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WO2025177319A2 - Solid state forms of L-Arginine, (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopent[b]indole-3-acetate and processes for preparation thereof - Google Patents

Solid state forms of L-Arginine, (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopent[b]indole-3-acetate and processes for preparation thereof

Info

Publication number
WO2025177319A2
WO2025177319A2 PCT/IN2025/050278 IN2025050278W WO2025177319A2 WO 2025177319 A2 WO2025177319 A2 WO 2025177319A2 IN 2025050278 W IN2025050278 W IN 2025050278W WO 2025177319 A2 WO2025177319 A2 WO 2025177319A2
Authority
WO
WIPO (PCT)
Prior art keywords
arginine
etrasimod
solid dispersion
amorphous form
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IN2025/050278
Other languages
French (fr)
Other versions
WO2025177319A3 (en
Inventor
Thirumalai Rajan Srinivasan
Rajeshwar Reddy Sagyam
Bal Raju Kammari
Abhijit GARAI
Jhansi Edulakanti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSN Laboratories Pvt Ltd
Original Assignee
MSN Laboratories Pvt Ltd
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Publication date
Application filed by MSN Laboratories Pvt Ltd filed Critical MSN Laboratories Pvt Ltd
Publication of WO2025177319A2 publication Critical patent/WO2025177319A2/en
Publication of WO2025177319A3 publication Critical patent/WO2025177319A3/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • Etrasimod L-arginine is discovered by Arena Pharmaceuticals, with subsequent development by Pfizer.
  • the present invention provides novel solid state forms of Etrasimod L-arginine and processes for preparation thereof.
  • the present invention further provides process for the preparation of amorphous form of Etrasimod L-arginine.
  • Solid state forms of Etrasimod L-arginine of the present invention are useful for the preparation of various pharmaceutical compositions.
  • the first embodiment of the present invention is to provide a process for the preparation of amorphous form of Etrasimod L-arginine.
  • the second embodiment of the present invention is to provide amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients.
  • Figure- 1 Illustrates the PXRD (Powder X-Ray Diffraction) pattern of amorphous form of Etrasimod L-arginine obtained according to Example 1
  • Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32
  • Figure-6 Illustrates the PXRD (Powder X-Ray Diffraction) pattern of amorphous form of Etrasimod L-arginine obtained according to Example 6
  • solvent used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE), 1,2-dimethoxyethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl THF), 2-methoxyethyl ether (Diglyme), 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate, n-butyl acetate, iso
  • the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in a solvent or mixture of solvents, b) obtaining amorphous form of Etrasimod L-arginine.
  • the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, acetonitrile, water or mixtures thereof.
  • the solvent is methanol.
  • step-a) provided in different ways.
  • the solution can be prepared by dissolving Etrasimod L-arginine in a solvent or mixture of solvents at a suitable temperature ranges from 25°C to 100°C.
  • the solution can be prepared by reacting Etrasimod with L-arginine in presence of a solvent or mixture of solvents at a suitable temperature ranges from 25 °C to 100°C.
  • the first aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) reacting Etrasimod with L-arginine in presence of methanol, b) obtaining amorphous form of Etrasimod L-arginine.
  • Obtaining amorphous form in the above processes can be done by removal of the solvent from the solution.
  • Various techniques that are used for the removal of solvent can be selected from but not limited to filtration optionally under reduced pressure, cooling the solution followed by filtration, evaporation, distillation optionally under reduced pressure, combining the solution with a suitable second solvent and filtering the solid optionally under reduced pressure, spray-drying, freeze-drying or lyophilization and the like.
  • the third aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in methanol, b) spray drying the solution to obtain amorphous form of Etrasimod L-arginine.
  • the fourth aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in a mixture of acetonitrile and water, b) lyophilization of the solution to obtain amorphous form of Etrasimod L-arginine.
  • the present invention provides stable amorphous form of Etrasimod L-arginine.
  • the amorphous form of Etrasimod L-arginine is stable at 0-5°C.
  • the amorphous form of Etrasimod L-arginine of the present invention is stable at 25-30°C.
  • the amorphous form of Etrasimod L-arginine is found to be stable at 25-30°C when stored it for a period of about 12 months.
