DESC:FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention – A solid dispersion of Ponatinib hydrochloride and process of preparation thereof.

2. Applicant(s)

(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED

(b) NATIONALITY: An Indian Company.

(c) ADDRESS : Alembic Research Centre, Alembic Road,
Vadodara-390 003, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which it is to be performed :

TECHNICAL FIELD:
The present subject matter relates to a solid oral pharmaceutical composition comprising ponatinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. The present subject matter also relates to pharmaceutical compositions comprising a solid dispersion of ponatinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. Furthermore, it also relates to process of preparation of such compositions, and uses thereof.

BACKGROUND:
Ponatinib hydrochloride, has a chemical name 3-(imidazo[1,2-b]pyridazin-3ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) phenyl}benzamide hydrochloride. Ponatinib hydrochloride is represented by the following chemical structure according to Formula (I).
.HCl
Formula I
Ponatinib hydrochloride is a kinase inhibitor which is indicated for the treatment of chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
US 8,114,874 describe Ponatinib and its hydrochloride salt and a process for the preparation thereof. US 9,493,470 describe crystalline Ponatinib hydrochloride Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K and a process of preparation thereof; further US ’470 patent discloses amorphous form of Ponatinib hydrochloride. US 9,725,454 describe Form 1 and Form 8 of Ponatinib hydrochloride and a process of preparation of thereof. WO 2015085973 describes crystal modification 2 to modification 10 and amorphous form of Ponatinib HCl, and a process of preparation thereof. US 10,221,184 describe Form alpha a propylene glycol solvate and Form beta a benzyl alcohol solvate of Ponatinib hydrochloride and a process of preparation thereof. WO 2018232501 describes Form APO-I, Form APO-III, Form APO-IV and Form APO-V of Ponatinib hydrochloride and process of preparation thereof. WO 2019246479 describes Form Z an acetic acid solvated hydrate of Ponatinib hydrochloride and a process of preparation thereof.
In pharmaceutical dosage forms such as tablets, the conversion of one polymorphic form into another polymorphic form can be unfavourable, and results in different dissolution, hygroscopicity and pharmacokinetic properties. Thereby, the bioavailability of the active agent might be undesirably unpredictable due to polymorphic conversion. Therefore, active agents having different interchangeable polymorphs may lead to regulatory and commercial disadvantages. Consequently, there is a need to develop a solid form of Ponatinib hydrochloride salt having better stability and desired solubility and preparation thereof, which is commercially viable.
Solid dispersions of drugs are generally known to improve the stability and solubility of drug products. However, some of such amorphous solid dispersions are found to be unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present subject matter however provides stable amorphous solid dispersions of Ponatinib hydrochloride with improved solubility and stability and pharmaceutical composition comprising such solid dispersion containing Ponatinib hydrochloride and at least one pharmaceutical acceptable polymer and /or excipient.

SUMMARY OF THE SUBJECT MATTER:
An aspect of the present subject matter is to provide a solid dispersion of Ponatinib hydrochloride together with atleast one pharmaceutically acceptable excipient.
The solid dispersion of the present subject matter may be manufactured by processes such as adsorption, solvent evaporation, hot melt extrusion, freeze drying, spray drying, lyophilisation, complexation and use of anti-solvent precipitation and Supercritical fluid (SCF) technology.
Another aspect of the present subject matter is to provide process for preparation of solid dispersion comprising;
a. providing a solution comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipients;
b. removing solvent from the solution obtained in step (a); and
c. isolating a solid dispersion comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipient.
Another aspect of the present subject matter is to provide process for preparing a solid dispersion containing an amorphous form of ponatinib hydrochloride and one or more pharmaceutically acceptable carriers, which comprises;
a. providing a solution of Ponatinib or its salt and pharmaceutically acceptable carrier in suitable solvent(s),
b. adding antisolvent to the above solution of step (a)
c. isolating a solid dispersion containing an amorphous form of Ponatinib or its salt and one or more pharmaceutically acceptable carrier.

