FIELD OF THE INVENTION
The present invention relates to an improved, efficient, and industrially advantageous process for preparation of solid forms of Bruton's Tyrosine Kinase (BTK) inhibitor, Ibrutinib of formula I.

Particularly, the present invention provides process for the preparation of Crystalline Form A and Crystalline Form C of Ibrutinib.

BACKGROUND OF THE INVENTION
Ibrutinib of formula I, a Bruton’s tyrosine kinase (BTK) inhibitor, marketed under the trade name IMBRUVICA®, is an orally administered drug. Ibrutinib has been indicated for the treatment of Mantle cell lymphoma (MCL), Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL), Small lymphocytic lymphoma (SLL) with 17p deletion, Waldenstrom’s macroglobulinemia (WM), Marginal zone lymphoma (MZL), and Chronic graft versus host disease (cGVHD)
Ibrutinib (CAS No. 936563-96-1) is chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one.
US Patent No. 7,514,444 first discloses l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one, its pharmaceutically acceptable salts and process for the preparation thereof. It involves isolation of ibrutinib as a white solid by flash chromatography using a mixture of methylene chloride and methanol solvent system.
PCT Publication 2013/184572 discloses crystalline forms including solvates of ibrutinib that are marked as Form A, B, C, D, E and F; and processes for the preparation thereof. Form A is prepared by dissolving amorphous form in a solvent [methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, methanol, nitromethane, 10% aqueous acetone, or 10% aqueous isopropyl alcohol or heptane (10 volumes), dioxane (1 volume), toluene (10 volumes), MTBE (10 volumes), DIPE (10 volumes), anisole (1 volume), ethyl acetate (10 volumes), isopropyl acetate (10 volumes), tetrahydrofuran (1 volume), DCM (1 volume), MIBK (10 volumes), MEK (10 volumes), acetone (10 volumes), methanol (10 volumes), ethanol (10 volumes), acetonitrile (10 volumes), nitromethane (1 volume), water (10 volumes), or 10% aqueous isopropyl alcohol (1 volume)]. Form C is prepared by suspending Ibrutinib in methanol.
Chinese Patent Application 104327085 discloses crystal Form A. It has described three preparation methods. In first method, the crude ibrutinib is dissolved in a mixed solution of isopropanol and n-heptane. Crystal Form A is furnished by stirring at a speed of 750 revolutions per minute at room temperature. In second method, the crude ibrutinib is dissolved in a mixed solvent of isopropanol and n-heptane, and reduced the temperature from 50°C to 5°C at a cooling rate of 0.1°C/min to obtain crystal Form A. In third method, the crude ibrutinib is dissolved in acetone, and then slowly in n-heptane. The alkane is stirred at 1000 revolutions per minute for 1 day to obtain crystal Form A.
Journal literature (Crystal Growth & Design, 2018, 18: 1315-1326) reported three anhydrates of ibrutinib crystal Form A, crystal Form B and crystal Form C and their preparation methods. Form A is prepared by slowly adding water as an anti-solvent to the methanol solution of Ibrutinib; Form B is prepared by rapidly adding water as an anti-solvent to the methanol solution of Ibrutinib; Form C is prepared by recrystallization of Ibrutinib in methanol.
PCT Publication 2016/170545 describes an improved process for the preparation of amorphous, crystalline Form-C and crystalline Form-A of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one.
Chinese Patent Application 106995445 describes 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one crystal Form A and preparation by dissolving ibrutinib in an organic solvent such as: acetone/petroleum ether mixture, trichloroethylene, ethyl acetate, triethanolamine, styrene, perchloroethylene, glacial acetic acid, ethylene glycol ether, butyl acetate. Further, the process involves refluxing, crystallization, and vacuum drying steps.
PCT Publication 2017/134684 also describes process for the preparation of Crystalline Form A and Form C of Ibrutinib. Form A is prepared by dissolving 1- [(3R)-3-[4-amino-3-(4-phenoxyphenyl)-pyrazolo-[3,4-d]pyrimidin-1-yl]-1-piperidyl]prop-2-en-l-one in ethyl acetate at 25-35°C. The product is filtered, crystallized, and dried to yield pure Ibrutinib crystalline Form-A. Form C is prepared by dissolving Ibrutinib in methanol at 50-55°C. Further, the product is filtered, crystallized, and dried to yield pure Ibrutinib crystalline Form-C having HPLC Purity: 99.68%; chiral purity: 99.9%.
PCT Publication 2017/174044 also describes preparation of a crystalline solid form of ibrutinib (Form C) with a variable size of the primary particles and their clusters.
Chinese Patent Application 111303156 describes a crystal form of Ibrutinib marked as crystal Form C2 and a preparation method thereof. Crystal Form C2 is prepared by dissolving ibrutinib in methanol at 40°C, stirring for 1 hour, temperature is lowered to 5°C, a solid precipitated out, crystal slurry is stirred for 30 minutes, filter and dried to obtain crystal Form C2.
Another Chinese Patent Application 111138436 describes crystal Form A single crystal of ibrutinib and a preparation method thereof.
Nevertheless, despite the existing forms of ibrutinib and processes for the preparation thereof, there is still the need in the art for further new modifications to establish economical viable, efficient, and industrially advantageous process. The present invention relates to an improved, economical viable and efficient process for the preparation of crystalline Form-A and crystalline Form-C of ibrutinib.

