Related Application:

This application claims the benefit of priority of our Indian patent application number 202241020537 filed on 05 April 2022, which is incorporated herein by reference.

Field of the Invention:

The present invention relates to a solid dispersion of 3-(2,6-difluoro-3,5- dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-te trahydro-2H-pyrrolo[3',2':5,6] pyrido[4,3-d]pyrimidin-2-one and process for its preparation thereof.

Background of the Invention:

Pemigatinib is chemically known as 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8- (morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5 ,6]pyrido[4,3-d]pyrimidin-2-one, represented by the following structural formula.

Formula- 1

Pemigatinib is a small molecule tyrosine kinase inhibitor of fibroblast growth factor receptor family (FGFR1, FGFR2, FGFR3 and FGFR4). Pemigatinib inhibits FGFR phosphorylation and signalling and decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements.

Pemigatinib is approved in the USFDA and Europe for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. Pemigatinib is being marketed by Incyte under the brand name Pemazyre. 3-(2,6-difhioro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4- ylmethyl)-l,3,4,7- tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one was disclosed in US9611267 B2 (herein described as US ‘267).

US’267 discloses process for the preparation of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l- ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo [3',2':5,6]pyrido[4,3-d]pyrimidin- 2-one.

Solid forms of 3-(2,6-difhioro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4- ylmethyl)- l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimid in-2-one was disclosed in WO2019213544 A2.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.

Brief description of the Invention:

The present invention relates to a solid dispersion of Pemigatinib.

The present invention also relates to a process for the preparation of solid dispersion of Pemigatinib. Brief description of Drawings:

Figure-1: Illustrates the PXRD pattern of solid dispersion of Pemigatinib with HPMC-E5.

Detailed description of the Invention:

As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2- dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3- pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.

As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one -phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.

As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.

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

In the first embodiment, the present invention provides a solid dispersion of Pemigatinib of formula- 1 with one or more pharmaceutically acceptable excipients.

In the first embodiment, the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macro gol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

In the second embodiment, the present invention provides a process for the preparation of solid dispersion of Pemigatinib of formula- 1 with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Pemigatinib of formula- 1 , b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Pemigatinib of formula- 1 with one or more pharmaceutically acceptable excipients.

In the process of the second embodiment, providing a solution of Pemigatinib of formula- 1 in step-a) comprises dissolving Pemigatinib of formula- 1 in a suitable solvent or a mixture of solvents at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

In the process of second embodiment, the suitable solvent used in step-a) is selected from alcohol solvent and chloro solvent.

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

In the first aspect of the second embodiment, the present invention provides a process for the preparation of solid dispersion of Pemigatinib of formula- 1 with HPMC-E5, which comprises: a) providing a solution of Pemigatinib of formula- 1 , b) adding HPMC-E5 to the solution obtained in step-a), and c) isolating the solid dispersion of Pemigatinib of formula- 1 with HPMC-E5.

In the process of the first aspect of the second embodiment, providing a solution of Pemigatinib of formula- 1 in step-a) comprises dissolving Pemigatinib of formula- 1 in methanol and dichloromethane at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free. The solid dispersion of Pemigatinib of formula- 1 with HPMC-E5 is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure- 1.

In the process of second embodiment, isolating involves removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or by any other suitable techniques known in the art.

In the process of the second embodiment, drying solid dispersion of Pemigatinib of formula- 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 than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

Solid dispersion of Pemigatinib prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.

In the present invention, the starting material of Pemigatinib of formula- 1 can be used in the form of amorphous or crystalline or any other physical form which is prepared from any of the processes known in the art.

In the present invention, pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.

In the process of the present invention the resulting, solid dispersion of Pemigatinib can be amorphous, crystalline or a mixture thereof. It is an object of the present invention to provide storage stable solid dispersions of Pemigatinib.

The stability of solid dispersion of Pemigatinib is determined by storing the samples at 2°C to 8°C temperature for about 12 months. The samples were analyzed by X-ray powder diffraction pattern (XRPD). The solid dispersion of Pemigatinib is found to be stable at 2°C to 8°C temperature for about 12 months.

After storage, the PXRD diffractogram of solid dispersions of Pemigatinib were found to be similar the initial PXRD as illustrated in Figure- 1.

Therefore, the objective of the present invention is achieved through the preparation of storage stable solid dispersion of Pemigatinib.

In yet another embodiment, pharmaceutical composition comprising solid dispersion of Pemigatinib of formula- 1 and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

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

P-XRD Method of Analysis:

PXRD analysis of solid dispersion of Pemigatinib was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of solid dispersion of Pemigatinib with HPMC-E5.

Methanol (150.0 ml) and dichloromethane (50.0 ml) were added to Pemigatinib (2.0 gm) at 25-30°C. Heated the mixture to 60-65°C and stirred for 20 minutes. Filtered the mixture to make it particle free. HPMC-E5 (3.0 gm) was added to the mixture at 25-30°C and stirred for 15 minutes. Spray dried the obtained solution using spray dryer through following conditions: Inlet temperature: 60-65°C

Feed rate: 10 ml/min

Aspirator flow rate: 70%

Nitrogen pressure: 2.0 kg / cm ²

Yield: 0.8 gm; The PXRD pattern of the obtained compound is illustrated in figure- 1.