  • the PXRD pattern of amorphous form of Etrasimod L-arginine of the present invention after storing at 25-30°C for a period of about 12 months is substantially similar to the PXRD pattern of initial sample i.e., Figure- 1.
  • the second embodiment of the present invention provides amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients.
  • the “pharmaceutically acceptable excipient” can be selected from but not limited to polyvinylpyrrolidone (povidone or PVP), PVP K29/32, polyvinylpolypyrrolidone, polysorbate, syloid, eudragit, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hyprome
  • the excipient is selected from but not limited to HPMC AS, HPMC E5, PVP K29/32 and the like.
  • the first aspect of the second embodiment of the present invention provides an amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS of the present invention is stable.
  • the present invention provides stable amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS is stable at 0-5°C.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS is stable at 25-30°C.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS of the present invention is stable at 25-30°C for a period of about 12 months.
  • the PXRD pattern of the amorphous solid dispersion comprising Etrasimod L- arginine and HPMC AS of the present invention after storing at 25-30°C for a period of 12 months is substantially similar to the PXRD pattern of the initial sample i.e., Figure-2.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5 of the present invention is stable.
  • the present invention provides stable amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5 is stable at 25-30°C for a period of about 12 months.
  • the PXRD pattern of the amorphous solid dispersion comprising Etrasimod L- arginine and HPMC E5 of the present invention after storing at 25-30°C for a period of 12 months is substantially similar to the PXRD pattern of the initial sample i.e., Figure-3.
  • the third aspect of the second embodiment of the present invention provides an amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 of the present invention is stable.
  • the present invention provides stable amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 is stable at 0-5°C.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 is stable at 25-30°C.
  • the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 is stable at 25-30°C for a period of about 12 months.
  • the PXRD pattern of the amorphous solid dispersion comprising Etrasimod L- arginine and PVP K29/32 of the present invention after storing at 25-30°C for a period of 12 months is substantially similar to the PXRD pattern of the initial sample i.e., Figure-4.
  • the weight ratio of the Etrasimod L-Arginine to the excipient(s) in the solid dispersion can be selected from about 1:0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1.0, about 1:1.5, about 1:2.0, about 1:2.5, about 1:3.0, about 1:3.5, about 1:4.0, about 1:4.5 or about 1:5 or any other suitable weight ratio falling between thereof.
  • the third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and an excipient in a solvent or mixture of solvents, b) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient.
  • the excipient in step-a) can be selected from those as defined above in second embodiment of the present invention.
  • the solvent can be selected from but not limited to those as defined above.
  • the solvent is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol or mixtures thereof.
  • the solvent is methanol.
  • An aspect of the third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and the excipient in methanol, b) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient.
  • Another aspect of the third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and the excipient(s) in a solvent or mixture of solvents, b) heating the reaction mixture, c) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient.
  • the reaction mixture in step-b) of the above process can be heated to a temperature ranging from 35-100°C.
  • Providing a solution of Etrasimod L-arginine and the excipient in a solvent or mixture of solvents can be done in various methods.
  • Etrasimod L- arginine dissolving Etrasimod L- arginine and the excipient in a solvent or mixture of solvents.
  • it can be carried out by dissolving Etrasimod L-arginine in a first solvent, adding the excipient and optionally adding the second solvent to the solution.
  • the first solvent and the second solvent can be selected from the solvents as defined above in the present invention.
  • the solution(s) obtained can be filtered optionally to make it particle free.
  • Obtaining amorphous form of Etrasimod L-arginine and amorphous solid dispersion comprising Etrasimod L-arginine and an excipient in the above processes of the present invention can be carried out by removal of the solvent from the solution.
  • Etrasimod and Etrasimod L-arginine which are used as input in the present invention can be synthesized by any of the processes known in the art. For example, they can be synthesized by the processes as descried in US8580841B2 and US10301262B2.
  • Etrasimod, Etrasimod L-arginine and the excipients which are used as inputs in the processes of the present invention can be in the form of crystalline or amorphous.
  • solid state forms of compound of formula- la of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 a is present in the composition in at least one polymorphic form mentioned.
  • the fourth embodiment of the present invention provides the use of amorphous form of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.
  • the fifth embodiment of the present invention provides the use of amorphous solid dispersion of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.
