WO2018198101A2 - Processes for the preparation of crystalline form of eluxadoline - Google Patents
Processes for the preparation of crystalline form of eluxadoline Download PDFInfo
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- WO2018198101A2 WO2018198101A2 PCT/IB2018/053134 IB2018053134W WO2018198101A2 WO 2018198101 A2 WO2018198101 A2 WO 2018198101A2 IB 2018053134 W IB2018053134 W IB 2018053134W WO 2018198101 A2 WO2018198101 A2 WO 2018198101A2
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- eluxadoline
- crystalline form
- reaction mass
- xrpd
- depicted
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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
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- 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
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- 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
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- 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
Definitions
- the present invention relates to processes for the preparation of a crystalline form of eluxadoline.
- 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).
- 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 forms alpha and beta crystals of eluxadoline and processes thereof.
- PCT Publication No. WO2009/009480 discloses that form alpha crystals can be prepared by storing the zwitterion of eluxadoline at 0-25% relative humidity (RH) for 3 days and form beta crystals can be prepared by storing the zwitterion of eluxadoline at greater than 60% RH for 3 days.
- RH relative humidity
- PCT Publication No. WO2017/015606 purportedly discloses amorphous form, crystalline forms I, II, III and IV, and processes for their preparation and a process for the preparation of form alpha crystal of eluxadoline. Summary of the Invention
- the present invention relates to processes for the preparation of a crystalline form of eluxadoline.
- Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline form of eluxadoline.
- Figure 2 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline form of eluxadoline.
- XRPD X-Ray Powder Diffraction
- room temperature refers to the temperature in the range of 25°C to 35°C.
- contacting refers to dissolving, slurrying, stirring, heating, suspending, or combinations thereof.
- reaction mass refers to suspension, solution, emulsion, or precipitate.
- a first aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising contacting eluxadoline with a solvent.
- Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
- solvents examples include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 35°C to about 75°C.
- the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 35°C to about 70°C.
- the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 40°C to about 65°C.
- the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 45°C to 65°C.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 4 hours to about 24 hours. In an embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 8 hours to about 22 hours. In another embodiment, the preparation of crystalline form of eluxadoline as depicted in Figure 1 is carried out for about 10 hours to about 18 hours. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 12 hours to about 16 hours.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
- a second aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising:
- reaction mass ii) heating the reaction mass at 35°C to 70°C followed by optional distillation of the solvent to obtain a reaction mass
- Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
- solvents examples include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 4 hours to about 24 hours. In an embodiment, the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 5 hours to about 22 hours.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 10 hours to about 18 hours. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 12 hours to about 16 hours.
- reaction mass of step i) is treated with activated carbon.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
- a third aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising:
- reaction mass ii) heating the reaction mass followed by partial distillation of the solvent to obtain a reaction mass
- step iv) storing the crystalline form of step iii) at 25°C to 45°C and relative
- Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
- solvents include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
- the heating of the reaction mass of step ii) is carried out at a temperature of about 35°C to 85°C. In an embodiment, the heating of the reaction mass of step ii) is carried out at a temperature of about 38°C to about 82°C.
- the partial distillation of the solvent of step ii) is carried out at a temperature of about 35°C to 85°C. In an embodiment, the partial distillation of the solvent of step ii) is carried out at a temperature of about 38°C to about 82°C.
- the crystalline form of step iii) is stored for about 1 day to about 7 days. In an embodiment, the crystalline form of step iii) is stored for about 3 days to about 5 days.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
- XRPD of the samples was determined by using a PANalytical ® instrument; Model X'pert PRO; Detector: X'celerator ® .
