DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN201841027926 filed on July 25, 2018.
FIELD OF THE INVENTION
The present invention relates to amorphous form of brigatinib, amorphous solid dispersion of brigatinib with pharmaceutically acceptable carriers and processes for their preparation thereof.

BACKGROUND OF THE INVENTION

Brigatinib (also known as AP26113) is an investigational small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals. Brigatinib acts as both a anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

Brigatinib is chemically known as 5-chloro-N4-[2-(dimethylphosphinyl) phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-pyrimidine diamine, having the structure below:

Formula-I

Brigatinib is marketed by ARIAD Pharmaceuticals, Inc under the brand name of ALUNBRIG for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

U.S. Patent No. 9,012,462 discloses Brigatinib and process for its preparation.
PCT Publication No. WO2016065028A1 discloses various crystalline forms of brigatinib and also amorphous form.
The inventors of the present disclosure have developed processes for the preparation of amorphous brigatinib, amorphous solid dispersion of brigatinib with pharmaceutically acceptable carriers.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a process for the preparation of amorphous brigatinib, which comprises:
a) dissolving brigatinib in an organic solvent or mixture of organic solvent and water; and
b) removing the solvent and isolating the amorphous brigatinib.

A second aspect of the present invention is to provide a process for the preparation of amorphous solid dispersion of brigatinib with pharmaceutically acceptable carriers, which comprises:
a) dissolving brigatinib in an organic solvent or mixture of organic solvent and water;
b) adding pharmaceutically acceptable carrier to the solution obtained in step (a); and
c) removing the solvent and isolating the amorphous solid dispersion of brigatinib.

BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure. 1 is an X-ray powder diffractogram of amorphous brigatinib.
Figure. 2 is an X-ray powder diffractogram of amorphous solid dispersion of brigatinib.

DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The polymorph of the present disclosure is characterized by its X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of the polymorphs of the disclosure were measured on BRUKER D-8 Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

The present disclosure relates to processes for the preparation of amorphous brigatinib, amorphous solid dispersion of brigatinib with pharmaceutically acceptable carriers.

In one embodiment, the present invention provides a process for the preparation of amorphous brigatinib, which comprises:
a) dissolving brigatinib in an organic solvent or mixture of organic solvent and water; and
b) removing the solvent and isolating the amorphous brigatinib.

Within the context of this embodiment of the present invention, the organic solvent employed may include water miscible organic solvents such as acetone, acetonitrile methanol, ethanol, propanol, or mixtures thereof. In particular useful embodiments of the present invention the organic solvent is acetonitrile or methanol.

Within the context of this embodiment of the present invention, removing of solvent can be done using any techniques in the art such as, filtration by gravity or suction, centrifugation, slow evaporation, distillation, spray drying or lyophilization. In particular useful embodiments of the present invention the solvent is removed by spray drying or lyophilization.

Yet another embodiment of the present invention is to provide amorphous solid dispersion of brigatinib with pharmaceutically acceptable carriers.

Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Brigatinib with pharmaceutically acceptable carriers, which comprises:
a) dissolving brigatinib in an organic solvent or mixture of organic solvent and water;
b) adding pharmaceutically acceptable carrier to the solution obtained in step (a); and
c) removing the solvent and isolating the amorphous solid dispersion of brigatinib
Within the context of this embodiment of the present invention, the organic solvent employed may include water miscible organic solvents such as acetone, acetonitrile methanol, ethanol, propanol, or mixtures thereof. In particular useful embodiments of the present invention the organic solvent is methanol or acetonitrile.

Within the context of this embodiment of the present invention, pharmaceutically acceptable carrier employed may include, povidone, copovidone, silicon dioxide, microcrystalline cellulose, lactose monohyrate or mixtures thereof. Said povidone is selected from povidone K-17, povidone K-25, povidone K-30 and the like; said copovidone is selected from such as copovidones of which the brand names are Plasdone S-630 or Kollidon VA64 and the like. In particular useful embodiments of the present invention pharmaceutically acceptable carrier selected is silicon dioxide, microcrystalline cellulose or lactose monohyrate.

