WO2018185711A1 - Solvates of eluxadoline - Google Patents
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- WO2018185711A1 WO2018185711A1 PCT/IB2018/052380 IB2018052380W WO2018185711A1 WO 2018185711 A1 WO2018185711 A1 WO 2018185711A1 IB 2018052380 W IB2018052380 W IB 2018052380W WO 2018185711 A1 WO2018185711 A1 WO 2018185711A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Definitions
- 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).
- IBS-D irritable bowel syndrome with diarrhea
- Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2,6- dimethylphenyl] - 1 -oxopropyl] [(15)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino]methyl]-2- methoxybenzoic acid, represented by Formula I.
- Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
- PCT Publication No. WO2009/009480 purportedly discloses Form a and Form ⁇ crystals of eluxadoline and processes thereof.
- PCT Publication No. WO2017/015606 purportedly discloses amorphous Form, crystalline Forms I, II, III and IV, and a process for the preparation of Form a crystal of eluxadoline.
- WO2017/015606 purportedly discloses amorphous Form, crystalline Forms I, II, III and IV, and a process for the preparation of Form a crystal of eluxadoline.
- 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).
- IBS-D irritable bowel syndrome with diarrhea
- solvates of eluxadoline of the present invention exhibit good thermodynamic stability, solubility, and bioavailability.
- Figure 1 depicts an XRPD pattern of dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
- Figure 2 depicts a DSC thermogram of dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
- Figure 3 depicts an XRPD pattern of ethanol solvate of eluxadoline designated as crystalline Form S7.
- Figure 4 depicts a DSC thermogram of ethanol solvate of eluxadoline designated as crystalline Form S7.
- Figure 5 depicts an XRPD pattern of isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
- Figure 6 depicts a DSC thermogram of isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
- Figure 7 depicts an XRPD pattern of amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
- Figure 8 depicts a DSC thermogram of amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
- Figure 9 depicts an XRPD pattern of acetone solvate of eluxadoline designated as crystalline Form S10.
- Figure 10 depicts a DSC thermogram of acetone solvate of eluxadoline designated as crystalline Form S 10.
- contacting refers to dissolving, slurring, stirring, suspending, or combinations thereof.
- solvate 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.
- 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.
- 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 solvates of eluxadoline are in a crystalline form or in an amorphous form.
- a second aspect of the present invention provides dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
- Crystalline Form S6 is characterized by an XRPD pattern having peaks at d-spacings of about 13.9, 6.9, 4.9, 3.8, and 2.8 A, and further characterized by additional peaks at d-spacings of about 5.7, 4.2, 4.1, 4.0, and 3.7 A.
- Table 1 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S6.
- Crystalline Form S6 is characterized by a DSC thermogram having endothermic peaks at about 67.3°C, 143.3°C, 187.8°C, and 199.5°C.
- Crystalline Form S6 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 ethanol solvate of eluxadoline designated as crystalline Form S7.
- Crystalline Form S7 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.9, 4.9, 3.8, and 2.8 A, and further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.7, 4.2, and 3.7 A.
- Table 2 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S7.
- Crystalline Form S7 is characterized by a DSC thermogram having endothermic peaks at about 65.3 °C, 184.5°C, 195.2°C, and 202.5°C. Crystalline Form S7 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 isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
- Crystalline Form S8 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, 4.2, 3.9, and 2.8 A.
- Table 3 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S8.
- Crystalline Form S8 is characterized by a DSC thermogram having endothermic peaks at about 62.6°C and 191.7°C.
- Crystalline Form S8 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 amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
- Crystalline Form S9 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 4.9, 3.8, 3.6, and 2.8 A, and further characterized by additional peaks at d-spacings of about 6.8, 6.4, 5.9, 5.7, and 4.2 A.
- Table 4 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S9.
- Crystalline Form S9 is characterized by a DSC thermogram having endothermic peaks at about 64.5°C, 141.9°C, 182.3°C, and 199.8°C.
- Crystalline Form S9 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 acetone solvate of eluxadoline designated as crystalline Form SIO.
- Crystalline Form SIO is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 13.8, 6.8, 4.9, and 3.8 A, and further characterized by additional peaks at d-spacings of about 6.7, 4.6, 4.2, 4.1, and 3.7 A.
- Table 5 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form SIO.