In another aspect, the present subject matter provides a pharmaceutical composition comprising solid dispersion of Ponatinib hydrochloride and atleast one pharmaceutical acceptable excipient.
In another aspect, the present subject matter relates to a pharmaceutical composition of Ponatinib. More particularly, this subject matter relates to pharmaceutical composition comprising amorphous Ponatinib, and to pharmaceutical compositions comprising a solid dispersion containing Ponatinib and at least one polymer / excipients. Furthermore present subject matter relates to methods for manufacturing such formulations and compositions and use thereof.

BRIEF DESCRIPTION OF THE DRAWINGS:
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Betadex-HPB obtained from example 5.
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Silicon dioxide obtained from example 18.
Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Hypromellose acetate succinate (1:3) obtained from example 12.
Fig 4 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Carbopol 71 G obtained from example 15.
Fig 5 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with HPC (1:3) obtained from example 7.
DETAILED DESCRIPTION OF THE SUBJECT MATTER:
The solid dispersion of the present subject matter may be manufactured by processes such as adsorption, solvent evaporation, hot melt extrusion, freeze drying, spray drying, lyophilisation, complexation and use of anti-solvent precipitation and Supercritical fluid (SCF) technology.
In an embodiment of the present subject matter is to provide a solid dispersion of Ponatinib hydrochloride together with atleast one pharmaceutically acceptable excipient, prepared by process comprising;
a. providing a solution comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipients;
b. removing solvent from the solution obtained in step (a); and
c. isolating a solid dispersion comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipient.
Another embodiment of the present subject matter is to provide process for preparing a solid dispersion containing an amorphous form of ponatinib hydrochloride and one or more pharmaceutically acceptable carriers, which comprises;
a. providing a solution of ponatinib or its salt and pharmaceutically acceptable carrier in suitable solvent(s),
b. adding antisolvent to the above solution of step (a)
c. isolating a solid dispersion containing an amorphous form of ponatinib or its salt and one or more pharmaceutically acceptable carrier.

In another aspect, the present subject matter provides a pharmaceutical composition comprising solid dispersion of Ponatinib hydrochloride and atleast one pharmaceutical acceptable excipient.

In another aspect, the present application relates to a pharmaceutical composition of ponatinib. More particularly, this invention relates to pharmaceutical composition comprising amorphous Ponatinib, and to pharmaceutical compositions comprising a solid dispersion containing Ponatinib and at least one polymer / excipients. Furthermore present subject matter relates to methods for manufacturing such formulations and compositions and to their use.

In yet another aspect, the solid dispersion comprising Ponatinib and the polymer and /or excipients is further mixed with one or more pharmaceutically acceptable excipients and / or additives to prepare pharmaceutical composition.

