DESC:Field of the invention
The present invention relates to an amorphous form of Ibrutinib and processes for preparation thereof.

The present complete specification is prepared by cognating the contents provisional patent specification of application numbered 201621013805 dated April 20, 2016 with the contents of the specification of patent application no. 201621022795 dated July 01, 2016. The combined contents of the present specification constitute a single invention within the meaning of the Act.

Background of the invention
Ibrutinib is a first-in class anticancer drug targeting B-cell malignancies. It is an orally- administered, selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase (BTK), a protein necessary for the growth and survival of B-cells. It is a small-molecule inhibitor of BTK, a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. As an irreversible covalent inhibitor, Ibrutinib continues to inhibit BTK even after the drug is metabolized. Ibrutinib prevents the activation of downstream pathways affected by BTK, promotes cancer-cell apoptosis, and inhibits cell proliferation.
It is chemically described as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and structurally represented by formula (I) as given below.

Ibrutinib has been approved under the trade name ImbruvicaTM indicated for the treatment of patients with Mantle cell lymphomas (MCL) who have received at least one prior therapy, chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, chronic lymphocytic leukemia (CLL) with 17p deletion and Waldenström’s macroglobulinemia (WM).
U.S. Pat. No. 7,514,444 and family disclose Ibrutinib and process for preparation of the same.
International Patent Publication Number WO2013/184572A2 discloses crystalline forms including solvates of Ibrutinib that are marked as Forms A, B, C, D, E and F. Also disclosed is an amorphous form of Ibrutinib.
International Patent Publication Number WO2015/081180 discloses crystalline Form-I of Ibrutinib characterised by PXRD.
International Patent Publication Number WO2015/145415 discloses various crystalline forms, and amorphous form of Ibrutinib and process of preparing the same. The processes disclosed for preparation of stable amorphous Ibrutinib includes spray drying, milling in a ball-mill and freeze-drying of Ibrutinib.
International patent publication number WO2016/25720A1 discloses crystalline Form G, Form J and Form K.
IP.Com Disclosure No IPCOM000238881D (2014) discloses amorphous form of Ibrutinib.
International Patent Publication Number WO2016/088074 discloses process for preparation of amorphous Ibrutinib and solid dispersion of Ibrutinib.
International Patent Publication Number WO2016/20172 discloses process for preparation of amorphous Ibrutinib.
However, there is a need for stable amorphous form of Ibrutinib, with improved physicochemical behaviour to modulate the pharmacological properties, and efficient processes for preparing such forms. The embodiments of the present disclosure provide such a form and processes for preparation thereof.
Object of the invention
It is an object of the present invention to provide an amorphous form of Ibrutinib.
It is another object of the present invention to provide process for preparation of said amorphous form of Ibrutinib.
It is yet another object of the present invention to provide a composition comprising said amorphous form of Ibrutinib of the present invention.
Brief description of the drawing
Figure-1: PXRD pattern of the amorphous form of Ibrutinib of the present invention
Description of the invention
Embodiments of the present invention relates to a stable amorphous form of Ibrutinib.
Embodiments of the present invention relates to a stable amorphous form of Ibrutinib characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure-1.
Embodiments of the present invention also relates to a process for the preparation of said amorphous form of Ibrutinib.
The processes of the present invention are specifically useful as these are efficient processes for the preparation of the stable amorphous form of Ibrutinib.
In one aspect, the present disclosure provides a process for the preparation of the stable amorphous form of Ibrutinib comprising of:
a) providing Ibrutinib at pH of about 1 to about 5 to obtain a solution;
b) adjusting the pH of the solution of step (a) to about 8 to about 12 and,
c) isolating the stable amorphous form of Ibrutinib from the reaction mixture.
In step (a) Ibrutinib is contacted with an acid, preferably in the presence of a water miscible solvent to obtain a solution at pH of about 1 to about 5. The pH of the solution is about 1 to about 5, preferably about 2 to about 4. Such an acid is preferably an organic acid, for example, formic acid, acetic acid and the like.