  • the sixth embodiment of the present invention provides a pharmaceutical composition comprising amorphous form of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
  • the seventh embodiment of the present invention provides a pharmaceutical composition comprising amorphous solid dispersion of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
  • the eighth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous form of compound of formula- la of the present invention.
  • the ninth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous solid dispersions of the present invention.
  • the amorphous form of compound of formula- la produced by the process of the present invention is having particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
  • the amorphous form of compound of formula- la is having particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm.
  • the amorphous solid dispersions of compound of formula- la produced by the processes of the present invention are having particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
  • the amorphous solid dispersions of compound of formula- la are having particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm.
  • the compound of formula- la produced by various processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
  • PXRD analysis was carried out by using BRUKER/D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A 0 and at a continuous scan speed of 0.03°/min.
  • Etrasimod L-arginine can be prepared by the process as described below.
  • R represents Ci-Ce straight chain or branched chain alkyl, acetyl, substituted/unsubstituted arylalkyl, aroyl groups; ‘X’ represents halogen.
  • Example-2 Preparation of amorphous solid dispersion comprising Etrasimod L- arginine and HPMC AS
  • Example-3 Preparation of amorphous solid dispersion comprising Etrasimod L- arginine and HPMC E5
  • Example-4 Preparation of amorphous solid dispersion comprising Etrasimod L- arginine and PVP K29/32
  • Acetonitrile Water (100 ml; 1:9) was added to a mixture of Etrasimod (0.5 gm) and E-arginine (190.3 mg) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 70-75°C and stirred for 15 min at the same temperature. Filtered the solution to make it particle free. The obtained solution was subjected to lyophilization to get the title compound.

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Abstract

The present invention provides new solid state forms of L-Arginine, (3R)-7-[[4- cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopent[b]indole-3- acetate represented by the following structural formula-1a and processes for preparation thereof The present invention also provides various processes for the preparation of amorphous form of L-Arginine, (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4- tetrahydrocyclopent[b]indole-3-acetate. The present invention further provides pharmaceutical compositions comprising solid state forms of compound of formula-1a.

Description

Solid state forms of L-Arginine, (3R)-7-IT4-cvclopentyl-3- (trifluoromethyl)phenyllmethoxyl-l,2,3,4-tetrahvdrocvclopentrblindole-3-acetate and processes for preparation thereof
Related Applications:
This application claims the benefit of priority of our Indian patent applications IN202441012763 filed on February 22, 2024 and IN202441016042 filed on March 07, 2024 which are incorporated herein by reference.
Field of the Invention:
The present invention provides solid state forms of L-Arginine, (3R)-7-[[4- cyclopentyl-3 -(trifluor omethyl)phenyl] methoxy] -1,2,3, 4-tetrahy drocy cl opent[b] indole-3 - acetate which is represented by the following structural formula- la and processes for preparation thereof.
Background of the Invention:
L- Arginine, (3R)-7- [ [4-cyclopentyl-3 -(trifluoromethyl)phenyl] methoxy] - 1 ,2, 3 ,4- tetrahydrocyclopent[b] indole-3 -acetate is commonly known as Etrasimod L-arginine.
Etrasimod L-arginine is discovered by Arena Pharmaceuticals, with subsequent development by Pfizer.
Etrasimod L-arginine is a sphingosine 1 -phosphate (SIP) receptor modulator. It is approved by USFDA under the brand name VELSIPITY and is indicated for the treatment of ulcerative colitis in adults. US8580841B2 describes Etrasimod, its salts and processes for preparation thereof.
US10301262B2 describes crystalline free-plate habit of Etrasimod L-arginine salt and is characterized by PXRD, DSC, dynamic moisture sorption profile.
IPCOM000273435D describes amorphous form of Etrasimod L-arginine and its process for preparation by using cryogenic ball milling.
Still, there is a need to develop novel solid state forms of Etrasimod L-arginine which are suitable for the preparation of various pharmaceutical compositions.
The present invention provides novel solid state forms of Etrasimod L-arginine and processes for preparation thereof.
The present invention further provides process for the preparation of amorphous form of Etrasimod L-arginine.
The solid state forms of Etrasimod L-arginine of the present invention are useful for the preparation of various pharmaceutical compositions.
Brief Description of the Invention:
The first embodiment of the present invention is to provide a process for the preparation of amorphous form of Etrasimod L-arginine.
The second embodiment of the present invention is to provide amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients.
