DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of crystalline form a of Eluxadoline. The present invention also relates to crystalline form M of Eluxadoline and process for their preparation. The present invention also relates to a process for the purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine, which is useful intermediate in the preparation of Eluxadoline thereof.

The present complete specification is prepared by cognating the contents provisional patent specification of application numbered 201621041401 dated December 03, 2016 with the contents of the specification of patent application no. 201621041734 dated December 06, 2016 and 201621043890 dated December 22, 2016. The combined contents of the present specification constitute a single invention within the meaning of the Act.

BACKGROUND OF THE INVENTION
Diarrhea-predominant irritable bowel syndrome is a chronic disorder that affects about 28 million patients. Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. Opioid ligands can be usefully employed to normalize altered visceral sensitivity in IBS patients. Mu (µ), kappa (?), and delta (d) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized.

Eluxadoline (designated as VIBERZI®) chemically represented as 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxy benzoic acid is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D). Its chemical structure is represented by Formula (I).

WO 2005/090315 discloses Eluxadoline and it’s pharmaceutically acceptable salt; methods for its preparation; pharmaceutical composition; and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.

WO 2009009480 covers crystalline form a and ß of Eluxadoline and process for its preparation. Example 2 of WO’480 describes the process for the preparation of crystalline form a of Eluxadoline by storing the zwitterion of Eluxadoline at 0-25% relative humidity for 3 days. This method for the preparation of crystalline form a (alpha) of Eluxadoline is difficult to operate at large scale and thus rendering them unsuitable for commercial scale. Therefore, there remains a need for the environmental friendly, highly pure, cost effective and industrially applicable process for the preparation of crystalline form a Eluxadoline.

In the pharmaceutical industry, the discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Thus, there remains a need to provide alternate form of Eluxadoline and process for their preparation.

According to ICH guidelines, process impurities should be maintained below limit by specifying the quality of starting or raw material and controlling process parameters. Impurities, side product or by-product present in raw or starting material will in most cases also be present in the final active pharmaceutical ingredients. Raw or starting material with high purity to comply with pharmaceutical standards. (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine is an intermediate in the synthesis of Eluxadoline. It can be obtained commercially or prepared by any method known in the art. However, being an intermediate in the preparation of Eluxadoline, the purity of this intermediate affects the ultimate purity of Eluxadoline. Therefore it is important to utilize this intermediate in a level of high purity. Thus there is a need to develop a process for purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine of formula (II), which will produce highly pure Eluxadoline and its pharmaceutically acceptable salts thereof. While developing the process, the inventor comes across the cost effective and industrially applicable process for the purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of crystalline form a of Eluxadoline. The present invention also relates to crystalline form M of Eluxadoline and process for their preparation. The present invention also relates to a process for the purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine, which is useful intermediate in the preparation of Eluxadoline and its pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE FIGURE
Fig. 1: depicts the X-ray powder diffraction pattern of crystalline form M of Eluxadoline obtained according to the procedure of Example 2.

DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of crystalline form a of Eluxadoline; comprising the steps of:
(a) providing solution of Eluxadoline in suitable alcohol solvent or mixtures thereof;
(b) heating the reaction mixture;
(c) cooling the said solution;
(d) isolating the crystalline form a of Eluxadoline.

Providing solution of Eluxadoline in step (a) includes:
(i) direct use of reaction mixture containing Eluxadoline that is obtained during its synthesis; or
(ii) dissolving Eluxadoline in suitable alcohol solvent.

Any physical form (i.e., crystalline or amorphous) of Eluxadoline that may be utilized for providing the solution of Eluxadoline in step (a). Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art (for e.g., WO 2005/090315 A1 & WO 2009009480 A1).

A suitable alcohol solvent that may be used in step (a) is selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, or mixtures thereof in any suitable proportion. More preferably methanol may be used in any suitable proportion.

The reaction mixture obtained in step (a) may be heated at reflux temperature of the solvent. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.

The solution obtained in step (b) may be cooled to a tempearature from about 0°C to about room temperature, preferably at room temperature. The stirring may be carried for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 3 hours. Optionally, the resultant mixture may be further seeded with previously prepared crystals of a form of Eluxadoline. As used herein, the term “room temperature” refers to a temperature in the range of about 20°C to about 30°C.

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The obtained crystalline form a of Eluxadoline may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at a temperature about 35°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.

