WO2025146702A1 - Solid state forms of 1-{(2s,5r)-2-methyl-5-[(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino] piperidine-1-yl}prop-2-en-1-one 4-methylbenzene-1-sulfonic acid - Google Patents
Solid state forms of 1-{(2s,5r)-2-methyl-5-[(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino] piperidine-1-yl}prop-2-en-1-one 4-methylbenzene-1-sulfonic acid Download PDFInfo
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- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- 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
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- the present invention relates to a solid state forms of l- ⁇ (2S,5R)-2-Methyl-5-[(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-l-yl ⁇ prop-2-en-l-one 4-methylbenzene-l- sulfonic acid, which is referred to as Ritlecitinib tosylate and represented by the following structural formula- 1.
- the present invention also provides a process for the preparation of solid state forms of Ritlecitinib tosylate.
- Ritlecitinib is a highly selective and orally bioavailable Janus Kinase 3 (JAK3) inhibitor that represents a potential immunomodulatory therapy. With the favorable efficacy, safety profile and ADME properties, this JAK3 -specific covalent inhibitor has been under clinical investigation for the treatment of alopecia areata, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.
- JAK3 Janus Kinase 3
- Ritlecitinib tosylate is approved in the USFDA and Europe for the treatment severe alopecia areata in adults and adolescents 12 years and older.
- Ritlecitinib tosylate is being marketed by Pfizer under the brand name Litfulo.
- US9617258 B2 discloses Ritlecitinib or a pharmaceutically acceptable salt. This patent also discloses a process for the preparation of Ritlecitinib.
- US20210387989 Al discloses Ritlecitinib tosylate and process for its preparation. US’989 also discloses crystalline form-I of Ritlecitinib tosylate and process for its preparation.
- Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
- Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
- solid dispersion refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer.
- solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way.
- the two or more components form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
- the suitable pharmaceutically acceptable excipient used in step-a) is same as defined in the fourth embodiment.
- Ritlecitinib tosylate (200.0 mg) was dissolved in methanol (10.0 ml) at 25-30°C and stirred for 15 minutes. Filtered the mixture to make it particle free. To the obtained mixture was added to HPC (200.0 mg) at 25-30°C and stirred for 10 minutes. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound.
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Abstract
The present invention relates to a solid state forms of 1-{(2S,5R)-2-Methyl-5-[(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-yl}prop-2-en-1-one 4-methylbenzene-1- sulfonic acid, which is referred to as Ritlecitinib tosylate and represented by the following structural formula-1, Formula-1 The present invention also relates to a process for the preparation of solid state forms of 1-{(2S,5R)-2-Methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-yl}prop-2- en-1-one 4-methylbenzene-1-sulfonic acid.
Description
Solid state forms of l- (2S,5R)-2-Methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]
piperidine-l-vnprop-2-en-l-one 4-methylbenzene-l-sulfonic acid
Related Application:
This application claims the benefit of priority of our Indian patent application number 202441000495 filed on 03rd January 2024 which is incorporated herein by reference.
Field of the invention:
The present invention relates to a solid state forms of l-{(2S,5R)-2-Methyl-5-[(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-l-yl}prop-2-en-l-one 4-methylbenzene-l- sulfonic acid, which is referred to as Ritlecitinib tosylate and represented by the following structural formula- 1.
The present invention also provides a process for the preparation of solid state forms of Ritlecitinib tosylate.
Background of the invention:
Ritlecitinib is a highly selective and orally bioavailable Janus Kinase 3 (JAK3) inhibitor that represents a potential immunomodulatory therapy. With the favorable efficacy, safety profile and ADME properties, this JAK3 -specific covalent inhibitor has been under clinical investigation for the treatment of alopecia areata, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.
Ritlecitinib tosylate is approved in the USFDA and Europe for the treatment severe alopecia areata in adults and adolescents 12 years and older. Ritlecitinib tosylate is being marketed by Pfizer under the brand name Litfulo.
US9617258 B2 discloses Ritlecitinib or a pharmaceutically acceptable salt. This patent also discloses a process for the preparation of Ritlecitinib.
