DESC:RELATED APPLICATION:
This application claims the benefit of priority of our Indian Provisional Patent Application No. 201921004592 filed on Feb. 05, 2019.
FIELD OF THE INVENTION
The present invention relates to solid forms of Filgotinib base as well as Filgotinib maleate and the preparation method thereof. Further, the present invention provides solid premix of Filgotinib maleate with at least one pharmaceutically acceptable excipient and process for preparations thereof.
BACKGROUND OF THE INVENTION
Filgotinib, has a chemical name N-(5-{4-[(1,1-Dioxido-4-thiomorpholinyl) methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropancarboxamide. Filgotinib is represented by the following chemical structure according to Formula (I).

Formula I
Filgotinib is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. The JAK1 selective inhibitor Filgotinib is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib is currently in a Phase 3 study in Crohn’s disease.
US8853240 first discloses Filgotinib, its process for preparation and its method of use. US8088764 also discloses Filgotinib and a process for the preparation of Filgotinib. US9382247 (herein after referred to as the ‘247 patent) discloses crystalline and amorphous form of a Filgotinib base, amorphous form of Filgotinib HCl, crystalline form of Filgotinib HCl, Filgotinib HCl.MeOH, Filgotinib.HCl.3H2O, Filgotinib.HCl.1.5HCOOH and also disclose a process of preparation of Filgotinib maleate.
WO2017012770A1, WO2017012771 and WO2017012773 disclose different crystalline forms of Filgotinib free base as well as crystalline forms of different salts of Filgotinib such as HCl, sulphate, mesylate, Tosylate, esylate, besylate and ethanedisulfonate.
In pharmaceutical dosage forms such as tablets, the conversion of one polymorphic form into another polymorphic form can be unfavourable, and results in different dissolution, hygroscopicity, and pharmacokinetic properties. Thereby, the bioavailability of the active agent might be undesirably unpredictable due to polymorphic conversion. Therefore, active agents having different interchangeable polymorphs may lead to regulatory and commercial disadvantages. Consequently, there is a need to develop a solid form of Filgotinib and its maleate salts having better stability, desired solubility, and hygroscopicity and preparation thereof, which is commercially viable.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide novel crystalline solid form Form AL-1 of Filgotinib maleate and process of preparation thereof.
Another of the present invention is to provide amorphous form of Filgotinib maleate and process of preparation thereof.
Yet another aspect of the present invention is to provide solid premix composition comprising amorphous form of Filgotinib maleate and at least one pharmaceutically acceptable excipient. Also, the present invention further encompasses a process for preparation of Filgotinib maleate premix.
Further another aspect of the present invention is to provide to a novel crystalline solvates of Filgotinib base such as benzyl alcohol hemi solvate and process of preparation thereof.
Still another aspect of the present invention relates to a novel crystalline Form-AL-(b) of Filgotinib base and process of preparation thereof.
Yet another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Filgotinib or Filgotinib maleate obtained according to present invention, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of Form AL-1 of Filgotinib maleate.
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of amorphous form of Filgotinib maleate.
Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of benzyl alcohol hemi solvate form of Filgotinib.
Fig 4 shows the X-ray powder diffractogram ("PXRD") pattern of Form AL-(B) of Filgotinib.
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention relates to crystalline solid form AL-1 of Filgotinib maleate.
In an embodiment of the invention, crystalline solid form AL-1 of Filgotinib maleate is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 2-theta (XRPD) peaks 5.6, 7.8, 9.3, 9.8, 10.48, 11.22, 15.31, 16.36, 16.51, 17.10, 17.46, 18.20, 18.40, 18.79, 19.25, 19.42, 19.68, 20.14, 20.58, 20.90, 21.70, 22.51, 22.69, 22.88, 23.56, 24.12, 24.43, 25.24, 25.88, 26.17, 26.61, 27.15, 29.69, 30.65 and 31.68.
In another embodiment of the present invention, the crystalline form AL-1 of Filgotinib maleate is characterized by having PXRD peaks as shown in Fig-1.
Another aspect of the invention relates to a process of preparation of novel crystalline form AL-1 of Filgotinib maleate comprising;
a. providing solution of Filgotinib maleate in a suitable solvent, preferably sulfolane;
b. isolating crystalline form AL-1 of Filgotinib maleate.
