PRIORITY:

This application claims the benefit under Indian Provisional Application No. IN201741020875, filed on 15 ^th Jun 2017 entitled "Novel polymorphs of eluxadoline and its solvates, process for its preparation and pharmaceutical composition thereof", the content of which is incorporated by reference herein.

FIELD OF THE INVENTION:

The present invention relates to novel polymorphs of eluxadoline and its solvates thereof, process for their preparation and pharmaceutical composition comprising the same.

BACKGROUND OF THE INVENTION:

Eluxadoline is chemically known as 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2, 6- dimethyl-phenyl]-propionyl]-[l-(4-phenyl-lH-imidazol-2-yl) ethyl] amino] methyl]-2- methoxybenzoic acid and represented by the following structural formula;

Eluxadoline is a peripherally acting mixed μ-opioid receptor agonist-5-opioid receptor antagonist and κ-opioid receptor agonist with minimal oral bioavailability. Eluxadoline works directly in intestines to slow the movement of food during digestion. Eluxadoline also makes the nerves in intestines less sensitive to stimulation.

Eluxadoline which was originated from Janssen Pharmaceutica and developed by Actavis, was approved by the United States Food and Drug Administration as Viberzi for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D) on May 27, 2015. Viberzi is administered orally as a tablet of 75 Mg and 100 Mg strength.

Eluxadoline free base is an approved form and process for the preparation of dihydrochloride salt of Eluxadoline was first described in U.S. Patent No. 7741356. However this patent does not discloses any characteristic details of Eluxadoline free base or Eluxadoline dihydrochloride salt.

U.S. Patent No. 8691860 discloses crystalline form a and form β forms of Eluxadoline free base characterized by PXRD, DSC and TGA. Crystalline form a of Eluxadoline was obtained by storing Eluxadoline zwitter ion under relative humidity of 0-25% for 3 days; whereas Crystalline Form β of Eluxadoline was obtained by storing Eluxadoline zwitter ion under relative humidity of greater than 60% for 3 days. This publication further discloses preparation of zwitterion of Eluxadoline comprising neutralizing acid addition salt of Eluxadoline with an inorganic base; preferably upon neutralizing Eluxadoline dihydrochloride salt with Sodium hydroxide.

WO2017015606 publication discloses stable Eluxadoline form alpha having TGA weight loss of up to 1.3%. This publication further discloses amorphous Eluxadoline, Eluxadoline Form I, Form II, Form III and Form IV along with its PXRD. WO2018046028 publication discloses crystalline form of Eluxadoline free base characterized by PXRD and DSC. This publication further discloses salt of eluxadoline with an acid in the solid form, the acid being selected from the group consisting of benzoic acid, sulphuric acid, hydrobromic acid, methane sulfonic acid, benzenesulfonic acid, phosphoric acid and tartaric acid characterized by PXRD.

WO2018047131 publication discloses amorphous eluxadoline characterized by an XRPD, DSC and IR.

Development of a specific commercial drug candidate involves many steps, such as development of a cost effective synthetic method which is efficient in large scale manufacturing process. Also, in formulation of drug compositions, it is important for the active pharmaceutical ingredient to be in a form, in which it can be conveniently handled and processed. Convenient handling is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of subsequent manufacture of pharmaceutical formulations comprising the active pharmaceutical ingredient. The drug development therefore involves research regarding finding suitable pharmaceutically acceptable forms of a drug.

Crucial parameters such as melting point, hygroscopicity and crystallinity are of paramount importance in the selection of the most suitable form of the drug. In addition, bulk properties such as particle size, moisture content, chemical purity and shape can affect the manufacturing of a drug product. Therefore it may be desirable to explore and discover various new polymorphic forms of a drug substance providing new opportunities to improve the performance characteristics of the drug.

Eluxadoline is one of such important drug candidate available in the market for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D). Hence it's important to discover new polymorphic forms of Eluxadoline and its solvates, which may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. Hence the main object of the present invention is to provide novel polymorphic forms of Eluxadoline and its solvates thereof.

