SOLVATES OF ELUXADOLINE

Field of the Invention

The present invention relates to solvates of eluxadoline, processes for their preparation, pharmaceutical compositions comprising these solvates, and their use for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

Background of the Invention

Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2,6- dimethylphenyl] - 1 -oxopropyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino]methyl]-2- methoxybenzoic acid, represented by Formula I.

Formula I

Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

U.S. Patent No. 7,741,356 describes a process for the preparation of eluxadoline.

U.S. Patent Nos. 7,629,488 and 8,710,256 describe processes for the preparation of intermediates of eluxadoline.

PCT Publication No. WO 2009/009480 purportedly discloses Form a and Form β crystals of eluxadoline and processes thereof.

PCT Publication No. WO 2017/015606 purportedly discloses amorphous Form, crystalline Forms I, II, III and IV and a process for the preparation of Form a crystal of eluxadoline. In the pharmaceutical industry, there is a need for stable solvates of eluxadoline, which exhibit good solubility and better stability and may be formulated even after prolonged storage times.

Summary of the Invention

The present invention relates to solvates of eluxadoline, processes for their preparation, pharmaceutical compositions comprising these solvates, and their use for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

The solvates of eluxadoline of the present invention exhibit good thermodynamic stability, solubility, and bioavailability.

Brief Description of the Drawings

Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of methanol solvate of eluxadoline designated as crystalline Form S 1.

Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of methanol solvate of eluxadoline designated as crystalline Form SI .

Figure 3 depicts an XRPD pattern of isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2.

Figure 4 depicts a DSC thermogram of isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2.

Figure 5 depicts an XRPD pattern of n-butanol solvate of eluxadoline designated as crystalline Form S3.

Figure 6 depicts a DSC thermogram of n-butanol solvate of eluxadoline designated as crystalline Form S3.

Figure 7 depicts an XRPD pattern of n-pentanol solvate of eluxadoline designated as crystalline Form S4.

Figure 8 depicts a DSC thermogram of n-pentanol solvate of eluxadoline designated as crystalline Form S4.

Figure 9 depicts an XRPD pattern of diisopropyl ether solvate of eluxadoline designated as crystalline Form S5. Figure 10 depicts a DSC thermogram of diisopropyl ether solvate of eluxadoline designated as crystalline Form S5.

Detailed Description of the Invention

The term "about," as used herein, refers to any value which lies within the range defined by a number up to ± 10% of the value .

The term "contacting," as used herein, refers to dissolving, slurring, stirring, suspending, or combinations thereof.

The term "solvate," as used herein, refers to an aggregate of eluxadoline of Formula I with one or more molecules of a solvent, wherein the solvent is present in a stoichiometric or in a non-stoichiometric amount. Examples of solvents include methanol, isopropyl alcohol, n-butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2- dimethoxy benzene.

A first aspect of the present invention provides solvates of eluxadoline.

In an embodiment, the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.

In another embodiment, the solvates of eluxadoline are in a crystalline form or in an amorphous form.

A second aspect of the present invention provides methanol solvate of eluxadoline designated as crystalline Form S 1. Crystalline Form S 1 is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacings of about 12.2, 4.6, 4.5, 3.9, and 3.6 A, and further characterized by additional peaks at d-spacings of about 7.6, 7.3, 5.9, 4.3, and 4.1 A.

Table 1 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S 1. Table 1

Crystalline Form SI is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 77.9°C and 197.2°C.

Crystalline Form S 1 is also characterized by an XRPD pattern substantially as depicted in Figure 1, or a DSC thermogram substantially as depicted in Figure 2.

A third aspect of the present invention provides isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2. Crystalline Form S2 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.9, 4.9, 3.8, and 3.6 A, and further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.6, 4.6, and 4.2 A.

Table 2 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S2.

Table 2

Crystalline Form S2 is characterized by a DSC thermogram having endothermic peaks at about 80.4°C, 101.1°C, and 168.9°C.

Crystalline Form S2 is also characterized by an XRPD pattern substantially as depicted in Figure 3, or a DSC thermogram substantially as depicted in Figure 4. A fourth aspect of the present invention provides n-butanol solvate of eluxadoline designated as crystalline Form S3. Crystalline Form S3 is characterized by an XRPD pattern having peaks at d-spacings of about 13.8, 6.9, 4.9, 3.8, and 2.8, A, and further characterized by additional peaks at d-spacings of about 6.4, 5.7, 4.2, 4.0, and 3.7 A.

Table 3 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S3.

Table 3

2.7 33.0 9.4

2.7 33.5 5.4

2.5 35.3 2.6

2.4 36.8 2.9

2.3 38.4 5.7

Crystalline Form S3 is characterized by a DSC thermogram having endothermic peaks at about 87.1°C and 178.8°C.

Crystalline Form S3 is also characterized by an XRPD pattern substantially as depicted in Figure 5, or a DSC thermogram substantially as depicted in Figure 6.

