WO2018046028A1

WO2018046028A1 - Solid forms of eluxadoline

Info

Publication number: WO2018046028A1
Application number: PCT/CZ2017/000056
Authority: WO
Inventors: Pavel ZVATORA; Ondrej Dammer; Lukas KREJCIK; Jan STOVICEK
Original assignee: Zentiva, K.S.
Priority date: 2016-09-07
Filing date: 2017-08-30
Publication date: 2018-03-15
Also published as: CZ2016548A3

Abstract

The object of the invention provides pharmaceutically acceptable solid forms of eluxadoline of formula (I) and methods of their preparation. These solid forms of eluxadoline are prepared by crystallization of eluxadoline free base in a suitable solvent or by a reaction of eluxadoline free base with suitable inorganic or organic acids in a suitable solvent or mixtures of solvents. The prepared solid forms have suitable physicochemical characteristics for use in the pharmaceutical industry and formulation of new drug forms. (Formula (I))

Description

Solid forms of eluxadoline

Field of the Invention

The invention relates to solid forms of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimemylphenyl)propanoyl][(lS)-l-(4-pte

methoxybenzoic acid of formula I, known as eluxadoline, methods of its preparation and use in a drug form.

(I)

Background Art

Eluxadoline (CAS RN 864821-90-9) is an agonist of μ- and κ-opioid receptors and an antagonist of δ-opioid receptors that acts locally in the enteric nervous system and is intended for the treatment of diarrhea and abdominal pain in individuals with the diarrhea-predominant irritable bowel syndrome (IBS-D).

Preparation of eluxadoline and its isolation in the form of the eluxadoline dihydrochloride salt was first described in the patent application WO 2005/090315, in Example 9. The patent application WO 2009/009480 described preparation and characterization methods of two crystalline zwitterions of eluxadoline (form a and form β). Many pharmaceutical solid compounds can exist in various crystalline forms that are considered as polymorphs and hydrates/solvates, or possibly salts or cocrystals, having different crystal units and thus different physicochemical properties as the melting point, solubility, dissolution rate as well as biological availability. To distinguish individual solid phases of a compound, several solid-state analytic methods can be used, e.g. X-ray powder diffraction, solid-state NMR, Raman spectroscopy as well as thermoanalytical methods. Discovering new solid phases (polymorphs, solvates, hydrates, cocrystals or salts) of an active pharmaceutical ingredient offers an opportunity to select a suitable modification with desired physicochemical properties and processability and improve the characteristics of the chemical product. For this reason, there is an obvious need of novel solid forms (polymorphs, solvates, hydrates, salts) of eluxadoline.

Disclosure of the Invention

The object of the invention provides pharmaceutically acceptable solid forms of eluxadoline of formula I and methods of their preparation. These solid forms of eluxadoline of formula I are prepared by crystallization of eluxadoline free base in a suitable solvent or by a reaction of eluxadoline free base with suitable inorganic or organic acids in a suitable solvent or mixtures of solvents.

The prepared solid forms have suitable physicochemical characteristics for use in the pharmaceutical industry and formulation of new drug forms. An object of the invention is a crystalline form of eluxadoline free base, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of Cu a radiation: 6.7; 11.4; 14.8; 19.2 and 21.7 ± 0.2 °2-theta. In some embodiments, the crystalline form of eluxadoline free base exhibits more reflections in the X-ray powder pattern: 78.1; 13.4; 17.2 and 20.3 ± 0.2 °2-theta. In some embodiments, the crystalline form of eluxadoline free base is further characterized by the differential scanning calorimetry curve with the melting point at 157°C.

Another object of the invention is a preparation method of the crystalline form of eluxadoline free base wherein eluxadoline is suspended in tetrahydrofuran at an elevated temperature in the range from 25°C to the boiling point of the solvent for at least 14 days. Another object of the invention is a 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, methanesulfonic acid, benzenesulfonic acid, phosphoric acid and tartaric acid.