SUMMARY OF THE INVENTION: The present invention provides novel polymorphic forms of Eluxadoline and its solvates thereof, process for their preparation and pharmaceutical compositions comprising one or more of the novel polymorphic forms of Eluxadoline and its solvates.

The novel polymorphic forms of Eluxadoline and its solvates of the present invention have advantageous properties selected from at least one of: particle size, moisture content, chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

In one embodiment, the present invention provides novel polymorphic form of Eluxadoline; which is designated herein as crystalline Eluxadoline Form A.

In another embodiment, the present invention provides crystalline Eluxadoline Form A characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides crystalline Eluxadoline Form A characterized by a powder X-Ray diffraction pattern having one or more peaks at about 8.08, 8.80, 10.67, 10.92, 13.31, 14.08, 14.65, 15.06, 15.71, 16.23, 16.59, 17.02, 17.64, 18.08, 19.50, 19.90, 21.19, 21.82, 22.72, 23.85, 25.24, 25.86, 26.15, 26.59, 28.34, 28.81, 29.51, 30.39, 30.96, 32.79, 33.18, 36.44, 38.53 and 43.87 + 0.2° 2Θ.

In another embodiment, the present invention provides crystalline Eluxadoline Form A, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.

In another embodiment, the present invention provides crystalline Eluxadoline Form A, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.

In another embodiment, the present invention provides crystalline Eluxadoline Form A, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1, a differential scanning calorimetry (DSC) substantially in accordance with Figure 2, and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.

In another embodiment the present invention provides a process for the preparation of crystalline Eluxadoline Form A, comprising:

a) providing a solution of eluxadoline in an organic solvent,

b) precipitating the reaction mass,

c) optionally isolating the eluxadoline solvate, and

d) converting the step b) reaction mass or step c) eluxadoline solvate to crystalline Eluxadoline of Form A. In another embodiment, the present invention provides a process for the preparation of crystalline Eluxadoline Form A comprising: drying eluxadoline solvate under heating at a temperature of about 45 °C to 95 °C for about 2 hours to about 36 hours. In another embodiment, the solvate used herein for preparing crystalline Eluxadoline Form A is selected from Eluxadoline 1-butanol solvate, Eluxadoline isobutanol solvate and Eluxadoline t-butanol solvate.

In another embodiment the present invention provides novel solvates of Eluxadoline such as 1-butanol solvate, isobutanol solvate and t-butanol solvate.

In another embodiment the present invention provides a process for the preparation of novel solvates of Eluxadoline comprising:

a) providing a solution of eluxadoline in an organic solvent,

b) precipitating the reaction mass, and

c) isolating the eluxadoline solvate.

In another embodiment, the present invention provides novel Eluxadoline 1-butanol solvate.

In another embodiment the present invention provides a process for the preparation of Eluxadoline 1-butanol solvate, comprising:

a) providing a solution of Eluxadoline in 1-butanol solvent,

b) precipitating the reaction mass, and

c) isolating Eluxadoline 1-butanol solvate.

In another embodiment, the present invention provides novel Eluxadoline isobutanol solvate. In another embodiment the present invention provides a process for the preparation of Eluxadoline isobutanol solvate, comprising:

a) providing a solution of Eluxadoline in isobutanol solvent,

b) precipitating the reaction mass, and

c) isolating Eluxadoline isobutanol solvate.

In another embodiment, the present invention provides novel Eluxadoline t-butanol solvate.

In another embodiment the present invention provides a process for the preparation of Eluxadoline t-butanol solvate, comprising:

a) providing a solution of Eluxadoline in t-butanol solvent,

b) precipitating the reaction mass, and

c) isolating Eluxadoline t-butanol solvate. In another embodiment, the present invention provides a pharmaceutical composition comprising the novel polymorphic forms of Eluxadoline and solvates thereof described above and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS :

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of Eluxadoline Form A.

Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of Eluxadoline Form A.

Figure 3 is the characteristic thermo gravimetric analysis (TGA) of Eluxadoline Form A.

Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline eluxadoline 1-butanol solvate.

Figure 5 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline eluxadoline 1-butanol solvate. Figure 6 is the characteristic thermo gravimetric analysis (TGA) of crystalline eluxadoline 1-butanol solvate.

Figure 7 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline eluxadoline isobutanol solvate.

Figure 8 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline eluxadoline isobutanol solvate.

Figure 9 is the characteristic thermo gravimetric analysis (TGA) of crystalline eluxadoline isobutanol solvate.

Figure 10 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline eluxadoline t-butanol solvate. Figure 11 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline eluxadoline t-butanol solvate.

Figure 12 is the characteristic thermo gravimetric analysis (TGA) of crystalline eluxadoline t-butanol solvate. DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides novel polymorphic forms of Eluxadoline and its solvates thereof, process for their preparation and pharmaceutical compositions comprising one or more of the novel polymorphic forms of Eluxadoline and its solvates.

The novel polymorphic forms of Eluxadoline and its solvates of the present invention have advantageous properties selected from at least one of: bulk properties - such as particle size, moisture content, chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. For example, when the solvent is 1- butanol, the solvate is referred to as a " 1-butanol solvate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount. The polymorphic forms of Eluxadoline and its solvates of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, Differential scanning calorimetry (DSC) and Thermo gravimetric analysis (TGA).

The X-Ray powder diffraction can be measured by an X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=2°/minute.

All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 2°C per minute with an Indium standard.

All TGA data reported herein were analysed using TGA Q500 V 20.8 build 34 in platinum pan with a temperature rise of about 5°C/min in the range of about 30°C to about 300°C.

In one embodiment, the present invention provides crystalline Eluxadoline of Form A.

In another embodiment, the present invention provides crystalline Eluxadoline Form A characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides crystalline Eluxadoline Form A characterized by a powder X-Ray diffraction pattern having one or more peaks at about 8.08, 8.80, 10.67, 10.92, 13.31, 14.08, 14.65, 15.06, 15.71, 16.23, 16.59, 17.02, 17.64, 18.08, 19.50, 19.90, 21.19, 21.82, 22.72, 23.85, 25.24, 25.86, 26.15, 26.59, 28.34, 28.81, 29.51, 30.39, 30.96, 32.79, 33.18, 36.44, 38.53 and 43.87 ± 0.2° 2Θ. In another embodiment, the present invention provides crystalline Eluxadoline Form A, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.

In another embodiment, the present invention provides crystalline Eluxadoline Form A, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3. In another embodiment, the present invention provides crystalline Eluxadoline Form A, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1, a differential scanning calorimetry (DSC) substantially in accordance with Figure 2, and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.

In another embodiment the present invention provides a process for the preparation of crystalline Eluxadoline Form A comprising:

a) providing a solution of eluxadoline in an organic solvent,

b) precipitating the reaction mass,

c) optionally isolating the eluxadoline solvate, and

d) converting the step b) reaction mass or step c) eluxadoline solvate to crystalline Eluxadoline of Form A.

The starting material eluxadoline is known in the art and can be prepared by any known method. The eluxadoline in an organic solvent may be any crystalline, amorphous or other form of eluxadoline, including various salts, solvates and hydrates thereof.

In step a) of the aforementioned process, providing a solution of Eluxadoline in an organic solvent first include adding eluxadoline to an organic solvent and afterward, subjecting to dissolution by stirring the mixture at a suitable temperature of about 35 °C to reflux temperature of the solvent, preferably at about 55°C to 75°C.

The organic solvent used herein is selected from alcohols such as methanol, ethanol, isopropanol, 1-butanol, isobutanol, t-butanol and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, 1,2-dimethoxy ethane, and the like; amides such as dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; water or mixtures thereof; preferably 1-butanol, isobutanol, t-butanol, water and mixtures thereof. Step b) of the forgoing process, the precipitation of Eluxadoline solvate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature to about 30°C or less.

