DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. IN201841042652, filed on Nov 13, 2018; Indian provisional patent application No. IN201841034785, filed on Sep 14, 2018; and Indian provisional patent application No. IN 201841031919, filed on Aug 27, 2018, the entire contents of each of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates generally to pharmaceutically active compounds and more specifically to crystalline Form M1 of Avatrombopag, crystalline Form M2 of Avatrombopag, crystalline Form M3 of Avatrombopag , crystalline Form M4 of Avatrombopag, crystalline Form M5 of Avatrombopag, crystalline Form M1 of Avatrombopag maleate, crystalline Form M2 of Avatrombopag maleate, crystalline Form M3 of Avatrombopag maleate, amorphous Avatrombopag, amorphous Avatrombopag maleate, amorphous solid dispersions of Avatrombopag maleate and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
Avatrombopag is first disclosed in U.S Patent No. 7,638,536. Avatrombopag is chemically known as 1-[3-Chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]amino]carbonyl]-2-pyridinyl]-4-piperidinecarboxylic acid, having the below structure:

Avatrombopag maleate is specifically disclosed in WO2004029049A1.
WO2013018362A1 patent publication discloses crystalline forms A, B and C of Avatrombopag maleate, wherein Form C and Form B are commercially suitable for industrial scaleup, but Form B has inferior oral absorption compared to Form C and Form A.
The inventors of the invention disclosed herein have developed The present invention relates generally to pharmaceutically active compounds and more specifically to crystalline Form M1 of Avatrombopag, crystalline Form M2 of Avatrombopag, crystalline Form M3 of Avatrombopag , crystalline Form M4 of Avatrombopag, crystalline Form M5 of Avatrombopag, crystalline Form M1 of Avatrombopag maleate, crystalline Form M2 of Avatrombopag maleate, crystalline Form M3 of Avatrombopag maleate, amorphous Avatrombopag, amorphous Avatrombopag maleate, amorphous solid dispersions of Avatrombopag maleate and processes for the preparation thereof.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide amorphous Avatrombopag maleate.

In a specific aspect, the present invention is to provide amorphous Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 10.

Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate which comprises:
a) dissolving Avatrombopag maleate in a mixture of organic solvent or organic solvent and water at elevated temperature,
b) cooling the solution to room temperature,
c) isolating the amorphous Avatrombopag maleate.
Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in organic solvent,
b) adding an anti-solvent,
c) isolating the amorphous Avatrombopag maleate.
Another aspect of the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate.

In a specific aspect, the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 11.48, 17.67,18.85, 22.00 and 23.55 ±0.2°.

In a specific aspect, the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 6.

Another aspect of the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethylsulfoxide at elevated temperature;
b) cooling the solution to 20-30°C
c) adding to an anti-solvent, optionally containing a seed of avatrombopag maleate crystalline form M1;
d) isolating the crystalline Form M1 of Avatrombopag maleate.

Another aspect of the present invention is to provide novel crystalline Form M3 of Avatrombopag maleate.

In a specific aspect, the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 4.94, 8.47, 9.75 and 17.95±0.2°.
In a specific aspect, crystalline Form M3 of Avatrombopag maleate is characterized by powder X-ray diffraction pattern as shown in Figure 8.

Another aspect of the present invention is to provide a process for the preparation of crystalline Form M3 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethyl acetamide or a mixture of dimethyl acetamide and 2-ethoxyethanol at elevated temperature;
b) cooling the solution to 20-30°C;
c) optionally treating with an anti-solvent;
d) isolating the crystalline Form M3 of Avatrombopag maleate.

BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present invention 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 crystalline Form M1 of Avatrombopag.
Figure 2 is an X-ray powder diffractogram of crystalline Form M2 of Avatrombopag.
Figure 3 is an X-ray powder diffractogram of crystalline Form M3 of Avatrombopag.
Figure 4 is an X-ray powder diffractogram of crystalline Form M4 of Avatrombopag.
Figure 5 is an X-ray powder diffractogram of crystalline Form M5 of Avatrombopag.
Figure 6 is an X-ray powder diffractogram of crystalline Form M1 of Avatrombopag maleate.
Figure 7 is an X-ray powder diffractogram of crystalline Form M2 of Avatrombopag maleate.
Figure 8 is an X-ray powder diffractogram of crystalline Form M3 of Avatrombopag maleate.
Figure 9 is an X-ray powder diffractogram of amorphous Avatrombopag.
Figure 10 is an X-ray powder diffractogram of amorphous Avatrombopag maleate.
Figure 11 is an X-ray powder diffractogram of amorphous solid dispersions of Avatrombopag maleate.
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure relates generally to pharmaceutically active compounds and more specifically to crystalline Form M1 of Avatrombopag, crystalline Form M2 of Avatrombopag, crystalline Form M3 of Avatrombopag , crystalline Form M4 of Avatrombopag, crystalline Form M5 of Avatrombopag, crystalline Form M1 of Avatrombopag maleate, crystalline Form M2 of Avatrombopag maleate, crystalline Form M3 of Avatrombopag maleate, amorphous Avatrombopag, amorphous Avatrombopag maleate, amorphous solid dispersions of Avatrombopag maleate and processes for the preparation thereof.
Within the context of the present disclosure, the term “about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees. Within the context of the present disclosure, the term “about” when modifying an absolute measurement, such as time, mass, or volume, means the recited value plus or minus 10% of the value.

Within the context of the present disclosure, the term “elevated temperature” means the temperature above 25°C and it is depending on the solvent ratio and the concentration of Avatrombopag maleate.

