DESC:RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 202421023634 filed on Mar. 22, 2024 and Indian Provisional Patent Application No. 202421031118 filed on Apr. 17, 2024.
FIELD OF THE INVENTION:
The present invention relates to a solid form of acid addition salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate. More particularly, the invention relates to crystalline form of the fumarate salt of Ritlecitinib and process of preparation thereof. Further, the invention relates to the amorphous form of Ritlecitinib tosylate and the solid dispersion of Ritlecitinib tosylate.
BACKGROUND OF THE INVENTION:
LITFULO also known as Ritlecitinib tosylate approved by FDA on Jun. 23, 2023 has a chemical name 1-{(2S,5R)-2-Methyl-5-[(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino] piperidin-1-yl}prop-2-en-1-one 4-methylbenzene-1-sulfonicacid. Ritlecitinib tosylate is represented by the following chemical structure according to Formula (I).

Formula I
Ritlecitinib tosylate is a highly selective oral bioavailable Janus kinase 3 (JAK3) inhibitor developed by Pfizer, which represents a potential immune modulatory treatment. Due to its good efficacy, safety and ADME properties, this JAK3-specific covalent inhibitor has been used in the treatment of alopecia areata, rheumatoid arthritis, crohn's disease and ulcerative colitis. On September 5, 2018, the FDA granted PF-06651600 "breakthrough therapy" status for the treatment of alopecia areata, supported by positive results from a Phase 2 study.
US20210387989 discloses tosylate, phosphate and malonate salts of Ritlecitinib (PF-06651600) particularly in crystalline form.
US20230338380 discloses stable immediate release formulation of Ritlecitinib having dimer impurity and degradant.
Org. Process Res. Dev.2019, 23, 1872-1880: Process Development and scale up of a Selective JAK3Covalent Inhibitor PF-06651600, patent WO2020084435A1 both reported that PF-06651600 free base is not suitable for pharmaceutical synthesis due to poor stability and poor solubility.
CN111620880B discloses crystalline form of the DL-tartrate salt of Ritlecitinib. CN111620879B discloses crystalline form of the maleic acid salt of Ritlecitinib. WO2022012587 discloses crystal form A and Form B of malonate salt of Ritlecitinib.
Different salts and solid-state forms of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid-state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life.
Considering the importance of Ritlecitinib and its salts in the pharmaceutical field, there always remains a need for obtaining different solid forms of Ritlecitinib and its salts with properties such as improved stability, desired solubility and reduced hygroscopicity.
Accordingly, the discovery of novel acid addition salt of Ritlecitinib that exhibit these desired properties remains vital for drug development. Thus, the present disclosure describes different solid forms of acid addition salt of Ritlecitinib that may be used in pharmaceutical compositions.
SUMMARY OF THE INVENTION:
In an aspect, the present invention relates to solid form of an acid addition salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
In an aspect, the present invention provides either amorphous form or in crystalline form of an acid addition of salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
In an aspect, the present invention relates to a process for the preparation of an acid addition salt of Ritlecitinib comprising contacting the Ritlecitinib with suitable acid in the presence of a solvent and isolating the acid addition salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
In another aspect, the present invention relates to crystalline form of Fumarate salt of Ritlecitinib.
In another aspect, the present invention relates to crystalline form of fumarate salt of Ritlecitinib characterized by a powder X-ray diffraction pattern comprising peaks, in terms of 2?, having peaks at 6.27°, 11.64°, 14.19°, 17.05°, 19.64° and 24.87 ± 0.2 ° degrees 2-theta.
In further aspect, the present invention relates to a process for the preparation of crystalline form of Ritlecitinib fumarate, which comprises,
a. providing a solution comprising Ritlecitinib fumarate in one or more solvent(s); and
b. isolating the crystalline form of Ritlecitinib fumarate.
In further aspect, the present invention relates to a pharmaceutical composition comprising a Ritlecitinib fumarate and at least one pharmaceutically acceptable excipient.
In another aspect, the present invention also relates to a process for the preparation of amorphous form of Ritlecitinib tosylate comprising evaporating the solvent from the solution of Ritlecitinib tosylate at a temperature in the range of 0°C to 35 °C.