OBJECT OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of solid forms of Ibrutinib of formula I.

Particularly, the objective of the present invention is to provide processes for the preparation of crystalline Form A and crystalline Form C of Ibrutinib.
Yet another objective of the present invention is to provide an ecofriendly, simple, cost-effective, efficient, and industrially advantageous process for the preparation of crystalline Form A and crystalline Form C of Ibrutinib.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of solid forms of Ibrutinib of formula I.

In an aspect, the present invention provides processes for the preparation of crystalline Form A and crystalline Form C of Ibrutinib.
In another aspect, the present invention provides an improved process for the preparation of crystalline Form A of Ibrutinib.
In another aspect, the present invention provides an improved process for the preparation of crystalline Form C of Ibrutinib.
In another aspect, the present invention provides an improved process for the preparation of amorphous Ibrutinib.
In an aspect, the present invention provides an improved process for the preparation of crystalline Form A of Ibrutinib of formula I, comprising the steps of:

a) adding cyclopentyl methyl ether to Ibrutinib of formula I;
b) stirring the resulting reaction mixture of step (a) for a suitable time at a suitable temperature;
c) isolating Form A of Ibrutinib of formula I at a suitable temperature; and
d) drying finally isolated substantially pure Ibrutinib of formula I at a suitable temperature.

In an aspect, the present invention provides an improved process for the preparation of crystalline Form C of Ibrutinib of formula I, comprising the steps of:

a) adding Ibrutinib of formula I to a mixture of solvent at a suitable temperature to obtain a solution;
b) filtering the solution of step (a);
c) concentrating the solution of step (b) and filtering the concentrated solution;
d) stirring the filtrate of step (c) at a suitable temperature for a suitable time;
e) isolating Form C of Ibrutinib of formula I by adding water; and
f) drying finally isolated substantially pure Form C of Ibrutinib of formula I at a suitable temperature.
In yet another aspect, the present invention provides pharmaceutical compositions of solid state forms of Ibrutinib prepared according to present disclosure.
In yet another aspect, the solid state forms of Ibrutinib prepared according to present invention can be used to prepare other solid state forms of Ibrutinib.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form A of Ibrutinib of formula I prepared according to process of present invention.
Figure 2 shows differential scanning calorimetry (DSC) thermogram of crystalline Form A of Ibrutinib of formula I prepared according to process of present invention.
Figure 3 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form C of Ibrutinib of formula I prepared according to process of present invention.
Figure 4 shows differential scanning calorimetry (DSC) thermogram of crystalline Form C of Ibrutinib of formula I prepared according to process of present invention.
Figure 5 shows an X-ray powder diffraction (XRPD) pattern of amorphous Ibrutinib of formula I.
Figure 6 shows differential scanning calorimetry (DSC) thermogram of amorphous Ibrutinib of formula I.

DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses improved process for the preparation of solid forms of Ibrutinib of formula I.

Solid state properties of Ibrutinib can be influenced by controlling the conditions under which the Ibrutinib is obtained in solid form.
As discussed above, the processes described in the literature have significant disadvantages. More particularly, the process described in prior art employ organic solvent which increases environmental loading and cost.
Therefore, the reported processes may not be considered efficient, and industrially advantageous process for large scale production. The processes of the present invention can be adapted to produce Ibrutinib in an industrial scale.
In some embodiments, the solid forms of Ibrutinib prepared according to present invention are substantially free of any other forms of Ibrutinib, or of specified polymorphic forms of Ibrutinib.
As used herein, the modifier term "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 5 to about 10" also discloses the range "from 5 to 10." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number e.g., "about 10%" may indicate a range from 9% to 11%, and "about 1" may be from 0.9-1.1.
A reaction mixture may be characterized herein as being at or allowed to come to ‘room temperature’ or ‘ambient temperature’, also abbreviated as ‘RT’. Room temperature means that the temperature of the reaction mass or reaction mixture is close to, or the same as, that of the space in which the reaction mass or reaction mixture is located. Generally, RT is from about 20°C to about 30°C.
As used herein, and unless otherwise specified, the term "isolated" in reference to the compounds of the present invention, their salts or solid-state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
As used herein, and unless otherwise specified, the term "reduced pressure" refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.
A solid form may be referred to herein as being characterized by graphical data ‘as depicted in’ a Figure, for example, X-ray powder diffraction (XRPD). The graphical data or "fingerprint" provides additional technical information to further define the respective solid state form. Further, due to the variations in instrument response and variations in sample concentration and purity, it is understood to the skilled person that such graphical representations of data may be subject to small variations with respect to peak relative intensities and peak positions.
As used herein, and unless otherwise specified, the term "substantially free" is meant that the Ibrutinib of formula I contain about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or, or about 0.1% (w/w) less of a specified or unspecified impurity.
As used herein, and unless otherwise specified, the term "substantially pure" relates to compounds having a purity of about 95% or more. In other words, the term relates a compound, having a purity, measured as % area normalization by HPLC, of about 95% or more. In other embodiments, the term relates to compounds having a purity of about more than 97% area normalization by HPLC. In preferred embodiments, the term relates to compounds having a purity of about more than 98% (by HPLC; area normalization).
In an embodiment, the present invention provides an improved process for the preparation of solid forms of Ibrutinib of formula I.

In an aspect, the present invention provides processes for the preparation of crystalline Form A and crystalline Form C of Ibrutinib.
In a particular embodiment, the present invention provides an improved process for the preparation of crystalline Form A of Ibrutinib.
In a particular embodiment, the present invention provides an improved process for the preparation of crystalline Form C of Ibrutinib.
In some embodiment, the present invention provides an improved process for the preparation of amorphous Ibrutinib as per process as exemplified in example 11.
In an aspect, the present invention provides an improved process for the preparation of crystalline Form A of Ibrutinib of formula I, comprising the steps of:

a) adding cyclopentyl methyl ether to Ibrutinib of formula I;
b) stirring the resulting reaction mixture of step (a) for a suitable time at a suitable temperature;
c) isolating Form A of Ibrutinib of formula I at a suitable temperature; and
d) drying finally isolated substantially pure Ibrutinib of formula I at a suitable temperature.