The excipients and / or additives are not particularly limited, so long as they are pharmaceutically acceptable. Examples of the excipients and / or additives include filler, binder, disintegrant, lubricant, glidant and the like.
In general, the term “solid dispersion” refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term “solid dispersion” as used herein, refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers. Further the term “solid dispersion” as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers with or without adsorbent/absorbent. By “amorphous drug substance,” it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
In an embodiment of the present subject matter, a solution in step (a) includes direct use of a reaction mixture containing Ponatinib hydrochloride that is obtained in the course of its synthesis or dissolving Ponatinib hydrochloride and pharmaceutically acceptable carrier in a suitable solvent or a mixture of solvents.
In embodiments, providing a solution at step (a) may be carried out by dissolving crystalline or amorphous Ponatinib hydrochloride and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.
In embodiments, a solution of Ponatinib hydrochloride and the excipient at step (a) may be prepared at any suitable temperatures of about 0°C to reflux temperature of the solvent used.
In embodiments, a solution of Ponatinib hydrochloride and the excipient may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.
In embodiments of the present subject matter, in step (a) amorphous form of Ponatinib hydrochloride may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Ponatinib hydrochloride and at least one pharmaceutically acceptable excipient.
The pharmaceutically acceptable polymer / excipients in step (a) include, but are not limited to copovidone, graft copolymer of polyethylene glycol, polyvinyl acetate phthalate, Hypromellose Cp-15, Hypromellose-CP-06 (HP-CP-06): Polyvinyl pyrollidone-30 (PVP-30), Polyvinyl pyrrolidone-25 (PVP-25), Hypromellose-CP-06, Polyvinyl pyrollidine-90 (PVP-90), Plasdone S-630, Plasdone S-630 Ultra, Silicon dioxide, Silicon dioxide (Syloid 244FP), Silicon dioxide (Syloid AL-1FP/63FP), Silicon dioxide (Syloid XDP), Colloidal silicon dioxide (Aerosil 200 Pharma), Neusilin, Neusilin: Polyvinyl pyrollidine-90 (PVP-90), Hydroxypropyl cellulose (HPC), Hydroxypropyl cellulose (HPC): Polyvinyl pyrollidine-90 (PVP-90)¸ Hypromellose-CP-06 (HP-CP-06) : Polyvinyl pyrollidine-30 (PVP-30), Hydroxypropyl betadex (HPB-Betadex) and Carbapol-974-Ppolyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, 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), croscarmellose sodium (CCS), crospovidone, hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of the present subject matter. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of the present subject matter without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Ponatinib hydrochloride with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Hydroxypropyl betadex (HPB-Betadex).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with hydroxyl propyl methyl cellulose acetate succinate (HPMCAS).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Hydroxypropyl cellulose (HPC).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with croscarmellose sodium (CCS).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Carbopol 974 P.
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Carbopol 71 G.
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-90 (PVP-90).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-30 (PVP-90).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-25 (PVP-90).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-25 (PVP-25) and silicon dioxide (Syloid 244FP).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-30 (PVP-30) and silicon dioxide (Syloid 244FP).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-90 (PVP-90) and silicon dioxide (Syloid 244FP).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Copovidone and silicon dioxide (Syloid 244FP).
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride.
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Hydroxypropyl methyl cellulose.
In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with silicon dioxide.
The suitable solvent that can be used include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, anisole, 2-methyl tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as heptane, cyclohexane, toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
In an embodiment of the present subject matter, suitable techniques which can be used for the removal of solvent a solution in step (b) include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze drying, filtration or any other technique known in the art. The solid dispersion can also prepared by technique like hot-melt extrusion. The hot-melt extrusion is preferably carried out in the absence of solvent.
In embodiments, the isolation of a solid dispersion of Ponatinib hydrochloride with excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In embodiments, the solid dispersion of Ponatinib hydrochloride and excipient obtained from step b) may be optionally dried before or after isolating at step c).
Solid dispersion of Ponatinib hydrochloride obtained at step c) may be optionally combined with at least one additional pharmaceutically acceptable excipient.
In an embodiment, solid dispersion of Ponatinib hydrochloride may be combined with additional excipient using a technique known in art or according to the previous aspects of the present application.
The stable Ponatinib hydrochloride solid dispersions are suitable for powder handling and downstream processes and highly stable under mechanical stress such as grinding and blending.
Wherever applicable in the example of the present subject matter, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Still further, provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of Ponatinib hydrochloride obtained according to present application, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
The X-ray powder diffraction (XRPD) spectrum according to the present subject matter was measured on a PANalytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present subject matter were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree.
The present subject matter is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.