In an embodiment of the invention, the step of providing a solution of Filgotinib maleate salt in a suitable solvent is achieved by dissolving Filgotinib maleate in suitable solvent or preparing Filgotinib maleate by treating Filgotinib base with maleic acid in suitable solvent. The Filgotinib or its maleate salt can be obtained in the course of its synthesis as a residue or in a solid form including amorphous, crystalline form or mixtures thereof; wherein suitable solvent is preferably sulfolane.
Isolating crystalline Form AL-1 of Filgotinib maleate can preferably be carried out by filtering off the solid. Alternatively, the isolation can be effected by addition of an anti-solvent to the solution obtained in step a) and then filtering the solid.
In some embodiments of the invention, the novel solid forms of Filgotinib or its maleate salt may be solvated (stoichiometric or non-stoichiometric amounts of solvents), hydrate (including stoichiometric hydrates, non-stoichiometric hydrates), anhydrous or mixture thereof.
In few embodiments of the invention, the novel solid forms of Filgotinib and Filgotinib maleate according to the present invention includes pure crystalline forms, amorphous form, mixture of crystalline forms, or mixture of crystalline and amorphous forms.
An aspect of the invention relates to Filgotinib maleate amorphous form.
In an embodiment of the invention the amorphous form of Filgotinib maleate is characterized by having PXRD peaks as shown in Fig-2.
Another aspect of the invention relates to a process of preparation of amorphous Filgotinib maleate comprising:
a. providing solution of Filgotinib maleate in a suitable solvent;
b. isolating amorphous form of Filgotinib maleate.
In some embodiments the isolation of amorphous may be effected by removal of the solvent, the removal of solvent comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization).
Alternatively, the isolation can be effected by addition of an anti-solvent to the solution obtained in step a) and then filtering the solid.
Another aspect of the invention relates to a process for preparation of Filgotinib maleate premix comprising:
a) providing a solution of Filgotinib maleate in a suitable solvent;
b) adding suitable excipient(s) and;
c) removing the solvent(s).
In an embodiment suitable pharmaceutically acceptable excipients or polymers or carriers that are optionally dispersing agents which can be used for the preparation of solid dispersion include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalhne celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide (Syloid, Aerosil, Cab-o-sil etc.) and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like; celluloses (e.g., carboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxypropyl methylcelluloses); polysaccharides, heteropolysaccharides (pectins) ; poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid; mixtures of two or more thereof, copolymers thereof, derivatives thereof, and the like. Further examples of carriers include copolymer systems such as polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyvinylpyrrolidone -polyvinylalcohol (PVP- PVA), and derivatized copolymers such as copolymers of N-vinyl purine (or pyrimidine) derivatives and N-vinylpyrrolidone. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
An enteric coating polymer can also be used according to the present invention. Specific examples of the enteric coating polymers include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethyl cellulose phthalate, eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate and hydroxypropylmethyl trimellitate.
An aspect the invention relates to Filgotinib benzyl alcohol hemi solvate.
In an embodiment of the invention, the Filgotinib benzyl alcohol hemi solvate is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the peaks 8.3, 10.67, 11.26, 13.07, 13.50, 15.01, 16.03, 17.40, 17.66, 18.72, 19.33, 19.77, 20.01, 20.99, 22.24, 23.10, 27.77 and 28.37.
In another embodiment of the invention, the Filgotinib benzyl alcohol hemi solvate is characterized by having PXRD peaks as shown in Fig-3.
Another aspect of the invention relates to a process of preparation of Filgotinib benzyl alcohol hemi solvate comprising;
a. providing a solution of Filgotinib in benzyl alcohol solvent; and
b. isolating Filgotinib benzyl alcohol hemi solvate from the solution.
An aspect the present invention relates to novel crystalline form-AL-(B) of Filgotinib base.
In an embodiment of the invention, the novel crystalline form-AL-(B) of Filgotinib is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the peaks 11.38, 11.69, 12.29, 13.52, 14.15, 15.76, 16.65, 17.06, 17.92, 18.36, 19.42, 20.57, 20.76, 21.01, 21.62, 22.01, 22.91, 23.50, 23.88, 24.84, 25.94, 27.83, 28.59 and 31.66.
