A process for the preparation of solid forms of n-[4(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-3-yl) pyridine-3-carboxamide hydrogen chloride

Abstract

The present invention relates to a process for the preparation of solid-state forms of N-[4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H- pyrazol-3-yl) pyridine-3-carboxamide hydrogen chloride. More specifically, the present invention relates to a process for the preparation of solid dispersion of N-[4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyra zol-3-yl) pyridine-3-carboxamide hydrogen chloride with at least one pharmaceutically acceptable excipient without isolating N-[4 (Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyra zol-3-yl) pyridine-3-carboxamide hydrogen chloride. Formula (I).

Description

"A PROCESS FOR THE PREPARATION OF SOLID FORMS OF N- [4(CHLORODIFLUOROMETHOXY)PHENYL]-6-[(3R)-3- HYDROXYPYRROLIDIN-l-YL]-5-(lH-PYRAZOL-3-YL) PYRIDINE-3- CARBOXAMIDE HYDROGEN CHLORIDE"FIELD OF THE INVENTION

[0001] The present invention relates to a process for the preparation of solid-state forms of N- [4(Chlorodifluoromethoxy)phenyl] -6- [(3R)-3-hydroxypyrro lidin- 1 - yl]-5-(lH-pyrazol-3-yl) pyridine-3 -carboxamide hydrogen chloride. More specifically, the present invention relates to a process for the preparation of solid dispersion of N-[4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin- l-yl]-5-(lH-pyra zol-3-yl) pyridine-3-carboxamide hydrogen chloride with at least one pharmaceutically acceptable excipient without isolating N-[4 (Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-5-(lH-pyra zol-3-yl) pyridine-3 -carboxamide hydrogen chloride.BACKGROUND OF THE INVENTION

[0002] The N-[4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin- 1- yl]-5-(lH-pyrazol-3-yl) pyridine-3 -carboxamide hydrogen chloride is commonly known as Asciminib hydrochloride (1), which has the following chemical structure of compound (1).

[0003] Asciminib HC1 is marketed under brand name Scemblix, which is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (Ph+ CML-CP) previously treated with two or more tyrosine kinase inhibitors.

[0004] The W02020230099 described crystalline form A, form B and form HA of Asciminib hydrochloride (1) and its process for the preparation thereof.

[0005] The WO2021154980 described crystalline Form B (1,4-dioxane solvate) of Asciminib hydrochloride, Crystalline Form C of Asciminib hydrochloride, Amorphous form of Asciminib hydrochloride, Amorphous solid dispersion of Asciminib hydrochloride and Premix of Asciminib hydrochloride. However, this patent application has given no hint or suggestion to prepare Amorphous solid dispersion / premix of Asciminib hydrochloride (1).

[0006] The WO2022206937 described crystalline form L, Form F, Form J of Asciminib hydrochloride (1) and its process for the preparation thereof.

[0007] Our inventors have developed a process for the preparation of solid forms of Asciminib hydrochloride (1) to be stable over the time and reproducible. Hence, it is suitable for pharmaceutical preparations.OBJECTIVE OF THE INVENTION

[0008] Accordingly, one objective of the present invention is to provide a process for the preparation of solid-state forms of Asciminib hydrochloride (1).

[0009] In another objective, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient.

[0010] In another objective, the present invention provides a process for the preparation of solid dispersion comprising Asciminib free base with at least one pharmaceutically acceptable excipient.

[0011] In yet another objective, the present invention provides a process for the preparation of amorphous form of Asciminib hydrochloride (1).

[0012] The further objective of the present invention is to provide solid-state forms of Asciminib hydrochloride (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.SUMMARY OF THE INVENTION

[0011] Accordingly, in the first aspect, the present invention provides a process for the preparation of solid-state forms of Asciminib hydrochloride (1).

[0012] In the second aspect, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Asciminib hydrochloride (1).

[0013] In the third aspect, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient in a solvent to the mixture obtained in step a), and c) isolating the solid dispersion of Asciminib hydrochloride (1).

[0014] In the fourth aspect, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding a solution of hydrochloric acid to the solution obtained in step a),c) optionally, adding second solvent or mixture of solvents to step b), d) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-c), and e) isolating the solid dispersion of Asciminib hydrochloride (1). wherein the process involves without isolation of Asciminib hydrochloride.