In step c) of the forgoing process, optionally, involves isolating the Eluxadoline solvate precipitated according to step (b); wherein isolating Eluxadoline solvate may be carried out by any conventional process not limited to crystallization, solvent precipitation, drying, spray drying, freeze drying, agitated thin film evaporator (ATFE), evaporation on rotary evaporator under vacuum and the like; preferably, crystallization to isolate the eluxadoline in the form of solvate and followed by filtering the solid. In step d) of the forgoing process, converting the step b) reaction mass or step c) eluxadoline solvate to crystalline eluxadoline of Form A involves, drying of step b) reaction mass or desolvating the eluxadoline solvate of step c) by any conventional process not limited to spray drying or distillation to remove the solvent or drying under hot air oven or drying under vacuum. The drying may be performed at a temperature ranging from 45-95°C for a time ranging from about 2 to about 36 hours depending upon the physical attributes of the end product obtained i.e. pure Eluxadoline Form A; preferably the step d) may be carried out under drying of eluxadoline solvate of c) under vacuum. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. Eluxadoline recovered by the process as described above is characterized by at least one of the analytical techniques as follows: a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1, a differential scanning calorimetry (DSC) substantially in accordance with Figure 2, and thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.

In another embodiment the present invention provides novel solvates of Eluxadoline such asl-butanol solvate, isobutanol solvate and t-butanol solvate.

In another embodiment the present invention provides a process for the preparation of novel solvates of Eluxadoline comprising:

a) providing a solution of eluxadoline in an organic solvent,

b) precipitating the reaction mass, and

c) isolating the eluxadoline solvate; wherein the solvate is selected from the group consisting of eluxadoline 1-butanol solvate, eluxadoline isobutanol solvate and eluxadoline t-butanol solvate.

In step a) of the aforementioned process, providing a solution of Eluxadoline in 1- butanol, isobutanol, t-butanol or mixture of these solvents with water by stirring the mixture at a suitable temperature of about 35 °C to reflux temperature of the solvent, preferably at about 55°C to 75°C.

Step b) of the forgoing process, the precipitation of Eluxadoline solvate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature to about 30°C or less. In step c) of the forgoing process, isolating the Eluxadoline solvate precipitated according to step (b); wherein isolating the Eluxadoline solvate may be carried out by any conventional process known, for example: crystallization, solvent precipitation, drying, spray drying, freeze drying, agitated thin film evaporator (ATFE), evaporation on rotary evaporator under vacuum and the like; preferably, crystallization to isolate the eluxadoline in the form of solvate and followed by filtering the solid.

In another embodiment, the present invention provides novel eluxadoline 1-butanol solvate.

In another embodiment, the present invention provides eluxadoline 1-butanol solvate characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4. In another embodiment, the present invention provides crystalline eluxadoline 1-butanol solvate characterized by a powder X-Ray diffraction pattern having one or more peaks at about 4.9, 6.8, 7.1, 7.7, 8.8, 9.8, 10.7, 12.6, 13.1, 13.2, 14.2, 14.6, 15.5, 15.9, 16.6, 16.8, 17.4, 18.2, 18.5, 18.9, 19.5, 20.1, 20.4, 21.4, 21.8, 22.4, 22.9, 23.4, 24.8, 25.3, 26.0, 26.3, 29.8, 30.6, 32.9, 34.6 and 35.8 ± 0.2° 2Θ.

In another embodiment, the present invention provides crystalline eluxadoline 1-butanol solvate, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 5. In another embodiment, the present invention provides crystalline eluxadoline 1-butanol solvate, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 6.

In another embodiment, the present invention provides crystalline eluxadoline 1-butanol solvate, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4, a differential scanning calorimetry (DSC) substantially in accordance with Figure 5, and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 6. In another embodiment the present invention provides a process for the preparation of eluxadoline 1-butanol solvate, comprising:

a) providing a solution of eluxadoline in 1-butanol solvent,

b) precipitating the reaction mass, and

c) isolating eluxadoline 1-butanol solvate.