In another aspect, the present invention relates to a process for the preparation of an amorphous solid dispersion of acid addition salt of Ritlecitinib comprising evaporating the solvent from a solution of the Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients at a temperature in the range of 0°C to 35 °C, wherein the acid addition salt is selected from group consisting tosylate, oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
BRIEF DESCRIPTION OF THE DRAWINGS:
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of crystalline form of Ritlecitinib fumarate.
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of amorphous form of Ritlecitinib fumarate.
Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of amorphous form of Ritlecitinib tosylate.
DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment of the present invention relates to an acid addition salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
In an embodiment of the present invention provides either amorphous form or in crystalline form of an acid addition of salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
As used herein and unless otherwise specified, the term “crystal form(s)” and related terms refer to solid forms that are crystalline. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous forms and/or other crystal forms on a weight basis. In certain embodiments, a crystal form of a substance may be physically and/or chemically pure.
In certain embodiments, an acid addition salt of Ritlecitinib, may be about 99.9%, 99.5%, 99% 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or chemically pure.
In an embodiment, the present invention relates to a process for the preparation of an acid addition salt of Ritlecitinib comprising contacting the Ritlecitinib with suitable acid in the presence of solvent and isolating the acid addition salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
In an embodiment of the invention, contacting the Ritlecitinib with suitable acid in the presence of solvent and isolating the acid addition salt is carried out at a temperature in the range of 5 oC to 35 oC, preferably below 30 oC.
In an embodiment, the suitable solvent is selected from group comprising methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol, dichloromethane, 1,2-dichloroethane, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, di-isopropyl ether, methyl tert-butyl ether. 1 ,4-dioxane, toluene, xylene, acetonitrile, propionitrile, water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide or its mixture thereof.
In an embodiment of the present invention relates to a crystalline form of the Fumarate salt of Ritlecitinib.
In an embodiment of the present invention, the crystalline form of Ritlecitinib fumarate contains Ritlecitinib and fumaric acid in molar ratios ranging from 1:0.4 to 1:3. It may exist as Ritlecitinib hemifumarate; Ritlecitinib monofumarate or Ritlecitinib difumarate.
In another embodiment of the present invention, crystalline form of Ritlecitinib fumarate is characterized by a powder X-ray diffraction pattern comprising peaks, in terms of 2?, having peaks at 6.27°, 11.64°, 14.19°, 17.05°, 19.64° and 24.87 ± 0.2 ° degrees 2-theta.
In still another preferred embodiment, crystalline Form of Ritlecitinib fumarate is further characterized by its X-ray powder diffraction pattern peaks at about 3.94°, 6.27°, 6.79°, 7.75°, 8.38°, 9.16°, 9.80°, 10.56°, 11.64°, 12.49°, 14.19°, 14.80°, 15.17°, 16.16°, 16.62°, 17.05°, 17.64°, 17.80°, 18.43°, 18.79°, 19.64°, 19.95°, 20.29°, 20.73°, 21.14°, 21.74°, 22.16°, 22.81°, 23.79°, 24.87°, 25.62° and 26.61± 0.2 ° degree two theta.
In still another preferred embodiment, crystalline Form of Ritlecitinib fumarate obtained according to present invention process is characterized by PXRD pattern as shown in Fig-1.
In still another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Ritlecitinib fumarate, which comprises,
a) providing a solution comprising Ritlecitinib fumarate in one or more solvent(s);
b) isolating the crystalline form of Ritlecitinib fumarate.
In an embodiment of the invention, step (a) and step (b) is carried out at a temperature in the range of 0°C to 35 °C and stirring the reaction mixture for about 5 to 25 hours before isolation of the product.
In an embodiment of the invention, providing a solution comprising Ritlecitinib fumarate as in step (a) includes direct use of a reaction mixture containing Ritlecitinib fumarate that is obtained in the course of its synthesis or dissolving Ritlecitinib fumarate in a suitable solvent(s) or mixing of Ritlecitinib base and fumaric acid in a suitable solvent(s).
