Field of the Invention
The present invention relates to a process for preparation of Eluxadoline of compound of Formula-I in Crystalline Form a.

Background of the Invention
Eluxadoline is chemically known as 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-l-oxopropyl][(!S)-l-(4-phenyl-lH-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid, which has been approved as a tablet having dosage strength 75MG and 1OOMG under the trade name VIBERZI®, which is indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
Eluxadoline as well as its pharmaceutically acceptable salts were disclosed in US 7,741,356 B2 and US 8,609,709 B2 of Janssen Pharmaceuticals. Further, US'356 and US '709 also discloses the synthesis of Eluxadoline dihydrochloride salt and is as shown below:


Eluxadoline Crystalline Form a and p have been disclosed in US 8,691,860 B2 and US 7,994,206 B2. Further, US '860 and US '206 discloses the synthesis of Eluxadoline zwitterion and is as shown below:

Further, US '860 and US '206 discloses the synthesis of Eluxadoline Crystalline Form a and (3, which is as shown below:
Storing ol 0-25% Storing al >60%
relative humidity for 3 days _ . relative humidity for 3 days
Eluxadoline Form a -« Zwitterion of Eluxadoline * hluxadolinc Form p
Further, it has been noted that the Zwitterion of Eluxadoline in US '860 has been isolated as Amorphous form and storing of Amorphous form of Eluxadoline Zwitterion at specific RH yields the Euxadoline Crystalline Form a and p.
i WO 2017/015606 Al of Teva, discloses the Eluxadoline crystalline Form alpha,
Form I (THF solvate), Form II (Methanol solvate), Form III (Ethanol solvate) and Form
IV (THF solvate). WO '606 discloses the process for the preparation of Eluxadoline
crystalline Form a through crystalline solvates.
The present inventors has repeated the prior-art and observed that the provided process is not suitable industrially as for the conversion to the Crystalline Form carried out for 2 - 3 days at specific RH.
The present inventors have also observed that the provided Eluxadoline crystalline Form a process in prior-art involves the formation of solvates and are further converted to Eluxadoline crystalline Form a. This process yields Eluxadoline Crystalline

Form a, however as per the ICH the solvents has to be limited, which is difficult when formed solvates and hence, this process leads to the Eluxadoline having low purity and hence commercially not feasible as well as not suitable economically.
In view of the above, there is a need for a industrially applicable process for the preparation of Eluxadoline crystalline Form a.
Objectives of the Invention
An objective of the present invention is to provide a process for the preparation of Eluxadoline crystalline Form a, which is industrially viable.
An objective of the present invention is to provide a process for the preparation of Eluxadoline crystalline Form a, which is commercially viable and economically cost-effective.
Another objective of the present invention is to provide a process for the preparation of Eluxadoline crystalline Form a having high yield and purity.
Summary of the Invention
A process for the preparation of Eluxadoline Crystalline Form a, which comprises:
a) treating Eluxadoline with a solvent or mixture of solvents;
b) heating the obtained reaction mixture;
c) cooling the obtained reaction mixture; and
d) isolating the Eluxadoline in Crystalline Form;
wherein, solvent is selected from the group comprising of esters, alcohols and/or mixture thereof.
Detailed Description of the Invention
The present invention relates to a process for the preparation of Eluxadoline Crystalline Form, which comprises treating Eluxadoline with a solvent and/or mixture of solvents thereof selected from the group comprising of haiogenated solvents, alcohols,

ketone solvents, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents; heating the obtained reaction mixture to 50 - !00°C: optionally the obtained reaction mixture was subjected to carbon treatment; cooling the obtained reaction mixture to 10 - 30°C; and isolating the Eluxadoline crystalline Form a.
In another embodiment throughout the invention, the Eluxadoline is in the form crystalline or amorphous.
In another embodiment throughout the invention, isolation of Eluxadoline crystalline Form can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation and the like.
In another embodiment throughout the invention, the halogenated solvents are selected from the group comprising of dichloromethane (MDC), ethylene dichloride (EDC), chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, isopropanol, butanol and the'like; ketone solvents are selected from the group comprising of acetone, methyl isobutyl ketone, dimethylformamide and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether, methyl t-Bu ether (MTBE), dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of cyclohexane, hexane, heptane, n-hexane, n-heptane, toluene, xylene and the like; nitriles are selected from the group comprising of ' acetonitrile, propionitrile, butyronitrile, acrylonitrile and the like; Polar aprotic solvents are selected from the group comprising of dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile, dimethylsulfoxide (DMSO) and the like.
In another embodiment throughout the invention, the mixture of solvents means two or more solvents.

