WO2018185664A1 - Solvates of eluxadoline - Google Patents
Solvates of eluxadoline Download PDFInfo
- Publication number
- WO2018185664A1 WO2018185664A1 PCT/IB2018/052304 IB2018052304W WO2018185664A1 WO 2018185664 A1 WO2018185664 A1 WO 2018185664A1 IB 2018052304 W IB2018052304 W IB 2018052304W WO 2018185664 A1 WO2018185664 A1 WO 2018185664A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystalline form
- eluxadoline
- peaks
- spacings
- depicted
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- 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] [( IS)- 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. WO 2009/009480 purportedly discloses Form a and Form ⁇ 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.
- 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.
- 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 X-Ray Powder Diffraction (XRPD) pattern of methanol solvate of eluxadoline designated as crystalline Form S 1.
- XRPD X-Ray Powder Diffraction
- FIG. 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of methanol solvate of eluxadoline designated as crystalline Form SI .
- DSC Differential Scanning Calorimetry
- 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.
- 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 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.
- XRPD X-ray powder diffraction
- Table 1 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S 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.
- DSC differential scanning calorimetry
- 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 2 ⁇ values, and the relative intensity of crystalline Form S2.
- 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 2 ⁇ values, and the relative intensity of crystalline Form S3.
- 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 2 ⁇ values, and the relative intensity of crystalline Form S4.
- 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 2 ⁇ values, and the relative intensity of crystalline Form S5.
- 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.
- the first solvent and second solvent is methanol.
- the first solvent and second solvent are isopropyl alcohol.
- the first and second solvent are n-butanol.
- the first solvent is n-pentanol and the second solvent is diisopropyl ether.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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] [( 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 33.5 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 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
2.7 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 d6 + D20, 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 d6 + D20, 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
Claims
1. Solvates of eluxadoline, wherein the solvates are selected from methanol, isopropyl alcohol, n-butanol, n-pentanol, diisopropyl ether, ethyl acetate, 2-ethoxy ethanol, and 1,2- dimethoxy benzene.
2. The solvates of eluxadoline according to claim 1, which are in a crystalline form or in an amorphous form.
3. Methanol solvate of eluxadoline designated as crystalline Form S 1.
4. The crystalline Form S I according to claim 3, where the crystalline form 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.
5. The crystalline Form S 1 according to claim 4, where the crystalline form is further characterized by additional peaks at d-spacings of about 7.6, 7.3, 5.9, 4.3, and 4.1 A.
6. The crystalline Form S I according to claim 3, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 77.9°C and 197.2°C.
7. The crystalline Form S I 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. Isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2.
9. The crystalline Form S2 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 3.6 A.
10. The crystalline Form S2 according to claim 9, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.6, 4.6, and 4.2 A.
11. The crystalline Form S2 according to claim 8, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 80.4°C, 101.1°C, and 168.9°C.
12. The crystalline Form S2 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. n-Butanol solvate of eluxadoline designated as crystalline Form S3.
14. The crystalline Form S3 according to claim 13, wherein the crystalline form 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.
15. The crystalline Form S3 according to claim 14, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 6.4, 5.7, 4.2, 4.0, and 3.7 A.
16. The crystalline Form S3 according to claim 13, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 87.1°C and 178.8°C.
17. The crystalline Form S3 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. n-Pentanol solvate of eluxadoline designated as crystalline Form S4.
19. The crystalline Form S4 according to claim 18, wherein the crystalline form 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.
20. The crystalline Form S4 according to claim 19, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 12.0, 8.9, 8.1, 4.6, and 4.2 A.
21. The crystalline Form S4 according to claim 18, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 73.9°C and 186.5°C.
22. The crystalline Form S4 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. Diisopropyl ether solvate of eluxadoline designated as crystalline Form S5.
24. The crystalline Form S5 according to claim 23, 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.
25. The crystalline Form S5 according to claim 24, wherein the crystalline form is further characterized by additional peaks at d-spacings of about 9.8, 6.4, 5.9, 5.6, and 4.2 A.