In another embodiment of the invention, the novel crystalline form-AL-(B) of Filgotinib is characterized by having PXRD peaks as shown in Fig-4.
Another aspect of the invention relates to a process of preparation of novel crystalline form-AL-(B) of Filgotinib comprising;
a. providing a solution of Filgotinib in suitable solvent, preferably IPA and water; and
b. isolating crystalline form-AL-(B) of Filgotinib from the solution.
In an embodiment of the invention, providing a solution of Filgotinib in a suitable solvent is achieved by dissolving Filgotinib in a solvent, or such a solution may be obtained in the course of its synthesis as a residue or in a solid form. Providing a solution of Filgotinib optionally involves use of other suitable solvents capable of dissolving Filgotinib. Then optionally, filtering the solvent solution to remove any extraneous matter; and finally isolating by removing the solvent from the solution to afford Filgotinib. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid in step a).
In few embodiments of the present invention, involves dissolving Filgotinib in a suitable solvent, if needed involves stirring, heating and the combination thereof.
In few embodiments of the present invention, the isolation is performed by any conventional methods such as cooling, filtration or combination thereof.
In few embodiments of the present invention, the isolation further comprises optionally washing with a suitable solvent and drying.
In some embodiments of the present invention, the suitable solvent(s) is/are solvent in which Filgotinib or its maleate salt is soluble.
In some embodiments of the present invention, the suitable solvent used in present invention, is/are selected from but not limited to water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, benzyl alcohol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, benzonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, chloroform, hexane, heptanes, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.
In some embodiments of the present invention, the anti-solvents comprises one or more of hydrocarbons selected from hexanes, n-heptane, n-pentane, cyclohexane, and methylcyclohexane; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene; ethers selected diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, and 2-methoxy ethanol.
In some embodiments of the invention, 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 the excipients are selected from but not limited to cellulose powdered, silicified microcrystalline cellulose acetate, compressible sugar, confectioner's sugar, corn starch and pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, inhalation lactose, isomalt, kaolin, lactitol, lactose, anhydrous, monohydrate and corn starch, spray dried monohydrate and microcrystalline cellulose, maltodextrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, simethicone, sorbitol, pregelatinized starch, sterilizable maize, sucrose, sugar spheres, sulfobutylether ß-cyclodextrin, talc, tragacanth, trehalose, xylitol, canola oil, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, medium-chain triglycerides, mineral oil, light mineral oil, octyldodecanol, poloxamer, polyethylene glycol, polyoxyethylene stearates, polyvinyl alcohol, starch, hydrogenated vegetable oil, alginic acid, powdered cellulose, chitosan, colloidal silicon dioxide, corn starch and pregelatinized starch, crospovidone, glycine, guar gum, low-substituted hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, povidone, powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, or talc or mixtures thereof.
The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PANalytical 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.

The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and D10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining D10, D50 and D90 include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern) equipment.
Filgotinib or Filgotinib maleate obtained according to the process described herein or after performing size reduction operations such as milling or micronization, has a particle size distribution pattern of D10 less than or equal to about 150 µm, D50 less than or equal to about 300 µm, and D90 less than or equal to about 500 µm. There is no specific lower limit for any of the D values.
In another aspect the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Filgotinib maleate obtained according to present invention, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
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 another aspect the present invention relates to a pharmaceutical composition according to present invention can be used for preparing drugs for treating a disease which responds to inhibition of cyclin dependent kinases, (particular, cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9).
In an embodiment the disease includes include, but not limited to a further subject of the present invention is a method for treating and/or preventing systemic diseases, autoimmune diseases and/or inflammatory diseases, preferably multiple sclerosis, rheumatoid arthritis, or psoriasis, in particular multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to the present invention or the pharmaceutical composition according to the present invention.
