FIELD OF THE INVENTION
The present invention generally relates to process for preparation of amorphous form of Ibrutinib and pharmaceutical composition comprising the same.
BACKGROUND OF THE INVENTION
. Ibrutinib, also known as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-1 -yl]-l -piperidinyl]-2-propen-1 -one of Formula I:
Ibrutinib is marketed by Pharmacyclics in US under the trade name Imbruvica for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia with 17p deletion and Waldenstrom's Macroglobulinemia. In EP Ibrutinib is marketed by Janssen-Cilag International.
U.S. Patent No. 7,514,444 ("the '444 patent") discloses Ibrutinib and process for preparation thereof. The '444 patent process involves isolation of Ibrutinib as a white solid by flash chromatography using methylene chloride/ methanol as solvent system. However, the '444 patent does not disclose any polymorphic information on resulted Ibrutinib. Repetition of the '444 patent process by the present inventors and found that Ibrutinib obtained as an amorphous form and the same was characterized by XRD, DSC and TGA.
PCT Publication No. WO2013/184572 ("the '572 publication") discloses crystalline forms including solvates of Ibrutinib such as Form A, Form B, Form C, Form D (MIBK solvate), Form E (toluene solvate) and Form F (MeOH solvate) and its characterization data by XRD, DSC and TGA. The '572 publication further discloses preparation of amorphous form of Ibrutinib by dissolving crystalline Form A in methylene chloride and

the solvent was removed by rotary evaporation, occurring rapidly enough to prevent crystallization to provide amorphous Ibrutinib.
PCT Publication No. WO2015/081180 ("the '180 publication) discloses crystalline form of Ibrutinib polymorph Form I and its characterization data by XRD, DSC and TGA.
PGT Publication No. WO2015/145415 ("the '415 publication) discloses crystalline forms including solvates of Ibrutinib such as Form III (1,4-dioxane solvate), Form IV (1,2-dimethoxyethane solvate), Form V (methanol solvate), Form VI (anhydrous), Form VII (anisole solvate), Form VIII and Form DC (anisole solvate) and its characterization data by XRD, DSC and TGA. The '415 publication also discloses process for preparation of amorphous form by different methods such as ball milling, spray dry, column purification followed by spray dry and freezing method and its characterization data by XRD and DSC.
PCT Publication No. WO2016/022942 ("the '942 publication) discloses Ibrutinib solid dispersion pharmaceutical composition and its process for preparation by spray-dry method.
PCT Publication No. WO2016/025720 ("the '720 publication) discloses crystalline forms of Ibrutinib such as Form G (acetic acid solvate), Form J (anisole solvate) and Form K and its characterization data by XRD.
Patent Publication No. CN103923084A ("the '084 publication) discloses crystalline forms including solvates of Ibrutinib such as Form II, Form III, Form IV (THF solvate), Form V (chloroform solvate), Form VI (chloroform solvate), Form VII (chloroform solvate) and Form VIII and its characterization data by XRD, DSC and TGA.
IP.com Journal, Vol.: 14, Is.: 7B, Pages: 1-2, 2014 (IPCOM000237770D) discloses process for preparation of amorphous form of Ibrutinib from acetone or Me-THF and followed by solvent evaporation in rotovapor/Spray Drier (SD)/ Ekato Solidmix VPT3 D-7130 apparatus to give amorphous from as a crispy material.
The reported methods for amorphous Ibrutinib has certain drawbacks as rapid solvent distillation, drying techniques. such as spray drying or freeze drying and milling techniques such as ball milling are cumbersome, which are not suitable for commercial scale operations.
Hence, there is a need in the art for additional processes for preparation of Ibrutinib amorphous form, which is commercially feasible in large scale production with greater yield, higher purity and good stability.

