DESC:SOLID STATE FORMS OF RIPRETINIB
FIELD OF THE INVENTION
The present invention relates to solid state forms of Ripretinib and process for the preparation thereof. The present invention also relates to amorphous solid dispersion of Ripretinib with Eudragit and process for the preparation thereof.

BACKGROUND OF THE INVENTION
Ripretinib is the adopted name for a drug chemically described as 1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluoro-phenyl)-3-phenylurea and is represented by structural Formula I.

Formula I
Ripretinib is a kinase inhibitor and is marketed in USA under the brand name as QINLOCK ® tablets in 50 mg strength for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.
U.S. patent no. 8,461,179 discloses general procedure for the preparation of Ripretinib.
PCT publication no. WO2020185812A1 discloses solid state forms of Ripretinib, processes for preparation thereof.
PCT publication no WO2021138483A1 discloses amorphous solid dispersion of Ripretinib with HPMC-AS.
Polymorphism is an important aspect of pharmaceutical drug in terms of its solubility and bioavailability. One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. Different crystalline forms of polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The different solubility of the drug compound affects the bioavailability of drug at target site.
To improve the physicochemical properties of the Ripretinib compound, there remains a need for alternate solid forms of Ripretinib and their preparative processes. The inventors of present invention have found out novel solid state form of Ripretinib.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods, and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.08°, 8.10°, 11.2°, 12.0°, 14.3°, 15.0°, 16.5°, 18.18°, 19.5°, 21.71°, 22.39° and 23.96° ± 0.2° 2?.
In another embodiment, the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 2.
In another embodiment, the present invention provides a process for the preparation of crystalline form R2 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) isolating crystalline form R2 of Ripretinib.
In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form R2 of Ripretinib and at least one pharmaceutically acceptable excipient.
In another embodiment, the present application relates to amorphous solid dispersion of Ripretinib with a suitable pharmaceutically acceptable excipient.
In another embodiment, the present application relates to amorphous solid dispersion of Ripretinib with Eudragit.
In another embodiment, the present invention provides amorphous solid dispersion of Ripretinib with Eudragit (1: 3 w/w) characterized by X-ray diffraction pattern as depicted in Figure 3.
In another embodiment, the present invention provides amorphous solid dispersion of Ripretinib with Eudragit (1: 5 w/w) characterized by X-ray diffraction pattern as depicted in Figure 4.
In another aspect, the present invention provides a pharmaceutical composition comprising amorphous solid dispersion of Ripretinib with Eudragit and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of crystalline form R1 of Ripretinib obtained as per example-1.
Figure 2 is an illustration of a PXRD pattern of crystalline form R2 of Ripretinib obtained as per example-2.
Figure 3 is an illustration of a PXRD pattern of amorphous solid dispersion of Ripretinib with Eudragit (1: 3 w/w) obtained as per example 3.
Figure 4 is an illustration of a PXRD pattern of amorphous solid dispersion of Ripretinib with Eudragit (1: 5 w/w) obtained as per example 4.