In an embodiment of the invention, the solution comprising Ritlecitinib fumarate in step (a) may be prepared or maintained or dissolved at a temperature ranging from about 0°C to the reflux temperature of the solvent(s) used and more preferably at a temperature ranging from about 0°C to about 35°C.
In another embodiment of the invention, isolation of the Ritlecitinib fumarate in step (b) involves removing the solvent(s) from the solution obtained in step (a) or adding a suitable anti-solvent(s) to the solution obtained in step (a) or cooling the solution to an appropriate temperature, thereby resulting in the formation of Ritlecitinib fumarate.
The suitable techniques that can be used in step (b) for the removal of solvent(s) include but not limited to distillation, distillation under vacuum, evaporation, flash evaporation, simple evaporation, rotational drying or any other suitable technique known in the art.
The removal of the solvent(s) can be carried out at temperature lower than 50oC, more preferably lower than 35oC.
Accordingly, the evaporation is carried out by suitable method known herewith or in the art and after complete/partial evaporation, suitable anti solvent(s) such as methyl tert-butyl ether, cyclohexane, hexane, heptane, isopropyl ether and the like is added and stirred to get the crystalline form of Ritlecitinib fumarate. After adding a suitable anti-solvent(s) stirring is carried out for 5 to 25 hours.
The isolation of Ritlecitinib fumarate can also be carried out by employing any of the techniques as described herein or known in the art which include, but not limited to decantation, trituration followed by filtration by gravity or suction, evaporation of the solvent(s), concentrating the solution centrifugation, filtration and the like, and optionally washing with a solvent(s). The drying may be carried at normal pressure or under reduced pressure.
The amorphous form of Ritlecitinib fumarate obtained according to present invention process is characterized by PXRD pattern as shown in Fig-2.
The suitable solvent(s) that can be used in step (a) are those that can dissolve the Ritlecitinib fumarate, either alone or in combination with other solvents, and include, but are not limited to, and solvents selected from group comprising methanol, ethanol, isopropyl alcohol (IPA), n-propanol, 2-butanol, dichloromethane, 1 ,2-dichloroethane, acetone, ethyl methyl ketone (2-butanone), methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, di-isopropyl ether, methyl tert-butyl ether. 1 ,4-dioxane, toluene, xylene, acetonitrile, propionitrile, water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide or its mixture thereof. Preferable solvent include, but not limited to, methanol, ethanol, acetone, 2-butanone and the like.
In an embodiment, the present invention provides crystalline form of the fumarate salt of Ritlecitinib having purity of greater than 99% and more preferably greater than 99.7%. More particularly the present invention provides the crystalline form of the Fumarate salt of Ritlecitinib is substantially free of impurities, in particular one or more dimers of Ritlecitinib. More particularly the present invention provides crystalline form of the fumarate salt of Ritlecitinib that are having compiling genotoxic as well as nitrosoamine limit as specified by regulatory agencies. The term substantially free of impurities, as used herein, indicates that the fumarate salt of Ritlecitinib obtained according to the invention meets ICH guidelines, and the content of dimer impurity is less than 0.5%, more particularly, less than 0.15%.
In an embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of the fumarate salt of Ritlecitinib and at least one pharmaceutically acceptable excipient.
In an embodiment of the invention, Ritlecitinib base as used as starting material in present invention process can be in any polymorphic form and prepared according to the process known in prior arts.
In another embodiment, the present invention relates to a process for the preparation of amorphous form of Ritlecitinib tosylate comprising evaporating the solvent from the solution of Ritlecitinib tosylate at a temperature in the range of 0°C to 35 °C.
The suitable techniques that can be used for evaporation include but not limited to distillation, distillation under vacuum, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, rotary vacuum paddle dryer, agitated nutsche filter drying, pressure nutsche filter drying, fluid bed drying, tray drying, freeze -drying (lyophilization) or any other suitable technique known in the art. The drying may be carried at normal pressure or under reduced pressure.