Another object of the invention is the salt of eluxadoline with benzoic acid, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.3; 12.8; 19.0; 21.4 and 25.9 ± 0.2 °2-theta. In some embodiments, the salt of eluxadoline with benzoic acid exhibits more reflections in the X-ray powder pattern: 11.2; 15.2; 17.9 and 24.2 ± 0.2 °2-theta. In some embodiments, the salt of eluxadoline with benzoic acid is further characterized by a differential scanning calorimetry curve with the melting point at 137°C. Another object of the invention is the salt of eluxadoline with sulphuric acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation. In some embodiments, the salt of eluxadoline with sulphuric acid is further characterized by a differential scanning calorimetry curve with the glass transition temperature of 202°C.

Another object of the invention is the salt of eluxadoline with hydrobromic acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation. In some embodiments, the salt of eluxadoline with hydrobromic acid is further characterized by a differential scanning calorimetry curve with the glass transition temperature of 181°C.

Another object of the invention is the salt of eluxadoline with methanesulfonic acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation. In some embodiments, the salt of eluxadoline with methanesulfonic acid is further characterized by a differential scanning calorimetry curve with the glass transition temperature of 167°C.

Another object of the invention is the salt of eluxadoline with benzenesulfonic acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation. In some embodiments, the salt of eluxadoline with benzenesulfonic acid is further characterized by a differential scanning calorimetry curve with the glass transition temperature of 161°C.

Another object of the invention is the salt of eluxadoline with phosphoric acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation. In some embodiments, the salt of eluxadoline with phosphoric acid is further characterized by a differential scanning calorimetry curve with the glass transition temperature of 143°C.

Another object of the invention is the salt of eluxadoline with tartaric acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation. In some embodiments, the salt of eluxadoline with tartaric acid is further characterized by a differential scanning calorimetry curve with the glass transition temperature of 134°C. Another object of the invention is a preparation method of a salt of eluxadoline with an acid wherein eluxadoline free base is dissolved in a suitable solvent and subsequently, an acid is added that is selected from the group consisting of benzoic acid, sulphuric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonic acid, phosphoric acid and tartaric acid. A suitable solvent is a solvent selected from the group consisting of aliphatic C₁-C₄ alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.

Another object of the invention is the salt of eluxadoline with urea in the solid form. In some embodiments, the salt of eluxadoline with urea exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.3; 13.1 and 21.4 ± 0.2 °2-theta. In some embodiments, the salt of eluxadoline with urea exhibits more reflections in the X-ray powder pattern: 10.1; 15.9; 22.1 and 24.8 ± 0.2 °2-theta. In some embodiments, the salt of eluxadoline with urea is further characterized by a differential scanning calorimetry curve with the melting point at 129°C. Another object of the invention is a preparation method of the salt of eluxadoline with urea wherein the free base of eluxadoline is dissolved in a suitable solvent and urea is added subsequently. A suitable solvent is a solvent selected from the group consisting of aliphatic Ci-C₄ alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures. Another object of the invention is the use of a solid form of eluxadoline in accordance with the present invention for the preparation of a pharmaceutical composition.

Another object of the invention is a pharmaceutical composition comprising a solid form of eluxadoline in accordance with the present invention and at least one pharmaceutically acceptable excipient.

Brief description of the Drawings

Figure 1: X-ray powder pattern of a crystalline form of eluxadoline

Figure 2: X-ray powder pattern of a crystalline form of eluxadoline with benzoic acid

Figure 3: X-ray powder pattern of a crystalline form of eluxadoline with urea

Figure 4: X-ray powder pattern of eluxadoline with sulphuric acid

Figure 5: X-ray powder pattern of eluxadoline with hydrobromic acid Figure 6: X-ray powder pattern of eluxadoline with methanesulfonic acid

Figure 7: X-ray powder pattern of eluxadoline with benzenesulfonic acid

Figure 8: X-ray powder pattern of eluxadoline with phosphoric acid

Figure 9: X-ray powder pattern of eluxadoline with tartaric acid

Detailed description of the Invention

Although preparation of a salt by a reaction of an acid and base is a well-known method, it is always a problem to obtain the required salts in the solid phase and purity corresponding to the demands for their pharmaceutical use. Biological availability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more readily soluble, it cannot often be obtained in the required quality and it is also often unstable. Conversely, compared to the amorphous form, a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly.