In one embodiment, the present invention provides a process for the preparation of crystalline form a of Eluxadoline; comprising the steps of:
(a) providing solution of Eluxadoline in methanol;
(b) heating the reaction mixture to reflux temperature;
(c) cooling the said solution to room temperature;
(d) isolating the crystalline form a of Eluxadoline.

Providing solution of Eluxadoline in step (a) includes:
(i) direct use of reaction mixture containing Eluxadoline that is obtained during its synthesis; or
(ii) dissolving Eluxadoline in methanol in any suitable proportion.

Any physical form (i.e., crystalline or amorphous) of Eluxadoline that may be utilized for providing the solution of Eluxadoline in step (a). Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art (for e.g., WO 2005/090315 A1 & WO 2009009480 A1).

The solution obtained in step (a) may be heated at a reflux temperature, preferably at a temperature about 50°C to about 75°C. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.

The solution obtained in step (b) may be cooled to room temperature followed by stirring for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 3 hours. Optionally, the resultant mixture may be seeded with previously prepared crystals of a form of Eluxadoline.

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The obtained crystalline form a of Eluxadoline may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 35°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.

Analytical data (for e.g., PXRD, DSC, TGA) of crystalline form a of Eluxadoline prepared according to the processes of the present invention matches with crystalline form a of Eluxadoline as described in WO 2009009480 A1.

In an aspect of the present invention, crystalline form a of Eluxadoline prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% by weight as determined using high performance liquid chromatography.

In yet another aspect, the present invention provides pharmaceutical composition comprising crystalline form a of Eluxadoline prepared according to process of present invention with one or more pharmaceutically acceptable excipients and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors. The term “pharmaceutically acceptable excipients” used in the pharmaceutical composition of invention comprise but are not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants known in the art.

In another aspect, the present invention provides a crystalline form M of Eluxadoline.

In one embodiment, crystalline form M of Eluxadoline is characterized by X-ray powder diffraction pattern as depicted in Fig. 1.

In yet another aspect, the present invention provides a process for the preparation of crystalline form M of Eluxadoline; comprising the steps of:
(a) providing solution of Eluxadoline in suitable solvent or mixtures thereof;
(b) adding antisolvent to the solution of step (a) or vice versa;
(c) isolating crystalline form M of Eluxadoline.

Providing solution of Eluxadoline in step (a) includes:
(i) direct use of reaction mixture containing Eluxadoline that is obtained during its synthesis; or
(ii) dissolving Eluxadoline in suitable solvent or mixtures thereof.

Any physical form (i.e., crystalline or amorphous) of Eluxadoline that may be utilized for providing the solution of Eluxadoline in step (a). Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art.

Suitable solvents that may be used in step (a) include but are not limited to alcohol, amide, sulfoxide or mixtures thereof in any suitable proportion. Particularly preferred solvents are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, dimethylformamide (DMF), N-methyl pyrrolidone (NMP), dimethylacetamide (DMAc), formamide, acetamide, propanamide, dimethyl sulfoxide (DMSO) or mixtures thereof in any suitable proportion. More preferably methanol may be used in any suitable proportion.

The dissolution temperature may range from about 10°C to about reflux temperature of the solvent. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.

The anti-solvent for step (b) comprises ketone, ether, hydrocarbon, esters or mixtures thereof in any suitable proportion. Particularly preferred solvents selected from the group consisting of acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, or mixtures thereof in any suitable proportion. More preferably 2-methyltetrahydrofuran may be used as anti-solvent.

The treatment with the antisolvent may be carried out, for example, by adding the antisolvent into the solution of Eluxadoline or vice versa at temperature about -10°C to refluxing temperature, preferably at about 50°C to about 75°C. The treatment with antisolvent may be followed by stirring the mixture for a period of about 10 minutes to 30 hours, preferably about 1 hour to about 2 hours; at a temperature about -10°C to about 70°C, preferably at room temperature. Optionally, the reaction mixture obtained in step (b) may be further seeded with previously prepared crystals of form M of Eluxadoline. As used herein, the term “room temperature” refers to a temperature in the range of about 20°C to about 30°C.

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The obtained crystalline form M of Eluxadoline may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 35°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.