US20210387989 Al discloses Ritlecitinib tosylate and process for its preparation. US’989 also discloses crystalline form-I of Ritlecitinib tosylate and process for its preparation.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
Brief description of the invention:
The present invention relates to solid state forms of Ritlecitinib tosylate and process for its preparation.
Brief description of the Drawings:
Figure- 1: Illustrates the PXRD pattern of amorphous form of Ritlecitinib tosylate.
Figure-2: Illustrates the PXRD pattern of solid dispersion of Ritlecitinib tosylate with povidone-K30.
Figure-3: Illustrates the PXRD pattern of solid dispersion of Ritlecitinib tosylate with HPMC-E5.
Figure-4: Illustrates the PXRD pattern of solid dispersion of Ritlecitinib tosylate with HPMC-AS.
Figure-5: Illustrates the PXRD pattern of solid dispersion of Ritlecitinib tosylate with HPC. Figure-6: Illustrates the PXRD pattern of solid dispersion of Ritlecitinib tosylate with MCC.
Detailed description of the Invention:
As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2- methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3 -pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.
As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.
In the present application, solid dispersion and premix are used interchangeably to describe solid state disclosed herein.
In the first embodiment, the present invention provides an amorphous form of Ritlecitinib tosylate.
In an aspect of the first embodiment, the present invention provides an amorphous form of Ritlecitinib tosylate, which is storage stable.
In the second embodiment, the present invention provides a process for the preparation of amorphous form of Ritlecitinib tosylate, which comprises: a) providing a solution of Ritlecitinib tosylate in a solvent or mixture of solvents; and b) isolating the amorphous form of Ritlecitinib tosylate.
In the third embodiment, the present invention provides a process for the preparation of amorphous form of Ritlecitinib tosylate, which comprises: a) providing a mixture of Ritlecitinib freebase and para toluene sulfonic acid in a solvent or mixture of solvents; and b) isolating the amorphous form of Ritlecitinib tosylate.
In the process of the second and third embodiments, providing a solution of Ritlecitinib tosylate or Ritlecitinib freebase in step-a) comprises dissolving Ritlecitinib tosylate in a suitable solvent at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of second and third embodiments, the suitable solvent used in step-a) is selected from ester solvent, ether solvent, alcohol solvent, ketone solvent, nitrile solvent, polar-aprotic solvents, chloro solvent, hydrocarbon solvent, water or mixtures thereof.
The term “storage stable” includes amorphous Ritlecitinib tosylate that does not convert to any other solid form when stored at a temperature for example 2°C to 8°C and at a relative humidity of about 30 % to about 50 % for about twelve months or more.
The amorphous Ritlecitinib tosylate of the present invention is stable at different solvent treatments at different temperature conditions, below is the tabular representation for the same:
The amorphous Ritlecitinib tosylate of the present invention is also stable under below Polymorphic stress study conditions:
In the fourth embodiment, the present invention provides a solid dispersion of
Ritlecitinib tosylate with one or more pharmaceutically acceptable excipients.
In the fourth embodiment, the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone,
crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, 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, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose 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 and the like.
In the fifth embodiment, the present invention provides a process for the preparation of solid dispersion of Ritlecitinib tosylate with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients in a solvent or mixture of solvents; and b) isolating the solid dispersion of Ritlecitinib tosylate with one or more pharmaceutically acceptable excipients.
In the process of the fifth embodiment, providing a solution of Ritlecitinib tosylate in step-a) comprises dissolving Ritlecitinib tosylate in a suitable solvent at a suitable
temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of the fifth embodiment, further adding one or more pharmaceutically acceptable excipients to the obtained solution at a suitable temperature of about 25°C and above.
In the process of fifth embodiment, the suitable solvent used in step-a) is selected from alcohol solvents.
In the process of fifth embodiment, the suitable pharmaceutically acceptable excipient used in step-a) is same as defined in the fourth embodiment.
In the first aspect of the fifth embodiment, the present invention provides a process for the preparation of solid dispersion of Ritlecitinib tosylate with povidone-K30, which comprises: a) providing a solution comprising Ritlecitinib tosylate and povidone-K30; and b) isolating the solid dispersion of Ritlecitinib tosylate with povidone-K30.