26 The crystalline Form S5 according to claim 23, wherein the crystalline form is characterized by a DSC thermogram having endothermic peaks at about 63.3°C and 185.2°C.
27. The crystalline Form S5 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 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201711011993 | 2017-04-03 | ||
| IN201711011993 | 2017-04-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018185664A1 true WO2018185664A1 (en) | 2018-10-11 |
Family
ID=63713385
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2018/052304 WO2018185664A1 (en) | 2017-04-03 | 2018-04-03 | Solvates of eluxadoline |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2018185664A1 (en) |
Cited By (2)
| 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 |
| 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 (4)
| 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 |
| WO2017153471A1 (en) * | 2016-03-11 | 2017-09-14 | Euticals S.P.A. | New stable solvate crystalline forms of eluxadolina |
| WO2018046028A1 (en) * | 2016-09-07 | 2018-03-15 | Zentiva, K.S. | Solid forms of eluxadoline |
| WO2018047131A1 (en) * | 2016-09-09 | 2018-03-15 | Sun Pharmaceutical Industries Limited | Amorphous eluxadoline |
-
2018
- 2018-04-03 WO PCT/IB2018/052304 patent/WO2018185664A1/en active Application Filing
Patent Citations (4)
| 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 |
| WO2017153471A1 (en) * | 2016-03-11 | 2017-09-14 | Euticals S.P.A. | New stable solvate crystalline forms of eluxadolina |
| WO2018046028A1 (en) * | 2016-09-07 | 2018-03-15 | Zentiva, K.S. | Solid forms of eluxadoline |
| WO2018047131A1 (en) * | 2016-09-09 | 2018-03-15 | Sun Pharmaceutical Industries Limited | Amorphous eluxadoline |
Cited By (2)
| 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 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100463614B1 (en) | Process to Prepare Tolterodine | |
| EP3248983B1 (en) | Crystal form a of obeticholic acid and preparation method therefor | |
| JP5535082B2 (en) | Method for synthesizing bosentan, polymorphic forms thereof and salts thereof | |
| WO2013098775A1 (en) | Improved process for preparation of pure linagliptin | |
| KR20120033357A (en) | Polymorphs of dasatinib and process for preparation thereof | |
| EP3180343A1 (en) | Solid state forms of ibrutinib | |
| US20130123282A1 (en) | Solid state forms of linagliptin | |
| EP3229814A1 (en) | Co-crystal of dapagliflozin with citric acid | |
| EP3414256A1 (en) | Amine salt of obeticholic acid | |
| WO2018185711A1 (en) | Solvates of eluxadoline | |
| JP6985179B2 (en) | Method for producing proline amide compound | |
| WO2018185664A1 (en) | Solvates of eluxadoline | |
| WO2012098501A1 (en) | Febuxostat co-crystals | |
| WO2011080651A2 (en) | Polymorphic forms of febuxostat | |
| US20180273499A1 (en) | Salts and solid state forms of vortioxetine | |
| WO2018229704A1 (en) | Novel polymorphs of eluxadoline and its solvates, process for its preparation and pharmaceutical composition thereof | |
| US20140378472A1 (en) | Amorphous vilazodone hydrochloride, a process for its preparation and pharmaceutical compositions thereof | |
| WO2008051440A1 (en) | Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione | |
| WO2017191620A1 (en) | A crystalline form of a salt of sacubitril and a process of its preparation | |
| WO2017134606A1 (en) | Crystalline form of {(1r,2s,3s,4r,5s)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl}methyl acetate | |
| EP3374349A1 (en) | Process for the preparation of eltrombopag olamine | |
| US10294239B2 (en) | Ertugliflozin co-crystals and process for their preparation | |
| JP6462143B2 (en) | Solid crystalline form 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanenitrile | |
| JP3157171B2 (en) | Method for producing synergistine | |
| WO2011058521A2 (en) | Process for the preparation of crystalline form i of l-malic acid salt of sunitinib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18781278 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 18781278 Country of ref document: EP Kind code of ref document: A1 |