolve the Eluxadoline base is selected from the group consisting of but not limited to hydrocarbons, esters, ethers, alcohols, organic acids, ketones, nitriles, water and mixtures thereof.

Drying of the product is carried out for 10 to 35 hours. The water content in the amorphous Eluxadoline base is between 8.0 % (w/w) to 15% (w/w) by Karl Fischer method.

Amorphous Eluxadoline base as well as dihydrochloride salt according to the present invention can be characterized by various parameters like solubility, intrinsic dissolution, bulk density, tapped density, particle size.

The melting point of amorphous Eluxadoline dihydrochloride is in the range of 50 to 70°C.

The melting point of amorphous Eluxadoline base is in the range of 40 to 70°C.

In another embodiment, the present invention provides a solid dispersion of amorphous Eluxadoline with one or more pharmaceutically acceptable carrier(s).

In yet another embodiment, the present invention provides a process for preparation of solid dispersion of amorphous Eluxadoline or its salt with one or more pharmaceutically acceptable carrier(s) which process comprises:

a) providing a solution of Eluxadoline or its salt in combination with one or more pharmaceutically acceptable carrier(s) in a suitable solvent or a mixture of solvents; and

b) isolating solid dispersion comprising amorphous Eluxadoline or its salt and one or more pharmaceutically acceptable carrier(s). The suitable solvent used to dissolve the Eluxadoline or its salt is selected from the group consisting of but not limited to hydrocarbons, esters, ethers, alcohols, organic acids, ketones, nitriles, water and mixtures thereof.

The salt of Eluxadoline as referred herein in the description is hydrochloride salt of Eluxadoline.

Optionally the reaction mixture of step a) may be extruded prior to isolation of the solid dispersion.

Pharmaceutically acceptable carriers that may be used in step a) may be selected from the group but not limited to starch, pregelatinised starch, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropylcelluloses (HPC), hydroxymethylcelluloses, hydroxyethylcellulose, hydroxyethylmethylcellulose (HEMC), carboxymethylcellulose (CMC), carboxymethyl hydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethyl cellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropyl methylcelluloses (HPMC), hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

The preparation of solid dispersion of amorphous Eluxadoline comprises dissolution of Eluxadoline or its salt and the pharmaceutically acceptable carrier(s) either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.

The isolation of a solid dispersion of amorphous Eluxadoline together with one or more pharmaceutically acceptable carriers may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

In another embodiment of the present invention there is provided pharmaceutical composition comprising stable amorphous form of Eluxadoline base or its dihydrochloride salt and pharmaceutically acceptable carrier, diluent, glidant or excipients.

In yet another embodiment of the present invention there is provided use of pharmaceutical composition comprising stable amorphous form of Eluxadoline base or its dihydrochloride salt defined hereinabove for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d).

Another aspect of the present invention provides a method of treating a patient suffering from irritable bowel syndrome (IBS), pain or an opioid receptor disorder which method comprises administering to said patient a therapeutically effective amount of amorphous eluxadoline dihydrochloride provided in accordance with the invention. In one another embodiment, the present invention provides crystalline form E of Eluxadoline. Crystalline form E of Eluxadoline of the present invention can be characterized by its powder X-ray diffraction pattern. The XRPD of the crystalline form E of Eluxadoline was measured on a Rigaku Miniflex II X-ray powder diffractometer using a Cu Ka radiation source, and is characterized by its XRPD pattern substantially as depicted in Figure 3. The crystalline form E of Eluxadoline is further characterised by its Infra Red pattern, substantially as depicted in Figure 4.

The crystalline form E of Eluxadoline can also be further characterised by analytical methods including, but not limited to melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), MR, particle size, bulk density, tapped density, flow characteristics, solubility and intrinsic dissolution.

In another embodiment, the invention provides process for preparation of crystalline form E of Eluxadoline which comprises following steps;

a) Dissolving Eluxadoline base in a suitable solvent or mixture of solvents at suitable temperature;

b) Optionally cooling the solution;

c) Adding anti-solvent to the solution;

d) Optionally stirring the suspension followed by filtering and drying to obtain crystalline form E of Eluxadoline.