The third embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients.
Brief Description of the Drawings:
Figure- 1: Illustrates the PXRD (Powder X-Ray Diffraction) pattern of amorphous form of Etrasimod L-arginine obtained according to Example 1
Figure-2: Illustrates the PXRD pattern of amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5
Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32
Figure-5: Illustrates the PXRD (Powder X-Ray Diffraction) pattern of amorphous form of Etrasimod L-arginine obtained according to Example 5
Figure-6: Illustrates the PXRD (Powder X-Ray Diffraction) pattern of amorphous form of Etrasimod L-arginine obtained according to Example 6
Detailed Description of the Invention:
The “solvent” used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE), 1,2-dimethoxyethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl THF), 2-methoxyethyl ether (Diglyme), 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; “polar-aprotic solvents” such as dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane (DCM), dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and the like; “nitrile solvents” such as acetonitrile (ACN), propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol or isopropyl alcohol (IPA), n-butanol, iso-butanol, 2- butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; “polar solvents” such as water; formic acid, acetic acid (AcOH) and the like or mixture of any of the afore mentioned solvents. The first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in a solvent or mixture of solvents, b) obtaining amorphous form of Etrasimod L-arginine.
The solvent can be selected from but not limited to those as defined above.
In an aspect of the present invention, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, acetonitrile, water or mixtures thereof.
In an aspect of the present invention, the solvent is methanol.
The solution in step-a) provided in different ways.
In an aspect of the first embodiment of the present invention, the solution can be prepared by dissolving Etrasimod L-arginine in a solvent or mixture of solvents at a suitable temperature ranges from 25°C to 100°C.
In the other aspect of the first embodiment of the present invention, the solution can be prepared by reacting Etrasimod with L-arginine in presence of a solvent or mixture of solvents at a suitable temperature ranges from 25 °C to 100°C.
The first aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) reacting Etrasimod with L-arginine in presence of methanol, b) obtaining amorphous form of Etrasimod L-arginine.
The second aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) reacting Etrasimod with L-arginine in presence of methanol, b) heating the reaction mixture, c) obtaining amorphous form of Etrasimod L-arginine. In the above process, the reaction mixture in step-b) can be heated to 30-60°C.
Obtaining amorphous form in the above processes can be done by removal of the solvent from the solution. Various techniques that are used for the removal of solvent can be selected from but not limited to filtration optionally under reduced pressure, cooling the solution followed by filtration, evaporation, distillation optionally under reduced pressure, combining the solution with a suitable second solvent and filtering the solid optionally under reduced pressure, spray-drying, freeze-drying or lyophilization and the like.
The third aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in methanol, b) spray drying the solution to obtain amorphous form of Etrasimod L-arginine.
The fourth aspect of the first embodiment of the present invention provides a process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in a mixture of acetonitrile and water, b) lyophilization of the solution to obtain amorphous form of Etrasimod L-arginine.
The present invention provides stable amorphous form of Etrasimod L-arginine.
In an aspect of the first embodiment of the present invention, the amorphous form of Etrasimod L-arginine is stable at 0-5°C.
In another aspect of the first embodiment of the present invention, the amorphous form of Etrasimod L-arginine of the present invention is stable at 25-30°C.
In the other aspect of the first embodiment of the present invention, the amorphous form of Etrasimod L-arginine is found to be stable at 25-30°C when stored it for a period of about 12 months.
The PXRD pattern of amorphous form of Etrasimod L-arginine of the present invention after storing at 25-30°C for a period of about 12 months is substantially similar to the PXRD pattern of initial sample i.e., Figure- 1. The second embodiment of the present invention provides amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients.
The “pharmaceutically acceptable excipient” can be selected from but not limited to polyvinylpyrrolidone (povidone or PVP), PVP K29/32, polyvinylpolypyrrolidone, polysorbate, syloid, eudragit, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), HPMC HP50, HPMC E3, HPMC E5, hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether betacyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates, pharmacoat and the like.
In an aspect of the second embodiment of the present invention, the excipient is selected from but not limited to HPMC AS, HPMC E5, PVP K29/32 and the like. The first aspect of the second embodiment of the present invention provides an amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS.
The amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS of the present invention is stable.
The present invention provides stable amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS.
In an aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS is stable at 0-5°C.
