WO2023175632A1 - Solid state forms of (5s,6s,9r)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate and processes for preparation thereof - Google Patents
Solid state forms of (5s,6s,9r)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate and processes for preparation thereof Download PDFInfo
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- WO2023175632A1 WO2023175632A1 PCT/IN2023/050256 IN2023050256W WO2023175632A1 WO 2023175632 A1 WO2023175632 A1 WO 2023175632A1 IN 2023050256 W IN2023050256 W IN 2023050256W WO 2023175632 A1 WO2023175632 A1 WO 2023175632A1
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- Prior art keywords
- sulfate
- rimegepant
- solvent
- mixture
- cellulose
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000007787 solid Substances 0.000 title abstract description 13
- KRNAOFGYEFKHPB-ANJVHQHFSA-N [(5s,6s,9r)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl] 4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate Chemical compound C1([C@H]2[C@@H](C3=CC=CN=C3[C@H](OC(=O)N3CCC(CC3)N3C(NC4=NC=CC=C43)=O)CC2)N)=CC=CC(F)=C1F KRNAOFGYEFKHPB-ANJVHQHFSA-N 0.000 title abstract description 7
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000013856 polydextrose Nutrition 0.000 claims description 2
- 239000001259 polydextrose Substances 0.000 claims description 2
- 229940035035 polydextrose Drugs 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 2
- 239000004800 polyvinyl chloride Substances 0.000 claims description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 2
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 claims description 2
- 239000000770 propane-1,2-diol alginate Substances 0.000 claims description 2
- 235000013772 propylene glycol Nutrition 0.000 claims description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 31
- 239000000463 material Substances 0.000 description 8
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- 229940127597 CGRP antagonist Drugs 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229950004372 rimegepant Drugs 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K9/143—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 inorganic compounds
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention provides new solid state forms of (5S,6S,9R)-5-amino-6- (2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro- lH-imidazo[4,5-b]pyridin-l-yl)-l-piperidinecarboxylate hemisulfate represented by the following structural formula- la and processes for preparation thereof.
- NURTEC ODT is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults and preventive treatment of episodic migraine in adults.
- US 8314117B2 describes Rimegepant, its analogs and process for preparation thereof.
- the first embodiment of the present invention is to provide amorphous form of Rimegepant sulfate.
- the second embodiment of the present invention is to provide a process for the preparation of amorphous form of Rimegepant sulfate.
- the third embodiment of the present invention is to provide a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
- the fourth embodiment of the present invention is to provide a process for the preparation of solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
- the fifth embodiment of the present invention provides a novel crystalline polymorph of Rimegepant sulfate, herein designated as Form-M.
- the sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate.
- Figure- 1 Illustrates the PXRD (powder X-Ray diffraction) pattern of amorphous form of Rimegepant sulfate
- Figure-2 Illustrates the PXRD pattern of amorphous solid dispersion comprising
- Figure-3 Illustrates the PXRD pattern of amorphous solid dispersion comprising
- Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising
- Figure-5 Illustrates the PXRD pattern of amorphous solid dispersion comprising Rimegepant sulfate and HPC
- Figure-6 Illustrates the PXRD pattern of amorphous solid dispersion comprising
- Figure-7 Illustrates the PXRD pattern of amorphous solid dispersion comprising Rimegepant sulfate and Syloid
- Figure-8 Illustrates the PXRD pattern of amorphous solid dispersion comprising
- Figure-9 Illustrates the PXRD pattern of Rimegepant sulfate crystalline Form-M obtained according to example-9.
- Figure-10 Illustrates the PXRD pattern of Rimegepant sulfate crystalline Form-M obtained according to example- 10.
- the first embodiment of the present invention provides amorphous form of Rimegepant sulfate.
- the amorphous form of Rimegepant sulfate of the present invention is characterized by its PXRD pattern as illustrated in figure- 1.
- the second embodiment of the present invention provides a process for the preparation of amorphous form of Rimegepant sulfate, comprising: a) providing a solution of Rimegepant sulfate in a solvent, b) obtaining amorphous form of Rimegepant sulfate.