[0015] In the fifth aspect, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), c) isolating the solid dispersion of Asciminib free base, d) dissolving solid dispersion of Asciminib free base (2) in a solvent or mixture of solvents, e) adding a solution of hydrochloric acid to step c), and f) isolating the solid dispersion of Asciminib hydrochloride (1). wherein the process involves without isolation of Asciminib hydrochloride.

[0016] In the sixth aspect, the present invention provides a process for the preparation of solid dispersion comprising Asciminib free base (2) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Asciminib free base.

[0017] In the seventh aspect, the present invention provides a process for the preparation of amorphous form of Asciminib hydrochloride (1), comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, and b) isolating amorphous form of Asciminib hydrochloride (1).

[0018] In the eighth aspect, the present invention provides solid-state forms of Asciminib hydrochloride (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with total impurities less than 1.0%, more preferably less than 0.5%.BRIEF DESCRIPTION OF THE DRAWINGS:

[0019] Figure 1: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Asciminib hydrochloride (1).

[0020] Figure 2: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with PVP- K30.

[0021] Figure 3: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- AS.

[0022] Figure 4: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPC.

[0023] Figure 5: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with Copovidone.

[0024] Figure 6: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- E3.

[0025] Figure 7: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with Soluplus.

[0026] Figure 8: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- E3 (1:0.5 w / w)

[0027] Figure 9: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- E3 (1:0.8 w / w)

[0028] Figure 10: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- E3 (1: 1 w / w)

[0029] Figure 11: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- E3 (1: 1.5 w / w)

[0030] Figure 12: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC- E3 (1:2.5 w / w)

[0031] Figure 13: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Asciminib free base (2).DETAILED DESCRIPTION OF THE INVENTION

[0032] 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 nonordered 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.

[0033] 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.

[0034] In the present application, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.

[0035] Accordingly, in one embodiment, the present invention provides a process for the preparation of solid-state forms of Asciminib hydrochloride (1).

[0036] In the first embodiment, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Asciminib hydrochloride (1)

[0037] In the process of the first embodiment, the suitable solvent used in step-a) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, and the like; chloro solvents such as dichloromethane, 1, 2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; water or its mixture thereof.

[0038] In the process of the first embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butylether-P-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPpCD), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, Isomaltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or com 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, sulfo butyl ether 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, salcaprozate sodium, sodium caprylate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

[0039] In the process of first embodiment, isolating involve 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 by gravity or suction, thin film drying, centrifugation or any other suitable techniques known in the art.

[0040] In the process of the first embodiment, drying solid dispersion of Asciminib hydrochloride (1) 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 thanabout 40°C, or any other suitable temperatures. The drying can be carried out for any period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

[0041] Solid dispersion of Asciminib hydrochloride (1) 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 are not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or Micronisation may be performed before drying, or after the completion of drying of the product.

[0042] In the process of the first embodiment, the present invention provides the ratio of the amount of Asciminib hydrochloride (1) within the solid form to the amount of the excipient which ranges from about 1: 0.5 to about 1:5 (w / w).

[0043] In the second embodiment, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient in a solvent to the mixture obtained in step a), and c) isolating the solid dispersion of Asciminib hydrochloride (1).

[0044] In the process of the second embodiment, the suitable solvent used in step- a) is same as defined in the first embodiment.

[0045] In the process of the second embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.

[0046] In the process of the second embodiment, isolating involves removal of solvent from the mixture in step-c) is same as defined in the first embodiment.

[0047] In the present invention, the starting material Asciminib hydrochloride (1) can be used in the form of amorphous or crystalline or any other physical form.

[0048] In the present invention, the pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other solid- state form.

[0049] In the process of the present invention the resulting solid dispersion of Asciminib hydrochloride (1) can be amorphous, crystalline or a mixture thereof.

[0050] In the third embodiment, the present invention provides a process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding a solution of hydrochloric acid to the mixture obtained in step a), c) optionally, adding second solvent or mixture of solvents to step b), d) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-c), and e) isolating the solid dispersion of Asciminib hydrochloride (1). wherein the process involves without isolation of Asciminib hydrochloride.

[0051] In the process of the third embodiment, the suitable solvent used in step-a) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; or its mixture thereof.

[0052] In the process of the third embodiment, a solution of hydrochloric acid in step-b), comprises dissolving hydrochloric acid in a suitable solvent or a mixture of solvents

[0053] In the process of the third embodiment, wherein the solution of hydrochloric acid is selected from but not limited to alcoholic hydrochloric acid, aqueous hydrochloric acid, concentrated hydrochloric acid, ethyl acetate hydrochloric acid; wherein the alcoholic hydrochloric acid is selected from methanolic hydrochloric acid, ethanolic hydrochloric acid and the like.