SUMMARY OF THE INVENTION
The present invention encompasses processes for the preparation of amorphous from of Ibrutinib with high product yield and quality, and greater stability.
In accordance with one embodiment, the present invention provides a process for preparation of amorphous form of Ibrutinib, comprising:
a) providing a solution of Ibrutinib in one or more organic solvents (SI),
b) concentrating the solution to obtain a residue,
c) adding a suitable solvent (S2) to the residue of step b); and
d) isolating the amorphous form.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Ibrutinib, comprising:
a) providing a solution of Ibrutinib in one or more organic solvents (SI),
b) concentrating the solution to obtain a residue,
c) adding a suitable solvent (S2) to the residue of step b); and
d) isolating the amorphous form.
wherein the one or more organic solvents (SI) are selected from the group consisting of alcohols, esters, halogenated hydrocarbons, amides, sulfoxides, ethers and mixtures thereof; and the suitable solvent (S2) is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Ibrutinib, comprising:
a) providing a solution of Ibrutinib in one or more organic solvents (S3),
b) adding the solution of step a) into a suitable solvent (S4) or vice-versa; and
c) isolating the amorphous form.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Ibrutinib, comprising:
a) providing a solution of Ibrutinib in one or more organic solvents (S3),
b) adding the solution of step a) into a suitable solvent (S4) or vice-versa; and
c) isolating the amorphous form.
wherein the one or more organic solvents (S3) are selected from the group consisting of alcohols, esters, halogenated hydrocarbons, amides, sulfoxides, ethers and mixtures thereof; wherein the suitable solvent (S4) is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.

In accordance with another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of Ibrutinib with one or more pharmaceutically acceptable carrier, which comprising:
a) dissolving Ibrutinib and one or more pharmaceutically acceptable carrier in a suitable solvent (S5) or mixture of solvents, and
b) isolating the amorphous solid dispersion.
In accordance with another embodiment, the present invention provides an amorphous form of Ibrutinib having a HPLC purity of about 99.5% or more as determined by high performance liquid chromatography (HPLC).
In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Ibrutinib prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Ibrutinib prepared according to reference example-1.
Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of amorphous Ibrutinib prepared according to reference example-1.
Figure 3 is the characteristic thermo gravimetric analysis (TGA) of amorphous Ibrutinib prepared according to reference example-1.
. Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Ibrutinib prepared according to example-1.
Figure 5 is the characteristic differential scanning calorimetric (DSC) thermogram of amorphous Ibrutinib prepared according to example-1.
Figure 6 is the characteristic thermo gravimetric analysis (TGA) of amorphous Ibrutinib prepared according to example-1.
Figure 7 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous solid dispersion of Ibrutinib with polyvinylpyrrolidone.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of amorphous from of Ibrutinib and pharmaceutical compositions containing the same.
The amorphous from of Ibrutinib of the present invention obtained by process of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) curves and thermo gravimetric analysis (TGA).
The X-Ray powder diffraction can be measured by an X-ray powder Diffractometer . equipped with a Cu-anode (|X] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA. , Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°29; step width=0.020°; and scan speed=5°C/minute.
All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.
All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about 30°C to about 250°C.
As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient Ibrutinib dispersed among at least one other component, for example a polymer.
In one embodiment, the present invention provides a process for preparation of amorphous form of Ibrutinib, comprising:
a) providing a solution of Ibrutinib in one or more organic solvents (SI),
b) concentrating the solution to obtain a residue,
c) adding a suitable solvent (S2) to the residue of step b); and
d) isolating the amorphous form.
The Ibrutinib in the step a) may be any crystalline or other form of Ibrutinib, including various solvates, hydrates, salts and cocrystals as long as amorphous Ibrutinib is produced during the process of the invention or Ibrutinib obtaining as existing solution from a previous processing step.