The present invention provides several solid forms of eluxadoline in a crystalline or amorphous form, including salts of eluxadoline. The obtained crystalline forms exhibit a lower melting point and thus higher solubility and bioavailability than known crystalline forms of eluxadoline do.

An object of the invention are solid forms of eluxadoline prepared from organic solvents or their mixtures with hydrobromic acid, sulphuric acid, phosphoric acid, benzoic acid, benzenesulfonic acid, methanesulfonic acid, tartaric acid and urea in different molar ratios. Within the invention, 1:1 molar ratios are preferred.

Solid forms of eluxadoline with these acids can be prepared in adequate ratios and yields with high chemical purity in a crystalline form, amorphous form, or in a mixture of a crystalline and amorphous solid form. Another object of the invention is a crystalline form of eluxadoline free base prepared by crystallization of amorphous eluxadoline from tetrahydrofuran.

These solid forms can be both anhydrous and/or non-solvated, and they can have the form of hydrates/solvates of the respective solvents.

The prepared solid forms of eluxadoline may have various internal arrangements (polymorphism) with different physicochemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.

These solid forms are suitable for the preparation of eluxadoline with a high chemical purity.

The preparation of solid forms of eluxadoline (I) in accordance with the present invention is conducted by a reaction of eluxadoline with sulphuric acid, hydrobromic acid, phosphoric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid and with urea. The reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic CrC₄ alcohols, ketones, esters, nitriles, water or their mixtures are preferred. The most commonly used solvents are acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.

The final product is typically precipitated or crystallized at temperatures in the range of -30°C to the boiling point of the solvent.

Eluxadoline was prepared according to the procedure disclosed in the patent application WO 2009/009480. Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline zwitterion of eluxadoline (form a) of 191°C. Long-term stirring of amorphous eluxadoline in a suspension provided crystalline eluxadoline with the melting point of 157°C according to DSC. The crystalline salt of eluxadoline with benzoic acid and the new crystalline phase of eluxadoline in accordance with the present invention are characterized by a lower melting point than the thermodynamically most stable zwitterion of eluxadoline (form a). The crystalline form of eluxadoline with urea in accordance with the present invention also exhibits a lower melting point than the thermodynamically most stable zwitterion of eluxadoline (form a). Quick evaporation of the solvent from an acetone solution of eluxadoline provided amorphous eluxadoline, which shows the glass transition temperature of 166°C according to DSC. Amorphous salts of eluxadoline with hydrobromic acid and the amorphous salt of eluxadoline with sulphuric acid in accordance with the present invention are characterized by a higher glass transition temperature, and therefore a higher stability than the amorphous product prepared by quick evaporation of a solution of eluxadoline from acetone. Amorphous salts of eluxadoline with tartaric acid, methanesulfonic acid, phosphoric acid and benzenesulfonic acid in accordance with the present invention are characterized by a lower glass transition temperature than the amorphous product prepared by quick evaporation of a solution of eluxadoline from acetone.

The crystalline form of eluxadoline (prepared according to Example 1) is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of eluxadoline in accordance with the present invention with the use of CuKa radiation are: 6.7; 11.4; 14.8; 19.2 and 21.7 ± 0.2 °2-theta. Other diffraction peaks with the use of CuKa radiation are: 8.1; 13.4; 17.2 and 20.3 ± 0.2 °2-theta. The X-ray powder pattern is shown in Fig. 1.

Table 1

Interplanar spacing [A]

Position [°2Th.] [A]=0.1nm Rel. intensity [%]

6.65 13.283 100.0

7.86 11.244 21.6

8.14 10.856 64.3

9.43 9.375 14.1

10.39 8.509 19.1

11.44 7.729 32.2

11.91 7.427 17.7

13.43 6.590 29.3

14.12 6.268 21.9

14.45 6.126 21.3

14.84 5.963 33.3

15.87 5.580 13.7

16.20 5.467 13.6

17.26 5.135 20.0

18.50 4.792 12.1

19.22 4.614 31.6

20.31 4.369 16.9

21.72 4.088 23.6

22.28 3.987 9.2

22.93 3.875 11.8 23.88 3.723 19.2

24.56 3.621 5.3

25.20 3.532 11.3

25.89 3.438 7.2

Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of eluxadoline of 157°C.