[0054] In the process of third embodiment, the suitable pharmaceutically acceptable excipient used in step-c) is same as defined in the first embodiment.

[0055] In the process of the third embodiment, isolating involves removing the solvent from the mixture used in step-d) is same as defined in the first embodiment.

[0056] In the fourth embodiment, the present invention provides a process for the preparation of solid dispersion of Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-a), c) isolating the solid dispersion of Asciminib free base (2), d) dissolving solid dispersion of Asciminib free base (2) in a solvent or mixture of solvents e) adding a solution of hydrochloric acid to step c), and f) isolating the solid dispersion of Asciminib hydrochloride (1). wherein the process involves without isolation of Asciminib hydrochloride.

[0057] In the process of fourth embodiment, the suitable solvent used in step-a) is same as defined in the third embodiment.

[0058] In the process of the fourth embodiment, providing a solution of hydrochloric acid in step-d), comprises dissolving hydrochloric acid in a suitable solvent or a mixture of solvents.

[0059] In the process of the fourth embodiment, wherein the solution of hydrochloric acid is selected from but not limited to alcoholic hydrochloric acid, aqueous hydrochloric acid, concentrated hydrochloric acid, ethyl acetate hydrochloric acid; wherein the alcoholic hydrochloric acid is selected from methanolic hydrochloric acid, ethanolic hydrochloric acid, and the like.

[0060] In the process of the fourth embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.

[0061] In the process of the fourth embodiment, isolating involves removing the solvent from the mixture used in step-c) and in step-e) is same as defined in the first embodiment.

[0062] In the fifth embodiment, the present invention provides a process for the preparation of solid dispersion comprising Asciminib free base (2) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-a), and c) isolating the solid dispersion of Asciminib free base (2).

[0063] In the process of the fifth embodiment, the suitable solvent used in step-a) is same as defined in the third embodiment.

[0064] In the process of the fifth embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.

[0065] In the process of the fifth embodiment, isolating involves removing the solvent from the mixture used in step-c) is same as defined in the first embodiment.

[0066] In the process of the fifth embodiment, wherein the Asciminib free base (2) used in step-a) can be amorphous, crystalline or any other physical form.

[0067] The amorphous solid dispersion of Asciminib hydrochloride (1) or Asciminib free base (2) of the present invention can be further micronized or milled to achieve desired particle size distribution to make suitable formulation.

[0068] In the sixth embodiment, the present invention provides a process for the preparation of amorphous form of Asciminib hydrochloride (1), comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, and b) isolating the amorphous form of Asciminib hydrochloride (1).

[0069] In the process of the sixth embodiment, the suitable solvent used in step-a) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; or its mixture thereof.

[0070] In the process of the sixth embodiment, isolating involves removing the solvent from the mixture used in step-b) is same as defined in the first embodiment.

[0071] In the seventh embodiment, the present invention provides a process for the preparation of amorphous form of Asciminib hydrochloride (1), comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) optionally filtering the mixture obtained in step-a), andc) spray drying the filtrate obtained in step-a) or step-b) to get amorphous form of Asciminib hydrochloride (1).

[0072] In the process of the seventh embodiment, the suitable solvent used in step- a) is same as defined in sixth embodiment.

[0073] In the eighth embodiment, the present invention provides a process for the preparation of amorphous form of Asciminib hydrochloride (1), comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) optionally filtering the mixture obtained in step-a), and c) lyophilizing the filtrate obtained in step-a) or step-b) to get amorphous form of Asciminib hydrochloride (1).

[0074] In the process of the eighth embodiment, the suitable solvent used in step-a) is same as defined in sixth embodiment.

[0075] In the nineth embodiment, the present invention provides solid-state forms of Asciminib hydrochloride (1) having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with total impurities less than 1.0%, more preferably less than 0.5%.

[0076] In the tenth embodiment, the present invention provides solid-state forms of Asciminib hydrochloride (1) obtained according to the present invention is having loss on drying less than 10.0% (w / w), preferably less than 5.0% (w / w), more preferably less than 3.0% (w / w).