In the process of the first aspect of fifth embodiment, providing a solution of Ritlecitinib tosylate in step-a) comprises dissolving Ritlecitinib tosylate in methanol at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of the first aspect of fifth embodiment, further adding povidone-K30 to the obtained solution or adding the obtained solution to povidone-K30 at a suitable temperature of about 25°C and above.
In the second aspect of the fifth embodiment, the present invention provides a process for the preparation of solid dispersion of Ritlecitinib tosylate with HPMC-E5, which comprises: a) providing a solution comprising Ritlecitinib tosylate and HPMC-E5; and b) isolating the solid dispersion of Ritlecitinib tosylate with HPMC-E5.
In the process of the second aspect of fifth embodiment, providing a solution of Ritlecitinib tosylate in step-a) comprises dissolving Ritlecitinib tosylate in methanol at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of the second aspect of fifth embodiment, further adding HPMC-E5 to the obtained solution or adding the obtained solution to HPMC-E5 at a suitable temperature of about 25°C and above.
In the third aspect of the fifth embodiment, the present invention provides a process for the preparation of solid dispersion of Ritlecitinib tosylate with HPMC-AS, which comprises: a) providing a solution comprising Ritlecitinib tosylate and HPMC-AS; and b) isolating the solid dispersion of Ritlecitinib tosylate with HPMC-AS.
In the process of the third aspect of fifth embodiment, providing a solution of Ritlecitinib tosylate in step-a) comprises dissolving Ritlecitinib tosylate in methanol at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of the third aspect of fifth embodiment, further adding HPMC-AS to the obtained solution or adding the obtained solution to HPMC-AS at a suitable temperature of about 25°C and above.
In the fourth aspect of the fifth embodiment, the present invention provides a process for the preparation of solid dispersion of Ritlecitinib tosylate with HPC, which comprises: a) providing a solution comprising Ritlecitinib tosylate and HPC; and b) isolating the solid dispersion of Ritlecitinib tosylate with HPC.
In the process of the fourth aspect of fifth embodiment, providing a solution of Ritlecitinib tosylate in step-a) comprises dissolving Ritlecitinib tosylate in methanol at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of the fourth aspect of fifth embodiment, further adding HPC to the obtained solution or adding the obtained solution to HPC at a suitable temperature of about 25°C and above.
In the fifth aspect of the fifth embodiment, the present invention provides a process for the preparation of solid dispersion of Ritlecitinib tosylate with MCC, which comprises: a) providing a solution comprising Ritlecitinib tosylate and MCC; and
b) isolating the solid dispersion of Ritlecitinib tosylate with MCC.
In the process of the fifth aspect of fifth embodiment, providing a solution of Ritlecitinib tosylate in step-a) comprises dissolving Ritlecitinib tosylate in methanol at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of the fifth aspect of fifth embodiment, further adding MCC to the obtained solution or adding the obtained solution to MCC at a suitable temperature of about 25°C and above.
In another embodiment, solid dispersion of Ritlecitinib tosylate comprises, Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient(s) present in weight ratios ranging from about 0.5: 99.5 to about 99.5 : 0.5. Preferably, the ratio is about 50: 50.
In the process of present invention, isolating amorphous form or solid dispersion of Ritlecitinib tosylate involves removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art.
In the process of the present invention, drying amorphous form or solid dispersion of Ritlecitinib tosylate by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
Amorphous form or solid dispersion of Ritlecitinib tosylate prepared according to the present invention can be further micronized or milled in conventional techniques to get the 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 include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
In the present invention, the starting material of Ritlecitinib tosylate can be used in the form of amorphous or crystalline or any other physical form with the process prepared from present invention or any of the processes known in the art.
In the present invention, pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.
In the process of the present invention the resulting, solid dispersion of Ritlecitinib tosylate can be amorphous, crystalline or a mixture thereof.
In an embodiment, pharmaceutical composition comprising amorphous form of Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.
In yet another embodiment, pharmaceutical composition comprising solid dispersion of Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.
As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis:
PXRD analysis of compound of formula- 1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example- 1: Preparation of amorphous form of Ritlecitinib tosylate.
Ritlecitinib tosylate (500.0 mg) was dissolved in methanol (20.0 ml) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound.
Yield: 420.0 mg; The PXRD pattern of the obtained compound is illustrated in figure- 1.
Example-2: Preparation of solid dispersion of Ritlecitinib tosylate with povidone-K30.