- Crystalline Form S10 is characterized by a DSC thermogram having endothermic peaks at about 89.3°C, 170.6°C, and 195.9°C. Crystalline Form S10 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.
- the first solvent is dimethyl digol and second solvent is diisopropyl ether.
- the first solvent is ethanol and second solvent is diisopropyl ether.
- the first and second solvents are isopropyl acetate.
- the first solvent and the second solvent are amyl alcohol.
- the first solvent is acetone 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.
- 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.
- 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.
- IBS-D irritable bowel syndrome with diarrhea
- 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.
- NMR of the samples was determined using a Bruker ® instrument, Model Avance III 400, using 5 mm PABBO probe.
- Eluxadoline (240 mg) was dissolved in dimethyl digol (2.3 mL) and water (0.75 mL) to obtain a solution. The solution was left at 25°C to 30°C for 3 days to 4 days for slow crystallization. Diisopropyl ether (10 mL) was added to the solution. The solid mass was collected by filtration and then dried initially at 25°C under vacuum for 2 hours and further dried at 40°C for 4 hours to obtain the title compound.
- Eluxadoline 300 mg was dissolved in ethanol (1.5 mL) and water (0.5 mL) to obtain a solution. The solution was stirred at 25°C to 30°C for 4 hours. Diisopropyl ether (25 mL) was added to the solution and then 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 45 °C for 6 hours to obtain the title compound. Yield: 265 mg
- Eluxadoline 300 mg was dissolved in isopropyl acetate (30 mL) to obtain a slurry. The slurry was stirred at 60°C for 7 hours. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 4 hours and further dried at 55°C for 8 hours to obtain the title compound.
- Eluxadoline 150 mg was dissolved in amyl alcohol (1.5 mL) and water (0.5 mL) to obtain a solution. The solution was stirred overnight at 25°C to 30°C. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 55°C for 10 hours to obtain the title compound.
- Eluxadoline 200 mg was partially dissolved in acetone (10 mL) to obtain a slurry. The slurry was stirred at 55°C for 7 hours. Diisopropyl ether (15 mL) was added and further stirred overnight at 25 °C to 30°C. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 45 °C for 4 hours to obtain the title compound. Yield: 185 mg
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Abstract
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).
Description
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] [(15)- 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. WO2009/009480 purportedly discloses Form a and Form β crystals of eluxadoline and processes thereof.
PCT Publication No. WO2017/015606 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 XRPD pattern of dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
Figure 2 depicts a DSC thermogram of dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
Figure 3 depicts an XRPD pattern of ethanol solvate of eluxadoline designated as crystalline Form S7.
Figure 4 depicts a DSC thermogram of ethanol solvate of eluxadoline designated as crystalline Form S7.
Figure 5 depicts an XRPD pattern of isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
Figure 6 depicts a DSC thermogram of isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
Figure 7 depicts an XRPD pattern of amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
Figure 8 depicts a DSC thermogram of amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
Figure 9 depicts an XRPD pattern of acetone solvate of eluxadoline designated as crystalline Form S10.
Figure 10 depicts a DSC thermogram of acetone solvate of eluxadoline designated as crystalline Form S 10.
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 dimethyl digol solvate of eluxadoline designated as crystalline Form S6. Crystalline Form S6 is characterized by an XRPD pattern having peaks at d-spacings of about 13.9, 6.9, 4.9, 3.8, and 2.8 A, and further characterized by additional peaks at d-spacings of about 5.7, 4.2, 4.1, 4.0, and 3.7 A.
Table 1 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S6.
Table 1
8.5 10.4 10.6
8.0 11.0 5.6
6.9 12.8 47.7
6.4 13.7 33.3
6.2 14.2 14.3
6.0 14.8 14.4
5.8 15.2 29.9
5.7 15.6 45.5
5.5 16.0 15.6
5.1 17.3 15.7
5.0 17.7 10.2
4.9 18.1 68.7
4.8 18.4 18.7
4.7 18.8 19.1
4.6 19.5 12.3
4.4 20.2 21.8
4.2 21.2 36.1
4.1 21.6 35.1
4.0 22.1 38.5
3.8 23.1 49.2
3.8 23.4 14.1
3.7 24.0 40.7
3.6 24.6 23.6
3.5 25.7 12.2
3.4 26.0 9.8
3.4 26.4 10.9
3.3 27.2 15.1
3.2 28.1 22.0
3.1 28.8 13.8
3.0 29.3 7.6
3.0 29.9 8.0
2.8 31.7 87.2
2.8 32.3 6.4
2.7 33.0 8.2
2.7 33.5 7.0
2.5 35.3 2.4
2.5 35.8 3.7
2.4 36.7 4.5
2.3 38.3 6.5
Crystalline Form S6 is characterized by a DSC thermogram having endothermic peaks at about 67.3°C, 143.3°C, 187.8°C, and 199.5°C.