The water miscible solvent is selected from the group of alkanol, ketone, ether, amide and nitrile or a combination thereof in a suitable proportion. Preferably the alkanol is methanol, ethanol and isopropanol; the ketone is acetone; the ether is tetrahydrofuran; the amide is dimethylformamide; and the nitrile is acetonitrile.
The most preferred water miscible solvent is methanol.
The solution obtained after Ibrutinib is contacted with the acid may be a clear, transparent liquid or may be slightly turbid/opaque liquid, and is optionally filtered to obtain a clear solution.
In step (b), the solution obtained in step (a) is contacted with a base at about 0°C to about 15°C, preferably at about 5°C to about 10°C, to adjust the pH to about 8 to about 12.
The base used in step (b) is selected from the group consisting of ammonium hydroxide, an alkali metal hydroxide, carbonate or bicarbonate and a tertiary amine.
The alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide. The alkali metal carbonate and bicarbonate is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or lithium carbonate. The preferred tertiary amine is triethylamine.
The reaction mixture obtained in step (b) is optionally maintained at temperature of about 0°C to about 30°C, preferably at about 5°C to 25°C, more preferably at about 10°C to about 15°C for about 0.5 hrs to about 5 hrs to afford the stable amorphous form of Ibrutinib.
The stable amorphous form of Ibrutinib is isolated by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
In another aspect, the present invention provides a process for the preparation of a stable amorphous form of Ibrutinib comprising of:
a) contacting Ibrutinib with water;
b) adjusting pH to about 1 to about 5 to obtain a solution;
c) adjusting the pH of solution of step (b) to about 8 to about 12 and,
d) isolating the stable amorphous form of Ibrutinib from the reaction mixture.
In step (a) Ibrutinib is contacted with water at temperature of about 10°C to about 20°C.
The pH of the reaction mixture obtained in step (a) is adjusted to about 1 to about 5, preferably to about 1 to about 3, more preferably to about 1 to about 2 to obtain a solution, wherein the pH is adjusted using an acid. An inorganic acid is used for pH adjustment, preferably hydrochloric acid.
In step (c), a base is added to the solution obtained in step (b) at temperature of about 0°C to about 20°C, preferably at about 5°C to about 10°C, more preferably at about 10°C to about 20°C to adjust the pH to about 8 to about 12.
The base used in step (c) is selected from the group consisting of ammonium hydroxide, an alkali metal hydroxide, carbonate or bicarbonate and tertiary amine.
The alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide. The alkali metal carbonate and bicarbonate is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or lithium carbonate. The preferred tertiary amine is triethylamine.
The reaction mixture obtained in step (c) is optionally maintained at temperature of about 20°C to about 30°C for about 3 hrs to about 20 hrs to afford the stable amorphous form of Ibrutinib.
The stable amorphous form of Ibrutinib is isolated in step (d) by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
In yet another aspect, the present invention provides a process for the preparation of the stable amorphous form of Ibrutinib comprising of:
a) contacting Ibrutinib with a suitable solvent;
b) substantially removing the solvent to obtain a residue;
c) contacting the residue of step (b) with water or water and a water miscible co-solvent;
d) adjusting pH to about 1 to about 5 to obtain a solution;
e) adjusting the pH of the solution of step (d) to about 8 to about 12 and,
f) isolating the stable amorphous form of Ibrutinib from the reaction mixture.
In step (a) Ibrutinib is contacted with a suitable solvent such as alkanol, ketone, chlorinated hydrocarbon, ester and nitrile or combinations thereof to obtain a mixture. Preferably the alkanol is methanol, ethanol, propanol, isopropanol, butanol, 2-butanol and pentanol; the ketone is acetone and methyl ethyl ketone; the chlorinated hydrocarbon is dichloromethane; the ester is ethyl acetate and isopropyl acetate; and the nitrile is acetonitrile; wherein the volume of alkanol, ketone, ether, amide and nitrile or combinations thereof is in a suitable proportion.
The most preferred suitable solvent is dichloromethane.
The reaction mixture obtained in step (a) is optionally treated with activated carbon and filtered through celite to remove unwanted particles therefrom.
The residue obtained in step (b) after substantially removing the solvent is contacted with water or water and a water miscible co-solvent and is cooled to about 0°C to about 20°C, preferably to about 5°C to about 10°C, more preferably to about 10°C to about 20°C.