- providing a solution of Rimegepant sulfate in a solvent in step-a) can be carried out by combining Rimegepant sulfate with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used.
- the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared.
- the solvent for preparing amorphous form of Rimegepant sulfate by the above process is 2,2,2-trifluoroethanol.
- Obtaining amorphous form of Rimegepant sulfate in step-b) of the above process can be done by removing the solvent from the mixture.
- the technique that is used for the removal of solvent from the mixture is distillation optionally under reduced pressure.
- the Rimegepant sulfate compound of formula- 1 a which is used as input in the above process can be synthesized by any of the processes known in the art.
- the first aspect of the third embodiment of the present invention provides a process for the preparation of amorphous form of Rimegepant sulfate, comprising: a) providing a solution of Rimegepant sulfate in 2,2,2-trifluoroethanol, b) distilling off the solvent from the solution to provide amorphous form of Rimegepant sulfate.
- the third embodiment of the present invention provides a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
- the third embodiment of the present invention further provides amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
- the “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), 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 methyl
- the ratio of the weight of Rimegepant sulfate to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1 :0.05 to about 1:5.
- the fourth embodiment of the present invention provides a process for the preparation of a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Rimegepant sulfate and one or more excipients in a solvent, b) obtaining a solid dispersion comprising amorphous Rimegepant sulfate and the corresponding excipient(s).
- the fourth embodiment of the present invention further provides a process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Rimegepant sulfate and one or more excipients in a solvent, b) obtaining amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient(s).
- Providing a solution of Rimegepant sulfate and excipient(s) in a solvent in step-a) of the above processes can be carried out by combining Rimegepant sulfate and excipient(s) selected from those defined above with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used.
- the excipient that is used in the above process is selected from HPMCAS, copovidone, povidone, HPC, HPMC E3, Syloid & Eudragit.
- the solvent is 2,2,2-trifluoroethanol.
- Obtaining a solid dispersion comprising amorphous Rimegepant sulfate and the corresponding excipient(s) or amorphous solid dispersion comprising Rimegepant sulfate and excipient in step-b) of the above processes can be done by removing the solvent from the mixture.
- the technique that is used for removal of the solvent from the mixture is distillation optionally under reduced pressure.
- the first aspect of the fourth embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more excipient(s), comprising; a) providing a solution of Rimegepant sulfate and the excipient in 2,2,2-trifluoroethanol, b) distilling off the solvent from the solution to provide amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient.
- the excipient in the above process is selected from HPMCAS, copovidone, povidone, HPC, HPMC E3, Syloid & Eudragit.
- the fifth embodiment of the present invention provides a novel crystalline polymorph of Rimegepant sulfate, herein designated as Form-M.
- the crystalline Form-M of Rimegepant sulfate of the present invention is characterized by its PXRD pattern as illustrated in figure-9 or figure- 10.
- the sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a solvent or mixture of solvents, b) obtaining crystalline Form-M of Rimegepant sulfate.
- providing a solution of Rimegepant sulfate in a solvent or mixture of solvents in step-a) can be carried out by combining Rimegepant sulfate with a solvent or mixture of solvents at a temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 100°C based on the solvent used.
- the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared.
- the solvent for preparing crystalline Form-M of Rimegepant sulfate by the above process is methanol: dichloromethane: water mixture.
- Obtaining crystalline Form-M of Rimegepant sulfate in step-b) of the above process can be done by stirring the mixture and then removing the solvent from the mixture.
- the technique that is used for the removal of solvent from the mixture is filtration.
- the first aspect of the sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a mixture of methanol, dichloromethane and water, b) obtaining crystalline Form-M of Rimegepant sulfate.
- the Rimegepant sulfate compound of formula- 1 a which is used as input in the above processes can be synthesized by any of the processes known in the art.
- the Rimegepant sulfate 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 seventh embodiment of the present invention provides the use of any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.