In step a) of the aforementioned process, providing a solution of eluxadoline in 1-butanol solvent first include adding eluxadoline to 1-butanol or mixture of 1-butanol and water, and afterward, subjecting to dissolution by stirring the mixture at a suitable temperature of about 35 °C to reflux temperature of the solvent, preferably at about 55°C to about 75°C. In step b) of the forgoing process, the precipitation of eluxadoline 1-butanol solvate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature to about 30°C or less. In step c) of the forgoing process, isolating eluxadoline 1-butanol solvate may be carried out by filtering the precipitated solid and followed by drying under vacuum at room temperature to obtain eluxadoline 1-butanol solvate.

In another embodiment, the present invention provides novel eluxadoline isobutanol solvate.

In another embodiment, the present invention provides eluxadoline isobutanol solvate characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7.

In another embodiment, the present invention provides crystalline eluxadoline isobutanol solvate characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.0, 7.1, 8.0, 8.3, 8.9, 10.1, 10.3, 10.9, 11.3, 12.5, 12.9, 13.5, 13.9, 14.4, 14.8, 15.2, 15.6, 16.4, 16.9, 17.7, 17.9, 18.3, 18.7, 19.4, 19.7, 20.69, 21.64, 22.9, 23.4, 23.9, 24.5, 25.1, 26.4, 26.6, 27.3, 28.3, 28.5, 29.1, 29.7, 30.3, 30.8, 32.1, 32.7, 34.4, 35.1, 35.8, 38.0, 39.6, 40.7, 42.3 and 44.5 ± 0.2° 2Θ.

In another embodiment, the present invention provides crystalline eluxadoline isobutanol solvate, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 8.

In another embodiment, the present invention provides crystalline Eluxadoline isobutanol solvate, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 9.

In another embodiment, the present invention provides crystalline Eluxadoline isobutanol solvate, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7, a differential scanning calorimetry (DSC) substantially in accordance with Figure 8, and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 9.

In another embodiment the present invention provides a process for the preparation of Eluxadoline isobutanol solvate, comprising:

a) providing a solution of Eluxadoline in isobutanol solvent,

b) precipitating the reaction mass, and

c) isolating Eluxadoline isobutanol solvate.

In step a) of the aforementioned process, providing a solution of Eluxadoline in isobutanol solvent first include adding Eluxadoline to isobutanol or mixture of isobutanol and water, and afterward, subjecting to dissolution by stirring the mixture at a suitable temperature of about 35 °C to reflux temperature of the solvent, preferably at about 55°C to about 75°C.

In step b) of the forgoing process, the precipitation of Eluxadoline isobutanol solvate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature to about 30°C or less. In step c) of the forgoing process, isolating Eluxadoline isobutanol solvate may be carried out by filtering the precipitated solid followed by drying under vacuum at room temperature to obtain Eluxadoline isobutanol solvate.

In another embodiment, the present invention provides novel Eluxadoline t-butanol solvate.

In another embodiment, the present invention provides Eluxadoline t-butanol solvate characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 10.

In another embodiment, the present invention provides crystalline Eluxadoline t-butanol solvate characterized by a powder X-Ray diffraction pattern having one or more peaks at about 4.9, 6.8, 7.0, 7.7, 7.97, 8.22, 8.8, 9.8, 10.19, 10.75, 12.44, 13.08, 13.63, 14.0, 14.19, 14.7, 15.5, 15.9, 16.5, 17, 17.3, 18.2, 18.5, 18.9, 19.3, 19.9, 20.0, 20.4, 21.4, 21.7, 22.4, 22.9, 23.4, 23.6, 24.9, 25.3, 26.0, 26.3, 28.1, 29.0, 29.8, 30.3, 31.1, 32.7, 33.1, 34.3, 35.5, 40.2 and 41.3 ± 0.2° 2Θ. In another embodiment, the present invention provides crystalline Eluxadoline t-butanol solvate, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 11.

In another embodiment, the present invention provides crystalline Eluxadoline t-butanol solvate, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 12.