In another aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS is stable at 25-30°C.
In the other aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC AS of the present invention is stable at 25-30°C for a period of about 12 months.
The PXRD pattern of the amorphous solid dispersion comprising Etrasimod L- arginine and HPMC AS of the present invention after storing at 25-30°C for a period of 12 months is substantially similar to the PXRD pattern of the initial sample i.e., Figure-2.
The second aspect of the second embodiment of the present invention provides an amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5.
The amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5 of the present invention is stable.
The present invention provides stable amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5.
In an aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5 is stable at 0-5°C.
In another aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5 is stable at 25-30°C.
In the other aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and HPMC E5 is stable at 25-30°C for a period of about 12 months. The PXRD pattern of the amorphous solid dispersion comprising Etrasimod L- arginine and HPMC E5 of the present invention after storing at 25-30°C for a period of 12 months is substantially similar to the PXRD pattern of the initial sample i.e., Figure-3.
The third aspect of the second embodiment of the present invention provides an amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32.
The amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 of the present invention is stable.
The present invention provides stable amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32.
In an aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 is stable at 0-5°C.
In another aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 is stable at 25-30°C.
In the other aspect of the second embodiment of the present invention, the amorphous solid dispersion comprising Etrasimod L-arginine and PVP K29/32 is stable at 25-30°C for a period of about 12 months.
The PXRD pattern of the amorphous solid dispersion comprising Etrasimod L- arginine and PVP K29/32 of the present invention after storing at 25-30°C for a period of 12 months is substantially similar to the PXRD pattern of the initial sample i.e., Figure-4.
In an aspect of the present invention, the weight ratio of the Etrasimod L-Arginine to the excipient(s) in the solid dispersion can be selected from about 1:0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1.0, about 1:1.5, about 1:2.0, about 1:2.5, about 1:3.0, about 1:3.5, about 1:4.0, about 1:4.5 or about 1:5 or any other suitable weight ratio falling between thereof.
The third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and an excipient in a solvent or mixture of solvents, b) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient.
The excipient in step-a) can be selected from those as defined above in second embodiment of the present invention.
The solvent can be selected from but not limited to those as defined above.
In an aspect of the third embodiment of the present invention, the solvent is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol or mixtures thereof.
In an aspect of the third embodiment, the solvent is methanol.
An aspect of the third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and the excipient in methanol, b) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient.
Another aspect of the third embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and the excipient(s) in a solvent or mixture of solvents, b) heating the reaction mixture, c) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient. The reaction mixture in step-b) of the above process can be heated to a temperature ranging from 35-100°C.
Providing a solution of Etrasimod L-arginine and the excipient in a solvent or mixture of solvents can be done in various methods.
In an aspect of the present invention it can be carried out by dissolving Etrasimod L- arginine and the excipient in a solvent or mixture of solvents.
In another aspect of the present invention it can be carried out by dissolving Etrasimod L-arginine in a first solvent, dissolving the excipient in a second solvent and combining both the solutions.
In another aspect of the present invention it can be carried out by dissolving Etrasimod L-arginine in a first solvent, adding the excipient and optionally adding the second solvent to the solution.
The first solvent and the second solvent can be selected from the solvents as defined above in the present invention.
The solution(s) obtained can be filtered optionally to make it particle free.
Obtaining amorphous form of Etrasimod L-arginine and amorphous solid dispersion comprising Etrasimod L-arginine and an excipient in the above processes of the present invention can be carried out by removal of the solvent from the solution.
Various techniques that can be used for the removal of solvent can be selected from but not limited to filtration optionally under reduced pressure, cooling the solution followed by filtration, evaporation, distillation optionally under reduced pressure, combining the solution with a suitable second solvent and filtering the solid optionally under reduced pressure, spray-drying, freeze-drying or lyophilization and the like. Etrasimod and Etrasimod L-arginine which are used as input in the present invention can be synthesized by any of the processes known in the art. For example, they can be synthesized by the processes as descried in US8580841B2 and US10301262B2.
Etrasimod, Etrasimod L-arginine and the excipients which are used as inputs in the processes of the present invention can be in the form of crystalline or amorphous.
The solid state forms of compound of formula- la of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 a is present in the composition in at least one polymorphic form mentioned.
The fourth embodiment of the present invention provides the use of amorphous form of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.