- the eighth embodiment of the present invention provides a pharmaceutical composition comprising any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
- the ninth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a pharmaceutical composition comprising a therapeutically effective amount of any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- 1 a of the present invention.
- the compound of formula- la produced by the processes of the present invention may have particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
- the compound of formula- la may have 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.
- the PXRD analysis of compound of formula- la of the present invention 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.
- Example-1 Preparation of amorphous form of Rimegepant sulfate (Formula-la)
- Example-2 Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPMC AS
- Example-3 Preparation of amorphous solid dispersion comprising Rimegepant sulfate and copovidone
- Example-4 Preparation of amorphous solid dispersion comprising Rimegepant sulfate and povidone
- Example-6 Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPMC E3
- Example-7 Preparation of amorphous solid dispersion comprising Rimegepant sulfate and Syloid
- Example-8 Preparation of amorphous solid dispersion comprising Rimegepant sulfate and Eudragit
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to new solid state forms of (5S,6S,9R)-5-amino-6- (2,3difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro- 1H-imidazo[4,5-b] pyridin-1-yl)-1-piperidinecarboxylate hemisulfate represented by the following structural formula-1a which are useful for the preparation of various pharmaceutical formulations. The present invention further relates to processes for the preparation of new solid state forms of (5S,6S,9R)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b] pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-1- piperidinecarboxylate hemisulfate. Formula-1a
Description
Solid state forms of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-l-yl)-l- piperidinecarboxylate hemisulfate and processes for preparation thereof
Related Applications:
This application claims the benefit of priority of our Indian patent applications 202241014804 filed on March 17, 2022 and 202241072602 filed on December 15, 2022 which are incorporated herein by reference.
Field of the Invention:
The present invention provides new solid state forms of (5S,6S,9R)-5-amino-6- (2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro- lH-imidazo[4,5-b]pyridin-l-yl)-l-piperidinecarboxylate hemisulfate represented by the following structural formula- la and processes for preparation thereof.
Background of the Invention:
(5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b] pyridin-9-yl 4-(2-oxo-2, 3 -dihydro- 1 H-imidazo [4, 5 -b] pyridin- 1 -yl)- 1 -piperidinecarboxylate hemisulfate is commonly known as Rimeg epant sulfate. It is approved by USFDA on Feb 27, 2020 and is being marketed under the brand name NURTEC ODT
NURTEC ODT is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults and preventive treatment of episodic migraine in adults.
US 8314117B2 describes Rimegepant, its analogs and process for preparation thereof.
US8759372B2 describes Rimegepant sulfate and its crystalline polymorphs namely Form Hl.5-1, Form P22C, Form P33, Form P35 and processes for preparation thereof.
Still, there is a need to develop novel solid state forms of Rimegepant sulfate which are suitable for the preparation of various pharmaceutical compositions.
The present inventors after significant efforts have surprisingly found new solid state forms of Rimegepant sulfate which are useful for the preparation of various pharmaceutical compositions.
Brief Description of the Invention:
The first embodiment of the present invention is to provide amorphous form of Rimegepant sulfate.
The second embodiment of the present invention is to provide a process for the preparation of amorphous form of Rimegepant sulfate.
The third embodiment of the present invention is to provide a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
The fourth embodiment of the present invention is to provide a process for the preparation of solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
The fifth embodiment of the present invention provides a novel crystalline polymorph of Rimegepant sulfate, herein designated as Form-M.
The sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate.
Brief Description of the Drawings:
Figure- 1: Illustrates the PXRD (powder X-Ray diffraction) pattern of amorphous form of Rimegepant sulfate
Figure-2: Illustrates the PXRD pattern of amorphous solid dispersion comprising
Rimegepant sulfate and HPMC AS
Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising
Rimegepant sulfate and copovidone
Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising
Rimegepant sulfate and povidone
Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising Rimegepant sulfate and HPC
Figure-6: Illustrates the PXRD pattern of amorphous solid dispersion comprising
Rimegepant sulfate and HPMC E3
Figure-7: Illustrates the PXRD pattern of amorphous solid dispersion comprising Rimegepant sulfate and Syloid
Figure-8: Illustrates the PXRD pattern of amorphous solid dispersion comprising
Rimegepant sulfate and Eudragit
Figure-9: Illustrates the PXRD pattern of Rimegepant sulfate crystalline Form-M obtained according to example-9.