The crystalline form of eluxadoline with benzoic acid (prepared according to Example 2) is characterized by the reflections presented in Table 2. Table 2 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of eluxadoline with benzoic acid in accordance with the present invention with the use of CuKa radiation are: 6.3; 12.8; 19.0; 21.4 and 25.9 ± 0.2 °2-theta. Other diffraction peaks with the use of CuKa radiation are: 11.2; 15.2; 17.9 and 24.2 ± 0.2 °2-theta. The X-ray powder pattern is shown in Fig. 2.

Table 2

Interplanar spacing [A]

Position [°2Th.] [A]=0.1nm Rel. intensity [%]

6.32 13.972 92.3

7.11 12.431 9.0

8.04 10.983 10.7

8.85 9.982 41.5

9.90 8.923 6.7

10.58 8.355 13.2

11.19 7.898 52.1

11.72 7.546 19.9

12.84 6.889 100.0

14.15 6.255 8.1

14.59 6.066 18.3

15.18 5.833 45.2

15.82 5.597 24.5 16.29 5.439 20.0

17.09 5.184 3.8

17.87 4.959 42.4

19.04 4.658 40.5

19.80 4.480 27.2

20.16 4.401 26.0

21.45 4.140 39.9

22.85 3.889 24.5

24.20 3.674 33.8

25.90 3.437 48.1

26.63 3.345 11.1

27.50 3.240 9.2

28.61 3.117 8.7

29.27 3.048 11.3

30.52 2.927 7.9

32.12 2.784 4.3

Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of eluxadoline with benzoic acid of 137°C.

The crystalline form of eluxadoline with urea (prepared according to Example 3) is characterized by the reflections presented in Table 3. Table 3 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of eluxadoline with urea in accordance with the present invention with the use of CuKa radiation are: 6.3; 13.1 and 21.4 ± 0.2 °2-theta. Other diffraction peaks with the use of CuKa radiation are: 10.1; 15.9; 22.1 and 24.8 ± 0.2 °2-theta. The X-ray powder pattern is shown in Fig. 3.

Table 3

Interplanar spacing [A]

Position [°2Th.] [A]=0.1nm Rel. intensity [%]

6.30 14.010 100.0 6.84. 12.915 27.7

7.28 12.133 16.0

8.92 9.903 9.8

10.12 8.738 14.5

10.92 8.098 14.5

11.48 7.702 10.4

12.04 7.345 10.5

13.05 6.780 25.5

14.62 6.053 5.2

15.20 5.825 11.8

15.88 5.576 14.8

18.14 4.887 8.5

18.79 4.718 8.8

19.33 4.588 11.6

21.36 4.156 14.6

22.13 4.013 12.9.

22.90 3.881 12.8

, 24.81 3.585 14.1

Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of eluxadoline with urea of 129°C.

An X-ray powder pattern of the amorphous form of eluxadoline with sulphuric acid (prepared according to Example 4) is shown in Figure 4. Differential scanning calorimetry (DSC) was applied to measure the glass transition temperature of the amorphous form of eluxadoline with sulphuric acid of 202°C.

An X-ray powder pattern of the amorphous form of eluxadoline with hydrobromic acid (prepared according to Example 5) is shown in Figure 5. Differential scanning calorimetry (DSC) was applied to measure the glass transition temperature of the amorphous form of eluxadoline with hydrobromic acid of 181°C.

An X-ray powder pattern of the amorphous form of eluxadoline with methanesulfonic acid (prepared, according to Example 6) is shown in Figure 6. Differential scanning calorimetry (DSC) was applied to measure the glass transition temperature of the amorphous form of eluxadoline with methanesulfonic acid of 167°C.

An X-ray powder pattern of the amorphous form of eluxadoline with benzenesulfonic acid (prepared according to Example 7) is shown in Figure 7. Differential scanning calorimetry (DSC) was applied to measure the glass transition temperature of the amorphous form of eluxadoline with benzenesulfonic acid of 161°C.

An X-ray powder pattern of the amorphous form of eluxadoline with phosphoric acid (prepared according to Example 8) is shown in Figure 8. Differential scanning calorimetry (DSC) was applied to measure the glass transition temperature of the amorphous form of eluxadoline with phosphoric acid of 143°C.