In one embodiment, the present invention provides a process for the preparation of crystalline form M of Eluxadoline; comprising the steps of:
(a) providing solution of Eluxadoline in methanol;
(b) heating the reaction mixture;
(c) adding 2-methyl tetrahydrofuran into the solution of step (b);
(d) optionally seeding the resultant solution with crystals of form M of Eluxadoline;
(e) cooling the said mixture to room temperature;
(f) isolating crystalline form M of Eluxadoline.

Providing solution of Eluxadoline in step (a) includes:
(i) direct use of reaction mixture containing Eluxadoline that is obtained during its synthesis; or
(ii) dissolving Eluxadoline in methanol.

Any physical form (i.e., crystalline or amorphous) of Eluxadoline that may be utilized for providing the solution of Eluxadoline in step (a). Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art.

In step (a), methanol may be used in any suitable proportion. The reaction solution obtained in step (a) may be heated at reflux temperature of the solvent, preferably at a temperature about 50°C to about 75°C. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.

The treatment with the antisolvent such as 2-methyl tetrahydrofuran may be carried out at a temperature about -10°C to refluxing temperature, preferably at a temperature about 50°C to about 75°C. The treatment with antisolvent may be followed by stirring the mixture for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 2 hours at a temperature about -10°C to about 70°C, preferably at room temperature. Optionally, the reaction mixture obtained in step (c) may be further seeded with previously prepared crystals of form M of Eluxadoline. The stirring may be carried out at a temperature about 20°C to about 70°C for a period about 10 minutes to about 30 hours, preferably for about 1 hour to 2 hours.

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The obtained crystalline form M of Eluxadoline may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 35°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.

In yet another aspect, the present invention provides pharmaceutical composition comprising crystalline form M of Eluxadoline with one or more pharmaceutically acceptable excipients and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.

The term “pharmaceutically acceptable excipients” used in the pharmaceutical composition of invention comprise but are not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants known in the art.

In yet another aspect, the present invention provides a process for the purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine of formula (II);

comprising the steps of:
(a) providing solution of crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in suitable ester solvent or mixtures thereof;
(b) heating the reaction mixture;
(c) cooling the said solution;
(d) isolating the purified (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine.

Providing solution of crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in step (a) includes:
(i) direct use of reaction mixture containing (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine that is obtained during its synthesis; or
(ii) dissolving (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in suitable ester solvent.

(S)-1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art.

Suitable solvents that may be used in step (a) is selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, or mixtures thereof in any suitable proportion. More preferably ethyl acetate may be used in any suitable proportion.

The reaction mixture obtained in step (a) may be heated at reflux temperature of the solvent. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution. The stirring may be carried for a period of about 10 minutes to about 10 hours, preferably about 30 minutes to 1 hour.

The solution obtained in step (b) may be cooled to a tempearature from about 0°C to about room temperature, preferably at room temperature. The stirring may be carried for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 5 hours. As used herein, the term “room temperature” refers to a temperature in the range of about 20°C to about 30°C.

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The obtained purified (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at a temperature about 35°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.

In yet another embodiment, the present invention provides a process for the purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine of formula (II);

comprising the steps of:
(a) providing solution of crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in ethyl acetate;
(b) heating the reaction mixture at reflux temperature;
(c) stirring the reaction mixture;
(d) cooling the said solution at room temperature;
(e) stirring the reaction mixture;
(f) isolating the purified (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine.

Providing solution of crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in step (a) includes:
(i) direct use of reaction mixture containing (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine that is obtained during its synthesis; or
(ii) dissolving (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in ethyl acetate in any suitable proportion.

(S)-1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art.

The solution obtained in step (a) may be heated at a reflux temperature, preferably at a temperature in the range of from about 70°C to about 80°C. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution. The stirring may be carried out at same temperature for a period about 10 minutes to about 10 hours, preferably about 30 minutes to 1 hour.

The solution obtained in step (c) may be cooled to room temperature. The stirring may be carried for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 5 hours. As used herein, the term “room temperature” refers to a temperature in the range of about 20°C to about 30°C.

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with ethyl acetate. The obtained purified (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at a temperature about 35°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.

In yet another aspect of the present invention, purified (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine obtained according to the processes of the present invention can be utilized for the preparation of Eluxadoline and its pharmaceutically acceptable salts thereof.

In yet another aspect of the present invention, (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine obtained according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% by weight as determined using high performance liquid chromatography.

In yet another aspect of the present invention, (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine purified according to the processes of the present invention having a chiral purity greater than about 99% by weight as determined using chiral high performance liquid chromatography.