Crystalline Form S6 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 ethanol solvate of eluxadoline designated as crystalline Form S7. Crystalline Form S7 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.9, 4.9, 3.8, and 2.8 A, and further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.7, 4.2, and 3.7 A.
Table 2 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S7.
Table 2
Crystalline Form S7 is characterized by a DSC thermogram having endothermic peaks at about 65.3 °C, 184.5°C, 195.2°C, and 202.5°C.
Crystalline Form S7 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 isopropyl acetate solvate of eluxadoline designated as crystalline Form S8. Crystalline Form S8 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, 4.2, 3.9, and 2.8 A.
Table 3 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S8.
Table 3
Crystalline Form S8 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 amyl alcohol solvate of eluxadoline designated as crystalline Form S9. Crystalline Form S9 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 4.9, 3.8, 3.6, and 2.8 A, and further characterized by additional peaks at d-spacings of about 6.8, 6.4, 5.9, 5.7, and 4.2 A.
Table 4 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form S9.
Table 4
Crystalline Form S9 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 acetone solvate of eluxadoline designated as crystalline Form SIO. Crystalline Form SIO is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 13.8, 6.8, 4.9, and 3.8 A, and further characterized by additional peaks at d-spacings of about 6.7, 4.6, 4.2, 4.1, and 3.7 A.
Table 5 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of crystalline Form SIO.
Table 5
Crystalline Form S10 is characterized by a DSC thermogram having endothermic peaks at about 89.3°C, 170.6°C, and 195.9°C.
Crystalline Form S10 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 is dimethyl digol and second solvent is diisopropyl ether. In another embodiment, the first solvent is ethanol and second solvent is diisopropyl ether. In another embodiment, the first and second solvents are isopropyl acetate. In another embodiment, the first solvent and the second solvent are amyl alcohol. In another embodiment, the first solvent is acetone 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 samples was determined by using a PANalytical® instrument; Model
X'pert PRO; Detector: X'celerator®.
NMR of the samples was determined using a Bruker® instrument, Model Avance III 400, using 5 mm PABBO probe.
DSC of the samples 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 S6
Eluxadoline (240 mg) was dissolved in dimethyl digol (2.3 mL) and water (0.75 mL) to obtain a solution. The solution was left at 25°C to 30°C for 3 days to 4 days for slow crystallization. Diisopropyl ether (10 mL) was added to the solution. The solid mass was collected by filtration and then dried initially at 25°C under vacuum for 2 hours and further dried at 40°C for 4 hours to obtain the title compound.
Yield: 180 mg
¾ NMR (MeOD, 400 MHz): δ 7.53-7.63 (m, 3H), 7.27-7.33 (m, 4H), 7.16-7.19 (m, 2H), 6.67-6.77 (m, 2H), 5.52 (d, 1H), 4.80 (dd, 1H), 4.25 (dd, 1H), 3.74-3.80 (m, 3H), 3.72 (d, 3H), 3.39-3.69 (m, 7H), 3.20-3.29 (m, 7H), 2.92-3.12 (m, 2H), 2.27 (s, 3H), 2.07 (s, 3H), 0.72-1.36 (m, 15H)
Example 2: Preparation of crystalline Form S7
Eluxadoline (300 mg) was dissolved in ethanol (1.5 mL) and water (0.5 mL) to obtain a solution. The solution was stirred at 25°C to 30°C for 4 hours. Diisopropyl ether (25 mL) was added to the solution and then 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 45 °C for 6 hours to obtain the title compound.