An X-ray powder pattern of the amorphous form of eluxadoline with tartaric acid (prepared according to Example 9) is shown in Figure 9. Differential scanning calorimetry (DSC) was applied to measure the glass transition temperature of the amorphous form of eluxadoline with tartaric acid of 134°C. The invention is clarified in a more detailed way using the embodiment examples below. These examples, which illustrate the preparation of solid forms of eluxadoline only have an illustrative character and do not restrict the scope of the invention in any respect.

The solid forms of eluxadoline in accordance with the present invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets or capsules. Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc. Any of the solid forms of eluxadoline in accordance with the present invention can be mixed with the above mentioned excipients, screened through a sieve and the resulting mixture can be tabletted or filled into capsules. The tablets can be further coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol. Experimental part X-ray powder diffraction

The diffractograms were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti- dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 mm anti-dispersion slit were used.

Differential Scanning Calorimetry (DSC)

The records of the solid crystalline forms of eluxadoline were measured with the use of a DSC Pyris 1 device by Perkin Elmer. The sample charge in a standard Al pot was between 2.5-3 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 300°C at the heating rate of 10°C/min. As the carrier gas 4.0 N₂ was used at the flow of 20 ml/min.

The records of the amorphous forms of eluxadoline were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μΐ,) was between 4 and 5 mg and the heating rate was 5°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 250°C at the heating rate of 5°C/min (amplitude = 0.8°C and period = 60 s). As the carrier gas 5.0 N₂ was used at the flow of 50 ml/min. Ultra-high-performance liquid chromatography (UHPLC)

Separation of impurities of the novel solid forms of eluxadoline was carried out in an Acquity UPLC BEH RP18 column, 1.7 μπι, 2.1 x 100 mm with the use of a mobile phase gradient (see Table 4), 1.32 g of diammonium hydrogen phosphate in 1000 ml of water (pH 6.5) at the flow of 0.4 ml/min and separation temperature of 40°C. The injection volume of the analyzed sample was 0.4 μΐ. Eluxadoline and its impurities were detected by means of UV detection at 240 nm. The evaluation was carried out by internal normalization of peak areas. Table 4: Mobile phase gradient

Examples The crystalline zwitterion of eluxadoline (form a) was prepared according to the procedure disclosed in the patent application WO 2009/009480. Melting point according to DSC is 191 °C. UHPLC purity is 98.9%.

Amorphous eluxadoline was obtained by quick evaporation of the solvent of an eluxadoline solution in acetone. Glass transition temperature according to DSC was 166°C. UHPLC purity was 98.9%.

Example 1

Preparation of crystalline eluxadoline

The amorphous form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl] [( 1 S)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl]amino } methyi)-2- methoxybenzoic acid in the quantity of 130 mg (2.25 -10^"4 mol) was suspended in 25 ml of tetrahydrofuran. This suspension was stirred on a magnetic stirrer at 35°C for 4 weeks. Then, the solvent was freely evaporated. UHPLC purity was 98.8%. X-ray powder pattern in Fig. 1. Melting point according to DSC was 157°C.

Example 2

Salt of eluxadoline with benzoic acid

The amorphous form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl] [(IS)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoic acid in the quantity of 130 mg (2.25· 10^"4 mol) was dissolved in 2 ml of ethanol under reflux conditions. A solution that was prepared by dissolution of 28.62 mg (2.37-10^"4 mol) of benzoic acid (99%) in 1 ml of ethanol was added to this solution. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 86.0%. X-ray powder pattern in Fig. 2. Melting point according to DSC was 137°C.

Example 3

Salt of eluxadoline with urea

The amorphous form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylpheny l)propanoyl] [( 1 S)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl] amino } methyl)-2- methoxybenzoic acid in the quantity of 150 mg (2.60· 10^"4 mol) was dissolved in 2.5 ml of ethanol under reflux conditions. A solution that was prepared by dissolution of 16.4 mg (2.73-10^_4 mol) of urea (98.7%) in 1 ml of ethanol was added to this solution. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 98.7%. X-ray powder pattern in Fig. 3. Melting point according to DSC was 129°C.