Examples
Example 1: Preparation of Ponatinib hydrochloride solid dispersion with Hydroxypropyl betadex (HPB-Betadex):
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of isopropyl alcohol (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl alcohol and dried under vacuum at 40-50°C for 10 hours.
Example 2: Preparation of Ponatinib hydrochloride solid dispersion with Hydroxypropyl betadex (HPB-Betadex):
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of acetonitrile (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with acetonitrile and dried under vacuum at 40-50°C for 10 hours.
Example 3: Preparation of Ponatinib hydrochloride solid dispersion with Hydroxypropyl betadex (HPB-Betadex):
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of ethyl acetate (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with ethyl acetate and dried under vacuum at 40-50°C for 10 hours.
Example 4: Preparation of Ponatinib hydrochloride solid dispersion with Hydroxypropyl betadex (HPB-Betadex):
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of acetone (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with acetone and dried under vacuum at 40-50°C for 10 hours.
Example 5: Preparation of Ponatinib hydrochloride solid dispersion with Hydroxypropyl betadex (HPB-Betadex):
Ponatinib hydrochloride (5 g) was dissolved in methanol (300 ml) and followed by addition of Betadex-HPB (7.5 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained solution was dried in a spray dryer to obtain solid product.
Example 6: Preparation of Ponatinib hydrochloride solid dispersion with Hydroxypropyl betadex (HPB-Betadex):
Ponatinib hydrochloride (5 g) was dissolved in methanol (300 ml) and followed by addition of Betadex-HPB (6.25 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained solution was dried in a spray dryer to obtain solid product.
Example 7: Preparation of Ponatinib hydrochloride solid dispersion with HPC:
Ponatinib hydrochloride (4 g) was dissolved in methanol (300 ml) and followed by addition of HPC (12 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained solution was dried in a spray dryer to obtain solid product.
Example 8: Preparation of Ponatinib hydrochloride solid dispersion with HPC:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of HPC (3 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 9: Preparation of Ponatinib hydrochloride solid dispersion with hypromellose acetate succinate:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (3 g) followed by stirring and solvent concentrated under vacuum. Isopropyl ether (15 ml) added to the reaction mass and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl ether and dried under vacuum at 40-50°C for 10 hours.
Example 10: Preparation of Ponatinib hydrochloride solid dispersion with hypromellose acetate succinate:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (2.5 g) followed by stirring and solvent concentrated under vacuum. Isopropyl ether (15 ml) added to the reaction mass and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl ether and dried under vacuum at 40-50°C for 10 hours.
Example 11: Preparation of Ponatinib hydrochloride solid dispersion with hypromellose acetate succinate:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (2 g) followed by stirring and solvent concentrated under vacuum. Isopropyl ether (15 ml) added to the reaction mass and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl ether and dried under vacuum at 40-50°C for 10 hours.
Example 12: Preparation of Ponatinib hydrochloride solid dispersion with Hypromellose acetate succinate:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 13: Preparation of Ponatinib hydrochloride solid dispersion with Croscarmellose sodium (CCS)
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added CCS (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 14: Preparation of Ponatinib hydrochloride solid dispersion with carbopol 974 P:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added Carbopol 974 P (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 15: Preparation of Ponatinib hydrochloride solid dispersion with carbopol 71 G:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added Carbopol 71 G (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 16: Preparation of Ponatinib hydrochloride solid dispersion with Polyvinylpyrrolidone-90 (PVP-90):
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of PVP-90 (3 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 17: Preparation of Ponatinib hydrochloride solid dispersion with Hypromellose-CP-06 (HP-CP-06)):
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added CP-6 (HP-6cps) (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
Example 18: Preparation of Ponatinib hydrochloride solid dispersion with Silicon dioxide:
Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added Silicon dioxide (3 g) followed by stirring and solvent con centrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.

Example 19: Ponatinib hydrochloride formulation prepared with adsorption
S. No. Name of the Ingredients Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56
2 Povidone 14.56
3 Syloid 44.31
4 Methanol q.s
Extra granular Part
5 Microcrystalline cellulose 7.12
6 Lactose monohydrate 9.71
7 Sodium starch glycolate 4.85
8 Magnesium stearate 0.97
Film coating
9 Opadry white 2.91
10 Purified water q.s
Total 100.00

Procedure
1. Ponatinib hydrochloride and Povidone were dissolved in Methanol under stirring till clear solution was observed.
2. Syloid was added to step 1 and dispersion was stirred for 30 mins.
3. Solvent evaporation of step 2 dispersion was carried out in Rotavapor/ Spray Dryer/ Fluidised bed dryer. The solvent was removed under vacuum with desired process parameters.
4. The dried material was milled using suitable screen in quadro co-mill.
5. The dried milled material was blended with extra granular material in blender and compressed in to tablets.
6. The compressed tablets were film coated in perforated coating pan.