The step of providing a solution of Ibrutinib may include dissolving any form of Ibrutinib, in one or more organic solvents (SI). The organic solvents (SI) include, but are not limited to alcohols, esters, halogenated hydrocarbons, amides, sulfoxides, ethers and mixtures thereof.
The alcohols include, but are not limited to methanol, ethanol, 2-methoxy ethanol, propanol, isopropanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; ethers include, but are not limited to tetrahydrofiiran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixtures thereof.
In order to form a solution of step a), the contents may be heated to a suitable temperature. The temperature suitable for dissolving Ibrutinib depends on the solvent used and the amount of Ibrutinib in the solution. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. The solution may be prepared at other suitable temperatures as long as the Ibrutinib is sufficiently dissolved. Increasing the amount of Ibrutinib would generally require the use of higher temperatures. Routine experimentation will provide the approximate range of suitable temperatures for a given solvent and amount of Ibrutinib.
Step b) of the aforementioned process involves concentration of the solution obtained in step a) by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution. Evaporation can be achieved by a distillation, rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably, the solvent may be evaporated completely by distillation under vacuum at a temperature of about 25°C to about 90°C to obtain a residue..
To the obtained residue, suitable solvent (S2) may be added at less than 15°C to obtain the amorphous Ibrutinib, preferably, less than about 10°C. The suitable solvent (S2) include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to tetrahydrofiiran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited

to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof..
The amorphous Form of Ibrutinib can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about 10°C, preferably at about -5°C to 5°C.
The amorphous Form of Ibrutinib obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor.
In another embodiment, the present invention provides a process for preparation of amorphous form of Ibrutinib, comprising:
a) providing a solution of Ibrutinib in one or more organic solvents (S3),
b) adding the solution of step a) into a suitable solvent (S4) or vice-versa; and
c) isolating the amorphous form.
The Ibrutinib in the step a) may be any crystalline or other form of Ibrutinib, including various solvates, hydrates, as long as amorphous Ibrutinib is produced during the process of the invention or Ibrutinib obtaining as existing solution from a previous processing step.
The step of providing a solution of Ibrutinib may include dissolving any form of Ibrutinib, in one or more organic solvents (S3). The organic solvents (S3) include, but are not limited to.alcohols, esters, halogenated hydrocarbons, amides, sulfoxides, ethers and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, 2-methoxy ethanol, propanol, isopropanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixtures thereof.
In order to form a solution of step a), the contents may be heated to a suitable temperature. The temperature suitable for dissolving Ibrutinib depends on the solvent used and the amount of Ibrutinib in the solution. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. The solution may be prepared at other

suitable temperatures as long as the Ibrutinib is sufficiently dissolved. Increasing the amount of Ibrutinib would generally require the use of higher temperatures. Routine experimentation will provide the approximate range of suitable temperatures for a given solvent and amount of Ibrutinib.
Step b) of the aforementioned process involves addition of Ibrutinib solution obtained from step a) into a suitable solvent (S4) or suitable solvent (S4) may be added in to step a) solution. The suitable solvent (S4) include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof The ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof
The addition may be carried out at less than 25°C to obtain the amorphous Ibrutinib, preferably, less than about 10°C. The amorphous Form of Ibrutinib can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about 10°C, preferably at about -5°C to 5°C.
The amorphous Form of Ibrutinib obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor.
In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of Ibrutinib with one or more pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of Ibrutinib with one or more pharmaceutically acceptable carrier, which comprising:
a) dissolving Ibrutinib and one or more pharmaceutically acceptable carrier in a suitable
solvent (S5) or mixture of solvents, and
b) isolating the amorphous solid dispersion.
The pharmaceutically acceptable carriers includes but are not limited to hydrophilic carriers such as polymers of N-vinylpyrrolidone commonly known as polyvinylpyrrolidone or "PVP" or "povidone", polyvinyl caprolactam, polyvinyl acetate,