Analytical Methods:
Powder X-ray Diffraction:
Powder X-ray diffraction can be obtained under following conditions: XRPD pattern is made using Cu K-a1 radiation at a voltage 40 mA & 45 kV. XRPD pattern was observed at 25°C and scanned from 3.5 to 40 two theta values.

HPLC Methods:
Column: Ascentis® Express C18, 2.7 µm;
Flow rate: 1 ml/minute;
Detector: UV at 210 nm;
Injection volume: 5 µl;
Temperature: 25°C;
Run time: 57 minutes.

One skilled in the art will recognize that additional starting compounds and/or reagents are commercially available or may be easily prepared according to conventional methods well known to these skilled in the art.
EXAMPLES
Following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.

Example 1: Preparation of crystalline form a of Eluxadoline
Eluxadoline (4 gm) was dissolved in methanol (40 ml). The resultant solution was heated at 60°C and further stirred for 1 hour. The mixture was cooled to room temperature and further stirred for 160 minutes. The solid precipitate was filtered, washed with methanol and further dried to obtain a crystal of Eluxadoline (Yield: 2.5 gm).

Example 2: Preparation of crystalline form M of Eluxadoline
Eluxadoline (5 gm) was dissolved in methanol (15 ml). The resultant solution was heated at 55°C to 60 °C and further stirred for 5 minutes to 10 minutes. To this stirring mixture was added 2-methyltetrahydrofuran (35 ml) and further stirred at same temperature for 40 minutes. The reaction mixture was cooled to room temperature and further stirred for 2 hours. The solid precipitate was filtered, washed with 2-methyltetrahydrofuran and further dried to obtain crystalline form M of Eluxadoline (Yield: 3.58 gm). IR (cm-1, KBr): 3387, 3212, 2969, 2147, 1670, 1644, 1591, 1568, 1494, 1460, 1395, 1241, 1142, 1106, 978, 822, 808, 764, 698, 676.

Example 3: Purification of crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine
Crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine (25 gm; HPLC Purity: 97.93%) was added to ethyl acetate (125 ml). The resultant mixture was heated at refluxing temperature and further stirred for a period of 30 minutes to 1 hour. The mixture was cooled to room temperature and further stirred. The solid precipitate was filtered, washed with ethyl acetate and further dried to obtain pure title compound. [Yield: 0.9 gm; HPLC Purity: 99.87%; Assay (HPLC method): 99.3%; Chiral purity: 99.69%].
,CLAIMS:1. A process for the purification of (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine of formula (II);

comprising the steps of:
(a) providing solution of crude (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine in suitable ester solvent or mixtures thereof;
(b) heating the reaction mixture;
(c) cooling the said solution; and
(d) isolating the purified (S)-1-(4-phenyl-1H-imidazol-2-yl)-ethylamine.

2. The process according to claim 1, wherein ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, or mixtures thereof.
3. The process according to claim 1, wherein ester solvent is ethyl acetate.
4. A process for the preparation of crystalline form a of Eluxadoline; comprising the steps of:
(a) providing solution of Eluxadoline in suitable alcohol solvent or mixtures thereof;
(b) heating the reaction mixture;
(c) cooling the said solution; and
(d) isolating the crystalline form a of Eluxadoline.

5. The process according to claim 4, wherein alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, t-butyl alcohol, 1-pentanol, 2-pentanol and amyl alcohol, or mixtures thereof.

6. The process according to claim 4, wherein suitable alcohol solvent is methanol.

7. The process according to claim 4, wherein step (b) is conducted at reflux temperature of the alcohol solvent and step (c) is conducted at a temperature of about 0°C to about room temperature.

8. The process according to claim 4, wherein crystalline form a of Eluxadoline is isolated by filtration.

9. Crystalline form M of Eluxadoline which is characterized by X-ray powder diffraction pattern as depicted in Fig. 1.

10. A process for the preparation of crystalline form M of Eluxadoline; comprising the steps of:
(a) providing solution of Eluxadoline in methanol;
(b) heating the reaction mixture;
(c) adding 2-methyl tetrahydrofuran into the solution of step (b);
(d) optionally seeding the resultant solution with crystals of form M of Eluxadoline;
(e) cooling the said mixture to room temperature; and
(f) isolating crystalline form M of Eluxadoline.