The amorphous form of Ritlecitinib tosylate obtained according to present invention process is characterized by PXRD pattern as shown in Fig-3 and having purity of greater than 99% and more preferably greater than 99.7%. More particularly the present invention provides the amorphous form of Ritlecitinib tosylate of Ritlecitinib is substantially free of impurities, in particular dimer impurity. The term substantially free of impurities, as used herein, indicates that the amorphous form of Ritlecitinib tosylate obtained according to the invention meets ICH guidelines, and the content of dimer impurity is less than 0.5%, more particularly, less than 0.15%.
The suitable solvent(s) that can be used to prepare solution of Ritlecitinib tosylate are those that can dissolve the Ritlecitinib tosylate, either alone or in combination with other solvents, and include but are not limited to methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol, dichloromethane, 1 ,2-dichloroethane, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, di-isopropyl ether, methyl tert-butyl ether. 1 ,4-dioxane, toluene, xylene, acetonitrile, propionitrile, water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide or its mixture thereof.
In an embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of acid addition salt of Ritlecitinib comprising evaporating the solvent from the solution of Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients at a temperature in the range of 0°C to 35 °C, wherein the acid addition salt is selected from group consisting tosylate, oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.
In an embodiment of the invention, solution of Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients includes dissolving Ritlecitinib acid addition salt and pharmaceutically acceptable carrier in one or more suitable solvent(s).
In an embodiment of the invention, solution of Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients may be carried out by dissolving crystalline or amorphous Ritlecitinib acid addition salt and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvent(s).
In an embodiment of the invention solution of Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment of the invention, evaporating the solvent from the solution of Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients at a temperature in the range of 0°C to 35 °C. Suitable techniques which can be used for the evaporation of solvent include but not limited to flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze drying, filtration or any other technique known in the art.
In an embodiment of the invention, solid dispersion of Ritlecitinib acid addition salt may be combined with additional excipient using a technique known in art or according to the previous aspects of the present application.
The pharmaceutically acceptable excipients include, but are not limited to copovidone, graft copolymer of polyethylene glycol, polyvinyl acetate phthalate, Hypromellous Cp-15, Hypromellous-CP-06 (HP-CP-06):Polyvinyl pyrollidine-30 (PVP-30), Hypromellous-CP-06, Polyvinyl pyrollidine-90 (PVP-90), Silicon dioxide, Neusilin, Neusilin: Polyvinyl pyrollidine-90 (PVP-90), Hydroxypropyl cellulose (HPC), Hydroxypropyl cellulose (HPC): Polyvinyl pyrollidine-90 (PVP-90)¸ Hypromellous-CP-06 (HP-CP-06) : Polyvinyl pyrollidine-30 (PVP-30), Hydroxypropyl betadex (HPB-Betadex) and Carbapol-974-Ppolyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, ethylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hypromellose or hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, glyceryl dibehenate, lactose monohydrate, microcrystalline cellulose, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), croscarmellose sodium (CCS), crospovidone, hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Ritlecitinib acid addition salt with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
The excipients or pharmaceutically acceptable excipients includes but not limited to diluents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof.
In another embodiment, Ritlecitinib acid addition salts of the present application can be optionally subjected to particle size reduction procedures before or after the completion of drying of the product to produce desired particle sizes and distributions. Milling or micronization can be performed to achieve the desired particle sizes or distributions. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