polyethylene glycol graft copolymer (Soluplus ), polyvinylpyrrolidone/vinyl acetate co-polymer (PVP-VA), polysorbate, plasdone, meglumine, gum, cellulose derivatives such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose^ hydroxyethyl cellulose, hydroxypropyl cellulose (HPC or hypromellose), hydroxymethyl cellulose, hydroxypropyl cellulose acetate-succinate, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, carboxymethylene hydroxyethylcellulose, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl ethyl cellulose (HPEC), cellulose acetate phosphate, cyclodextrins, gelatin, hypromellose phthalate, lactose, polyhydric alcohols, polyethylene glycols (PEGs), polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, acrylic acid, acrylamide, maleic anhydride polymer, polyvinyl alcohols, and propylene glycol derivatives, fatty acids, fatty alcohols, or esters of fatty acids; or its derivatives thereof.
Useful pyrrolidones include, but are not limited to homopolymers or copolymers of N-vinylpyrrolidone. Such polymers can form complexes with a variety of compounds. The water-soluble forms of N-vinylpyrrolidone are available in a variety of viscosity and molecular weight grades such as but not limited to PVP K-12, PVP K-15, PVP KT17, PVP K-25, PVP K-30, PVP K-90, PVP K-120 and crospovidone.
Polyethylene glycols, condensation polymers of ethylene oxide and water, are commercially available from various manufacturers in average molecular weights ranging from about 300 to about 10,000,000 Daltons. Some of the grades that are useful in the present invention include, but are not limited to, PEG 1500, PEG 4000, PEG 6000, PEG 8000, etc.
Among various cyclodextrins a-, (}-, y- and s-cyclodextrins or their methylated or hydroxyalkylated derivatives may be used.
The Ibrutinib in the step a) may be any crystalline, amorphous or other form of Ibrutinib, including various solvates, hydrates, salts and cocrystals as long as amorphous solid dispersion of Ibrutinib is produced during the process of the invention or Ibrutinib obtaining as existing solution from a previous processing step.
In step a) of aforementioned process, dissolution of Ibrutinib and one or more pharmaceutically acceptable carrier as described above, in a suitable solvent (S5) or mixture of solvents is carried out at a suitable temperature of at about 25°C to about reflux. The suitable solvent (S5) or mixture of solvents used for dissolution is selected from the group consisting of halogenated solvents such as methylene chloride, ethylene chloride, chloroform and the like; alcohols such as methanol, ethanol, isopropanol and

the like; ketone solvents such as acetone, methylisobutylketone, methylethylketone and the like; and mixtures thereof.
In step b) of isolation of solid dispersion of amorphous Ibrutinib can be carried out by removal of solvent or cooling the solution to precipitation or by addition of anti-solvent to precipitation followed by filtration.
The step b) of concentration of the solution obtained in step a) by removal of solvent from the solution for example, substantially complete evaporation of the solvent, concentrating the solution. Evaporation can be achieved by a distillation, rotational drying (such as with the Buchi Rotavapor), fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably, the solvent may be evaporated completely by distillation under vacuum at a temperature of about 25°C to about 90°C.
The amorphous form can be separated by slurring with a suitable aliphatic hydrocarbon solvent such as hexane, heptane, cyclohexane, methyl cyclohexane and the like and mixtures thereof followed by filtration and drying.
The step of cooling the solution is carried out by cooling the step a) solution to less than 20°C followed by filtering to isolate the amorphous form.
The step of addition of anti-solvent can be carried out by adding a suitable anti-solvent to the step a) solution followed by optional step of cooling the solution to less than 20°C and filtering to isolate the amorphous form. The suitable anti-solvent used herein is selected from aliphatic hydrocarbons such as hexane, heptane, cyclohexane, methyl cyclohexane and the like and mixtures thereof.
The resultant amorphous solid dispersion of Ibrutinib may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like;
In another embodiment, the present invention provides amorphous solid dispersion of Ibrutinib with polyvinylpyrrolidone.
In another embodiment, the present invention provides amorphous solid dispersion of Ibrutinib with polyvinylpyrrolidone characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
In another embodiment, the present invention provides an amorphous form of Ibrutinib obtained by the process as descibed just above having a HPLC purity of about 98% or