DETAILED DESCRIPTION OF THE INVENTION
While the specification concludes with the claims particularly pointing and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25oC and normal pressure unless otherwise designated. All temperatures are in Degrees Celsius unless specified otherwise. The present invention can comprise (open ended) of the components of the present invention as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The starting materials used in this aspect, Ripretinib, may be obtained according to any method known in the art.
In one embodiment, the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.08°, 8.10°, 11.2°, 12.0°, 14.3°, 15.0°, 16.5°, 18.18°, 19.5°, 21.71°, 22.39° and 23.96° ± 0.2° 2?.
In another embodiment, the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 2.
In another embodiment, the present invention provides a process for the preparation of crystalline form R2 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) isolating crystalline form R2 of Ripretinib.
In a preferred embodiment the suitable organic solvent or anti-solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, water or mixtures thereof.
In another aspect, the starting material Ripretinib is any crystalline form known in the literature. In yet another embodiment, the starting material Ripretinib is crystalline form R1 of Ripretinib.
In another embodiment, the present invention provides a process for the preparation of crystalline form R2 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) optionally, adding seed crystals of crystalline form of Ripretinib;
iv) isolating crystalline form R2 of Ripretinib.
In aforementioned embodiment, once obtained, the crystals of Form R2 of Ripretinib may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
In one aspect, the crystalline form R2 of Ripretinib is an anhydrous form.
In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form R2 of Ripretinib and at least one pharmaceutically acceptable excipient.
In another embodiment, the crystalline form R2 of Ripretinib of the present invention is stable under thermal, humid and stress conditions. Further, the crystalline form R2 of Ripretinib of the present invention exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Ripretinib.
In another embodiment, the crystalline form R2 of Ripretinib of the present invention or the pharmaceutical compositions thereof, comprises Ripretinib with a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
The suitable ‘organic solvent’ or "solvent" or “anti-solvent” at any stage of the process of the present invention may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, octanol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol; ethers, such as diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate and t-butyl acetate; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; nitriles, such as acetonitrile; hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and tetraline; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, carbon disulphide, acetic acid and the like; water; or mixtures thereof.
The removal of solvent at any stage of the process of the present invention may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present invention may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques. The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In an embodiment, Ripretinib of present invention has average particle size of particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less than 10 µm, less than 5 µm or any other suitable particle sizes. In another embodiment, Ripretinib of present invention may have particle size distribution: D10 of particles smaller than 20 µm, smaller than 15 µm, smaller than 10 µm, or smaller than 5 µm; D50 of particles smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm; D90 of particles smaller than 200 µm, smaller than 175 µm, smaller than 150 µm, smaller than 140 µm, smaller than 130 µm, smaller than 120 µm, smaller than 110 µm, smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Ripretinib particles may be measured using any techniques known in the art. For example, particle size distributions of Ripretinib particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term “D10” in the context of the present invention is 10% of the particles by volume are smaller than the D10 value and 90% particles by volume are larger than the D10 value. “D50” in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. “D90” in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.
In an embodiment, Ripretinib of present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.

In another embodiment, the present application relates to amorphous solid dispersion of Ripretinib with a suitable pharmaceutically acceptable excipient.
In another embodiment, the present application relates to amorphous solid dispersion of Ripretinib with Eudragit.
The amount of Ripretinib in amorphous solid dispersion with Eudragit may be about 2% w/w to about 98% w/w, or about 5% w/w to about 95% w/w, or about 10% w/w to about 90% w/w, or about 20% w/w to about 80% w/w, or about 30% w/w to about 70% w/w, or about 40% w/w to about 60% w/w, or about 50% w/w.
In another embodiment, the present application relates to a process for preparing amorphous solid dispersion of Ripretinib comprising:
i) dissolving a mixture of Ripretinib and Eudragit in a suitable solvent and
ii) isolating amorphous solid dispersion of Ripretinib.
Any physical form of Ripretinib may be used for the preparation of solid dispersion of Ripretinib of the present invention.
The suitable solvent for dissolving Ripretinib in step a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran; esters such as ethyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform; alcohols such as methanol, ethanol, propanol, isopropanol; water; mixtures thereof. In yet another embodiment, the solvent for dissolving Ripretinib may be a mixture of THF and water.
The step a) may be performed at a temperature of about 0 °C to about the boiling point of the solvent. In embodiments of step a), the solution comprising a suitable pharmaceutically acceptable excipient and Ripretinib in a suitable solvent is stirred for a sufficient time.
In embodiments of step a), Eudragit may be mixed with Ripretinib and the mixture may be dissolved in a suitable solvent. Alternatively, Eudragit may be added to a solution of Ripretinib in a suitable solvent.
In embodiments of step b), isolating amorphous solid dispersion of Ripretinib may involve one or more methods including removal of solvent (by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like), cooling, concentrating the reaction mass, adding seed crystals to induce precipitation, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. Specifically, techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of Ripretinib. More specifically, distillation using a rota-vapor device such as a Buchi Rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of Ripretinib with a suitable pharmaceutically acceptable excipient.
The solid obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous solid dispersion of Ripretinib.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The obtained amorphous solid dispersions may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
It was found that the amorphous solid dispersion of Ripretinib with Eudragit is stable and has excellent physico-chemical properties. The amorphous solid dispersion of the present application may be easily formulated into a pharmaceutical composition comprising Ripretinib.
In one embodiment, the amorphous solid dispersion of Ripretinib with Eudragit may have no more than about 5% w/w of any crystalline form of Ripretinib.
Suitable temperatures for the reaction at any stage of the process of the present invention may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures.
The removal of solvent at any stage of the process of the present invention may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present invention may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques. The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In another embodiment, the present invention provides pharmaceutical compositions comprising crystalline form R2 of Ripretinib or amorphous solid dispersion of Ripretinib, prepared according to method disclosed herein alone. Further the present invention provides a process of preparing a pharmaceutical composition comprising alone or in combination with other drugs. Conveniently various pharmaceutically acceptable excipients can be employed in a process according to the present invention.
In another embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present invention. A thorough discussion of pharmaceutically acceptable excipients is presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference.
The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray diffraction was measured using PANalytical X-ray diffractometer, Model: Empyrean. System description: CuK-Alpha 1 wavelength= 1.54060, voltage 45 kV, current 40 mA, divergence slit = 1/4°; Sample stage=Reflection-spinner. Revolution time [s]: 1.000; Scan type: Pre-set time; Detector – Pixcel; Measurement parameters: Start Position [°2Th.]: 3.0066; End Position [°2Th.]: 39.9916; Step Size [°2Th.]: 0.0130; Scan Step time [s]: 1.000.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2o) of 7.9o" means "having a diffraction peak at a diffraction angle (2?) of 7.7o to 8.1o”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