Yield: 265 mg
Ή NMR (MeOD, 400 MHz): δ 7.54-7.64 (m, 3H), 7.26-7.35 (m, 4H), 7.18 (s, 2H), 6.66- 6.74 (m, 2H), 5.56 (d, 1H), 4.84 (dd, 1H), 4.36 (dd, 1H), 3.92-3.98 (m, 1H), 3.55-3.68 (m, 5H), 2.29 (s, 3H), 2.07 (s, 3H), 1.37 (d, 1H), 1.01 (d, 12H), 0.81 (d, 2H)
Example 3: Preparation of crystalline Form S8
Eluxadoline (300 mg) was dissolved in isopropyl acetate (30 mL) to obtain a slurry. The slurry was stirred at 60°C for 7 hours. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 4 hours and further dried at 55°C for 8 hours to obtain the title compound.
Yield: 260 mg
*H NMR (MeOD, 400 MHz): δ 7.58-7.63 (m, 2H), 7.53 (s, 1H), 7.27-7.35 (m, 4H), 7.18 (s, 2H), 6.66-6.76 (m, 2H), 5.57 (d, 1H), 4.83 (dd, 1H), 4.35 (dd, 1H), 3.96-4.00 (m, 1H), 3.55-3.68 (m, 5H), 2.89-3.24 (m, 2H), 2.29 (s, 3H), 2.07 (s, 3H), 1.36 (d, 1H), 1.01 (d, 12H), 0.79 (d, 2H)
Example 4: Preparation of crystalline Form S9
Eluxadoline (150 mg) was dissolved in amyl alcohol (1.5 mL) and water (0.5 mL) to obtain a solution. The solution was stirred overnight at 25°C to 30°C. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 55°C for 10 hours to obtain the title compound.
Yield: 124 mg
Ή NMR (MeOD, 400 MHz): δ 7.58-7.63 (m, 2H), 7.53 (s, 1H), 7.28-7.35 (m, 3H), 7.16- 7.19 (m, 1H), 6.85-6.94 (m, 2H), 6.67-6.75 (m, 2H), 5.60 (d, 1H), 4.79 (dd, 1H), 4.36 (dd, 1H), 3.97-4.01 (m, 1H), 3.63 (d, 3H), 3.39 (t, 2H), 3.05-3.24 (m, 2H), 2.29 (s, 3H), 2.07 (s, 3H), 0.77-1.63 (m, 12H)
Example 5: Preparation of crystalline Form S 10
Eluxadoline (200 mg) was partially dissolved in acetone (10 mL) to obtain a slurry. The slurry was stirred at 55°C for 7 hours. Diisopropyl ether (15 mL) was added and further stirred overnight at 25 °C to 30°C. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 45 °C for 4 hours to obtain the title compound.
Yield: 185 mg
Ή NMR (MeOD, 400 MHz): δ 7.59-7.63 (m, 2H), 7.53 (s, IH), 7.31-7.35 (m, 3H), 7.16- 7.19 (m, IH), 6.87-6.92 (m, 2H), 6.68-6.75 (m, 2H), 5.60 (d, IH), 4.79 (dd, IH), 4.36 (dd, IH), 3.97-4.01 (m, IH), 3.57-3.71 (m, 5H), 3.06-3.20 (m, 2H), 2.30 (s, 3H), 2.06 (s, 3H), 1.37 (d, IH), 1.01 (d, 12H), 0.82 (d, 2H)
Claims
1. Solvates of eluxadoline, wherein the solvates are selected from dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate.
2. The solvates of eluxadoline according to claim 1, which are in a crystalline form or in an amorphous form.
3. Dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
4. The crystalline Form S6 according to claim 3, wherein the crystalline form is characterized by an XRPD pattern having peaks at d-spacings of about 13.9, 6.9, 4.9, 3.8 and 2.8 A.
5. The crystalline Form S6 according to claim 4, wherein the crystalline is further characterized by additional peaks at d-spacings of about 5.7, 4.2, 4.1, 4.0, and 3.7 A.
6. The crystalline Form S6 according to claim 3, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 67.3°C, 143.3°C, 187.8°C, and 199.5°C.
7. The crystalline Form S6 according to claim 3, wherein the crystalline form is characterized by an XRPD pattern substantially as depicted in Figure 1, or a DSC thermogram substantially as depicted in Figure 2.
8. Ethanol solvate of eluxadoline designated as crystalline Form S7.
9. The crystalline Form S7 according to claim 8, wherein the crystalline form is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.9, 4.9, 3.8, and 2.8 A.