In another embodiment, the present invention provides crystalline Eluxadoline t-butanol solvate, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 10, a differential scanning calorimetry (DSC) substantially in accordance with Figure 11, and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 12.

In another embodiment the present invention provides a process for the preparation of Eluxadoline t-butanol solvate, comprising:

a) providing a solution of Eluxadoline in t-butanol solvent.

b) precipitating the reaction mass, and

c) isolating Eluxadoline t-butanol solvate. In step a) of the aforementioned process, providing a solution of Eluxadoline in t-butanol solvent first include adding Eluxadoline to t-butanol or mixture of t-butanol and water, and afterward, subjecting to dissolution by stirring the mixture at a suitable temperature of about 35 °C to reflux temperature of the solvent, preferably at about 55°C to about 75°C. In step b) of the forgoing process, the precipitation of Eluxadoline t-butanol solvate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature to about 30°C or less. In step c) of the forgoing process, isolating Eluxadoline t-butanol solvate may be carried out by filtering the precipitated solid followed by drying under vacuum at room temperature to obtain Eluxadoline t-butanol solvate.

As used herein above, the starting material eluxadoline is known in the art and can be prepared by any known method. The eluxadoline in an organic solvent may be any crystalline, amorphous or other form of eluxadoline, including various salts, solvates and hydrates thereof.

In another embodiment, the present invention provides a process for the preparation of crystalline Eluxadoline Form A comprising: drying eluxadoline solvate under heating at a temperature of about 45 °C to 95 °C for about 2 hours to about 36 hours.

In another embodiment, the solvate used herein for preparing crystalline Eluxadoline Form A is selected from Eluxadoline 1-butanol solvate, Eluxadoline isobutanol solvate and Eluxadoline t-butanol solvate and the drying is carried out in a hot air oven until the solvent completely removed from the crystal lattice; preferably for a period of about 2 hours to about 36 hours at a temperature of about 45 °C to 95 °C.

In another embodiment, the present invention provides a pharmaceutical composition comprising the novel polymorphic forms of Eluxadoline and solvates thereof described above and at least one pharmaceutically acceptable excipient.

EXAMPLES

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Example 1; Preparation of Amorphous form of Eluxadoline.

BoC-protected Eluxadoline (100 g) was added to the mixture of acetone (1000 ml) and Con. HC1 (50 ml) at 40-45°C, stirred the suspension for 2-4h and allowed to cool to 25- 35°C. The solvent was removed under vacuum and crude eluxadoline was isolated by neutralisation with Aq. NaOH in water, dried and further purified in methanol to get the pure material. The obtained pure material was further dissolved in a mixture of methanol and water at 60-65°C, concentrated the reaction mass, dried in rota cone drier at 60-65°C for 2-4 hours, and the solid was further dried in vacuum oven at 50-55°C for 10-15 hours to get the title compound. Yield: 53g.

Example 2: Preparation of Eluxadoline

BoC-protected Eluxadoline (100 g) was added to the mixture of acetone (1000 ml) and Conc.HCl (50 ml) at 40-45°C, the suspension was stirred at 40-45°C for 2-4h, and cooled the reaction mass to 25-35°C and the solvent was removed by decantation, further eluxadoline crude was isolated by neutralisation with Aq.NaOH in water, isolated material was further dried and purified in mixture of methanol and water to get title compound. Yield: 50g

Example 3: Preparation of Eluxadoline 1-butanol solvate Amorphous Eluxadoline (10 g) was added to the mixture of 1-butanol (41 ml) and water (9 ml) at 25-35°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 16 hours. The solid obtained was filtered, washed with 1-butanol, suck dried, and the wet solid was further dried at 25-35°C for 16 hours to get the title compound. Yield: 10.5 g.

Example 4: Preparation of Eluxadoline 1-butanol solvate

Amorphous Eluxadoline (4 g) was added to the mixture of 1-butanol (13.1 ml) and water (2. 9 ml) at 25-35°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 22 hours. The solid obtained was filtered, washed with 1-butanol, suck dried, and the wet solid was further dried at 25-35°C for 7 hours to get the title compound. Yield: 4.4 g.