[0077] In the eleventh embodiment, the present invention provides solid-state forms of Asciminib hydrochloride (1) obtained in the present invention is free of any degradation impurities preferably less than 0.15% and more preferably less than 0.10%(w / w).

[0078] In the twelfth embodiment, the present invention provides solid-state forms of Asciminib hydrochloride (1) obtained in the present invention is having Acid impurity and THP impurity are less than 0.15%, preferably not detected.Acid impurity THP impurity

[0079] In the thirteenth embodiment, the present invention provides solid-state forms of Asciminib hydrochloride (1) is essentially free of residual solvents. “Essentially free of residual solvents” herein refers to solid-state forms of Asciminib hydrochloride (1) having less than 5000ppm of each solvent and preferably less than 3000 pm and still more preferably less than 100 ppm. Organic solvents used in the present invention involve methanol, ethanol, methyl tertiary butyl ether, isopropyl acetate, tetrahydrofuran, toluene, and ethyl acetate.

[0080] It is an object of the present invention to provide stable solid dispersions of Asciminib hydrochloride (1).

[0081] In the fourteenth embodiment, the physical stability of solid-state forms of Asciminib hydrochloride (1) with different ratios of excipients was determined by storing the samples at 40°C / 75% relative humidity (RH) and 2-8°C. The samples were tested by PXRD analysis. The solid dispersion of Asciminib hydrochloride (1) with different ratios of excipients was found to be physically stable at 40°C / 75% relative humidity (RH) conditions and 2-8°C up to 6 months

[0082] Therefore, the objective of the present invention is achieved through the preparation of storage stable solid-state forms of Asciminib hydrochloride (1).

[0083] In the fifteenth embodiment, pharmaceutical composition comprising solid- state forms of Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient is formulated in a manner suitable for the route of administration to be used.

[0084] As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0085] In the sixteenth embodiment, the solid-state form of Asciminib hydrochloride (1) dispersion with suitable excipient, is characterized by particle size distribution wherein, d90 is less than 200 pm, preferably less than 100 pm and more preferably not more than 50 pm.

[0086] In the seventeenth embodiment, the solid-state form of Asciminib hydrochloride (1) dispersion with suitable excipient, is characterized by particle size distribution wherein, d50 is less than 100 pm, preferably less than 50 pm and more preferably less than 25 pm.

[0087] In the eighteenth embodiment, the solid-state form of Asciminib hydrochloride (1) dispersion with suitable excipient, is characterized by particle size distribution wherein, dlO is less than 20 pm, preferably less than 10 pm and more preferably less than 5 pm.P-XRD Method of Analysis:

[0088] PXRD analysis of solid dispersion of Asciminib hydrochloride (1) was carried out by using BRUKER / D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A0and continuous scan speed of 0.037min.

[0089] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.Examples

[0090] Example- 1: Preparation of amorphous form of Asciminib hydrochloride (1).Asciminib hydrochloride (5.0 g) was added to methanol (200 mL) at room temperature and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 46%; The PXRD pattern of the obtained compound is shown in figure 1.

[0091] Example-2: Preparation of amorphous form of Asciminib hydrochloride (1).Asciminib hydrochloride (500 mg) was added to dimethylsulfoxide (10 mL) at room temperature and stirred to get a clear solution. Freeze dried (lyophilization) the obtained solution at -10 to -40°C and dried to obtain amorphous form of Asciminib hydrochloride (1). Yield: 90%.

[0092] Example-3: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with hydroxypropyl beta cyclodextrin (HPpCD)Asciminib hydrochloride (1) (100 mg) was added to methanol (25 mL) at 25 30°C. To this hydroxypropyl beta cyclodextrin (HPpCD) (250 mg) was added. The solution was transferred into a Buchi flask and heated to 45-55°C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound. Yield: 91.5%.

[0093] Example-4: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Salcaprozate sodiumAsciminib hydrochloride (1) (100 mg) was added to methanol (25 mL) at 25 30°C. To this Salcaprozate sodium (250 mg) was added. The solution was transferred into a Buchi flask and heated to 45-55°C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound.Yield: 91.5%.

[0094] Example-5: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with hydroxypropyl beta cyclodextrin (HPpCD)Asciminib hydrochloride (1) (3 g) was added to methanol (300 mL) at room temperature. To this hydroxypropyl beta cyclodextrin (HPpCD) (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 46.66%.