The suitable temperature in step (b) is in the range of 0°C-100°C. Preferably, the temperature is in the range of 25°C-40°C. Most preferably, the temperature is in the range of 40°C-50°C.
The reaction mass at room temperature is in the form of suspension, which on heating turns to a clear solution.
The suitable time in step (b) is in the range of 30-60 minutes.
Form A of Ibrutinib is isolated as solid in step (c) by filtration. Preferably, the isolation by filtration is performed at room temperature.
Form A of Ibrutinib isolated as solid in step (c) is dried by any conventional method known in the prior art at a suitable temperature. Preferably, the drying is performed at a temperature in the range of 40°C-50°C.
In an aspect, the present invention provides an improved process for the preparation of crystalline Form C of Ibrutinib of formula I, comprising the steps of:

a) adding Ibrutinib of formula I to a mixture of solvent at a suitable temperature to obtain a solution;
b) filtering the solution of step (a);
c) concentrating the solution of step (b) and filtering the concentrated solution;
d) stirring the filtrate of step (c) at a suitable temperature for a suitable time;
e) isolating Form C of Ibrutinib of formula I by adding water; and
f) drying finally isolated substantially pure Form C of Ibrutinib of formula I at a suitable temperature.

The mixture of solvent in step (a) is a mixture of alcohol solvents and chlorinated solvents.
The alcohol solvent may be selected from, but not limited to, methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, or the like.
The chlorinated solvent may be selected from, but not limited to, dichloromethane (DCM), dichloroethane or the like.
Preferably, the mixture of solvent in step (a) is a mixture of methanol and dichloromethane.
Most preferably, the solution of step (a) is a clear solution.
The suitable temperature in step (a) is in the range of 0°C-50°C. Preferably, the temperature range is in the range of 15°C-30°C.
The concentration of the solution in step (c) is performed by any conventional method known in the prior art. Preferably, the concentration is performed by distillation in the temperature range of 35°C-50°C. Optionally, the concentrated solution is filtered.
The suitable temperature in step (d) is in the range of 0°C-50°C. Preferably, the temperature range is in the range of 0°C-10°C.
A person skill in the art can vary the reaction temperature viz. below 0°C in step (d) .
The suitable time period for stirring in step (d) is in the range of 1-5 hours. Most preferably, the stirring is done for 2-3 hours. Form C of Ibrutinib isolated as solid in step (e) is dried by any conventional method known in the prior art at a suitable temperature. Preferably, the drying is performed at a temperature in the range of 40°C-50°C.
In yet another aspect, the present invention provides pharmaceutical compositions of solid state forms of Ibrutinib prepared according to present disclosure.
In yet another aspect, the solid state forms of Ibrutinib prepared according to present invention can be used to prepare other solid state forms of Ibrutinib.
The progress of the reaction and purity can be monitored by suitable chromatographic techniques such as high-pressure liquid chromatography (HPLC), gas chromatography (GC), ultra-pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and the like.
The solid forms of Ibrutinib are confirmed by pattern and data of X-ray powder diffraction (XRPD) performed on XRPD instrument PAN alytical X’Pert Pro, and differential scanning calorimetry (DSC) performed on DSC instrument Mettler Toledo DSC823e.

The following examples are provided to describe the invention in further detail.