Ritlecitinib tosylate (200.0 mg) was dissolved in methanol (10.0 ml) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. Povidone-K30 (200.0 mg) was added to the mixture at 25-30°C and stirred for 15 minutes. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound.
Yield: 330.0 mg; The PXRD pattern of the obtained compound is illustrated in figure-2.
Example-3: Preparation of solid dispersion of Ritlecitinib tosylate with HPMC-E5.
Ritlecitinib tosylate (200.0 mg) was dissolved in methanol (10.0 ml) at 25-30°C and stirred for 15 minutes. Filtered the mixture to make it particle free. HPMC-E5 (200.0 mg) was added to the mixture at 25-30°C and stirred for 20 minutes. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound.
Yield: 320.0 mg; The PXRD pattern of the obtained compound is illustrated in figure-3.
Example-4: Preparation of solid dispersion of Ritlecitinib tosylate with HPMC-AS.
Ritlecitinib tosylate (200.0 mg) was dissolved in methanol (10.0 ml) at 25-30°C and stirred for 15 minutes. Filtered the mixture to make it particle free. To the obtained mixture was added to HPMC-AS (200.0 mg) at 25-30°C and stirred for 10 minutes. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound. Yield: 332.0 mg; The PXRD pattern of the obtained compound is illustrated in figure-4.
Example-5: Preparation of solid dispersion of Ritlecitinib tosylate with HPC.
Ritlecitinib tosylate (200.0 mg) was dissolved in methanol (10.0 ml) at 25-30°C and stirred for 15 minutes. Filtered the mixture to make it particle free. To the obtained mixture was added to HPC (200.0 mg) at 25-30°C and stirred for 10 minutes. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound.
Yield: 328.0 mg; The PXRD pattern of the obtained compound is illustrated in figure-5.
Example-6: Preparation of solid dispersion of Ritlecitinib tosylate with MCC.
Ritlecitinib tosylate (200.0 mg) was dissolved in methanol (10.0 ml) at 25-30°C and stirred for 15 minutes. Filtered the mixture to make it particle free. MCC (200.0 mg) was added to the mixture at 25-30°C. Distilled off the solvent completely from the mixture at 50°C under vacuum to get the title compound. Yield: 319.0 mg.
The PXRD pattern of the obtained compound is illustrated in figure-6.
Example-7: Preparation of amorphous form of Ritlecitinib tosylate.
Ritlecitinib (300 mg) and para toluene sulfonic acid (181 mg) were dissolved in methanol (30 ml) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture to get the title compound. Yield: 325 mg; The PXRD pattern of the obtained compound is illustrated in figure- 1.
Claims
1. An amorphous form of Ritlecitinib tosylate of formula- 1
2. The amorphous form of Ritlecitinib tosylate as claimed in claim- 1, which is storage stable.
3. The amorphous form of Ritlecitinib tosylate as claimed in claim- 1, characterized by powdered X-ray diffraction pattern as illustrated in figure- 1.
4. A process for the preparation of amorphous Ritlecitinib tosylate, which comprises; a) providing a solution of Ritlecitinib tosylate in a solvent or mixture of solvents, b) isolating amorphous form of Ritlecitinib tosylate.
5. A process for the preparation of amorphous Ritlecitinib tosylate, which comprises; a) providing a mixture of Ritlecitinib freebase and para toluene sulfonic acid in a solvent or mixture of solvents, b) isolating amorphous form of Ritlecitinib tosylate.
6. The process as claimed in claims 4 and 5, wherein the solvent in step-a) is selected from ester solvent, ether solvent, alcohol solvent, ketone solvent, nitrile solvent, polar- aprotic solvents, chloro solvent, hydrocarbon solvent, water or mixtures thereof.
7. A solid dispersion of Ritlecitinib tosylate with one or more pharmaceutically acceptable excipients.
8. A process for the preparation of solid dispersion of Ritlecitinib tosylate with one or more pharmaceutically acceptable excipients, which comprises; a) providing a solution comprising of Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients in a solvent or mixture of solvents, b) isolating the solid dispersion of Ritlecitinib tosylate with one or more pharmaceutically acceptable excipients.