10. The crystalline Form S7 according to claim 9, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.7, 4.2, and 3.7 A.
11. The crystalline Form S7 according claim 8, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 65.3°C, 184.5°C, 195.2°C, and 202.5°C.
12. The crystalline Form S7 according to claim 8, wherein the crystalline form is characterized by an XRPD pattern substantially as depicted in Figure 3, or a DSC thermogram substantially as depicted in Figure 4.
13. Isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
14. The crystalline Form S8 according to claim 13, wherein the crystalline form 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.
15. The crystalline Form S8 according to claim 14, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 9.8, 6.4, 4.2, 3.9, and 2.8 A.
16. The crystalline Form S8 according to claim 13, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 62.6°C and 191.7°C.
17. The crystalline Form S8 according to claim 13, wherein the crystalline form is characterized by an XRPD pattern substantially as depicted in Figure 5, or a DSC thermogram substantially as depicted in Figure 6.
18. Amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
19. The crystalline Form S9 according to claim 18, wherein the crystalline form is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 4.9, 3.8, 3.6, and 2.8 A.
20. The crystalline Form S9 according to claim 19, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 6.8, 6.4, 5.9, 5.7, and 4.2 A.
21. The crystalline Form S9 according to claim 18, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 64.5°C, 141.9°C, 182.3°C, and 199.8°C.
22. The crystalline Form S9 according to claim 18, wherein the crystalline form is characterized by an XRPD pattern substantially as depicted in Figure 7, or a DSC thermogram substantially as depicted in Figure 8.
23. Acetone solvate of eluxadoline designated as crystalline Form S I 0.
24. The crystalline Form S 10 according to claim 23, wherein the crystalline form is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 13.8, 6.8, 4.9, and 3.8 A.
25. The crystalline Form S 10 according to claim 24, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 6.7, 4.6, 4.2, 4.1, and 3.7 A.
26. The crystalline Form S 10 according to claim 23, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 89.3°C, 170.6°C, and 195.9°C.
27. The crystalline Form S 10 according to claim 23, wherein the crystalline form is characterized by an XRPD pattern substantially as depicted in Figure 9, or a DSC thermogram substantially as depicted in Figure 10.
28. A process for the preparation of solvates of eluxadoline according to claim 1, comprising contacting eluxadoline with a first solvent and optionally with a second solvent.
29. The process according to claim 28, wherein 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.
30. A process for the preparation of eluxadoline comprising drying the solvate of eluxadoline according to claim 1.
31. A pharmaceutical composition comprising solvates of eluxadoline according to claim 1, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
32. 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 according to claim 1.
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| IN201711012314 | 2017-04-05 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10314819B2 (en) | 2015-07-23 | 2019-06-11 | Teva Pharmaceuticals International Gmbh | Solid state forms of Eluxadoline |
| WO2020039333A1 (en) * | 2018-08-20 | 2020-02-27 | Allergan Holdings Unlimited Company | Polymorphs of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid |
| WO2021198780A1 (en) * | 2020-03-30 | 2021-10-07 | Allergan Holdings Unlimited Company | Forms of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017015606A1 (en) * | 2015-07-23 | 2017-01-26 | Teva Pharmaceuticals International Gmbh | Solid state forms of eluxadoline |
| WO2018047131A1 (en) * | 2016-09-09 | 2018-03-15 | Sun Pharmaceutical Industries Limited | Amorphous eluxadoline |
-
2018
- 2018-04-05 WO PCT/IB2018/052380 patent/WO2018185711A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017015606A1 (en) * | 2015-07-23 | 2017-01-26 | Teva Pharmaceuticals International Gmbh | Solid state forms of eluxadoline |
| WO2018047131A1 (en) * | 2016-09-09 | 2018-03-15 | Sun Pharmaceutical Industries Limited | Amorphous eluxadoline |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10314819B2 (en) | 2015-07-23 | 2019-06-11 | Teva Pharmaceuticals International Gmbh | Solid state forms of Eluxadoline |
| WO2020039333A1 (en) * | 2018-08-20 | 2020-02-27 | Allergan Holdings Unlimited Company | Polymorphs of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid |
| WO2021198780A1 (en) * | 2020-03-30 | 2021-10-07 | Allergan Holdings Unlimited Company | Forms of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid |
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