A fifth aspect of the present invention provides n-pentanol solvate of eluxadoline designated as crystalline Form S4. Crystalline Form S4 is characterized by an XRPD pattern having peaks at d-spacings of about 14.1, 6.9, 5.7, 4.9, and 3.8 A, and further characterized by additional peaks at d-spacings of about 12.0, 8.9, 8.1, 4.6, and 4.2 A.

Table 4 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S4.

Table 4

Crystalline Form S4 is characterized by a DSC thermogram having endothermic peaks at about 73.9°C and 186.5°C.

Crystalline Form S4 is also characterized by an XRPD pattern substantially as depicted in Figure 7, or a DSC thermogram substantially as depicted in Figure 8.

A sixth aspect of the present invention provides diisopropyl ether solvate of eluxadoline designated as crystalline Form S5. Crystalline Form S5 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.8, 4.9, 3.8, and 3.6 A, and further characterized by additional peaks at d-spacings of about 9.8, 6.4, 5.9, 5.6, and 4.2 A.

Table 5 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S5.

Table 5

2.8 32.0 9.3

2.7 32.8 10.2

2.5 35.4 3.9

2.4 37.7 4.2

Crystalline Form S5 is characterized by a DSC thermogram having endothermic peaks at about 63.3°C and 185.2°C.

Crystalline Form S5 is also characterized by an XRPD pattern substantially as depicted in Figure 9, or a DSC thermogram substantially as depicted in Figure 10.

A seventh aspect of the present invention provides a process for the preparation of solvates of eluxadoline, comprising contacting eluxadoline with a first solvent and optionally with a second solvent.

Eluxadoline may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7,741,356.

The first solvent and second solvent are selected from the group consisting of methanol, isopropyl alcohol, n-butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, 1,2- dimethoxy benzene, water or a mixture thereof. In an embodiment, the first solvent and second solvent is methanol. In another embodiment, the first solvent and second solvent are isopropyl alcohol. In another embodiment, the first and second solvent are n-butanol. In another embodiment, the first solvent is n-pentanol and the second solvent is diisopropyl ether. In another embodiment, the first solvent is methanol and the second solvent is diisopropyl ether.

Eluxadoline is contacted with a solvent for about one hour to about 5 days. In an embodiment, the eluxadoline is contacted with the solvent for about 2 hours to about 4 days. In another embodiment, the eluxadoline is contacted with the solvent for about 5 hours to about 3 days. In another embodiment, the eluxadoline is contacted with the solvent for about 8 hours to about 4 days. In another embodiment, the eluxadoline is contacted with the solvent for about 15 hours to about 2 days.

Eluxadoline is contacted with a solvent at a temperature of about 20°C to about

65°C. In an embodiment, the eluxadoline is contacted with the solvent at a temperature of about 25°C to about 60°C. In another embodiment, the eluxadoline is contacted with the solvent at a temperature of about 35°C to about 55°C. In an embodiment, the eluxadoline is contacted with the solvent at a temperature of about 50°C to about 55°C.

The solvates of eluxadoline may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The solvates of eluxadoline may be dried by drying under reduced pressure, by air drying, suck drying, or vacuum tray drying.

An eighth aspect of the present invention provides a process for the preparation of eluxadoline comprising drying a solvate of eluxadoline.

In an embodiment, the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.

The solvate of eluxadoline is dried for about one hour to about 7 hours. In an embodiment, the solvate of eluxadoline is dried for about 2 hours to about 6 hours. In another embodiment, the solvate of eluxadoline is dried for about 3 hours to about 5 hours. In another embodiment, the solvate of eluxadoline is dried for about 3.5 hours to about 4 hours.

The solvate of eluxadoline is dried at a temperature of about 40°C to about 80°C. In an embodiment, the solvate of eluxadoline is dried at a temperature of about 50°C to about 70°C. In another embodiment, the solvate of eluxadoline is dried at a temperature of about 55°C to about 65°C.

Eluxadoline may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Eluxadoline may be dried by drying under reduced pressure, by air drying, suck drying, or vacuum tray drying.

A ninth aspect of the present invention provides a pharmaceutical composition comprising solvates of eluxadoline, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In an embodiment, the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene. A tenth aspect of the present invention provides a method for treating irritable bowel syndrome with diarrhea (IBS-D) comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising solvates of eluxadoline.

In an embodiment, the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.

While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

Methods

XRPD of the sample was determined by using a PANalytical ^® instrument; Model X'pert PRO; Detector: X'celerator ^® .

NMR of the sample was determined using a Bruker ^® instrument, Model Avance III 400, using 5 mm PABBO probe.

DSC of the sample was recorded using a Mettler-Toledo ^® 82 le instrument.