Example 5: Preparation of Eluxadoline isobutanol solvate

Amorphous Eluxadoline (4 g) was added to the mixture of 1-butanol (13.1 ml) and water (2. 9 ml) at 25-35°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 22 hours. The solid obtained was filtered, washed with 1-butanol, suck dried, and the wet solid was further dried at 25-35°C for 7 hours to get the title compound. Yield: 4.4 g.

Example 6: Preparation of Eluxadoline Form A

Eluxadoline (45g) obtained according to Example-2 was added to the mixture of 1- butanol (185 ml) and water (45 ml) at 60-65°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 15-20 hours. The solid obtained was filtered, washed with 1- butanol, suck dried, and the wet solid was further dried at 25-35°C for 2 hours to obtain wet solid of Eluxadoline 1-butanol solvate. The obtained solvate was taken and further subjected to drying in hot air oven at 80-85°C for 18-24 hours to get the title compound. Yield: 39.6g.

Example 7: Preparation of Eluxadoline Form A

Eluxadoline (55g) obtained according to Example-2 was added to the mixture of 1- butanol (226 ml) and water (49 ml) at 60-65°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 15-20 hours. The solid obtained was filtered, washed with 1- butanol, suck dried, and the wet solid was further dried at 25-35°C for 2 hours to obtain wet solid of Eluxadoline 1-butanol solvate. The obtained solvate was taken and further subjected to drying in hot air oven at 80-85°C for 18-24 hours to get the title compound. Yield: 44g.

Example 8: Preparation of Eluxadoline isobutanol solvate Amorphous Eluxadoline (3 g) was added to the mixture of isobutanol (4.8 ml) and water (18 ml) at 60-65°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for one hour. The solid obtained was filtered, washed with isobutanol, suck dried, and the wet solid was further dried at 25-35°C for 16 hours to get the title compound. Yield: 3.04 g.

Example 9: Preparation of Eluxadoline t-butanol solvate

Amorphous Eluxadoline (3 g) was added to the mixture of t-butanol (24 ml) and water (36 ml) at 60-65°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 1.5 hours. The solid obtained was filtered, washed with t-butanol, suck dried, and the wet solid was further dried at 25-35°C for 14 hours to get the title compound. Yield: 3.3 g.

Example 10: Preparation of Eluxadoline Form A

Amorphous Eluxadoline (1 g) was added to the mixture of 1-butanol (3.3 ml) and water (0.7 ml) at 60-65°C. The suspension was stirred at 60-65°C until a clear solution was formed. Cooled the reaction mass to 25-35°C and the suspension was stirred for 15 hours. The solid obtained was filtered, washed with 1-butanol, suck dried, and the wet solid was further dried at 25-35°C for 2 hours to obtain wet solid of Eluxadoline 1-butanol solvate (1.1 gms). The obtained wet solid (0.5 g) was taken and further subjected to drying in hot air oven at 80-85°C for 18 hours to get the title compound. Yield: 441 mg.

Example 11; Preparation of Eluxadoline Form A

Eluxadoline 1-butanol solvate (2 g) obtained according to Example 1, was taken and further subjected to drying in hot air oven at 80-85°C for 24 hours to get the title compound. Yield: 1.81 g. Example 12: Preparation of Eluxadoline Form A

Eluxadoline 1-butanol solvate (2 g) obtained according to Example 1, was taken and further subjected to drying in hot air oven at 80-85°C for 16 hours to get the title compound. Yield: 1.78 g.

Example 13: Preparation of Eluxadoline Form A

Eluxadoline isobutanol solvate (2 g) obtained according to Example 3, was taken and further subjected to drying in hot air oven at 80-85°C for 19 hours to get the title compound. Yield: 1.78 g.

Example 14: Preparation of Eluxadoline Form A Eluxadoline t-butanol solvate (1.5 g) obtained according to Example 5, was taken and further subjected to drying in hot air oven at 80-85°C for 21 hours to get the title compound. Yield: 1.2 g.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.