Example 20: Ponatinib hydrochloride formulation prepared with solvent evaporation technology:
S. No. Name of the Ingredients Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56
2 Dichloromethane q.s
3 Methanol q.s
Extra granular Part
4 Microcrystalline cellulose 32.36
5 Lactose monohydrate 43.34
6 Sodium starch glycolate 4.85
7 Magnesium stearate 0.97
Film coating
8 Opadry white 2.91
9 Purified water q.s
Total 100.00

Procedure
1. Ponatinib hydrochloride was dissolved in solvent mixture of Methanol and Dichloromethane under stirring.
2. The solution was subjected for solvent evaporation in Rotavapor/ Spray Dryer/ Fluidised bed dryer.
3. The semi dried mass was dried till LOD is NMT 2.0%.
4. The dried material was milled through desired screen in quadro co mill.
5. The milled intra granular material was blended with extra granular material and compressed in to tablets.
6. The compressed tablets were film coated with Opadry white.
Example 21: Ponatinib hydrochloride formulation containing polymer prepared with solvent evaporation technology
S. No. Name of the Ingredients Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56
2 HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or PEG 43.69
3 Methanol q.s
Extra granular Part
4 Microcrystalline cellulose 9.71
5 Lactose monohydrate 22.30
6 Sodium starch glycolate 4.85
7 Magnesium stearate 0.97
Film coating
8 Opadry white 2.91
9 Purified water q.s
Total 100.00

Procedure
1. Ponatinib hydrochloride with HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or Polyethylene glycol was dissolved in solvent methanol under stirring.
2. The solution was subjected to solvent evaporation in Rotavapor/ Spray Dryer/ Fluidised spray dryer.
3. The semi dried mass was dried till LOD is NMT 2.0%.
4. The dried material was milled through desired screen in quadro co mill.
5. The milled intra granular material was blended with extra granular material followed by compression.
6. The compressed tablets were film coated with Opadry white.

Example 22: Preparation of Ponatinib hydrochloride formulation containing surfactants prepared with solvent evaporation
S. No. Name of the Ingredients Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56
2 HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or PEG 43.69
3 Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamers/ Vit. E TPGS 1.62
4 Methanol q.s
Extra granular Part
5 Microcrystalline cellulose 9.71
6 Lactose monohydrate 20.69
7 Sodium starch glycolate 4.85
8 Magnesium stearate 0.97
Film coating
9 Opadry white 2.91
10 Purified water q.s
Total 100.00

Procedure
1. Ponatinib hydrochloride with HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or Polyethylene glycol was dissolved in solvent methanol under stirring.
2. Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamer was dissolved in water.
3. Surfactant solution of step 2 was added to API and polymer mix under stirring.
4. The solution was subjected for solvent evaporation in Rotavapor/ Spray Dryer/ Fluidised spray dryer.
5. The semi dried mass was dried till LOD is NMT 2.0%.
6. The dried material was milled through desired screen in quadro co mill.
7. The milled intra granular material was blended with extra granular material and compressed in to tablet.
8. The compressed tablets were film coated with Opadry white.