In another embodiment the starting material Ritlecitinib acid addition salts, such as for example Ritlecitinib tosylate is prepared by dissolving Ritlecitinib base in suitable solvent, to the clear solution optionally a small amount of an antioxidant such as, but not limited to, citric acid, ascorbic acid, triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol (BHT), butylated hydroxyanisole, a mixture of 2-tert-butylhydroxy anisole and 3-tert-butylhydroxy anisole (BHA), ethyl gallate (EtG) and propyl gallate (PrG) is added, followed by the addition of corresponding acid such as p-toluene sulphonic acid. said acid addition salts are isolated by a conventional means.
In yet another embodiment, Ritlecitinib acid addition salt prepared according to the present invention is packed under stringent packaging condition to avoid moisture and oxygen entry, optionally in presence of oxygen absorbent and / or desiccant.
In an embodiment of the invention, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Ritlecitinib and its salt obtained according to present invention, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
An aspect of the present application relates to a solid pharmaceutical composition comprising Ritlecitinib or a salt thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include, but are not limited to, diluents/fillers, binders, disintegrants, glidants, lubricants, preservatives, antioxidants, surfactants, pH adjusters, coating agents, colorants, sweeteners, or combinations thereof.
The term “anti-oxidant” generally refers to a substance that inhibits the oxidation and/or formation of nitrosamine drug substance-related impurities (NDSRIs) or nitrosamine impurities in a drug product. In certain embodiments, an anti-oxidant is added to the pharmaceutical composition comprising Ritlecitinib or a salt thereof.
In an embodiment, the present application relates to a solid pharmaceutical composition comprising Ritlecitinib or its acid addition salt, an antioxidant, and one or more other pharmaceutically acceptable excipients. The antioxidant may be selected from, but not limited to, ascorbic acid (vitamin C), ascorbate salt (such as sodium ascorbate), alpha-tocopherol/ tocopherol (vitamin E), or propyl gallate, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium salt, sodium sulfite, sodium metabisulfite, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, thioglycerol, thioglycolic acid, D-a tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS).
The “at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient” can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
In an embodiment of the invention, the present invention relates to a pharmaceutical composition according to present invention can be used for preparing drugs for treating a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigoid, inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Alzheimer's disease, lupus, nephritis, systemic lupus erythematosus, psoriasis, eczema dermatitis, pruritus or other pruritic conditions, vitiligo, alopecia, autoimmune thyroid disorders, multiple sclerosis, major depression disorder, allergy, asthma, Sjogren's disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, membranous glomerulopathy, organ transplant rejection, graft-versus-host disease, organ and cell transplant rejection, xenotransplantation, Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, complications from diabetes, thyroiditis, chronic pulmonary obstructive disorder, acute respiratory disease, cachexia, cancer, alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, mast cell tumor, squamous cell carcinoma, breast, mammary cancer, ovarian cancer, prostate cancer, leukemia, adult T cell leukemia activated B-cell like, diffuse large B cell lymphoma, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma, oral or metastatic melanoma, Kaposi's sarcoma septic shock, cardiopulmonary dysfunction, acute myeloid leukemia, T cell acute lymphoblastic leukemia, multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, angiogenic-associated disorders, solid tumors, pancreatic cancer, brain tumors, gliomas, astrocytoma, oligodendroglioma, glioblastoma, acute CNS trauma, traumatic brain injury, encephalitis, stroke, spinal cord injury, epilepsy, seizures, chronic neuroinflammation associated with neurodegeneration, Parkinson's disease, Amyotropic Lateral Sclerosis, Huntington's disease, cerebral ischemia, fronto-temporal lobe dementia, neuropsychiatric disorders, schizophrenia, bipolar disorder, treatment-resistant depression, Post Traumatic Stress Disorder, anxiety, auto-antibodies-mediated encephalopathies, eye diseases, autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis, uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization.
In an embodiment of the invention, Ritlecitinib or its acid addition salt used as starting material in present invention process can be prepared according to the process known in prior arts or as by method disclosed in the following schemes.