EXAMPLES:
Example 1: Preparation of Ibrutinib

A) Preparation of 2-[Hydroxy(4-phenoxyphenyl) methylene] propanedinitrile:
Thionyl chloride (67.6 ml, 0.933 mole) was added slowly to 4-Phenoxybenzoic acid (100.0 g, 0.467 mole) at 20-30°C. The resulting reaction mixture was heated under stirring at temperature 60-65°C for 4-5 hours. After completion of reaction by HPLC, thionyl chloride was distilled off under vacuum below 70°C. Toluene (200 ml) was added to the oily residue and distilled off under vacuum below 70°C to remove traces of thionyl chloride to obtained 4-phenoxybenzoyl chloride as a viscous oil. Thus, the obtained viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (200 ml) and added to a solution of malononitrile (40 g, 0.60 mole) and diisopropylethylamine (203 ml, 1.16 mole) in THF (200 ml) maintaining temperature of reaction mass 0-10°C. The reaction mass was stirred for 60 minutes at 20-30°C. After completion of reaction by HPLC, the reaction mass was quenched with demineralized water (500 ml) and extracted with ethyl acetate (2 x 500 ml). The organic layer was successively washed with 1N aqueous HCl solution and aqueous sodium chloride solution. The organic layer then distilled off completely under vacuum. Isopropyl alcohol (200 ml) was added to the crude mass, slowly added concentrated HCl (300 ml) and then stirred for 30-60 minutes at 20-30°C. Demineralized water (500 ml) was added to the reaction mass, stirred 30-60 minutes, filtered, and washed with demineralized water (1000 ml) to obtained crude mass. To the crude material dissolved in methanol (300 ml), demineralized water (500 ml) was added slowly, and the precipitated material was filtered and washed with demineralized water (100 ml). The wet material dried to obtained 2-[Hydroxy(4-phenoxyphenyl) methylene] propanedinitrile as brownish to yellow colored solid (109.0 g, 89%) with HPLC purity >97%.
B) Preparation of 3-(p-Phenoxyphenyl)-1H-1,2,5,7-tetraazainden-4-ylamine:
Dimethyl sulfate (54.3 ml,0.572 mole) and sodium bicarbonate (48 g,0.572 mole) were added to a solution of 2-[Hydroxy(4-phenoxyphenyl) methylene] propanedinitrile (100 g,0.381 mole) in acetone (1000 ml) at 20-30°C. Thereafter, temperature of reaction mass was raised to 50-55°C and stirred for 24 hours. After completion of reaction by HPLC, the reaction mass was cooled to 20-30°C and filtered to remove inorganic salts. The filtrate then concentrated under vacuum to afford [Methoxy(p-phenoxyphenyl)methylidene]propanedinitrile as an oily mass. To the concentrated oily mass, added toluene (100 ml) and again concentrated to remove traces of acetone. To the concentrated oily mass added 80% hydrazine hydrate (34.8 ml) at 0-10°C and stirred for 1-2 h at 25-35°C. After completion of reaction by HPLC, the reaction mass was filtered and washed with toluene (200 ml) to get 3-Amino-5-(p-phenoxyphenyl)-2H-pyrazole-4-carbonitrile with wet purity by HPLC >96%.
The above wet material 3-Amino-5-(p-phenoxyphenyl)-2H-pyrazole-4-carbonitrile (197 g) was suspended in Formamide (1000 ml) and heated at l40°C-150°C. After completion of reaction by HPLC, the reaction mixture was cooled to 50-60°C followed by addition of demineralized water (1000 ml), then cooled to 20-30°C and stirred for 60 minutes at 20-30°C. The resulting solid was filtered, washed with demineralized water (1000 ml) and then slurry washed with acetone (200 ml) to get crude wet solid. To the crude wet solid was added N-methyl-2-pyrrolidone (400 ml) and heated to 60-65°C for dissolution. The reaction mass cooled to 20-30°C, then added isopropyl alcohol (1200 ml) slowly. The precipitated material was filtered, washed with isopropyl alcohol (100 ml) and dried to afford pure 3-(p-Phenoxyphenyl)-1H-1,2,5,7-tetraazainden-4-ylamine compound (85.5g,73%) as a light yellow to dark brown solid with purity by HPLC >98%.