Eluxadoline base used in the process for preparation of Form E may be in any form like amorphous, crystalline, solvate and the like.

The solvent for the dissolution of eluxadoline may be selected from the group consisting of alcohol, polyether, hydrocarbons, organic acids, nitriles, water or mixtures thereof. Other solvents such as N-methyl pyrrolidone ( MP), dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO) can also be used. One preferred solvent used for dissolution of eluxadoline is polyethylene glycol- 300.

Accordingly, in a preferred embodiment, the crystalline eluxadoline form E is characterized by having PEG content of about 22 to 35%.

In another preferred embodiment, the crystalline eluxadoline form E is characterized by having water content of about 1 to 3%.

In another preferred embodiment, the crystalline eluxadoline form E is provided with a purity of >99%.

Suitable temperature may be the temperature at which eluxadoline dissolves in the given solvent.

After heating the reaction mixture to the desired temperature to dissolve the solid, the solution may further be cooled, if required, and antisolvent is added to it.

Suitable antisolvent may be selected from the group consisting of ketone, ether, esters or mixtures thereof. Preferably, the antisolvent is selected from ethyl acetate, acetone, THF, methanol and mixture thereof.

After the addition of antisolvent, the suspension obtained may be stirred, filtered and then dried to get the final crystalline polymorph E.

In an alternate embodiment, Eluxadoline may be directly obtained from reactants wherein the process involves following steps:

a) Dissolving compound (II) in a suitable solvent;

b) Adding solution of hydrochloric acid to the above solution;

c) Treating the solution obtained in step b) with base; and

d) Washing and drying the obtained product. The solvent used for dissolution of compound (II) is selected from the group comprising of alcohol, ketone, ether, esters or mixtures thereof. The base used in step c) is selected from organic base and inorganic base.

Yet another aspect of present invention provides pharmaceutical composition comprising crystalline form E of Eluxadoline. In addition to active ingredient(s) the pharmaceutical composition of the present invention may contain one or more pharmaceutically acceptable carriers, diluent, glidant or excipients.

The composition of the present invention can be formulated into variety of dosage forms, such as tablets, capsules, pills, caplets, lozenges, dispersible granules, dry powder syrup, ready to use suspension; parenteral dosage forms available in the art; various inhalation formulations; transdermal formulations, and the like. These formulations can be prepared using the processes known in the art.

Further aspect of this invention provides use of pharmaceutical composition comprising crystalline form E of Eluxadoline defined hereinabove for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d).

Another aspect of the present invention provides a method of treating a patient suffering from irritable bowel syndrome (IBS), pain or an opioid receptor disorder which method comprises administering to said patient a therapeutically effective amount of crystalline form E of Eluxadoline provided in accordance with the invention.

The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention. EXAMPLES:

Example 1:

Preparation of amorphous Eluxadoline dihydrochloride

Compound (II) Eluxadoline Dihydrochloride

15 g of Compound (II) was charged in 150 ml of ethyl acetate and stirred well at 25±5°C. Hydrochloric acid in Ethyl acetate was charged to the reaction mass and reaction was monitored by TLC. After the completion of the reaction, the reaction mass was filtered under nitrogen and the solid was washed with 45 ml of ethyl acetate. The product (amorphous Eluxadoline dihydrochloride) was then dried at 45-50°C under high vacuum for 16 hours.

Dry wt. = 12.5 g.

Purity: > 95%

Moisture content: 8.0 %

Example 2:

Preparation of amorphous Eluxadoline dihydrochloride

15 g of Compound (II) was charged in 600 ml of ethyl acetate and 150 ml of THF and stirred well at 25±5°C. The reaction mass was then cooled to 10-15 °C. Dry HCl gas was purged into reaction mass up to pH 2-2.5. The temperature was then raised to 25±5°C. After completion of the reaction, the reaction mass was filtered under nitrogen and the solid obtained was washed with 45 ml of ethyl acetate. The product (amorphous Eluxadoline dihydrochloride) was then dried at 45-50°C under high vacuum for 16 hours. Dry wt. = 12.5 g.