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 crystalline Filgotinib maleate
Filgotinib maleate amorphous (2 g) and water (10 ml) were added into a stirring apparatus. The reaction mixture was heated at 80 ± 3°C and stirred for 15-30 mins. Reaction mass was cooled at 27 ± 3°C and stirred for 10-12 hrs. Reaction mass was filtered at room temperature. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 1.5 g)
Example 2: Preparation of crystalline Filgotinib maleate
Filgotinib maleate amorphous (2 g) and ethyl acetate (20 ml) were added into a stirring apparatus. The reaction mixture was heated at 75 ± 3°C and stirred for 45-60 mins. Reaction mass was cooled at 27 ± 3°C and stirred for 1-2 hrs. Reaction mass was filtered at room temperature. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 1.5 g)
Example 3: Preparation of crystalline solid form AL-1 of Filgotinib maleate
Filgotinib (2 g) and sulfolane (30 ml) were added into a stirring apparatus. The reaction mixture was heated at 75 ± 3°C and stirred till clear solution obtained. The reaction mass was filtered at 75 ± 3°C. Maleic acid in sulfolane (1.14 g in 5 ml) was charged in filtrate at 75 ± 3°C and stirred for 10-15 mins. Reaction mass was cooled at 27 ± 3°C and ethyl acetate (75 ml) was added then stirred for 10-12 hrs. Reaction mass was filtered at room temperature. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 2.5 g)
Example 4: Preparation of crystalline solid form AL-1 of Filgotinib maleate
Filgotinib maleate amorphous (2 g) and sulfolane (15 ml) were added into a stirring apparatus. The reaction mixture was heated at 75 ± 3°C and stirred for 15-30 mins. Reaction mass was cooled at 27 ± 3°C and ethyl acetate (75 ml) was added then stirred for 1-2 hrs. Reaction mass was filtered at room temperature. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 2.5 g).
Example 5: Preparation of amorphous form of Filgotinib maleate
Filgotinib (20 g) and dichloromethane (600 ml) were added into a stirring apparatus. The reaction mixture was heated at 35 ± 3°C and stirred for 15-30 mins. The reaction mass was filtered at 35 ± 3°C. Maleic acid in tetrahydrofuran (5.45 g in 30 ml) was charged in filtrate at 35 ± 3°C and stirred for 10-30 mins. Reaction mass was filtered and filtrate was heated at 39 ± 3°C and stirred, distilled. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 20 g).
Example 6: Preparation of amorphous form of Filgotinib maleate
Filgotinib (2 g), methanol (190 ml) and water (16 ml) were added into a stirring apparatus. The reaction mixture was heated at 65 ± 3°C and stirred for 15-30 mins. The reaction mass was filtered at 65 ± 3°C. Maleic acid in tetrahydrofuran (0.54 g in 4 ml) was charged in filtrate at 65 ± 3°C and stirred for 10-30 mins followed by distillation. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 2.25 g).
Example 7: Preparation of amorphous form of Filgotinib maleate
Filgotinib (2 g), tetrahydrofuran (50 ml) and water (10 ml) were added into a stirring apparatus. The reaction mixture was heated at 65 ± 3°C and stirred for 15-30 mins. The reaction mass was filtered at 65 ± 3°C. Maleic acid in tetrahydrofuran (0.54 g in 6 ml) was charged in filtrate at 65 ± 3°C and stirred for 10-30 mins followed by distillation. The obtained solid was dried under vacuum at 55 ± 3°C (yield: 2.3 g).
Example 8: Preparation of Filgotinib benzyl alcohol hemi solvate
Filgotinib base (2 g) and Benzyl alcohol (10 ml) were added into a stirring apparatus. The reaction mixture was heated at 70 ± 3°C and stirred for 15-30 mins. Reaction mass was filtered at 70 ± 3°C and cooled to room temperature. Solid material was isolated by filtration and washed with Benzyl alcohol (1ml). The obtained solid was dried under vacuum at 55 ± 3°C (yield: 2.3 g).
Example 9: Preparation of crystalline form-AL-(B) of Filgotinib
Filgotinib base (2 g) and IPA (Isopropyl alcohol) (200 ml) were added into a stirring apparatus. The reaction mixture was heated at 75 ± 3°C followed by addition of water (30 ml) and stirred for 15-30 mins. Reaction mass was filtered at 75 ± 3°C and cooled to room temperature and stirred for 10-12 hrs. Solid material was isolated by filtration and washed with IPA (4ml). The obtained solid was dried under vacuum at 55 ± 3°C (yield: 2.3 g).