C) Preparation of (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-
d]pyrimidin-4-amine:
Diisopropyl azodicarboxylate (249.3 ml, 1.27 mole) and triphenylphosphine (333.12 g, 1.27 mole) were added lot wise to a solution of l-tert­butyloxycarbonyl-3-(S)-hydroxypiperidine (170.0 g, 0.84 mole), and 3-(p-phenoxyphenyl)-1 ,2,5,7-tetraza-lH-inden-4-ylamine (85.6 g, 0.283 mole) in ethyl acetate (856 ml) and stirred for 4-5 h at 25-40°C. After completion of reaction by HPLC, the solvent was distilled off completely under vacuum. Cyclohexane (865 ml) was added to a concentrated mass, stirred and then filtered at 20-30°C. To the resulting solid material, added THF (428 ml) and demineralized water (856 ml), the reaction mass was cooled to 0-10°C followed by addition of concentrated HCl (342.4 ml) and then stirred overnight at 25-35°C. After completion of reaction by HPLC, the reaction mass washed thrice with MDC (513.6 ml x 3) and layers were separated followed by pH adjustment ~10-12 of aqueous layer by using 30% aqueous NaOH solution maintaining at 0-10°C. The reaction mass was further stirred for 1-2 h at 20-30°C, filtered and washed with demineralized water (85.6 ml). To the resulting solid was then added methanol (513.6 ml) and heated to reflux temperature for dissolution followed by slow addition of demineralized water (513.6 ml). The resulting solid material then cooled to 20-30°C and stirred for 30-60 minutes, filtered and washed with a mixture of methanol and demineralized water (1:9), wet material dried to afford (74.6 g,68%) (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light yellow to cream colored solid with HPLC purity =99.0%.
D) 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-
1-yl]piperidin-1-yl]prop-2-en-1-one (Ibrutinib)
(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.0 g, 0.129 mole ) was taken in a mixture of methanol (250 ml) and MDC (400 ml) then cooled to -80°C to -70°C followed by addition of N,N-diisopropylethylamine (33.6 ml,0.194 mole). Distilled acryloyl chloride (12.6 ml, 0.156 mole) solution in MDC (100 ml) was added to the reaction mass slowly at -80°C to -70°C and stirred for 30-60 minutes at -80 to -70°C. After completion of reaction by HPLC, demineralized water (250 ml) was added and then layers were separated. Aqueous layer was re-extracted with MDC (250 ml). Combined organic layer was washed with 1% aqueous citric acid solution (250 ml) and washed with demineralized water (250 ml). To the organic layer activated carbon 10% by weight was added, stirred for 20-30 minutes at 20-30°C, filtered through hyflo and concentrated under atmospheric pressure to get oily mass. To the oily mass toluene (500 ml) was added and then concentrated under vacuum until the distilled volume (100 ml) of toluene was attained. The reaction mass was cooled to 20-30°C and stirred for 2h, filtered and washed with toluene (100 ml) to get crude ~ 60 g off white to white solid with HPLC purity >98%.
The above crude wet material (~60.0 g) was dissolved in MDC (200 ml), activated carbon 10% by weight was added and stirred for 20-30 minutes at 20-30°C followed by filtration through hyflo bed, then washing of bed with MDC (150 ml). The filtrate was then concentrated at atmospheric pressure to get oily mass. To the oily mass toluene (500 ml) was added and then concentrated under vacuum until attained the distilled volume (100 ml). The reaction mass was cooled to 20-30°C and stirred for 2h, then filtered and washed with toluene (100 ml) to get white to off white solid ~ 55 g with HPLC purity >99.0%.
The above wet material (~55.0 g) was dissolved in MDC (200 ml), activated carbon 10% by weight was added and stirred for 20-30 minutes at 25-30°C followed by filtration through hyflo bed, then washing of bed with MDC (150 ml). The filtrate was then concentrated at atmospheric pressure to get oily mass. To the oily mass toluene (500 ml) was added and then concentrated under vacuum until attained the distilled volume (100 ml). The reaction mass was cooled to 20-30°C and stirred for 2h, then filtered and washed with toluene (100 ml) to get white to off white solid ~ 50 g with HPLC purity >99.5%.