Examples
Example 1: Preparation of crystalline form R1 of Ripretinib:
Ripretinib (Formula I, 7.3 g) was charged into reactor. DMF (29 mL) was charged at room temperature and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (21 mL). The solid was charged into reactor and DMF (20 mL) was added and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (20 mL). The solid was charged into reactor and water (24 mL) was added at 25-35°C and the reaction mass was stirred for 30-40 min. The solid was filtered under suction and the solid was washed with water (6 mL). The solid was dried under vacuum at 45-50° C for 1-2 h to obtain crystalline form R1 of Ripretinib.

Example 2: Preparation of crystalline form R2 of Ripretinib:
Ripretinib (1 g) was suspended in ethanol (10 mL). The reaction mass was stirred at 25°C for about 3-4 hours. The reaction mass was filtered under vacuum and dried in VTD at 80°C about 4-5 hours to obtain crystalline form R2 of Ripretinib.

Example 3: Preparation of amorphous solid dispersion of Ripretinib with Eudragit L100:
Ripretinib (0.1 g) and Eudragit L100 (0.3 g) was subjected to milling in ball mill (Agate jar, frequency: 25Hz time: 2 hours). The obtained solid corresponds to amorphous Ripretinib as confirmed by PXRD.

Example 4: Preparation of amorphous solid dispersion of Ripretinib with Eudragit L100:
Ripretinib (0.1 g) and Eudragit L100 (0.5 g) was dissolved in mixture of THF (7.2 mL) and water (0.8 mL) at 55-60 °C and subjected to dry distillation over rotavapour under vacuum at 55-60°C. The obtained solid corresponds to amorphous Ripretinib as confirmed by PXRD.

,CLAIMS:WE CLAIM:

1) A crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.08°, 8.10°, 11.2°, 12.0°, 14.3°, 15.0°, 16.5°, 18.18°, 19.5°, 21.71°, 22.39° and 23.96° ± 0.2° 2?.

2) The crystalline form R2 of Ripretinib, as claimed in claim 1, characterized by X-ray diffraction pattern as depicted in Figure 2.

3) A process for the preparation of crystalline form R2 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) isolating crystalline form R2 of Ripretinib.

4) The process of claim 3, wherein the suitable organic solvent is ethanol.

5) An amorphous solid dispersion of Ripretinib with Eudragit.

6) The amorphous solid dispersion as claimed in claim 5, wherein Eudragit is Eudragit L100.

7) The amorphous solid dispersion of Ripretinib with Eudragit, characterized by PXRD pattern of Fig. 3 or Fig. 4.

8) A process for preparing amorphous solid dispersion of Ripretinib comprising:
i) dissolving a mixture of Ripretinib and Eudragit in a suitable solvent and
ii) isolating amorphous solid dispersion of Ripretinib.

9) The process as claimed in claim 8, wherein the suitable solvent is a mixture of THF and water.