Purity: 95.66 %

Moisture content: 8.72%

Example 3:

Preparation of amorphous Eluxadoline base

15 g of Compound (II) was charged in 600 ml of ethyl acetate and 150 ml of THF and stirred well at 25±5°C. The reaction mass was then cooled to 10-15 °C. Dry HCl gas was purged into reaction mass up to pH 2-2.5. The temperature was then raised to 25±5°C. After completion of the reaction, the reaction mass was filtered under nitrogen and the solid obtained was washed with 45 ml of ethyl acetate. The product (amorphous Eluxadoline dihydrochloride) was then dried at 45-50°C under high vacuum for 16 hours.

The product thus obtained was dissolved in 5 volumes of water and pH was adjusted to 6 to 7 by using 3M sodium hydroxide solution at 0 to 5°C. The obtained precipitate was filtered and dried under vacuum below 40°C for 10 hours.

Dry wt - 11 g

Purity: 97.29%

Moisture content: 8.5%

Example 4:

Amorphous solid dispersion of Eluxadoline base

0.5 g of Eluxadoline and 5 ml of methanol were charged into a round bottom flask at 25 °C. The contents were heated to 55-60 °C and filtered. PVP K-30 (0.5 g) was added to the filtrate and the contents were distilled under reduced pressure at 35°C. The distilled product was dried in the rotavapor at 35°C for 60 minutes to afford the title compound. Example 5:

Preparation of amorphous Eluxadoline base

Charge 100 g of Compound (II) in 1000 ml of ethyl acetate and stirred well at 25±5°C followed by addition of 1400 ml Ethyl Acetate and about 8 to 12% of HC1 into reaction mass. After completion of the reaction, the reaction mass was filtered under nitrogen and the solid was washed with 200 ml of ethyl acetate. The wet cake was transferred into a 4.0 Neck RBF & following by addition of water (l .OLtr.). The pH was adjusted to 10-12 by using 10% NaOH solution and the reaction mass was washed with ethyl acetate (1000*3 Times). The aqueous layer was collected & the pH was adjusted to 6.5-7 by using 5% HC1 solution at 0-5°C. The stirring was maintained for 2.0 hours at 0-5°C. The reaction mass was washed with water 25.0 ml, sucked well & the material was dried under vacuum below 50°C.

Wet wt:-200.0 g

Dry wt:-50-60.0 g.

Example 6:

Preparation of Form E Eluxadoline

5 g of amorphous Eluxadoline was dissolved into 40 ml of polyethylene glycol-300 at 80-90°C, cooled to 50°C and 40 ml of acetone was added to this solution. The solution was filtered and again heated to 55-60°C and stirred for 2 hours. The solution was gradually cooled to 25-30°C, stirred for 12 hours. The obtained suspension was filtered, washed with acetone and the white solid obtained was dried at 70°C under vacuum.

PEG content - 32.57%

Moisture content -2.46 %

Purity - 99.37%

Example 7:

Preparation of Form E Eluxadoline

5 g of amorphous Eluxadoline was dissolved into 40 ml of polyethylene glycol-300 at 80-90°C. The solution was filtered. The clear filtrate was heated to 60-65°C, followed by addition of 40 ml of tetrahydrofuran and stirred for 2 hours. The solution was gradually cooled to 25-30°C and stirred for 12 hours. The obtained suspension was filtered, washed with tetrahydrofuran and the white solid thus obtained was dried at 70°C under vacuum.

PEG content - 24.6%

Moisture content -1.21 %

Purity - 99.16%

Example 8:

Preparation of Form E Eluxadoline

5 g of amorphous Eluxadoline was dissolved into 40 ml of polyethylene glycol-300 at 80-90°C and filtered. The clear filtrate was heated to 60-65°C, followed by addition of 40 ml of Ethyl acetate and stirred for 2 hours. The solution was gradually cooled to 25-30°C and stirred for 12 hours. The obtained suspension was filtered, washed with ethyl acetate and the white solid thus obtained was dried at 70°C under vacuum.

PEG content - 25.8%

Moisture content -1.30 %

Purity - 99.00%

Example 9:

Preparation of Form E Eluxadoline

5 g of amorphous Eluxadoline was dissolved into 40 ml of methanol at 55-60°C followed by addition of 40 ml of polyethylene glycol-300. The solution was filtered. The clear filtrate was heated to 50°C to which 40 ml of Acetone was added and stirred for 2 hours. The solution was gradually cooled to 25-30°C and stirred for 12 hours. The obtained suspension was filtered, washed with Acetone and the white solid thus obtained was dried at 70°C under vacuum.