Example 2: Process for the preparation of crystalline Form C of Ibrutinib
To the above material were added methanol (600 ml) and MDC (100 ml), then heated at 45-50°C and stirred for complete dissolution. The reaction mass was filtered through sintered funnel and washed with methanol (100 ml). The filtrate was concentrated under reduced pressure to get the residue volume ~400 ml at 35-50°C. The residue was filtered through celite bed and then washed with methanol (100 ml). The reaction mass was cooled to 15-20°C, stirred for 1.0 h and then cooled to 0-5°C. The resulting crystals were stirred for 60-180 at 0-5°C followed by slow addition of demineralized water (850 ml). The resulting solid was filtered and washed with demineralized water (50 ml). The wet solid finally dried at 45-50°C to get polymorph-C with yield 70% and purity 99.8% by HPLC.
Example 3: Process for the preparation of crystalline Form C of Ibrutinib
To the Ibrutinib (10.0 g) were added methanol (120 ml) and MDC (20 ml), then heated at 45-50°C and stirred for complete dissolution. The reaction mass was filtered through sintered funnel and washed with methanol (20 ml). The filtrate was concentrated under reduced pressure to get the residue volume ~80 ml at 35-50°C. The filtrate was filtered through celite bed and then washed with methanol (20 ml). The reaction mass was cooled to 15-20°C, stirred for 1.0 h and then cooled to 0-5°C. The resulting crystals were stirred for 60-180 at 0-5°C followed by slow addition of demineralized water (170 ml). The resulting solid was filtered and washed with demineralized water (10 ml). The wet solid finally dried at 45-50°C to get polymorph-C with yield 90% and purity 99.7% by HPLC.
Example 4: Process for the preparation of crystalline Form A of Ibrutinib
To the Ibrutinib (5 g) cyclopentyl methyl ether (50 ml) was added, heated at 90-100°C and stirred for complete dissolution. The reaction mixture was stirred for 30-60 minutes at 90-100°C and then cooled slowly to 20-30ºC. The slurry was filtered and washed with cyclopentyl methyl ether (5 ml). The wet solid finally dried at 45-50°C to get polymorph-A with yield 4.5 g and purity 99.8% by HPLC.

Example 5: Process for the preparation of crystalline Form A of Ibrutinib
To the Ibrutinib (5 g) cyclopentyl methyl ether (50 ml) was added and stirred for 60 minutes at 25-35°C. The slurry was filtered and washed with cyclopentyl methyl ether (5 ml). The wet solid finally dried at 45-50°C to get polymorph-A with yield 4.6 g and purity 99.8% by HPLC.

Example 6: Process for the preparation of crystalline Form A of Ibrutinib
The Ibrutinib (5 g) was dissolved in methylene chloride (25 ml), Filtered and concentrated under reduced pressure to dryness at 30-40°C. To the reaction mixture cyclohexane (50 ml) was added. The reaction mixture was stirred for 30 minutes at 25-30°C. The slurry was filtered and washed with cyclohexane (5 ml). The wet solid finally dried at 40-45°C to obtained polymorph-A with yield 4.5g.

Example 7: Process for the preparation of crystalline Form A of Ibrutinib
The Ibrutinib (5 g) was dissolved in methylene chloride (25 ml), Filtered and concentrated under reduced pressure to dryness at 30-40°C. To the reaction mixture n-Heptane (50 ml) was added. The reaction mixture was stirred for 30 minutes at 25-30°C. The slurry was filtered and washed with n-heptane (5 ml). The wet solid finally dried at 40-45°C to obtained polymorph-A with yield 4.6g.

Example 8: Process for the preparation of crystalline Form A of Ibrutinib
The Ibrutinib (5 g) was dissolved in DMSO (25 ml) and to the reaction mixture water (100 ml) was added slowly. The reaction mixture was stirred for 60 minutes at 20-30°C. The slurry was filtered and washed with water (5 ml). The wet solid finally dried at 40-45°C to obtained polymorph-A with yield 4.4g.