Examples 23A and 23B: Ponatinib hydrochloride formulation prepared with hot melt extrusion
S. No. Name of the Ingredients Example 23A Qty. %w/w Example 23B Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56 15.56
2 HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or PEG 43.69 43.69
3 Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamers/ Vit. E TPGS - 1.62
Extra granular Part
4 Microcrystalline cellulose 9.71 9.71
5 Lactose monohydrate 22.30 20.69
6 Sodium starch glycolate 4.85 4.85
7 Magnesium stearate 0.97 0.97
Film coating
8 Opadry white 2.91 2.91
9 Purified water q.s q.s
Total 100.00 100.00

Procedure
1. Ponatinib and polymer was melt granulated in HME for Example 23A and Ponatinib and polymer along with surfactant were melt granulated in HME for Example 23B.
2. The melt granulated material was milled using suitable screen in quadro co-mill.
3. The milled material was blended with extra granular material in blender and compressed in to tablets.
4. The compressed tablets were film coated in perforated coating pan.

Examples 24A and 24B: Ponatinib hydrochloride formulation prepared with lyophilization
S. No. Name of the Ingredients Example 24A Qty. %w/w Example 24B Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56 15.56
2 HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or PEG 43.69 43.69
3 Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamers/ Vit. E TPGS/ Mannitol - 1.62
4 Water q.s q.s.
Extra granular Part
5 Microcrystalline cellulose 9.71 9.71
6 Lactose monohydrate 22.30 20.69
7 Sodium starch glycolate 4.85 4.85
8 Magnesium stearate 0.97 0.97
Film coating
9 Opadry white 2.91 2.91
10 Purified water q.s q.s
Total 100.00 100.00

Procedure
1. Ponatinib hydrochloride with HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or Polyethylene glycol was dissolved in solvent Methanol under stirring.
2. Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamers/ Vit. E TPGS / Mannitol were dissolved in water for Example 24B.
3. Solution of step 2 was added to API and polymer Mix under stirring for Example 24B.
4. The solution obtained for Example 24A and 24B was subjected for solvent evaporation in lyophilizer with desired process parameters.
5. The dried material was sifted through desired screen.
6. The milled intra granular material was blended with extra granular material and compressed in to tablets.
7. The compressed tablets were film coated with Opadry white.

Examples 25A, 25B and 25C: Ponatinib hydrochloride formulation prepared with complexation
S. No. Name of the Ingredients Example 25A Qty. %w/w Example 25B Qty. %w/w Example 25C Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56 15.56 15.56
2 ß Cyclodextrin 43.69 43.69 43.69
3 Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamers/ Vit. E TPGS - 1.62 -
4 Methanol q.s q.s. -
5 Water q.s - -
Extra granular Part
6 Microcrystalline cellulose 9.71 9.71 9.71
7 Lactose monohydrate 22.30 20.69 22.30
8 Sodium starch glycolate 4.85 4.85 4.85
9 Magnesium stearate 0.97 0.97 0.97
Film coating
10 Opadry white 2.91 2.91 2.91
11 Purified water q.s q.s q.s
Total 100.00 100.00 100.00

Procedure
1. Ponatinib hydrochloride with ß Cyclodextrin was dissolved in solvent mixture of methanol and water under stirring for Example 25A.
2. Ponatinib hydrochloride with ß Cyclodextrin and surfactant was dissolved in methanol under stirring for Example 25B.
3. The solution was subjected for solvent evaporation in Rotavapor/ Spray Dryer/ Fluidised spray dryer with desired process parameters.
4. The semi dried mass was dried till LOD is NMT 2.0%.
5. The dried material was milled through desired screen in quadro co mill.
6. The milled intra granular material was blended with extra granular material and compressed in to tablets.
7. The compressed tablets were film coated with Opadry white.
Procedure for Example 25C
1. Ponatinib hydrochloride with ß Cyclodextrin was blended in a blender for 60 mins.
2. The blended intra granular material was mixed with extra granular material and compressed in to tablets.
3. The compressed tablets were film coated with Opadry white.