The fifth embodiment of the present invention provides the use of amorphous solid dispersion of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.
The sixth embodiment of the present invention provides a pharmaceutical composition comprising amorphous form of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
The seventh embodiment of the present invention provides a pharmaceutical composition comprising amorphous solid dispersion of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
The eighth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous form of compound of formula- la of the present invention.
The ninth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous solid dispersions of the present invention. The amorphous form of compound of formula- la produced by the process of the present invention is having particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
In one aspect of the present invention, the amorphous form of compound of formula- la is having particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm.
The amorphous solid dispersions of compound of formula- la produced by the processes of the present invention are having particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
In one aspect of the present invention, the amorphous solid dispersions of compound of formula- la are having particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm.
The compound of formula- la produced by various processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
P-XRD Method of Analysis:
PXRD analysis was carried out by using BRUKER/D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A0 and at a continuous scan speed of 0.03°/min.
In an aspect of the present invention, Etrasimod L-arginine can be prepared by the process as described below.
Scheme:
Formula-2 Formula-4
F rm l 3
Etrasimod L-Arginine Etrasimod Formula-la Formula-1
‘R’ represents Ci-Ce straight chain or branched chain alkyl, acetyl, substituted/unsubstituted arylalkyl, aroyl groups; ‘X’ represents halogen.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of amorphous form of Etrasimod L-arginine (Formula-la)
Methanol (500 ml) was added to a mixture of Etrasimod (5 gm) and L-arginine (1.9 gm) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 50-55°C and stirred for 10 min at the same temperature. Filtered the solution to make it particle free. Distilled off the solvent from the filtrate and dried the obtained solid to get the title compound.
The PXRD pattern of the obtained compound is shown in Figure- 1.
Yield: 5.4 gm.
Example-2: Preparation of amorphous solid dispersion comprising Etrasimod L- arginine and HPMC AS
Methanol (50 ml) was added to a mixture of Etrasimod L-arginine (0.5 gm) and HPMC AS (0.5 gm) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 50-55°C and stirred for 10 min at the same temperature. Filtered the solution to make it particle free. Distilled off the solvent from the filtrate and dried the obtained solid to get the title compound.
The PXRD pattern of the obtained compound is shown in Figure-2.
Yield: 0.51 gm.
Example-3: Preparation of amorphous solid dispersion comprising Etrasimod L- arginine and HPMC E5
Methanol (50 ml) was added to a mixture of Etrasimod L-arginine (0.5 gm) and HPMC E5 (0.5 gm) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 50-55°C and stirred for 10 min at the same temperature. Filtered the solution to make it particle free. Distilled off the solvent from the filtrate and dried the obtained solid to get the title compound.
The PXRD pattern of the obtained compound is shown in Figure-3.
Yield: 0.62 gm. Example-4: Preparation of amorphous solid dispersion comprising Etrasimod L- arginine and PVP K29/32
Methanol (50 ml) was added to a mixture of Etrasimod L-arginine (0.5 gm) and PVP K29/32 (0.5 gm) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 50-55°C and stirred for 10 min at the same temperature. Filtered the solution to make it particle free. Distilled off the solvent from the filtrate and dried the obtained solid to get the title compound.
The PXRD pattern of the obtained compound is shown in Figure-4.
Yield: 0.73 gm.
Example-5: Preparation of amorphous form of Etrasimod L-arginine
Methanol (200 ml) was added to a mixture of Etrasimod (2 gm) and E-arginine (761.2 mg) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 55-60°C and stirred for 10 min at the same temperature. Filtered the solution to make it particle free. The obtained solution was subjected to spray drying to get the title compound. The PXRD pattern of the obtained compound is shown in Figure-5.
Yield: 1.8 gm.
Example-6: Preparation of amorphous form of Etrasimod L-arginine
Acetonitrile: Water (100 ml; 1:9) was added to a mixture of Etrasimod (0.5 gm) and E-arginine (190.3 mg) at 25-30°C and stirred the mixture for 5 min at the same temperature. Heated the mixture to 70-75°C and stirred for 15 min at the same temperature. Filtered the solution to make it particle free. The obtained solution was subjected to lyophilization to get the title compound.
The PXRD pattern of the obtained compound is shown in Figure-6.