more, of about 99% or more, of about 99.5% or more as determined by high performance liquid chromatography (HPLC).
In another embodiment, the present invention provided a pharmaceutical composition comprosing an amorphous form of Ibrutinib preparaed by the process described above, together with one or more pharmaceutically acceptable excipients. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.
EXAMPLES
The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
REFERENCE EXAMPLE:
Preparation of amorphous form, of Ibrutinib
The following examples were carried out following the teaching of Example la of US 7,514,444 (methylene chloride + methanol)
[i] Ibrutinib (2 g) was dissolved in methylene chloride (50 mL) and methanol (2 mL) at ambient temperature. The solvent was distilled completely at 35°C under vacuum in a Buchi Rotavapor and maintained for about 20 min after complete evaporation. The obtained solids were dried at 55°C under vacuum for 8 hrs. Yield: 1.82 g; Moisture content: 1.3% w/w.
[ii] Ibrutinib (2 g) was dissolved in methylene chloride (50 mL) and methanol (2 mL) at ambient temperature. The solvent was distilled completely at 20°C under vacuum in a Buchi Rotavapor and maintained for about 15 min after complete evaporation. The obtained solids were dried at 55°C under vacuum for 8 hrs. Yield: 1.86 g.
[iii] Ibrutinib (5 g) was dissolved in methylene chloride (50 mL) and methanol (2 mL) at 25°C. The solvent was distilled completely at 40°C under vacuum to afford amorphous form. Yield: 4.5 g.
[iv] Ibrutinib (0.3 g) was dissolved in methylene chloride (25 mL) and methanol (1 mL) at 25°C. The solvent was distilled completely at 70°C under vacuum to afford amorphous form. Yield: 220 mg.

[v] Ibrutinib Form A (4 g) was dissolved in methylene chloride (12 mL) and methanol (0.5 mL) at 25°C. The solvent was distilled completely at 45°C u/v. The obtained solids (2 g) were dried at 55°C under vacuum for 16 hrs to afford amorphous form. Yield: 1.86 g.
Amorphous Form obtained according to the reference examples [i] to [v] was analyzed by PXRD, DSC and TGA and are represented according to Fig. 1, Fig. 2 and Fig. 3 respectively.
EXAMPLE 1:
Preparation of amorphous form of Ibrutinib (dimethyl sulfoxide + water)
Ibrutinib (4 g) was dissolved in dimethyl sulfoxide (8 mL) at 42°C. The dimethyl sulfoxide solution was added to pre-cooled water (100 mL) at 2°C. The resultant suspension was stirred for 30 min at 2°C. The obtained solid was filtered, washed with chilled water (40 mL), suck dried under vacuum at 25°C for 15 hrs to yield 2.5 g. 2 g of this material was further dried at 52°C for 8 hrs to yield Ibrutinib amorphous form. Yield: 1.9 g; Moisture content: 1.4% w/w; hygroscopicity: 3.5%; PXRD: Fig. 4; DSC: Fig. 5; TGA: Fig. 6.
EXAMPLE 2:
Preparation of amorphous form of Ibrutinib (dimethyl sulfoxide + water)
Ibrutinib (4 g) was dissolved in dimethyl sulfoxide (8 mL) at 42 °C. The dimethyl sulfoxide solution was added to pre-cooled water (100 mL) at 2°C. The resultant suspension was stirred for 30 min at 2°C. The obtained solid was filtered, washed with chilled water (40 mL), suck dried under vacuum at 25°C for 15 hrs and followed by at 52°C for 8 hrs to yield Ibrutinib amorphous form. Yield: 3.3 g; Moisture content: 1.6% w/w; hygroscopicity: 3.2%.
EXAMPLE 3:
Preparation of amorphous form of Ibrutinib (dimethyl formamide + water)
Ibrutinib (0.4 g) was dissolved in dimethyl formamide (0.8 mL) at 25°C. The dimethyl formamide solution was added to pre-cooled water (10 mL) at 0°C. The resultant suspension was stirred for 30 min at 2°C. The obtained solid was filtered, washed with water (2 mL), suck dried under vacuum at 25°C for 30 min to yield Ibrutinib amorphous form. Yield: 650 mg.