The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PAN alytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree.
DSC method:
The melting points are measured using Differential Scanning Calorimetry (DSC). The equipment is a TA-Instruments DSC-Q1000 calibrated at 10°/min to give the melting point as onset value. About 2 mg of sample is heated 10°/min in a loosely closed pan under nitrogen flow.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material, like EDTA, to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Preparation of Ritlecitinib fumarate
To a stirred solution of Ritlecitinib base (1 gm) in isopropanol was added fumaric acid (1 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass filtered and dried to obtain Ritlecitinib fumarate.
Example 2: Preparation of amorphous Ritlecitinib fumarate
To a stirred solution of Ritlecitinib base (1 gm) in methanol was added fumaric acid (1 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass filtered immediately and dried to obtain Ritlecitinib fumarate.
Example 3: Preparation of crystalline Ritlecitinib fumarate
To a stirred solution of Ritlecitinib base in ethanol (2 vol.) was added fumaric acid (1 eq.) and ethanol (4 vol.) followed by addition of methyl tert-butyl ether (12.5 vol.). The solvent was distilled out completely below 35oC under vacuum and to the residue methyl tert-butyl ether (5 vol.) was added. The reaction mass stirred for about 5-13 hours, filtered and dried to obtain desired product (HPLC purity >99.5%).
Example 4: Preparation of crystalline Ritlecitinib fumarate
To a stirred solution of Ritlecitinib base in methanol (5 vol.) was added fumaric acid (1 eq.) lot wise. The reaction mixture was heated to 30°C for 30 min, followed by distillation of methanol under vacuum below 30°C. Methyl tert-butyl ether (3 vol.) was added to the residue and stirred to 30°C for 30 min. The reaction mass distilled completely under vacuum below 30°C. Methyl tert-butyl ether (7 vol.) was added to the residue and stirred to 30°C for 10 hours. The reaction mixture was kept without stirring for 6 hours. The solid was filtered and dried 40°C to obtain desired product. The PXRD of the isolated product is shown in Fig -1 (HPLC purity >99.5%).
Example 5: Preparation of amorphous Ritlecitinib tosylate
To a stirred solution of Ritlecitinib base (1 gm) in methanol was added para-toluene sulfonic acid (1 eq.). The solvent was distilled out completely below 30oC under vacuum and methyl tert-butyl ether was added. The reaction mass stirred, filtered and dried to obtain desired product. The PXRD of the isolated product is shown in Fig -3.
Example 6: Preparation of amorphous Ritlecitinib tosylate
Ritlecitinib tosylate was dissolved in methanol, followed by spray drying.
Example 7: Preparation of solid dispersion of Ritlecitinib tosylate with hypromellose (HPMC)
Ritlecitinib tosylate and HPMC are dissolved in methanol and the clear solution was subjected to spray drying.
Example 8: Preparation of solid dispersion of Ritlecitinib tosylate with microcrystalline cellulose
Ritlecitinib tosylate and microcrystalline cellulose are dissolved in methanol and the clear solution was subjected to spray drying.
Example 9: Preparation of solid dispersion of Ritlecitinib oxalate with Copovidone
Ritlecitinib oxalate and copovidone are dissolved in methanol and the clear solution was subjected to spray drying.
Example 10: Preparation of solid dispersion of Ritlecitinib fumarate with Copovidone
Ritlecitinib fumarate and copovidone are dissolved in methanol and the clear solution was subjected to spray drying.
Example 11: Preparation of Ritlecitinib oxalate
To a stirred solution of Ritlecitinib base (1 gm) in isopropanol was added oxalic acid (1 eq.). The reaction mass stirred for 15 hours, filtered and dried to obtain Ritlecitinib oxalate.
Example 12: Preparation of Ritlecitinib hydrochloride
To a stirred solution of Ritlecitinib base (1 gm) in acetone and water was added HCl solution (1 eq.). The solvent was distilled out completely below 35oC under vacuum and acetone was added. The reaction mass stirred, filtered and dried to obtain Ritlecitinib hydrochloride.
Example 13: Preparation of Ritlecitinib sulphate
To a stirred solution of Ritlecitinib base (1 gm) in acetone and water was added sulfuric acid (0.55 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass stirred, filtered and dried to obtain Ritlecitinib sulphate.
Example 14: Preparation of Ritlecitinib acetate
To a stirred solution of Ritlecitinib base (1 gm) in acetone was added acetic acid (1 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass stirred, filtered and dried to obtain Ritlecitinib acetate.
Example 15: Preparation of Ritlecitinib formate
To a stirred solution of Ritlecitinib base (1 gm) in acetone was added formic acid (1 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass stirred, filtered and dried to obtain Ritlecitinib formate.
Example 16: Preparation of Ritlecitinib methanesulfonate
To a stirred solution of Ritlecitinib base (1 gm) in 2-butanone was added methane sulfonic acid (1 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass stirred, filtered and dried to obtain Ritlecitinib methanesulfonate.
Example 17: Preparation of Ritlecitinib succinate
To a stirred solution of Ritlecitinib base (1 gm) in 2-butanone was added succinic acid (1 eq.). The solvent was distilled out completely below 35oC under vacuum and methyl tert-butyl ether was added. The reaction mass stirred, filtered and dried to obtain Ritlecitinib succinate.