PEG content - 28.8 %

Moisture content -2.19 %

Purity - 99.50%

Claims

We claim,

1. Amorphous eluxadoline dihydrochloride.

2. The amorphous eluxadoline dihydrochloride according to claim 1, which is further characterized by the X-ray powder diffraction pattern substantially as depicted in FIG. 1.

3. The amorphous eluxadoline dihydrochloride as claimed in any one of the preceding claims having water content between 7.5% (w/w) and 15%(w/w).

4. A process for the preparation of amorphous eluxadoline dihydrochloride comprising steps of:

a) dissolving compound (II) in a suitable solvent;

b) adding hydrochloric acid or passing hydrogen chloride gas through the reaction mass;

c) stirring the reaction mass for about 25 hours to about 35 hours;

d) isolating the product formed; and

e) drying the obtained product at 40 to 50°C.

5. The process according to the claim 4, wherein the solvent is selected from the group consisting of hydrocarbons, esters, ethers, alcohols, organic acids, ketones, nitriles, water, and mixtures thereof.

6. The process according to the claim 5, wherein the solvent is selected from ethyl acetate, acetone, THF, water and mixture thereof.

7. A crystalline form E of eluxadoline characterized by the X-ray powder

diffraction pattern substantially as depicted in FIG. 3.

8. The crystalline form E of eluxadoline according to claim 7, wherein, the Form E is further characterized by Infrared diffractogram substantially as depicted in FIG. 4.

9. The crystalline form E of eluxadoline according to claim 7, wherein, the Form E is further characterized by having PEG content of about 22 to 35%.

10. A process for the preparation of crystalline form E of eluxadoline comprising steps of:

a) dissolving eluxadoline base in a suitable solvent or mixture of solvents at a suitable temperature;

b) optionally cooling the solution;

c) adding anti-solvent to the solution;

d) optionally stirring the suspension;

e) filtering; and

f) drying the obtained product.

11. The process according to the claim 10, wherein the eluxadoline base is in the amorphous form.

12. The process according to the claim 10, wherein the solvent is selected from the group consisting of alcohol, polyether, hydrocarbons, organic acids, nitriles, water, polar aprotic solvents such as N-methyl pyrrolidone ( MP), dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO), polyethylene glycol-300 or mixtures thereof.

13. The process according to the claim 12, wherein the solvent is polyethylene glycol-300.

14. The process according to the claim 10, wherein the antisolvent is selected from the group consisting of ketone, ether, esters or mixtures thereof.

15. The process according to the claim 14, wherein the solvent is selected from ethyl acetate, acetone, THF, methanol and mixture thereof.

16. A process for the preparation of eluxadoline comprising steps of:

a) Dissolving compound (II) in a suitable solvent;

b) adding a solution of hydrochloric acid to the above solution;

c) treating the solution obtained in step b) with a base;

d) washing; and

e) drying the obtained product.

17. The process according to the claim 16, wherein the solvent is selected from the group consisting of alcohol, ketone, ether, esters or mixtures thereof.

18. The process according to the claim 16, wherein the base is selected from organic base and inorganic base.

19. A pharmaceutical composition comprising therapeutically effective amount of amorphous eluxadoline dihydrochloride of claim 1, and a pharmaceutically acceptable carrier, diluent, glidant or excipients.

20. A pharmaceutical composition comprising therapeutically effective amount of crystalline form E of eluxadoline of claim 7, and a pharmaceutically acceptable carrier, diluent, glidant or excipients.

21. A method of treating a patient suffering from irritable bowel syndrome (IBS), pain or an opioid receptor disorder comprising administering to said patient a therapeutically effective amount of amorphous eluxadoline dihydrochloride of claim 1 .

22. A method of treating a patient suffering from irritable bowel syndrome (IBS), pain or an opioid receptor disorder comprising administering to said patient a therapeutically effective amount of crystalline form E of eluxadoline of claim 7.