EXAMPLE 4:
Preparation of amorphous form of Ibrutinib (dimethyl acetamide + water)
Ibrutinib (0.3 g) was dissolved in dimethyl acetamide (0.6 mL) at 25°C. The dimethyl acetamide solution was added to pre-cooled water (10 mL) at 2°C. The resultant suspension was stirred for 30 min at 2°C. The obtained solid was filtered, washed with water (2 mL), suck dried under vacuum at 25°C for 30 min to yield Ibrutinib amorphous form. Yield: 320 mg.
EXAMPLE 5:
Preparation of amorphous form of Ibrutinib (dioxane + water)
Ibrutinib (0.3 g) was dissolved in dioxane (0.6 mL) at 25°C. The dioxane solution was added to pre-cooled water (10 mL) at 2°C. The resultant suspension was stirred for 30 min at 2°C. The obtained solid was filtered, washed with water (2 mL), suck dried under vacuum at 25°C to yield Ibrutinib amorphous form. Yield: 315 mg.
EXAMPLE 6:
Preparation of amorphous form of Ibrutinib (methylene chloride + methanol + water)
Ibrutinib (0.5 g) was dissolved in methylene chloride (12 mL) and methanol (0.5 mL)at 25°C. The solvent was distilled completely at 25°C u/v. To the reaction mass chilled water (5 mL) was charged and stirred the suspension at 2°C for 30min. The solid was filtered, washed with chilled water (2 mL), dried under vacuum for 1 hr to yield Ibrutinib amorphous form. Yield: 418 mg.
EXAMPLE 7:
Preparation of amorphous form of Ibrutinib (methylene chloride + methanol + water)
Ibrutinib (1 g) was dissolved in methylene chloride (3 mL), methanol (5 mL) was added at 25°C and stirred the suspension for clear solution at the same temperature. The solvent was distilled completely at 60°C u/v. To the reaction mass chilled water (10 mL) was charged and stirred the suspension at 0-5°C for 30min. The solid was filtered, washed with chilled water (2 mL), dried under vacuum at 52°C for 1 hr to yield Ibrutinib amorphous form. Yield: 771 mg.

EXAMPLE 8:
Preparation of amorphous form of Ibrutinib (methylene chloride + water)
Ibrutinib (1 g) was dissolved in methylene chloride (3 mL) at 25°C. The solvent was distilled completely at 40°C u/v. To the reaction mass chilled water (10 mL) was charged and stirred the suspension at 0-5°C for 30min. The solid was filtered, washed with chilled water (2 mL), dried under vacuum at 52°C for 1 hr to yield Ibrutinib amorphous form. Yield: 900 mg.
EXAMPLE 9:
Preparation of amorphous form of Ibrutinib (methylene chloride + methyl tertiary butyl ether)
Ibrutinib (1 g) was dissolved in methylene chloride (3 mL) at 30°C. The methylene chloride solution was added to methyl tertiary butyl ether (30 mL) and stirred at -40°C for 30 min. The solid was filtered, dried under vacuum at 50°C for 6 hrs to yield Ibrutinib amorphous form. Yield: 520 mg.
EXAMPLE 10:
Preparation of amorphous form of Ibrutinib (methylene chloride + diisopropyl ether)
Ibrutinib (1 g) was dissolved in methylene chloride (3 mL) at 30°C. The methylene chloride solution was added to diisopropyl ether (25 mL) at -40°C and the resultant suspension was further stirred at -40°C for 30 min. The solid was filtered, dried under vacuum at 50°C for 7 hrs to yield Ibrutinib amorphous form. Yield: 850 mg.
EXAMPLE 11:
Preparation of amorphous solid dispersion of Ibrutinib
Ibrutinib (400 mg) and polyvinylpyrrolidone (125 mg) was dissolved in methanol (30 mL) at 62°C. The solvent was distilled completely at 50°C u/v and maintained at same temperature for 30 min to yield amorphous solid dispersion of Ibrutinib. Yield: 320 mg; PXRD: Fig. 7.

EXAMPLE 12:
Preparation of amorphous solid dispersion of Ibrutinib
Ibrutinib (400 mg) and polyvinylpyrrolidone (125 mg) was dissolved in methylene chloride (4 mL) at 30°C. To the reaction mass methanol (4 mL) was added and stirred for 50°C. The solvent was distilled completely at 50°C u/v and maintained at same temperature for 30 min to yield amorphous solid dispersion of Ibrutinib. Yield: 330 mg.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.