- Example 1 Preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1
- Method A Eluxadoline (10 g) was added to iso-propyl alcohol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was then heated to 60°C to obtain a suspension. The suspension was stirred for 5 hours at 60°C to 66°C, and then cooled to 25°C. The product was filtered, suck dried for 5 minutes and then washed with isopropyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method B Eluxadoline (10 g) was added to n-propyl alcohol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 5 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with n-propyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method C Eluxadoline (10 g) was added to methyl isobutyl ketone (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with methyl isobutyl ketone (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method D Eluxadoline (10 g) was added to ethyl acetate (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with ethyl acetate (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method F Eluxadoline (10 g) was added to n-butanol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with n-butanol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method G Eluxadoline (10 g) was added to a mixture of n-propyl alcohol (300 mL) and dichloromethane (400 mL) at 35°C to 38°C to obtain a reaction mass. The reaction mass was heated to 38°C to 40°C to obtain a suspension and then distilled up to a volume of 300 mL at 38°C to 42°C. The suspension was stirred for 3 hours at 50°C to 55°C and then cooled to 25 °C. The product obtained was filtered, and then washed with n-propyl alcohol (20 mL) to obtain a solid. The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method H Eluxadoline (20 g) was added to a mixture of n-propyl alcohol (10 mL) and methanol (800 mL) at 40°C to 45°C and then stirred for 5 minutes to obtain a clear solution. The solution was filtered through Hyflo® and then washed with methanol (40 mL). The filtrate was heated at 60°C to 65 °C and then distilled up to a volume of 200 mL at 60°C to 65 °C to obtain a suspension. The suspension was stirred for 4 hours at 60°C to 65 °C and then cooled to 5°C to 10°C. The product obtained was filtered and then washed with methanol (40 mL) to obtain a solid. The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- the suspension was stirred for 4 hours to 5 hours at 60°C to 65°C and then cooled to 0°C to 5°C.
- the product obtained was filtered and then washed with methanol (160 mL) to obtain a solid.
- the solid was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 15 hours to obtain the title compound.
- Method I Eluxadoline (10 g) was added to isopropyl alcohol (1200 mL) at 72°C to obtain a reaction mass. The reaction mass was heated to 82°C and then distilled up to a volume of 100 mL at 80°C to 82°C to obtain a suspension. The suspension was stirred for 4 hours at 80°C to 82°C and then cooled to 30°C. The product obtained was filtered, suck dried for 5 minutes and then washed with isopropyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 60°C to 65 °C for 12 hours. The solid (2.0 g) was stored at 25 ⁇ 2°C/60 ⁇ 5% RH for 3 days and then further dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
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Abstract
The present invention relates to processes for the preparation of a crystalline form of eluxadoline.
Description
PROCESSES FOR THE PREPARATION OF CRYSTALLINE FORM
OF ELUXADOLINE
Field of the Invention
The present invention relates to processes for the preparation of a crystalline form of eluxadoline.
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 forms alpha and beta crystals of eluxadoline and processes thereof. PCT Publication No. WO2009/009480 discloses that form alpha crystals can be prepared by storing the zwitterion of eluxadoline at 0-25% relative humidity (RH) for 3 days and form beta crystals can be prepared by storing the zwitterion of eluxadoline at greater than 60% RH for 3 days.
PCT Publication No. WO2017/015606 purportedly discloses amorphous form, crystalline forms I, II, III and IV, and processes for their preparation and a process for the preparation of form alpha crystal of eluxadoline.
Summary of the Invention
The present invention relates to processes for the preparation of a crystalline form of eluxadoline.
Brief Description of the Drawings
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline form of eluxadoline.
Figure 2 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline form of eluxadoline.
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 "room temperature," as used herein, refers to the temperature in the range of 25°C to 35°C.
The term "contacting", as used herein refers to dissolving, slurrying, stirring, heating, suspending, or combinations thereof.
The term "reaction mass", as used herein refers to suspension, solution, emulsion, or precipitate.
A first aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising contacting eluxadoline with a solvent.
Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
Examples of solvents include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
The preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 35°C to about 75°C. In an embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 35°C to about 70°C. In
another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 40°C to about 65°C. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 45°C to 65°C.
The preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 4 hours to about 24 hours. In an embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 8 hours to about 22 hours. In another embodiment, the preparation of crystalline form of eluxadoline as depicted in Figure 1 is carried out for about 10 hours to about 18 hours. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 12 hours to about 16 hours.
The crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
A second aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising:
i) contacting eluxadoline with a solvent to obtain a reaction mass;
ii) heating the reaction mass at 35°C to 70°C followed by optional distillation of the solvent to obtain a reaction mass; and
iii) filtering the reaction mass to obtain the crystalline form characterized by
XRPD as depicted in Figure 1.
Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
Examples of solvents include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
The preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 4 hours to about 24 hours. In an embodiment, the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 5 hours to about 22 hours. In another embodiment, the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 10 hours to about 18 hours. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 12 hours to about 16 hours.
In an embodiment, the reaction mass of step i) is treated with activated carbon.
The crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
A third aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising:
i) contacting eluxadoline with a solvent to obtain a reaction mass;
ii) heating the reaction mass followed by partial distillation of the solvent to obtain a reaction mass;
iii) filtering the reaction mass to obtain a crystalline form characterized by XRPD as depicted in Figure 2;
iv) storing the crystalline form of step iii) at 25°C to 45°C and relative
humidity at 60% to 95%; and
v) drying to obtain the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1.
Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
Examples of solvents include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
The heating of the reaction mass of step ii) is carried out at a temperature of about 35°C to 85°C. In an embodiment, the heating of the reaction mass of step ii) is carried out at a temperature of about 38°C to about 82°C.
The partial distillation of the solvent of step ii) is carried out at a temperature of about 35°C to 85°C. In an embodiment, the partial distillation of the solvent of step ii) is carried out at a temperature of about 38°C to about 82°C.
The crystalline form of step iii) is stored for about 1 day to about 7 days. In an embodiment, the crystalline form of step iii) is stored for about 3 days to about 5 days.
The crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
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.
Method
XRPD of the samples was determined by using a PANalytical® instrument; Model X'pert PRO; Detector: X'celerator®.
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 of eluxadoline characterized by XRPD as depicted in Figure 1
Method A: Eluxadoline (10 g) was added to iso-propyl alcohol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was then heated to 60°C to obtain a suspension.
The suspension was stirred for 5 hours at 60°C to 66°C, and then cooled to 25°C. The product was filtered, suck dried for 5 minutes and then washed with isopropyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 7.8 g
Chromatographic Purity: 98.47%
Method B: Eluxadoline (10 g) was added to n-propyl alcohol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 5 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with n-propyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 7.30 g
Chromatographic Purity: 99.11%
Method C: Eluxadoline (10 g) was added to methyl isobutyl ketone (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with methyl isobutyl ketone (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 8.95 g
Chromatographic Purity: 97.99%
Method D: Eluxadoline (10 g) was added to ethyl acetate (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with ethyl acetate (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 8.40 g
Chromatographic Purity: 97.85%
Method E: Eluxadoline (10 g) was added to acetone (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with acetone (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 9.80 g
Chromatographic Purity: 98.34%
Method F: Eluxadoline (10 g) was added to n-butanol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with n-butanol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 7.80 g
Chromatographic Purity: 98.76%
Method G: Eluxadoline (10 g) was added to a mixture of n-propyl alcohol (300 mL) and dichloromethane (400 mL) at 35°C to 38°C to obtain a reaction mass. The reaction mass was heated to 38°C to 40°C to obtain a suspension and then distilled up to a volume of 300 mL at 38°C to 42°C. The suspension was stirred for 3 hours at 50°C to 55°C and then cooled to 25 °C. The product obtained was filtered, and then washed with n-propyl alcohol (20 mL) to obtain a solid. The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 8.58 g