Yield: 0.5 gm.

Claims

I/We Claim:
1. A process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in a solvent or mixture of solvents, b) obtaining amorphous form of Etrasimod L-arginine.
2. The process according to claim 1 , wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, acetonitrile, water or mixtures thereof.
3. The process according to claim 1, wherein obtaining amorphous form of Etrasimod L- arginine is carried out by removal of the solvent from the solution.
4. The process according to claim 3, wherein the technique that is used for the removal of the solvent from the solution include filtration optionally under reduced pressure, cooling the solution followed by filtration, evaporation, distillation optionally under reduced pressure, combining the solution with a second solvent and filtering the solid optionally under reduced pressure, spray-drying, freeze-drying or lyophilization.
5. A process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) reacting Etrasimod with L-arginine in presence of methanol, b) obtaining amorphous form of Etrasimod L-arginine.
6. A process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in methanol, b) spray drying the solution to obtain amorphous form of Etrasimod L-arginine.
7. A process for the preparation of amorphous form of Etrasimod L-arginine, comprising; a) providing a solution of Etrasimod L-arginine in a mixture of acetonitrile and water, b) lyophilization of the solution to obtain amorphous form of Etrasimod L-arginine.
8. The processes according to any of the preceding claims, wherein the obtained amorphous form is stable.
9. The process according to claim 8, wherein the obtained amorphous form is stable at
0-5°C.
10. The process according to claim 8, wherein the obtained amorphous form is stable at 25-30°C.
11. The process according to claim 8, wherein the obtained amorphous form is stable at 25-30°C when stored at this temperature for a period of 12 months.
12. An amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients.
13. The amorphous solid dispersion according to claim 12, wherein the pharmaceutically acceptable excipient is selected from polyvinylpyrrolidone (povidone or PVP), PVP K29/32, polyvinylpolypyrrolidone, polysorbate, syloid, eudragit, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), HPMC HP50, HPMC E3, HPMC E5, hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates, pharmacoat.
14. The amorphous solid dispersion according to claim 13, wherein the excipient is selected from HPMC AS, HPMC E5, PVP K29/32.
15. A process for the preparation of amorphous solid dispersion comprising Etrasimod L-arginine and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution of Etrasimod L-arginine and an excipient in a solvent or mixture of solvents, b) obtaining amorphous solid dispersion comprising Etrasimod L-arginine and corresponding excipient.
16. The process as claimed in claim 15, wherein, the excipient is selected from those as defined in claim 13 and the solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof.
17. The process as claimed in claim 15, wherein obtaining amorphous solid dispersion comprising Etrasimod L-arginine and the excipient is carried out by removal of the solvent from the solution.
18. The process according to claim 17, wherein the technique that can be used for the removal of the solvent is selected from filtration optionally under reduced pressure, cooling the solution followed by filtration, evaporation, distillation optionally under reduced pressure, combining the solution with a suitable second solvent and filtering the solid optionally under reduced pressure, spray-drying, freeze-drying or lyophilization.
19. The amorphous solid dispersion according to claim 12 and claim 13, which is stable.
20. The amorphous solid dispersion according to claim 19, which is stable at 0-5°C.
21. The amorphous solid dispersion according to claim 19, which is stable at 25-30°C.
22. The amorphous solid dispersion according to claim 21, which is stable at 25-30°C when stored at this temperature for a period of 12 months.
23. Use of amorphous form of Etrasimod L-arginine for the preparation of pharmaceutical formulations.
24. A pharmaceutical composition comprising amorphous form of Etrasimod L-arginine and at least one pharmaceutically acceptable excipient.
25. A method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous form of Etrasimod L-arginine.
26. Use of amorphous solid dispersion comprising Etrasimod L-arginine and at least one pharmaceutically acceptable excipient for the preparation of pharmaceutical formulations.
27. A pharmaceutical composition comprising amorphous solid dispersion of Etrasimod L- arginine of claim 26 and at least one pharmaceutically acceptable excipient.
28. A method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous solid dispersion comprising Etrasimod L- arginine and at least one pharmaceutically acceptable excipient.
PCT/IN2025/050278 2024-02-22 2025-02-24 Solid state forms of L-Arginine, (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopent[b]indole-3-acetate and processes for preparation thereof Pending WO2025177319A2 (en)

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