The water miscible co-solvent is alkanol, ketone, ether, amide and nitrile or combinations thereof in a suitable proportion. Preferably the alkanol is methanol, ethanol, isopropanol; the ketone is acetone; the ether is tetrahydrofuran; the amide is dimethylformamide; and the nitrile is acetonitrile.
The pH of the reaction mixture obtained in step (c) is adjusted to about 1 to about 5, preferably to about 1 to about 3, more preferably to about 1 to about 2 to obtain a solution, wherein the pH is adjusted using an acid. An organic or inorganic acid is used for pH change, preferably hydrochloric acid.
The base used in step (e) to adjust the pH of the solution obtained in step (d) to about 8 to about 12 is selected from the group consisting of ammonium hydroxide, an alkali metal hydroxide, carbonate or bicarbonate and tertiary amine.
The alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide. The alkali metal carbonate and bicarbonate is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or lithium carbonate. The preferred tertiary amine is triethylamine.
The reaction mixture obtained in step (e) is optionally maintained at temperature of about 20°C to about 30°C for about 3 hrs to about 20 hrs to afford the stable amorphous form of Ibrutinib. The stable amorphous form of Ibrutinib is isolated in step (f) by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
The isolated amorphous form of Ibrutinib is dried at a suitable temperature and pressure for a suitable time. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, rapid dryer and the like. The drying is carried out at atmospheric pressure or above, or under reduced pressures, preferably at temperatures less than about 80° C. and more preferably at less than about 60° C and most preferably at less than about 40° C.
The preferred drier is a rapid dryer with air flow rate of about 40 m3/min.
The stable amorphous form of Ibrutinib of the present disclosure is stable under stability conditions and is suitable for use in pharmaceutical preparations for therapeutic use. There is no physical change observed from amorphous form to crystalline form during stability studies.
Stability of amorphous form of Ibrutinib as prepared by the process described herein has been investigated at about 25 ± 2°C /60 ± 5% RH and at about 5 ± 3°C for over 2 months. Amorphous form of Ibrutinib of the present disclosure was stable under these conditions, as determined by the absence of PXRD peaks, in particular, by the absence of characteristic PXRD peaks of crystalline forms described in the literature.
In an embodiment of the present disclosure, the stable amorphous form of Ibrutinib prepared according to the present disclosure are substantially pure having a chemical purity greater than about 98.5%, or greater than about 99.0%, or greater than about 99.5 % by weight as determined using high performance liquid chromatography (HPLC). The stable amorphous form of Ibrutinib produced by a method of present disclosure are chemically pure Ibrutinib having purity greater than about 99.5% and contain no single impurity in amounts greater than about 0.15%, by HPLC. The stable amorphous form of Ibrutinib produced by the methods of present disclosure are chemically pure Ibrutinib having purity greater than about 99.8% and contain no single impurity in amounts greater than about 0.1% by HPLC.
Ibrutinib used as the input material for the preparation of the stable amorphous form of Ibrutinib of the present disclosure is, either isolated Ibrutinib or a reaction mixture containing Ibrutinib obtained by a process known to a person ordinary skilled in the art. In a specific embodiment, the input material is prepared by practicing the chemistry disclosed in US’444 or obtained from commercial sources.
In one more embodiment, the present disclosure provides a pharmaceutical composition comprising the stable amorphous form of Ibrutinib along with one or more pharmaceutically acceptable carriers, excipients, or diluents having greater stability.
The stable amorphous form of Ibrutinib of the present disclosure is useful as BTK inhibitor indicated for the treatment of B cell malignancies. Such pharmaceutical compositions are prepared by the methods known in the literature.
The embodiments of the present disclosure are further illustrated with the following non-limiting examples.
Example 1: Preparation of amorphous form of Ibrutinib
Ibrutinib (15 gm, 0.034mol) was dissolved in 52.5 mL acetic acid and filtered to obtain a solution. The solution of Ibrutinib in acetic acid was gradually added to 120 mL of 12.5% aqueous ammonia at 10°C - 15°C under stirring. Then the reaction mixture was stirred for 2 to 4 hrs. The precipitated solid was filtered, washed with water and dried under vacuum to afford 13.0 gm of amorphous Ibrutinib.
Example 2: Preparation of amorphous form of Ibrutinib