9. The solid dispersion of Ritlecitinib tosylate as claimed in claims 7 and 8, wherein the pharmaceutically acceptable excipient is selected from the group comprising of syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K- 60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone,
polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macro gol 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, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC- AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC) or its mixture thereof.
10. The solid dispersion of Ritlecitinib tosylate as claimed in claims 7 and 8, wherein the ratio of Ritlecitinib tosylate and pharmaceutically acceptable excipient(s) is about 0.5:99.5 to about 99.5:0.5.
11. The solid dispersion of Ritlecitinib tosylate as claimed in claims 7 and 8, wherein the solid dispersion of Ritlecitinib tosylate is in the amorphous form.
12. The process as claimed in claim 8, wherein the solvent in step-a) is selected from ester solvent, ether solvent, alcohol solvent, ketone solvent, nitrile solvent, polar-aprotic solvents, chloro solvent, hydrocarbon solvent, water or mixtures thereof.
13. The solid dispersion of Ritlecitinib tosylate as claimed in claim 8, wherein the pharmaceutically acceptable excipient is povidone-K30.
14. The solid dispersion of Ritlecitinib tosylate as claimed in claim 13, characterized by powdered X-ray diffraction pattern as illustrated in figure-2.
15. The solid dispersion of Ritlecitinib tosylate as claimed in claim 8, wherein the pharmaceutically acceptable excipient is HMPC-E5.
16. The solid dispersion of Ritlecitinib tosylate as claimed in claim 15, characterized by powdered X-ray diffraction pattern as illustrated in figure-3.
17. The solid dispersion of Ritlecitinib tosylate as claimed in claim 8, wherein the pharmaceutically acceptable excipient is HPMC -AS.
18. The solid dispersion of Ritlecitinib tosylate as claimed in claim 17, characterized by powdered X-ray diffraction pattern as illustrated in figure-4.
19. The solid dispersion of Ritlecitinib tosylate as claimed in claim 8, wherein the pharmaceutically acceptable excipient is HPC.
20. The solid dispersion of Ritlecitinib tosylate as claimed in claim 19, characterized by powdered X-ray diffraction pattern as illustrated in figure-5.
21. The solid dispersion of Ritlecitinib tosylate as claimed in claim 8, wherein the pharmaceutically acceptable excipient is MCC.
22. The solid dispersion of Ritlecitinib tosylate as claimed in claim 21, characterized by powdered X-ray diffraction pattern as illustrated in figure-6.
23. A pharmaceutical composition comprising amorphous Ritlecitinib tosylate as claimed in any of preceding claims and a pharmaceutically acceptable carrier or excipient.
24. A pharmaceutical composition comprising solid dispersion of Ritlecitinib tosylate as claimed in any of preceding claims and a pharmaceutically acceptable carrier or excipient.
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| WO2005117837A1 (en) * | 2004-06-01 | 2005-12-15 | Teva Gyógyszergyár Zàrtköruen Muködo Rèszvènytàrsasàg | Process for preparation of amorphous form of a drug |
| US9617258B2 (en) * | 2013-12-05 | 2017-04-11 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| IN201641008939A (en) * | 2016-03-15 | 2017-09-22 | ||
| WO2020084435A1 (en) * | 2018-10-22 | 2020-04-30 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine tosylate salt, crystalline form thereof and manufacturing process and intermediates thereto |
| WO2021108616A1 (en) * | 2019-11-27 | 2021-06-03 | Dot Therapeutics-1, Inc. | Solid dispersion of pan-raf kinase inhibitor |
| IN202341055410A (en) * | 2023-08-18 | 2025-02-21 |
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2025
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| WO2005117837A1 (en) * | 2004-06-01 | 2005-12-15 | Teva Gyógyszergyár Zàrtköruen Muködo Rèszvènytàrsasàg | Process for preparation of amorphous form of a drug |
| US9617258B2 (en) * | 2013-12-05 | 2017-04-11 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| IN201641008939A (en) * | 2016-03-15 | 2017-09-22 | ||
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| WO2021108616A1 (en) * | 2019-11-27 | 2021-06-03 | Dot Therapeutics-1, Inc. | Solid dispersion of pan-raf kinase inhibitor |
| IN202341055410A (en) * | 2023-08-18 | 2025-02-21 |
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