Example 4

Salt of eluxadoline with sulphuric acid

The amorphous form of 5-({[(2<S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl] [( 1 S)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl] amino } methyl)-2- methoxybenzoic acid in the quantity of 140 mg (2.43 -10^"4 mol) was suspended in 10 ml of acetone at the room temperature. 13.87 μΐ (2.55-10^"4 mol) of sulphuric acid (98.0%) was added to this suspension under continuous stirring. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 98.8%. X-ray powder pattern in Fig. 4. Glass transition temperature of the amorphous form of eluxadoline with sulphuric acid was 202°C. Example 5

Salt of eluxadoline with hydrobromic acid

The amorphous form of 5-({[(2S)-2-arnino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl][(lS)-l-(4-phenyl-lH-imidazol-2-yl)emyl]amino}m

methoxybenzoic acid in the quantity of 130 mg (2.25 -10^"4 mol) was dissolved in 2.5 ml of ethanol under reflux conditions. The amount of 26.78 μΐ (2.37-10^"4 mol) of hydrobromic acid (48.0%) was added to this solution under continuous stirring. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 97.2%. X-ray powder pattern in Fig. 5. Glass transition temperature of the amorphous form of eluxadoline with hydrobromic acid was 181 °C.

Example 6

Salt of eluxadoline with methanesulfonic acid

The amorphous form of 5-({[(2<S)-2-arnino-3-(4-carbamoyl-2,6- dimethylpheny l)propanoyl] [( 1 S)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl] amino } methyl)-2- methoxybenzoic acid in the quantity of 145 mg (2.51-10^"4mol) was suspended in 10 ml of acetone at the room temperature. The amount of 17.50 μΐ (2.64-10^"4 mol) of methanesulfonic acid (98.0%) was added to this solution under continuous stirring. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 98.9%. X-ray powder pattern in Fig. 6. Glass transition temperature of the amorphous form of eluxadoline with methanesulfonic acid was 167°C.

Example 7

Salt of eluxadoline with benzenesulfonic acid

The amorphous form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl] [( 1 £)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl] amino } methyl)-2- methoxybenzoic acid in the quantity of 142 mg (2.46· 10^"4 mol) was suspended in 10 ml of acetone at the room temperature. 43.54 mg (2.59· 10^"4 mol) of benzenesulfonic acid (94.0%) was added to this suspension under continuous stirring. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 96.9%. X-ray powder pattern in Fig. 7. Glass transition temperature of the amorphous form of eluxadoline with benzenesulfonic acid was 161°C. Example 8

Salt of eluxadoline with phosphoric acid

The amorphous form of 5-({[(2S -2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl] [( IS)- 1 -(4-phenyl- 1 H-irriidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoic acid in the quantity of 125 mg (2.17-10^"4 mol) was dissolved in 2.5 ml of ethanol under reflux conditions. The amount of 15.44 μΐ (2.28· 10^"4 mol) of phosphoric acid (85.0%) was added to this solution under continuous stirring. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was freely evaporated at the room temperature. UHPLC purity was 98.9%. X-ray powder pattern in Fig. 8. Glass transition temperature of the amorphous form of eluxadoline with phosphoric acid was 143°C.

Example 9

Salt of eluxadoline with tartaric acid

The amorphous form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl] [( 1 S)- 1 -(4-phenyl- 1 H-imidazol-2-yl)ethy 1] amino } methyl)-2- methoxybenzoic acid in the quantity of 137 mg (2.38-10^"4mol) was dissolved in 2.5 ml of ethanol under reflux conditions. A solution of tartaric acid that was prepared by dissolution of 37.82 mg (2.49-10^"4 mol) of tartaric acid (99.0%) in 1 ml of ethanol was added to this solution. The mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was evaporated at the room temperature. UHPLC purity was 98.8%. X-ray powder pattern in Fig. 9. Glass transition temperature of the amorphous form of eluxadoline with tartaric acid was 134°C.

Claims

1. A crystalline form of eluxadoline free base, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.7; 11.4; 14.8;

19.2 and 21.7 ± 0.2 °2-theta.