Examples 26A and 26B: Ponatinib hydrochloride formulation prepared with anti-solvent precipitation
S. No. Name of the Ingredients Example 26A Qty. %w/w Example 26B Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56 15.56
2 HPMC AS or HPMC phthalate or Kollidon VA64 or HPMC or HPC or Povidone or Eudragit or PEG 43.69 43.69
3 Sodium lauryl sulphate/ Tween/ Cremophor / Poloxamers/ Vit. E TPGS - 1.62
4 Methanol q.s q.s.
5 Water/ Isopropyl alcohol q.s q.s
Extra granular Part
6 Microcrystalline cellulose 9.71 9.71
7 Lactose monohydrate 22.30 20.69
8 Sodium starch glycolate 4.85 4.85
9 Magnesium stearate 0.97 0.97
Film coating
10 Opadry white 2.91 2.91
11 Purified water q.s q.s
Total 100.00 100.00

Procedure
1. Ponatinib hydrochloride and polymer and/or surfactant was dissolved in solvent mixture of methanol under stirring.
2. Anti-solvent (water, isopropyl alcohol) was added to the above solution.
3. The dispersion formed was subjected to solvent evaporation in Rotavapor/ Spray Dryer/ Fluidised spray dryer with desired process parameters.
4. The semi dried mass was dried till LOD is NMT 2.0%.
5. The dried material was milled through desired screen in quadro co mill.
6. The milled intra granular material was blended with extra granular material and compressed in to tablets.
7. The compressed tablets were film coated with Opadry white.

Examples 27: Ponatinib hydrochloride formulation prepared with supercritical fluid (SCF) technology
S. No. Name of the Ingredients Example 27 Qty. %w/w
Intra granular Part
1 Ponatinib HCl 15.56
2 Povidone 14.56
3 Methanol q.s
4 Water/ Isopropyl alcohol q.s
Extra granular Part
5 Microcrystalline cellulose 25.89
6 Lactose monohydrate 35.25
7 Sodium starch glycolate 4.85
8 Magnesium stearate 0.97
Film coating
9 Opadry white 2.91
10 Purified water q.s
Total 100.00

Procedure
1. Ponatinib hydrochloride and povidone were dissolved in solvent mixture of methanol under stirring.
2. The solution was subjected for solvent evaporation along with compressed anti-solvent such as supercritical carbon dioxide.
3. The semi dried mass was dried till LOD is NMT 2.0%.
4. The dried material was milled through desired screen in quadro co mill.
5. The milled intra granular material was blended with extra granular material and compressed in to tablets.
6. The compressed tablets were film coated with Opadry white.

Dated this: 27th of October 2021
(Signature):

(Sonal Ben Parimal Patel)
For Alembic Pharmaceuticals Limited
,CLAIMS:We claim:
1. A solid dispersion of ponatinib hydrochloride comprising ponatinib hydrochloride and one or more pharmaceutically acceptable carrier.
2. The pharmaceutically acceptable carrier as per claim 1 is selected from the group consisting of a polymer, a surfactant, a binder, a disintegrant, an adsorbent and a complexing agent.
3. The solid dispersion as per claim 1 is prepared by a process selected from the group consisting of adsorption process, solvent evaporation, hot melt extrusion, freeze drying, spray drying, lyophilisation, complexation, anti-solvent precipitation and supercritical fluid (SCF) technology
4. A process for preparing the solid dispersion of claim 1 comprising
a) preparing a solution of ponatinib hydrochloride and pharmaceutically acceptable carrier in suitable solvent(s),
b) removing the solvent from the solution to provide a solid amorphous dispersion of Ponatinib hydrochloride and the pharmaceutically acceptable carrier.
5. A process for preparing the solid dispersion of claim 1 comprising blending Ponatinib hydrochloride with a pharmaceutically acceptable carrier to form a solid mixture, and melting the solid mixture and forcing the solid mixture through an extruder orifice to form an extrudate and milling the extrudate.
6. A pharmaceutical composition according to claim 2 further comprises filler, binder, disintegrant, lubricant and glidant.

Dated this 27th Oct, 2021

(Signature):

(Sonal Ben Parimal Patel)
For Alembic Pharmaceuticals Limited