Figure-10: Illustrates the PXRD pattern of Rimegepant sulfate crystalline Form-M obtained according to example- 10.
Detailed Description of the Invention:
The first embodiment of the present invention provides amorphous form of Rimegepant sulfate. The amorphous form of Rimegepant sulfate of the present invention is characterized by its PXRD pattern as illustrated in figure- 1.
The second embodiment of the present invention provides a process for the preparation of amorphous form of Rimegepant sulfate, comprising: a) providing a solution of Rimegepant sulfate in a solvent, b) obtaining amorphous form of Rimegepant sulfate.
In one aspect of the present invention, providing a solution of Rimegepant sulfate in a solvent in step-a) can be carried out by combining Rimegepant sulfate with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used.
In another aspect of the present invention, the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared.
The solvent for preparing amorphous form of Rimegepant sulfate by the above process is 2,2,2-trifluoroethanol.
Obtaining amorphous form of Rimegepant sulfate in step-b) of the above process can be done by removing the solvent from the mixture. The technique that is used for the removal of solvent from the mixture is distillation optionally under reduced pressure.
The Rimegepant sulfate compound of formula- 1 a which is used as input in the above process can be synthesized by any of the processes known in the art.
The first aspect of the third embodiment of the present invention provides a process for the preparation of amorphous form of Rimegepant sulfate, comprising: a) providing a solution of Rimegepant sulfate in 2,2,2-trifluoroethanol, b) distilling off the solvent from the solution to provide amorphous form of Rimegepant sulfate.
The third embodiment of the present invention provides a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
The third embodiment of the present invention further provides amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipients.
The “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), 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 E3, 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 and the like.
In the present invention, the ratio of the weight of Rimegepant sulfate to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1 :0.05 to about 1:5.
The fourth embodiment of the present invention provides a process for the preparation of a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Rimegepant sulfate and one or more excipients in a solvent, b) obtaining a solid dispersion comprising amorphous Rimegepant sulfate and the corresponding excipient(s).
The fourth embodiment of the present invention further provides a process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Rimegepant sulfate and one or more excipients in a solvent, b) obtaining amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient(s).
Providing a solution of Rimegepant sulfate and excipient(s) in a solvent in step-a) of the above processes can be carried out by combining Rimegepant sulfate and excipient(s) selected from those defined above with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used.
The excipient that is used in the above process is selected from HPMCAS, copovidone, povidone, HPC, HPMC E3, Syloid & Eudragit.
The solvent is 2,2,2-trifluoroethanol.
Obtaining a solid dispersion comprising amorphous Rimegepant sulfate and the corresponding excipient(s) or amorphous solid dispersion comprising Rimegepant sulfate and excipient in step-b) of the above processes can be done by removing the solvent from the mixture. The technique that is used for removal of the solvent from the mixture is distillation optionally under reduced pressure.
The first aspect of the fourth embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more excipient(s), comprising; a) providing a solution of Rimegepant sulfate and the excipient in 2,2,2-trifluoroethanol, b) distilling off the solvent from the solution to provide amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient.
The excipient in the above process is selected from HPMCAS, copovidone, povidone, HPC, HPMC E3, Syloid & Eudragit.
The fifth embodiment of the present invention provides a novel crystalline polymorph of Rimegepant sulfate, herein designated as Form-M.
The crystalline Form-M of Rimegepant sulfate of the present invention is characterized by its PXRD pattern as illustrated in figure-9 or figure- 10.
The sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a solvent or mixture of solvents, b) obtaining crystalline Form-M of Rimegepant sulfate.