Example 10: Preparation of solid premix of Filgotinib maleate with PVPK-30 (1:1 w/w)
To a solution of Filgotinib maleate (500 mg) in dichloromethane (150 mL), polyvinylpyrrolidone (500 mg) was added. The mixture was stirred for clear solution and then subjected to solvent evaporation under 80 torr at about 45 ?C to afford the solid. The said solid was dried under vacuum at 45 ºC for about an hour.
Example 11: Preparation of solid premix of Filgotinib maleate with Co-povidone (1:1 w/w)
To a solution of Filgotinib maleate (500 mg) in dichloromethane (150 mL), co-povidone (500 mg) was added. The mixture was stirred for clear solution and then subjected to fast solvent evaporation under 3 torr vacuum pressure at about 45 ºC to afford the solid. The said solid was dried under vacuum at 3 torr pressure at about 45 ºC for about 2.5 hours.
Example 12: Preparation of solid premix of Filgotinib maleate with HPMC-AS (1:1 w/w)
Filgotinib maleate (250 mg) and HPMC-AS (250 mg) were dissolved in methanol (15 mL) at room temperature. The mixture was filtered to remove undissolved particles and then was subjected to fast solvent evaporation under 1 torr vacuum pressure at about 65 ºC to afford the title solid.
Example 13: Preparation of solid premix of Filgotinib maleate with Eudragit (1:1 w/w)
Filgotinib maleate (400 mg) and Eudragit (400 mg) were dissolved in methanol (25 mL) at room temperature. The mixture was filtered to remove un-dissolved particles and then was subjected to solvent evaporation under 1 torr at about 65 ºC to afford the title solid.
Example 14: Preparation of solid premix of Filgotinib maleate with PVPK30 and syloid (1:1 w/w)
Filgotinib maleate and PVPK30 amorphous solid dispersion/premix (200 mg) and syloid- 244 (100 mg) were taken in methanol (12 mL) at room temperature. The resultant cloudy solution was subjected to fast solvent evaporation under 10 mbar vacuum pressures at about 70 ºC to afford the title solid. ,CLAIMS:1. A process of preparation of amorphous Filgotinib maleate comprising:
a. providing solution of Filgotinib maleate in a suitable solvent;
b. isolating amorphous form of Filgotinib maleate.
2. The process as claimed in claim 1, wherein the suitable solvent is selected from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, benzyl alcohol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, benzonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, chloroform, hexane, heptanes, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.
3. A process for preparation of Filgotinib maleate premix comprising:
a. providing a solution of Filgotinib maleate in a suitable solvent;
b. adding suitable excipient(s) and;
c. removing the solvent(s).
4. The process as claimed in claim 3, wherein the solvent in step a) is selected from dichloromethane, methanol or mixture thereof.
5. The process as claimed in claim 3, wherein the excipient in step b) is selected from polyvinylpyrrolidone, co-povidone, HPMC-AS, Eudragit, syloid- 244 or mixture thereof.
6. A process of preparation of Crystalline Form AL-1 of Filgotinib maleate comprising:
a. providing solution of Filgotinib maleate in sulfolane;
b. isolating crystalline form AL-1 of Filgotinib maleate.
wherein the form AL-1 is characterized by having at least one or more 2-theta XRPD peaks at 7.8, 10.48, 11.2, 17.1, 18.2, 18.4, 19.6, and 21.7 ± 0.2°.
7. A process of preparation of novel crystalline form-AL-(B) of Filgotinib comprising:
a. providing a solution of Filgotinib in IPA and water; and
b. isolating crystalline Form-AL-(B) of Filgotinib from the solution.
wherein the form-AL-(B) is characterized by having at least one or more 2-theta XRPD peaks at 11.38, 11.69, 14.15, 15.76, 17.06, 17.92, 21.01, and 21.62 ± 0.2°.
8. A process of preparation of Filgotinib benzyl alcohol hemi solvate comprising;
a. providing a solution of Filgotinib in benzyl alcohol solvent; and
b. isolating Filgotinib benzyl alcohol hemi solvate from the solution.
wherein the Filgotinib benzyl alcohol hemi solvate form is characterized by having at least one or more 2-theta XRPD peaks at 13.07, 15.01, 17.66, 18.72, 20.1, 20.99, and 22.4 ± 0.2°.