[0095] Example-6: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Salcaprozate sodiumAsciminib hydrochloride (3 g) was added to methanol (400 mL) at room temperature. To this Salcaprozate sodium (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 49.5%

[0096] Example-7: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Polyvinylpyrrolidone-K-30 (PVP-K-30)Asciminib hydrochloride (3 g) was added to methanol (300 mL) at room temperature. To this PVP-K-30 (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 59%; The PXRD pattern of the obtained compound is shown in figure 2.

[0097] Example-8: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with SoluplusAsciminib hydrochloride (3 g) was added to methanol (250 mL) at room temperature. To this Soluplus (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 53.3%; The PXRD pattern of the obtained compound is shown in figure 7.

[0098] Example-9: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Eudragit.Asciminib hydrochloride (3 g) was added to methanol (380 mL) at room temperature. To this Eudragit (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 53.3%.

[0099] Example-10: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Sulfobutylether-P-cyclodextrin (SBCED).Asciminib hydrochloride (3 g) was added to methanol (380 mL) at room temperature. To this Sulfobutylether-P-cyclodextrin (SBCED) (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 53.3%.

[0100] Example-11: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib hydrochloride (3 g) was added to methanol (160 mL) at room temperature. To this Methylene dichloride (120 mL) and HPMC-E3 (7.5 g) were added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°C Outlet Temperature : 30°C Aspirator : 70% Feeding rate : 20 mL / min N2 Pressure : 2.0 kg / cm2Yield: 49.5%.

[0101] Example-12: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl cellulose (HPC)Asciminib hydrochloride (3 g) was added to Methanol (160 mL) at room temperature. To this Methylene dichloride (120 mL) and hydroxypropyl cellulose(7.5 g) were added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 49.5%; The PXRD pattern of the obtained compound is shown in figure-4.

[0102] Example- 13: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with CopovidoneAsciminib hydrochloride (3 g) was added to methanol (400 mL) at room temperature. To this Copovidone (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 56.2%; The PXRD pattern of the obtained compound is shown in figure-5.

[0103] Example-14: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose (HPMC)Asciminib hydrochloride (3 g) was added to a mixture of methanol and methylene dichloride (450 mL) at room temperature. To this Hydroxypropyl methylcellulose (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 56.2%; The PXRD pattern of the obtained compound is shown in figure-6.

[0104] Example- 15: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-AS (HPMC-AS)Asciminib hydrochloride (3 g) was added to a mixture of methanol and methylene dichloride (450 mL) at room temperature. To this Hydroxypropyl methylcellulose- AS (HPMC-AS) (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 56.2%; The PXRD pattern of the obtained compound is shown in figure-3.

[0105] Example-16: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with PEG-6000Asciminib hydrochloride (1) (3 g) was added to methanol (450 mL) at room temperature. To this PEG-6000 (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 56.2%.

[0106] Example- 17: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with hydroxypropyl beta cyclodextrin (HPpCD)Asciminib hydrochloride (1 g) was added to dimethyl sulfoxide (DMSO) (60 mL) and water (2.50 mL) at room temperature. To this Hydroxypropyl beta cyclodextrin (HPpCD) (2 g) was added and stirred. The reaction mass was freeze dried (lyophilization) at -10 to -40°C and dried to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with hydroxypropyl beta cyclodextrin (HPpCD) Yield: 88.6%.

[0107] Example- 18: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Salcaprozate sodiumAsciminib hydrochloride (1 g) was added to Dimethyl sulfoxide (DMSO) (60 mL) and water (2.50 mL) at room temperature. To this Salcaprozate sodium (2.5 g) was added and stirred. The reaction mass was freeze dried (lyophilization) at -10 to - 40°C and dried to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with Salcaprozate sodium. Yield: 85.7%.

[0108] Example- 19: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with maltodextrinAsciminib hydrochloride (100 mg) was added to Dimethyl sulfoxide (DMSO) (10 mL) and water (10 mL) at room temperature. To this Maltodextrin (250 mg) was added and stirred. The reaction mass was freeze dried (lyophilization) at -10 to - 40°C and dried to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with maltodextrin. Yield: 91.4%.

[0109] Example-20: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with mannitolAsciminib hydrochloride (1 g) was added to dimethyl sulfoxide (DMSO) (60 mL) and water (10 mL) at room temperature. To this Mannitol (2.5 g) was added and stirred. The reaction mass was freeze dried (lyophilization) at -10 to -40°C and dried to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with mannitol. Yield: 91.4%.