In one aspect of the present invention, providing a solution of Rimegepant sulfate in a solvent or mixture of solvents in step-a) can be carried out by combining Rimegepant sulfate with a solvent or mixture of solvents at a temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 100°C based on the solvent used.
In another aspect of the present invention, the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared.
The solvent for preparing crystalline Form-M of Rimegepant sulfate by the above process is methanol: dichloromethane: water mixture.
Obtaining crystalline Form-M of Rimegepant sulfate in step-b) of the above process can be done by stirring the mixture and then removing the solvent from the mixture. The technique that is used for the removal of solvent from the mixture is filtration.
The first aspect of the sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a mixture of methanol, dichloromethane and water, b) obtaining crystalline Form-M of Rimegepant sulfate.
The Rimegepant sulfate compound of formula- 1 a which is used as input in the above processes can be synthesized by any of the processes known in the art.
The Rimegepant sulfate 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 seventh embodiment of the present invention provides the use of any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.
The eighth embodiment of the present invention provides a pharmaceutical composition comprising any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
The ninth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a pharmaceutical composition comprising a therapeutically effective amount of any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- 1 a of the present invention.
The compound of formula- la produced by the processes of the present invention may have 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 compound of formula- la may have 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:
The PXRD analysis of compound of formula- la of the present invention 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.
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 Rimegepant sulfate (Formula-la)
A mixture of Rimegepant sulfate (0.5 gm) and 2,2,2-trifluoroethanol (60 ml) was stirred for 15 min at 25-30°C. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure- 1. Yield: 425 mg.
Example-2: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPMC AS
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. HPMC AS (200 mg) was added to the solution at 25-30°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 298 mg.
Example-3: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and copovidone
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Copovidone (200 mg) was added to the solution at 25-30°C and stirred the mixture for 15 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 350 mg.
Example-4: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and povidone
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Povidone (200 mg) was added to the solution at 25-30°C and stirred for 15 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-4. Yield: 375 mg.
Example-5: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPC
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 20 min at 25-30°C. HPC (200 mg) was added to the solution at 25-30°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 313 mg.
Example-6: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPMC E3
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 30 min at 25-30°C. HPMC E3 (200 mg) was added to the solution at 25-30°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-6. Yield: 328 mg.
Example-7: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and Syloid
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Syloid (200 mg) was added to the solution at 25-30°C and stirred for 5 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-7. Yield: 348 mg.
Example-8: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and Eudragit
A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Eudragit (200 mg) was added to the solution at 25-30°C and stirred for 10 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-8. Yield: 360 mg.
Example-9: Preparation of crystalline Form-M of compound of formula-la
Methanol: dichloromethane: water (37.5 ml; 1:1:1) mixture was added to Rimegepant sulfate (500 mg) at 25-30°C. Heated the mixture to 80-85°C and stirred for 2 hr at the same temperature. Filtered the solid and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-9. Yield: 300 mg.
Example-10: Preparation of crystalline Form-M of compound of formula-la
Methanol: dichloromethane: water (112.5 ml; 1: 1:1) mixture was added to Rimegepant sulfate (1.5 gm) at 25-30°C. Heated the mixture to 80-85°C and stirred for 5 hr at the same temperature. Filtered the solid and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure- 10. Yield: 0.95 gm.
Claims
1. Amorphous form of Rimegepant sulfate.
2. Amorphous form of Rimegepant sulfate according to claim 1 , which is characterized by its PXRD pattern as illustrated in figure- 1.
3. A process for the preparation of amorphous form of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a solvent, b) obtaining amorphous form of Rimegepant sulfate.
4. The process according to claim 3, wherein providing a solution of Rimegepant sulfate in a solvent in step-a) can be carried out by combining Rimegepant sulfate with a solvent at a temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used; or the solution can also be obtained directly from the synthetic process in which Rimegepant sulfate is prepared.
5. The process according to claim 3, wherein the solvent is 2,2,2-trifluoroethanol.
6. The process according to claim 3, wherein obtaining amorphous form of Rimegepant sulfate in step-b) can be done by removing the solvent from the mixture by distillation optionally under reduced pressure.
7. Amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipient(s).
8. The amorphous solid dispersion according to claim 7, wherein the excipient is selected from polyvinylpyrrolidone (povidone or PVP), 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 E3, hydroxy ethyl 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. A process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipient(s) according to claims 7 and 8, comprising; a) providing a solution of Rimegepant sulfate and one or more excipient(s) in a solvent, b) obtaining amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient(s). The process according to claim 9, wherein providing a solution of Rimegepant sulfate and excipient(s) in a solvent can be carried out by combining Rimegepant sulfate and excipient(s) with a solvent at a temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on solvent used.
The process according to claim 9, wherein, the solvent is 2,2,2-trifluoroethanol; and obtaining the solid dispersion in step-b) can be done by removing the solvent from the mixture by distillation optionally under reduced pressure. Crystalline Form-M of Rimegepant sulfate characterized by its PXRD pattern as illustrated in figure-9 or figure- 10. A process for the preparation of crystalline Form-M of Rimegepant sulfate characterized by its PXRD pattern as illustrated in figure-9 or figure- 10, comprising; a) providing a solution of Rimegepant sulfate in a solvent or mixture of solvents, b) obtaining crystalline Form-M of Rimegepant sulfate. The process according to claim 13, wherein providing a solution of Rimegepant sulfate in a solvent or mixture of solvents in step-a) can be carried out by combining Rimegepant sulfate with a solvent or mixture of solvents at a temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 100°C based on the solvent used or the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared. The process according to claims 13 and 14, wherein the solvent is a mixture of methanol, dichloromethane and water. The process according to claim 13, wherein obtaining crystalline Form-M of Rimegepant sulfate in step-b) can be done by stirring the mixture and then removing the solvent from the mixture by filtration. Use of amorphous form of Rimegepant sulfate for the preparation of pharmaceutical formulations. Use of crystalline form-M of Rimegepant sulfate of claim 12 for the preparation of pharmaceutical formulations.
Pharmaceutical composition comprising amorphous form of Rimegepant sulfate and at least one pharmaceutically acceptable excipient. Pharmaceutical composition comprising crystalline form-M of Rimegepant sulfate of claim 12 and at least one pharmaceutically acceptable excipient. A method of treating a patient in need thereof comprising administering to the said patient a pharmaceutical composition comprising a therapeutically effective amount of amorphous form of Rimegepant sulfate. A method of treating a patient in need thereof comprising administering to the said patient a pharmaceutical composition comprising a therapeutically effective amount of crystalline form-M of Rimegepant sulfate of claim 12.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202241014804 | 2022-03-17 | ||
| IN202241014804 | 2022-03-17 | ||
| IN202241072602 | 2022-12-15 | ||
| IN202241072602 | 2022-12-15 |
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| Publication Number | Publication Date |
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| WO2023175632A1 true WO2023175632A1 (en) | 2023-09-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2023/050256 WO2023175632A1 (en) | 2022-03-17 | 2023-03-17 | Solid state forms of (5s,6s,9r)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate and processes for preparation thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8759372B2 (en) * | 2012-02-27 | 2014-06-24 | Bristol-Myers Squibb Company | N-(5S,6S,9R)-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-ctclohepta[b]Pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-carboxylate salt |
| CA3172358A1 (en) * | 2020-02-27 | 2021-09-02 | Biohaven Pharmaceutical Holding Company Ltd. | Oral fast-dispersing dosage form of rimegepant |
-
2023
- 2023-03-17 WO PCT/IN2023/050256 patent/WO2023175632A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8759372B2 (en) * | 2012-02-27 | 2014-06-24 | Bristol-Myers Squibb Company | N-(5S,6S,9R)-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-ctclohepta[b]Pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-carboxylate salt |
| CA3172358A1 (en) * | 2020-02-27 | 2021-09-02 | Biohaven Pharmaceutical Holding Company Ltd. | Oral fast-dispersing dosage form of rimegepant |
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