The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1 : Preparation of crystalline Form S 1

Eluxadoline (1 g) was dissolved in methanol (40 mL) to obtain a solution. The solution was stirred at 60°C for 6 hours to obtain a solid mass. The solid mass was collected by filtration and then dried at 25°C to 30°C under vacuum for 2 hours to obtain the title compound.

Yield: 920 mg

¾ NMR (DMSO d ₆ + D ₂ 0, 400 MHz): δ: 7.53-7.61 (m, 3H), 7.28-7.34 (m, 3H), 7.24 (s, 1H), 7.16-7.20 (m, 2H), 6.65-6.75 (m, 2H), 5.60 (d, 1H), 4.79 (dd, 1H), 4.32 (dd, 1H), 3.79-3.83 (m, 1H), 3.72 (s, 3H), 3.61 (d, 3H), 3.07-3.26 (m, 2H), 2.51 (s, 3H), 2.07 (s, 3H), 0.76-1.36 (dd, 3H) Example 2: Preparation of crystalline Form S2

Eluxadoline (1 g) in isopropyl alcohol (40 mL) was stirred at 65°C for 2 hours and then at 25°C to 30°C for 2 hours to obtain a solid mass. The solid mass was collected by filtration and then dried at 25 °C to 30°C under vacuum for 4 hours to obtain the title compound.

Yield: 900 mg

Ή NMR (DMSO d ₆ + D ₂ 0, 400 MHz): δ: 7.54-7.61 (m, 3H), 7.27-7.35 (m, 3H), 7.14- 7.22 (m, 3H), 6.64-6.75 (m, 2H), 5.50 (d, IH), 4.82 (dd, IH), 4.32 (dd, IH), 3.73-3.79 (m, IH), 3.63 (d, 3H), 3.07-3.27 (m, 2H), 2.51 (s, 3H), 2.07 (s, 3H), 1.02 (d, 6H), 0.76-1.36 (dd, 3H)

Example 3: Preparation of crystalline Form S3

Eluxadoline (300 mg) was dissolved in n-butanol (12 mL) at 60°C to obtain a solution. The solution was stirred at 60°C for 2 hours and then at 25°C to 30°C overnight to obtain a solid mass. The solid mass so obtained was collected by filtration and then dried at 25°C to 30°C under vacuum for 2 hours to obtain the title compound.

Yield: 200 mg

*H NMR (MeOD, 400 MHz): δ 7.54-7.63 (m, 3H), 7.24-7.36 (m, 4H), 7.15-7.19 (m, 2H), 6.71-6.79 (m, 2H), 5.62 (d, IH), 4.86 (dd, IH), 4.42 (dd, IH), 4.03 (dd, IH), 3.64 (d, 3H), 3.34-3.37 (m, 2H), 2.91-3.21 (m, 2H), 2.32 (s, 3H), 2.07 (s, 3H), 0.86-1.39 (m, 10H) Example 4: Preparation of crystalline Form S4

Eluxadoline (300 mg) was dissolved in n-pentanol (10 mL) at 60°C to obtain a solution. The solution was stirred at 60°C for 2 hours and then at 25°C to 30°C overnight to obtain a solid mass. Diisopropyl ether (15 mL) was added to the solution and stirring was continued at 25°C to 30°C for 5 hours to obtain a solid mass. The solid mass was collected by filtration and then dried at 25°C to 30°C under vacuum for 2 hours to obtain the title compound.

Yield: 190 mg

Ή NMR (MeOD, 400 MHz): δ 7.53-7.63 (m, 3H), 7.18-7.36 (m, 4H), 7.12 (s, 2H), 6.61- 6.76 (m, 2H), 5.57 (d, IH), 4.80 (dd, IH), 4.26 (dd, IH), 3.73 (dd, IH), 3.60 (d, 3H), 3.34- 3.37 (m, 2H), 3.06-3.24 (m, 2H), 2.28 (s, 3H), 2.06 (s, 3H), 0.74-1.40 (m, 12H) Example 5: Preparation of crystalline Form S5

Eluxadoline (500 mg) was dissolved in methanol (2.5 mL) to obtain a solution. The solution was stirred at 25°C to 30°C for 4.5 hours. Diisopropyl ether (15 mL) was added and the mixture was further stirred at 25 °C to 30°C overnight to obtain a solid mass. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 70°C for 4 hours to obtain the title compound.

Yield: 445 mg

Ή NMR (MeOD, 400 MHz): δ 7.53-7.64 (m, 3H), 7.28-7.35 (m, 4H), 7.18 (s, 2H), 6.66- 6.74 (m, 2H), 5.57 (d, IH), 4.82 (dd, IH), 4.27 (dd, IH), 3.56-3.65 (m, 4H), 3.06-3.23 (m, 2H), 2.29 (s, 3H), 2.07 (s, 3H), 0.76-1.37 (m, 15H).

Example 6: Preparation of eluxadoline

Crystalline Form S2 (500 mg) was dried at 60°C under vacuum for 6 hours to obtain the title compound. Yield: 400 mg