Within the context of this embodiment of the present invention, removing of solvent can be done using any techniques in the art such as, filtration by gravity or suction, centrifugation, slow evaporation, distillation, lyophilization. In particular useful embodiments of the present invention the solvent is removed by distillation or lyophilization.

According to the present invention, the input brigatinib is prepared by any prior-art process for example U.S. Patent No. 9,012,462.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
Example 1: Preparation of amorphous Brigatinib
Brigatinib (0.2 g) was dissolved in a mixture of acetonitrile (2.5 mL) and water (5 mL) at 85±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to lyophilisation using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous brigatinib.
Yield: 0.18g

Example 2: Preparation of amorphous Brigatinib
Brigatinib (2 g) was dissolved in methanol (40 mL) at 60-65°C. Filtered the clear solution through hyflo to remove any undissolved particulate and washed with methanol. The resulting clear solution was cooled to 25-30°C, then subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 70°C with 100% aspiration to yield amorphous brigatinib.
Yield: 1.0g

Example 3: Preparation of amorphous solid dispersion of Brigatinib
Brigatinib (0.2 g) was dissolved in methanol (6 mL) at 60±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates. Added aeropril 300 (0.2 g) to the clear solution and distilled completely under vacuum using rotary evaporator at 55±5°C. The solid obtained was identified as amorphous solid dispersion of Brigatinib with aeropril 300.

Example 4: Preparation of amorphous solid dispersion of Brigatinib
Brigatinib (0.2 g) was dissolved in methanol (6 mL) at 60±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates. Added microcrystalline cellulose (0.2 g) to the clear solution and distilled completely under vacuum using rotary evaporator at 55±5°C. The solid obtained was identified as amorphous solid dispersion of Brigatinib with microcrystalline cellulose.

Example 5: Preparation of amorphous solid dispersion of Brigatinib
Brigatinib (0.2 g) was dissolved in a mixture of acetonitrile (5 mL) and water (10 mL) at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates. To the clear solution added silicon dioxide (0.2 g) and subjected to Lyophilisation using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Brigatinib.

Example 6: Preparation of amorphous solid dispersion of Brigatinib
Brigatinib (0.2 g) was dissolved in a mixture of acetonitrile (5 mL) and water (10 mL) at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates. To the clear solution added microcrystalline cellulose (0.2 g) and subjected to Lyophilisation using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Brigatinib.

Example 7: Preparation of amorphous solid dispersion of Brigatinib
Brigatinib (0.2 g) was dissolved in a mixture of acetonitrile (5 mL) and water (10 mL) at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates. To the clear solution added lactose monohydrate (0.2 g) and subjected to Lyophilisation using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Brigatinib.

,CLAIMS:1. A process for the preparation of amorphous brigatinib, which comprises:
a) dissolving brigatinib in an organic solvent or mixture of organic solvent and water; and
b) removing the solvent and isolating the amorphous brigatinib.

2. The process as claimed in claim 1, wherein organic solvent is selected from water miscible organic solvents such as acetone, acetonitrile methanol, ethanol, propanol, or mixtures thereof.

3. The process as claimed in claim 1, wherein solvent is removed by spray drying or lyophilization.

4. A process for the preparation of amorphous solid dispersion of Brigatinib with pharmaceutically acceptable carriers, which comprises:
a) dissolving brigatinib in an organic solvent or mixture of organic solvent and water;
b) adding pharmaceutically acceptable carrier to the solution obtained in step (a); and
c) removing the solvent and isolating the amorphous solid dispersion of brigatinib.

5. The process as claimed in claim 4, wherein organic solvent is selected from water miscible organic solvents such as acetone, acetonitrile methanol, ethanol, propanol, or mixtures thereof.

6. The process as claimed in claim 4, wherein pharmaceutically acceptable carrier selected from povidone, copovidone, silicon dioxide, microcrystalline cellulose, lactose monohyrate or mixtures thereof.

7. The process as claimed in claim 4, wherein solvent is removed by distillation or lyophilization.