[0110] Example-21: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with isomaltAsciminib hydrochloride (1 g) was added to dimethyl sulfoxide (DMSO) (60 mL) and water (10 mL) at room temperature. To this Isomalt (2.5 g) was added and stirred. The reaction mass was freeze dried (lyophilization) at -10 to -40°C and dried to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with isomalt. Yield: 94.3%.

[0111] Example-22: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Polyvinylpyrrolidone-K-30 (PVP-K-30)Asciminib free base (5.0 g) was added to methanol (150 mL) at room temperature and stirred to get a clear solution. To this 18-20% methanolic hydrochloric acid was added at the same temperature, then polyvinylpyrrolidone-K-30 (PVP-K-30) (12.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 60 %.

[0112] Example-23: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Polyvinylpyrrolidone-K-30 (PVP-K-30)Asciminib free base (5.0 g) was added to methanol (150 mL) at room temperature and stirred to get a clear solution. To this Polyvinylpyrrolidone-K-30 (PVP-K-30) (7.5 g) was added and stirred to get amorphous solid dispersion of Asciminib free base, then methanol was added to the obtained solid to get clear solution. To this Methanolic hydrochloric acid was added. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 60%

[0113] Example-24: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Polyvinylpyrrolidone-K-30 (PVP-K-30)Asciminib free base (5.0 g) was added to methanol (150 mL) at room temperature and stirred to get a clear solution. To this Polyvinylpyrrolidone-K-30 (PVP-K-30) (7.5 g) was added and stirred to get amorphous solid dispersion of Asciminib free base, then dimethyl sulfoxide was added to the obtained solid to get clear solution.To this aqueous hydrochloric acid was added to the reaction mixture. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 90%

[0114] Example-25: Preparation of amorphous solid dispersion of Asciminib with Hydroxypropyl cellulose (HPC)Asciminib free base (3 g) was added to methanol (160 mL) at room temperature. To this hydroxypropyl cellulose (HPC) (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2

[0115] Example-26: Preparation of amorphous solid dispersion of Asciminib with CopovidoneAsciminib free base (3 g) was added to methanol (400 mL) at room temperature. To this copovidone (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2

[0116] Example-27: Preparation of amorphous solid dispersion of Asciminib with SoluplusAsciminib free base (3 g) was added to methanol (400 mL) at room temperature. To this Soluplus (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2

[0117] Example-28: Preparation of amorphous solid dispersion of Asciminib with Polyvinylpyrrolidone-K-30 (PVP-K-30)Asciminib free base (3 g) was added to methanol (400 mL) at room temperature. To this polyvinylpyrrolidone-K-30 (PVP-K-30) (7.5 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2

[0118] Example-29: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to methanol (15 vol) at room temperature and stirred to get a clear solution. To the obtained solution, aqueous hydrochloric acid (1.1 eq) was added. To this methylene dichloride (25 vol) was added and stirred, then Hydroxypropyl methylcellulose-E3 (HPMC-E3) (4.0 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 9.

[0119] Example-30: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to a mixture of methanol (15 vol) and methylene dichloride (25 vol) at room temperature and stirred to get a clear solution. To this aqueous hydrochloric acid (1.1 eq) was added to the reaction mixture, thenHydroxypropyl methylcellulose-E3 (HPMC-E3) (4.0 g) was added and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 9.

[0120] Example-31: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to methanol (15 vol) at room temperature and stirred to get a clear solution. To the obtained solution, aqueous hydrochloric acid (1.1 eq) was added. To this methylene dichloride (25 vol) was added and stirred, then Hydroxypropyl methylcellulose-E3 (HPMC-E3) (2.5 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45 °CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 8.

[0121] Example-32: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to a mixture of methanol (15 vol) and methylene dichloride (25 vol) at room temperature and stirred to get a clear solution. To this aqueous hydrochloric acid (1.1 eq) was added to the reaction mixture, then Hydroxypropyl methylcellulose-E3 (HPMC-E3) (2.5 g) was added and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75°COutlet Temperature : 45°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 8.

[0122] Example-33: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to methanol (15 vol) at room temperature and stirred to get a clear solution. To the obtained solution, aqueous hydrochloric acid (1.1 eq) was added. To this methylene dichloride (25 vol) was added and stirred, then Hydroxypropyl methylcellulose-E3 (HPMC-E3) (5.0 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45 °CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 10.