Chromatographic purity: 99.7%
Method H: Eluxadoline (20 g) was added to a mixture of n-propyl alcohol (10 mL) and methanol (800 mL) at 40°C to 45°C and then stirred for 5 minutes to obtain a clear solution. The solution was filtered through Hyflo® and then washed with methanol (40 mL). The filtrate was heated at 60°C to 65 °C and then distilled up to a volume of 200 mL at 60°C to 65 °C to obtain a suspension. The suspension was stirred for 4 hours at 60°C to 65 °C and then cooled to 5°C to 10°C. The product obtained was filtered and then washed
with methanol (40 mL) to obtain a solid. The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 14.2 g
Chromatographic purity: 99.76%
Method Ha: Eluxadoline (80 g) was added to a mixture of n-propyl alcohol (16 mL) and methanol (3200 mL) at 40°C to 45 °C to get a clear solution. Activated carbon (1.6 g) was added to the solution and stirred for 15 minutes at 40°C to 45 °C. The solution was filtered through Hyflo® followed by micron filter and then washed with methanol (160 mL) at 40°C to 45°C. The filtrate was heated at 60°C to 65°C and then distilled up to a volume of 400 mL at 60°C to 65 °C to obtain a suspension. The suspension was stirred for 4 hours to 5 hours at 60°C to 65°C and then cooled to 0°C to 5°C. The product obtained was filtered and then washed with methanol (160 mL) to obtain a solid. The solid was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 15 hours to obtain the title compound.
Yield: 68.58 g
Chromatographic purity: 99.68%
Method I: Eluxadoline (10 g) was added to isopropyl alcohol (1200 mL) at 72°C to obtain a reaction mass. The reaction mass was heated to 82°C and then distilled up to a volume of 100 mL at 80°C to 82°C to obtain a suspension. The suspension was stirred for 4 hours at 80°C to 82°C and then cooled to 30°C. The product obtained was filtered, suck dried for 5 minutes and then washed with isopropyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 60°C to 65 °C for 12 hours. The solid (2.0 g) was stored at 25±2°C/60±5% RH for 3 days and then further dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Yield: 8.0 g
Method J: Eluxadoline (10 g) was added to ethanol (550 mL) at 70°C to obtain a reaction mass. The reaction mass was heated to 78°C to 79°C and then distilled up to a volume of 70 mL at 78 °C to 80°C to obtain a suspension. The suspension was stirred for 4 hours at 75°C to 79°C and then cooled to 25°C. The product obtained was filtered, suck dried for 5 minutes and then washed with ethanol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 60°C to 65°C for 12 hours. The solid (2.0 g) was
stored at 25±2°C/60±5% RH for 3 days and then further dried under vacuum at 55 °C to 60°C for 12 hours to obtain the title compound.
Yield: 7.0 g
Chromatographic Purity: 99.07%
Claims
1. A process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 , comprising contacting eluxadoline with a solvent.
2. The process according to claim 1 , wherein the solvent is selected from methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
3. The process according to claim 1 , wherein the eluxadoline is contacted with the solvent at a temperature of about 35°C to about 75°C.
4. A process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 , comprising
i) contacting eluxadoline with a solvent to obtain a first reaction mass;
ii) heating the reaction mass at 35°C to 70°C followed by optional distillation of the solvent to obtain a second reaction mass; and
iii) filtering the second reaction mass to obtain the crystalline form
characterized by XRPD as depicted in Figure 1.
5. The process according to claim 4, wherein the solvents are selected from methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
6. A process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising
i) contacting eluxadoline with a solvent to obtain a first reaction mass;
ii) heating the first reaction mass followed by partial distillation of the solvent to obtain a second reaction mass;
iii) filtering the second reaction mass to obtain a crystalline form characterized by XRPD as depicted in Figure 2;
iv) storing the crystalline form of step iii) at 25°C to 45°C and relative
humidity at 60% to 95%; and
v) drying to obtain the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1.
7. The process according to claim 6, wherein the solvents are selected from methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
8. The process according to claim 6, wherein the partial distillation of the solvent of step ii) is carried out at a temperature of about 35°C to 85°C.
9. The process according to claim 6, wherein the crystalline form of step iii) is stored for about 1 day to about 7 days.
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