Ibrutinib (5 gm, 0.011mol) was dissolved in 45 mL of 50% formic acid and filtered to obtain a solution. The solution of Ibrutinib in formic acid was gradually added to 45 mL of 12.5% aqueous ammonia at 10°C - 15°C under stirring. Then the reaction mixture was stirred for 10 to 30 min. The precipitated solid was filtered, washed with water and dried under vacuum to afford 4.4 gm of amorphous form of Ibrutinib.
Example 3: Preparation of amorphous form of Ibrutinib
Ibrutinib (10 gm, 0.022 mol) was dissolved in 40 mL methanol and 10 mL acetic acid and filtered to obtain a solution. The solution of Ibrutinib in acetic acid was gradually added to 100ml of 25% aqueous ammonia at 5°C - 10°C under stirring. Then the reaction mixture was stirred for 1 to 2 hrs. The precipitated solid was filtered, washed with water and dried under vacuum to afford 9.6 gm of amorphous form of Ibrutinib.
Example 4: Preparation of amorphous form of Ibrutinib
Ibrutinib (10 gm, 0.022mol) was dissolved in 40 mL of methanol and 10 mL acetic acid and filtered to obtain a solution. The solution of Ibrutinib in the mixture of methanol and acetic acid was gradually added to 322 mL of 5% aqueous sodium bicarbonate solution at 0°C - 5°C under stirring. Then the reaction mixture was stirred for 1 to 2 hrs. The precipitated solid was filtered, washed with water and dried under vacuum at to afford 8.1 gm of amorphous form of Ibrutinib.
Example 5: Preparation of amorphous form of Ibrutinib
Ibrutinib (10 gm, 0.022mol) was dissolved in 20 mL, mixture of methanol and acetic acid (20:80) and filtered to obtain a solution. The solution of Ibrutinib in the mixture of methanol and acetic acid was gradually added to 216 mL of 20% aqueous triethylamine solution at 0°C - 5°C under stirring. Then the reaction mixture was stirred for 1 to 2 hrs at 0°C - 5°C. The precipitated solid was filtered, washed with water and dried under vacuum at to afford 8.3 gm of amorphous form of Ibrutinib.
Example 6: Preparation of amorphous form of Ibrutinib
10 gm Ibrutinib was taken in 150 mL water and cooled to 10°C to 20°C followed by addition of 120 mL 5M hydrochloric acid. The reaction mixture was stirred at 10°C to 20°C for about 30 min. followed by addition of 170 mL 20% aqueous sodium hydroxide solution and the reaction mixture was stirred for 3 hrs to 4 hrs. The precipitated solid was filtered and slurry washed with 100 mL water and dried under vacuum at 50°C to 60°C to yield 7.4 gm of amorphous form of Ibrutinib with moisture content NMT 1.0%w/w.
Example 7: Preparation of amorphous form of Ibrutinib
10 gm Ibrutinib was taken in 150 mL water, cooled to 10°C to 20°C followed by addition of 80 mL 10% hydrochloric acid. The reaction mixture was stirred for 30 min. and then 60 mL aqueous ammonia was added and the reaction mixture was stirred for 15 hrs to 20 hrs. the precipitated solid was filtered, slurry washed with 150 mL water, filtered and washed with 50 mL water and dried under vacuum at 50°C to 60°C to yield 9.8 gm of amorphous form of Ibrutinib with moisture content NMT 1.0%w/w.
Example 8: Preparation of amorphous form of Ibrutinib
To 25 gm of Ibrutinib was added 250 mL dichloromethane and stirred for 20 min. followed by addition of 2.5 gm of charcoal and the reaction mixture was stirred for 30 min. Thereafter the reaction mixture was filtered through celite, the filtrate was distilled off under vacuum and to the residue was added 625 mL water, cooled to 10°C to 20°C and pH was adjusted to 1-2 with 30 mL 10% hydrochloric acid. Thereafter the reaction mixture was stirred for 30 min. and then the pH was adjusted to 10-11 with 40 mL 10% aqueous sodium hydroxide. The reaction mixture was stirred further for 4 hrs to 5 hrs and the precipitated solid was filtered. The wet cake was slurried twice with water (375 mL X 2), filtered, washed with 100 mL water and dried under vacuum at 50°C to 60°C to yield 22.5 gm of amorphous form of Ibrutinib with moisture content NMT 1.0%w/w.
,CLAIMS:1. A process for preparing a stable amorphous form of Ibrutinib comprising the steps of:
a) providing Ibrutinib at pH of about 1 to about 5 to obtain a solution;
b) adjusting the pH of the solution of step (a) to about 8 to about 12 and,
c) isolating the stable amorphous form of Ibrutinib from the reaction mixture.

2. The process according to claim 1 wherein the pH of about 1 to about 5 is provided by an acid.
3. The process according to claim 2 wherein the acid is acetic acid or formic acid.

4. The process according to claim 1 wherein the pH of about 1 to about 5 is maintained in the presence of a water miscible solvent.

5. The process according to claim 4 wherein the water miscible solvent is methanol.

6. The process according to claim 1 wherein the pH of about 8 to about 12 is adjusted using a base.

7. The process according to claim 6 wherein the base is ammonium hydroxide or sodium bicarbonate.