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.
The invention will-now be further described by the following examples, which are illustrative rather than limiting.
Examples Example 1: Preparation of Eluxadoline crystalline Form a
To the Eluxadoline.(100 gm), added Acetone (500 ml) at room temperature and heated to 50 - 55°C. To the obtained slurry was added methanol (500 ml) at 50 - 55°C and heated to 55 - 65°C. The obtained reaction mixture was stirred for 2 to 3 hours at 75 - 80°C. Cooled to 25 - 30°C and stirred for 2 to 3 hours at room temperature. The obtained solid was filtered and washed with Acetone and Methanol (50 ml and 50 ml) followed by drying at 55 - 60°C under vacuum for 8 hours to yield Eluxadoline Crystalline Form a. Yield: 80 gm Chromatographic purity (by HPLC): 99.75%
Example 2: Preparation of Eluxadoline crystalline Form a
To the Eluxadoline (100 gm), added Acetone (500 ml) at room temperature and heated to 50 - 55°C. To the obtained slurry was added ethanol (500 ml) at 50 - 55°C and heated to 75 - 80°C. The obtained reaction mixture was stirred for 2 to 3 hours at 75 -80°C. Cooled to 25 - 30°C and stirred for 2 to 3 hours at room temperature. The obtained solid was filtered and washed with Acetone and Ethanol (50 ml and 50 ml) followed by drying at 55 - 60°C under vacuum for 8 hours to yield Eluxadoline Crystalline Form a. Yield: 85 gm Chromatographic purity (by HPLC): 99.90%
Example 3: Preparation of Eluxadoline crystalline Form a
To Eluxadoline (70 gm), was added Acetone (700 ml) and heated to 50 - 60°C. To the obtained slurry was added ethanol (700 ml) and heated to 65 - 70°C and

maintained for 30 minutes. The obtained .reaction-mixture was cooled to 25 -30PC .:•.' " .'=. '■•
.•followed by filtration and washed with Acetone (50- ml)..Tcrtheobtained wet compound ' '.'-.: •/:»■ "■ • •:-
was added Methanol (500 ml) and heated to 65°C then.maintained for 30 minutes. '■''•.•
Cooled-to 25 - 30°C for 5 to 6 hours and filtered the solid, followed by drying at 45'C to -
yield Eluxadoline Crystalline Form a.'
Yield: 50 gm
..Chromatographic purity (by HPLC): 99.85% /• :•■■ v .- r- ' ■> ■ -\ ■•.:-■■'
■Example 4: Preparation of Eluxadoline crystallineiForm.a". <"'■".;'-■ ■■
.- To Eluxadoline amorphous (100 gm),1 was. added mixture of methanol &
:.-.-.etlwlacetate (500 ml & 500 ml) at 55 - 30°C: The obtained suspension was heated to 65 - .-.,-; .* -. --i '•■^\ ■:■-
' 70°C and maintained for 4 hours. The obtained reaction mixture was cooled to 25 -30°C ;.
■. and stir, for 61hours to 8 hours. The obtained solid was filtered.and washed with mixture.. * ■ . ■• "■
of methanol and ethyl acetate (25 ml and -25: ml). The obtained solid was dried in hot-air.
oven at 65 - 70°C for 8 hours to yield Eluxadoline crystalline Form a. ■ *"•".' ..:
Yield: 90 gm • Chromatographic purity (by HPLC): 99:78%
Example 5: Preparation of Eluxadoline crystalline Form a
To Eluxadoline amorphous (100 gm), was added methanol (500 ml) at 25 - 30°C ■
■ and stir for 30 to 45 minutes at 25 - 30°G. The obtained cJear solution, was filtered
through hy-flow bed and washed the bed with Methanol(25 ml). To the obtained filtrate,. "•'■ ':'■-■ '*■
■ Ethylacetate (525-ml) was added drop wise over a.period ofol hour at 25 - 30°C.'The-; ■: , -[;■''.
..reaction mixture was heated.to 65 - 70°C and .maintained-1 for 4 hours. The obtained ■ •:.'"..: .. -,■
reaction mixture was cooled to 25 T- 30°C and stir for..6.hours to 8- hours. The obtained - .:.'■■ ■ .'"-. ■.•*:
. -reaction: mixture was cooled to 15 -20°C and maintained .for one hour at 15 - 20°C; The' ■ .;■
obtained solid was filtered and washed with mixture.ofmethanoPand ethyl acetate (25'ml .
.. and-25-ml): The obtained solid was dried in hot air oven at 65 -70°C for 8 hours to-yield\-
Eluxadoline crystalline Form a. . ,.' ....::.:■ .-;.■-•=•:.
Yield: 92 gm "*.' • i '■'.:.■
••.Chromatographic purity (by HPLC): 99.77% ; ;- ;; ."..•■ : -;,. .,■ .

We claim:
1. A process for the preparation of Eluxadoline Crystalline Form a, which comprises:.
a) treating Eluxadoline with a solvent or mixture of solvents;
b) heating the obtained reaction mixture;
c) cooling the obtained reaction mixture; and
d) isolating the Eluxadoline in Crystalline Form;
wherein, solvent is selected from the group comprising of esters, alcohols and/or mixture thereof.
2. The process as claimed in claim 1, wherein esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; and alcohols are selected from the group comprising of methanol, ethanol, isopropanol, butanol and the like.
3. The process as claimed in claim I, wherein heating the reaction mixture of step b) to50-100°C.
4. The process as claimed in claim 1, wherein cooling the reaction mixture of step c) to I0-30°C.