2. The crystalline form of eluxadoline free base in accordance with claim 1, characterized by the following further reflections in the X-ray powder pattern: 78.1; 13.4; 17.2 and

20.3 ± 0.2 °2-theta.

3. The crystalline form of eluxadoline free base in accordance with claims 1 or 2, characterized by a differential scanning calorimetry curve with the melting point at 157°C.

4. A method for preparing the crystalline form of eluxadoline free base defined in claims 1 to 3, characterized in that eluxadoline is suspended in tetrahydrofuran at an elevated temperature in the range from 25°C to the boiling point of the solvent for at least 14 days.

5. A salt of eluxadoline with an acid in the solid form, characterized in that the acid is selected from the group consisting of benzoic acid, sulphuric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonic acid, phosphoric acid and tartaric acid.

6. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is benzoic acid, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.3 ; 12.8; 19.0; 21.4 and 25.9 ± 0.2 °2-theta.

7. A salt of eluxadoline with an acid in accordance with claim 6, characterized by the following further reflections in the X-ray powder pattern: 11.2; 15.2; 17.9 and 24.2 ± 0.2 °2-theta.

8. A salt of eluxadoline with an acid in accordance with claims 6 or 7, characterized by a differential scanning calorimetry curve with the melting point at 137°C.

9. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is sulphuric acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation.

10. A salt of eluxadoline with an acid in accordance with claim 9, characterized by a differential scanning calorimetry curve with the glass transition temperature of 202°C.

11. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is hydrobromic acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation.

12. A salt of eluxadoline in accordance with claim 11, characterized by a differential scanning calorimetry curve with the glass transition temperature of 181°C.

13. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is methanesulfonic acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation.

14. A salt of eluxadoline with an acid in accordance with claim 13, characterized by a differential scanning calorimetry curve with the glass transition temperature of 167°C.

15. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is benzenesulfonic acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation.

16. A salt of eluxadoline with an acid in accordance with claim 15, characterized by a differential scanning calorimetry curve with the glass transition temperature of 161°C.

17. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is phosphoric acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation.

18. A salt of eluxadoline with an acid in accordance with claim 17, characterized by a differential scanning calorimetry curve with the glass transition temperature of 143°C.

19. A salt of eluxadoline with an acid in accordance with claim 5, wherein the acid is tartaric acid, exhibiting the characteristic amorphous halo in the X-ray powder pattern with the use of CuKa radiation.

20. A salt of eluxadoline with an acid in accordance with claim 19, characterized by a differential scanning calorimetry curve with the glass transition temperature of 134°C.

21. A preparation method of a salt of eluxadoline with an acid as defined in claims 5 to 20, characterized in that eluxadoline free base is dissolved in a suitable solvent and subsequently, an acid is added that is selected from the group consisting of benzoic acid, sulphuric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonic acid, phosphoric acid and tartaric acid.

22. The preparation method in accordance with claim 21, characterized in that the suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.

23. A salt of eluxadoline with urea in the solid form.

24. The salt of eluxadoline with urea in accordance with claim 23, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.3; 13.1 and 21.4 ± 0.2 °2-theta.

25. The salt of eluxadoline with urea in accordance with claim 24, characterized by the following further reflections in the X-ray powder pattern: 10.1; 15.9; 22.1 and 24.8 ± 0.2 °2-theta.

26. The salt of eluxadoline with urea in accordance with claims 23 to 25, characterized by a differential scanning calorimetry curve with the melting point at 129°C.

27. A preparation method of the salt of eluxadoline with urea defined in claims 23 to 26, characterized in that eluxadoline free base is dissolved in a suitable solvent and urea is added subsequently.

28. The preparation method in accordance with claim 27, characterized in that a suitable solvent is a solvent selected from the group consisting of aliphatic Ci-C₄ alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.

29. Use of the solid form of a salt of eluxadoline as defined in claims 1 to 3, 5 to 20 and 23 to 26 for the preparation of a pharmaceutical composition.

30. A pharmaceutical composition, characterized in that it contains the solid form of eluxadoline as defined in claims 1 to 3, 5 to 20 and 23 to 26 and at least one pharmaceutically acceptable excipient.