[0123] Example-34: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to a mixture of methanol (15 volumes) and methylene dichloride (25 vol) at room temperature and stirred to get a clear solution. To this aqueous hydrochloric acid (1.1 eq) was added to the reaction mixture, thenHydroxypropyl methylcellulose-E3 (HPMC-E3) (5.0 g) was added and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45 °CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 10.

[0124] Example-35: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to methanol (15 vol) at room temperature and stirred to get a clear solution. To the obtained solution, aqueous hydrochloric acid (1.1 eq.) was added. To this methylene dichloride (25 vol) was added and stirred, then Hydroxypropyl methylcellulose-E3 (HPMC-E3) (7.5 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45 °CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 11.

[0125] Example-36: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)Asciminib free base (5.0 g) was added to a mixture of methanol (15 vol) and methylene dichloride (25 vol) at room temperature and stirred to get a clear solution. To this aqueous hydrochloric acid (1.1 eq) was added to the reaction mixture, then Hydroxypropyl methylcellulose-E3 (HPMC-E3) (7.5 g) was added and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:Inlet Temperature : 75 °COutlet Temperature : 45 °CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 75%; The PXRD pattern of the obtained compound is shown in figure 11.

Claims

We claim:

1. A process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding a solution of hydrochloric acid to the solution obtained in step a), c) optionally, adding second solvent or mixture of solvents to step b), d) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-c), and e) isolating the solid dispersion of Asciminib hydrochloride (1). wherein, the process involves without isolation of Asciminib hydrochloride (1); wherein the ratio of Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient ranges from about 1:0.5 to about 1:5 (w / w).

2. A process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), c) isolating the solid dispersion of Asciminib free base, d) dissolving solid dispersion of Asciminib free base (2) in a solvent or mixture of solvents e) adding a solution of hydrochloric acid to step d), and f) isolating the solid dispersion of Asciminib hydrochloride (1). wherein, the process involves without isolation of Asciminib hydrochloride (1); wherein the ratio of Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient ranges from about 1:0.5 to about 1:5 (w / w).

3. The process as claimed in claim 1 to 2, wherein the solution of hydrochloric acid is selected from but not limited to alcoholic hydrochloric acid, aqueoushydrochloric acid, concentrated hydrochloric acid or ethyl acetate hydrochloric acid.

4. The process as claimed in claim 3, wherein the alcoholic hydrochloric acid is selected from methanolic hydrochloric acid, ethanolic hydrochloric acid and the like.

5. A process for the preparation of solid dispersion comprising Asciminib free base (2) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Asciminib free base (2).

6. A process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with hydroxypropyl methylcellulose-E3 (HPMC-E3), comprising the steps of: a) dissolving Asciminib free base (2) in methanol, b) adding methanolic hydrochloric acid to the solution obtained in step a), c) adding hydroxypropyl methylcellulose-E3 (HPMC-E3) to the solution obtained in step-b), and d) isolating the solid dispersion of Asciminib hydrochloride (1). wherein, the process involves without isolation of Asciminib hydrochloride (1); wherein the ratio of Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient ranges from about 1:0.8.

7. A process for the preparation of solid dispersion comprising Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Asciminib hydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Asciminib hydrochloride (1).wherein the ratio of Asciminib hydrochloride (1) with at least one pharmaceutically acceptable excipient ranges from about 1: 0.5 to about 1:5 (w / w).

8. The process as claimed in claim 1 to 7 wherein, the solvent is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, and the like; chloro solvents such as dichloromethane, 1, 2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; water or its mixture thereof.

9. The process as claimed in claim 1 to 7 wherein, the pharmaceutically acceptable excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, Polyvinylpyrrolidone-K-30 (PVP-K-30), polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl beta cyclodextrin (HPpCD), Salcaprozate sodium, sodium caprylate, Soluplus, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-ES (HPMC-ES), hydroxyethyl methyl cellulose succinate (HEMCS), sulfobutylether-P-cyclodextrin (SBCED), Hydroxypropyl methylcellulose-E3 (HPMC-E3), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), syloid, eudragit, copovidone, maltodextrin, mannitol or isomalt.

10. The process as claimed in claim 1 to 7 wherein, isolating the solid dispersion of Asciminib free base (2) or its hydrochloride (1) involves removal of solvent by decantation, evaporation under reduced pressure, flash evaporation, vacuumdrying, 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 by gravity or suction, thin film drying, centrifugation.

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