Dated this: 21st day of March, 2025 Dr. S. Ganesan ,CLAIMS:1. A process for the preparation of acid addition salt of Ritlecitinib comprising contacting the Ritlecitinib with suitable acid in the presence of solvent and isolating the acid addition salt of Ritlecitinib, wherein the acid addition salt is selected from group consisting oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methane sulfonate and succinate, wherein contacting the Ritlecitinib with suitable acid in the presence of solvent and isolating the acid addition salt is carried out at a temperature in the range of 5 oC to 35 oC.

2. The process as claimed in claim 1, wherein the suitable solvent is selected from group comprising methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol, dichloromethane, 1,2-dichloroethane, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, di-isopropyl ether, methyl tert-butyl ether. 1 ,4-dioxane, toluene, xylene, acetonitrile, propionitrile, water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide or its mixture thereof.

3. A crystalline form of the Fumarate salt of Ritlecitinib having a powder X-ray diffraction pattern comprising peaks, in terms of 2?, having peaks at 6.27°, 11.64°, 14.19°, 17.05°, 19.64° and 24.87 ± 0.2 ° degrees 2-theta and characterized by an XRPD pattern substantially as depicted in Figure 1.

4. A process for the preparation of crystalline form of Ritlecitinib fumarate, which is substantially free of impurities, which comprises the steps of,
a) providing a solution comprising Ritlecitinib fumarate in one or more solvent(s);
b) isolating the crystalline form of Ritlecitinib fumarate.

5. The process as claimed in claim 4, wherein the solvent is selected from group comprising methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol, dichloromethane, 1 ,2-dichloroethane, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, di-isopropyl ether, methyl tert-butyl ether. 1 ,4-dioxane, toluene, xylene, acetonitrile, propionitrile, water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide or its mixture thereof.

6. The process as claimed in claim 4, wherein step (a) and step (b) is carried out at a temperature in the range of 0°C to 35 °C and stirring the reaction mixture for about 5 to 25 hours before isolation of the product.

7. A process for the preparation of amorphous form of Ritlecitinib tosylate comprising evaporating the solvent from the solution of Ritlecitinib tosylate at a temperature in the range of 0°C to 35 °C.

8. A process for the preparation of amorphous solid dispersion of acid addition salt of Ritlecitinib comprising evaporating the solvent from the solution of Ritlecitinib acid addition salt and one or more pharmaceutically acceptable excipients at a temperature in the range of 0°C to 35 °C, wherein the acid addition salt is selected from group consisting tosylate, oxalate, fumarate, hydrochloride, sulphate, acetate, formate, methanesulfonate and succinate.

9. The process as claimed in claim 8, wherein the one or more pharmaceutically acceptable excipients is selected from copovidone, graft copolymer of polyethylene glycol, polyvinyl acetate phthalate, Hypromellous Cp-15, Hypromellous-CP-06 (HP-CP-06):Polyvinyl pyrollidine-30 (PVP-30), Hypromellous-CP-06, Polyvinyl pyrollidine-90 (PVP-90), Silicon dioxide, Neusilin, Neusilin: Polyvinyl pyrollidine-90 (PVP-90), Hydroxypropyl cellulose (HPC), Hydroxypropyl cellulose (HPC): Polyvinyl pyrollidine-90 (PVP-90)¸ Hypromellous-CP-06 (HP-CP-06) : Polyvinyl pyrollidine-30 (PVP-30), Hydroxypropyl betadex (HPB-Betadex) and Carbapol-974-Ppolyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, ethylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hypromellose or hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, glyceryl dibehenate, lactose monohydrate, microcrystalline cellulose, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), croscarmellose sodium (CCS), crospovidone, hydroxyethyl cellulose, Soluplus? (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethyl cellulose, cyclodextrins, gelatins, hypromellose phthalates, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, polyethylene oxides and guanidine.

10. The process as claimed in claim 8 or claim 9, wherein the solvent is selected from group comprising methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol, dichloromethane, 1 ,2-dichloroethane, acetone, ethyl methyl ketone, methyl isobutyl ketone, or its mixture thereof.

Dated this: 21st day of March, 2025 Dr. S. Ganesan