Example 9: Process for the preparation of crystalline Form A of Ibrutinib
The Ibrutinib (5 g) was dissolved in DMF (25 ml) and to the reaction mixture water (100 ml) was added slowly. The reaction mixture was stirred for 60 minutes at 25-30°C. The slurry was filtered and washed with water (5 ml). The wet solid finally dried at 40-45°C to obtained polymorph-A with yield 4.3g.

Example 10: Process for the preparation of crystalline Form A of Ibrutinib
The Ibrutinib (5 g) was dissolved in methylethylketone (100 ml) at 70-75°C and concentrated under reduced pressure to dryness. Cyclohexane (25 ml) was added to the reaction mixture and stirred for 60 minutes at 25-30°C. The slurry was filtered and washed with cyclohexane (5 ml). The wet solid finally dried at 40-45°C to obtained polymorph-A with yield 4.5g.

Example 11: Process for the preparation of Amorphous Ibrutinib
The polymorph-A of Ibrutinib (5 g) was dissolved in methylene chloride (25 ml), filtered and concentrated under reduced pressure to dryness at 30-40°C. To the reaction mixture precooled quantity of demineralized water (100 ml) was added. The reaction mixture was stirred for 5-10 minutes at 0-5°C. The slurry was filtered and washed with chilled water (5 ml). The wet solid finally dried at 35-40°C to obtain an amorphous form with yield 4.8g.

CLAIMS:

WE CLAIM
Claim 1. An improved process for the preparation of crystalline Form A of Ibrutinib of formula I, comprising the steps of:

a) adding cyclopentyl methyl ether to Ibrutinib of formula I;
b) stirring the resulting reaction mixture of step (a) for a suitable time at a suitable temperature;
c) isolating Form A of Ibrutinib of formula I; and
d) drying finally isolated substantially pure Ibrutinib of formula I at a suitable temperature.
Claim 2. The process as claimed in claim 1, wherein suitable temperature in step (b) is in the range of 0°C to 100°C and preferably in the range of 25°C to 40°C.
Claim 3. The process as claimed in claim 1, wherein in step d) the drying is performed at a temperature in the range of 40°C to 50°C.
Claim 4. An improved process for the preparation of crystalline Form C of Ibrutinib of formula I, comprising the steps of:

a) adding Ibrutinib of formula I to a mixture of solvent at a suitable temperature to obtain a solution;
b) filtering the solution of step (a);
c) concentrating the filtered solution of the step (b) and filtering the concentrated solution;
d) stirring the filtrate of step (c) at a suitable temperature for a suitable time;
e) isolating Form C of Ibrutinib of formula I by adding water; and
f) drying finally isolated substantially pure Form C of Ibrutinib of formula I.
Claim 5. The process as claimed in claim 4, wherein in step a) a mixture of solvent is a mixture of alcohol solvents and chlorinated solvents.
Claim 6. The process as claimed in claim 5, wherein the alcohol solvent is selected from methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol and the chlorinated solvent is selected from dichloromethane (DCM) and dichloroethane.
Claim 7. The process as claimed in claim 4, wherein in step (a) and step d) the suitable temperature is in the range of 0°C to 50°C.
Claim 8. A process for the preparation of amorphous Ibrutinib of formula I, comprising the steps of:
a) dissolving crystalline Form A of ibrutinib in methylene chloride;
b) filtering and concentrating under reduced pressure to dryness;
c) adding precooled quantity of demineralized water to the dried crude to get a reaction mixture;
d) isolating amorphous Ibrutinib of formula I from the reaction mixture.
Claim 9. The process as claimed in claim 8, wherein in step (d) the reaction mixture is stirred for 5-10 minutes at 0-5°C for isolating amorphous Ibrutinib of formula I.