The polymorphs of the present disclosure are 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.

In one embodiment, the present invention is to provide a novel crystalline Form M1 of Avatrombopag.
In an embodiment, the present disclosure is to provide a novel crystalline Form M1 of Avatrombopag, having significant peaks at 2? angle positions of about 5.37, 9.02, 10.98, 13.85, 14.98, 15.48, 17.70, 18.49, 19.49, 20.48, 21.33, 22.71, 24.89, 26.16, 27.51 and 30.11±0.2°.
In an embodiment, the present disclosure is to provide a novel crystalline Form M1 of Avatrombopag that is characterized by powdered X-ray diffraction pattern as shown in Figure 1.

In an embodiment, the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag, which comprises:
a) dissolving Avatrombopag maleate in pyridine or mixture of pyridine and water at elevated temperature;
b) cooling the solution to 20-30°C;
c) optionally evaporating the portion of solvent;
d) optionally adding a seed of crystalline form M1;
e) optionally adding an anti-solvent; and
f) isolating the crystalline Form M1 of Avatrombopag.

Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in pyridine at elevated temperature. Within the context of this embodiment, Avatrombopag maleate may be dissolved at elevated temperature of about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved at about 85°C.

Within the context of this embodiment, Avatrombopag maleate may be dissolved in mixture of pyridine and water at about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in mixture of pyridine and water at about 85°C.

Within the context of this embodiment of the present invention, the portion of slow solvent evaporation is about 14 to 16 hours at room temperature. Within the context of this present embodiment, the portion of solvent may be 30% to 95% of initial solvent volume. In particular useful embodiments of the present invention 95% of the solvent is evaporated.

Within the context of this embodiment, the anti-solvent employed for this embodiment is water.

Within the context of this embodiment, the product is isolated by filtration, evaporation, centrifuge and distillation.

Yet another embodiment of the present invention, is to provide a process for the preparation of crystalline Form M1 of Avatrombopag, which comprises:
a) dissolving Avatrombopag maleate in a mixture of an organic solvents at elevated temperature;
b) cooling the solution to 20-30°C;
c) evaporating the portion of solvent; and
d) isolating the crystalline Form M1 of Avatrombopag.

Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in a mixture of an organic solvents at elevated temperature. The organic solvent employed may include 2-methoxy ethanol, dimethylsulfoxide (DMSO), formamide, and dimethyl formamide (DMF). In particular useful embodiments of the present invention solvent employed is mixture of 2-methoxy ethanol, 1,4-dioxane and dimethylsulfoxide or mixture of Formamide, dimethyl formamide and dimethylsulfoxide.

Within the context of this embodiment, Avatrombopag maleate may be dissolved at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present disclosure Avatrombopag maleate may be dissolved at about 85°C.

Within the context of this embodiment of the present disclosure, the portion of slow solvent evaporation is about 14 to 16 hours at room temperature. Within the context of this present embodiment, the portion of solvent may be 30% to 95% of initial solvent volume. In particular useful embodiments of the present disclosure 95% of the solvent is evaporated.

Within the context of this embodiment, the product is isolated by filtration, evaporation and distillation.

In another embodiment, the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag.

In an embodiment, the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag, having significant peaks at 2? angle positions of about 5.49, 9.05, 11.02, 11.73, 13.97, 14.98, 15.49, 18.18, 20.47, 20.84, 21.41, 22.10, 22.81, 23.52, 26.02, 27.65, 29.22 and 42.40±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag that is characterized by powdered X-ray diffraction pattern as shown in Figure 2.

In another embodiment of the present invention is to provide a process for the preparation of crystalline Form M2 of Avatrombopag, which comprises:
a) dissolving Avatrombopag maleate in a mixture of acetonitrile, dimethylformamide and water at elevated temperature;
b) isolating the crystalline Form M2 of Avatrombopag.

Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in a mixture of acetonitrile, dimethylformamide and water at elevated temperature. Within the context of this embodiment, Avatrombopag maleate may be dissolved at elevated temperature of about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved at about 85°C.

Within the context of this embodiment of the present invention, the compound is isolated by solvent removal using any techniques in the art such as filtration, centrifugation, slow evaporation, distillation, agitated thin film drier (ATFD), lyophilization and spray-drying. In particular useful embodiments of the present invention the solvent is removed by lyophilization.

In another embodiment, the present invention is to provide a novel crystalline Form M3 of Avatrombopag.

In an embodiment, the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag, having significant peaks at 2? angle positions of about 7.61, 10.37, 11.72, 13.52, 14.74, 15.29, 17.10, 17.91, 18.90, 20.81, 23.03, 24.00, 24.79, 28.54, 33.43, 34.26, 34.63 and 37.92±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag is characterized by powdered X-ray diffraction pattern as shown in Figure 3.

Another embodiment of the present invention is to provide a process for the preparation of crystalline Form M3 of Avatrombopag, which comprises:
a) dissolving Avatrombopag maleate in a mixture of morpholine and isobutyl acetate at elevated temperature;
b) cooling the solution to 20-30°C; and
c) isolating the crystalline Form M3 of Avatrombopag.

Within the context of this embodiment of the present invention, dissolving Avatrombopag maleate in a mixture morpholine and isobutyl acetate at elevated temperature. Within the context of this embodiment, Avatrombopag maleate may be dissolved in mixture of morpholine and isobutyl acetate at elevated temperature of about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in mixture of morpholine and isobutyl acetate at about 85°C.
Within the context of this embodiment, the product is isolated by filtration, evaporation and distillation.

In another embodiment, the present invention is to provide a provide novel crystalline Form M4 of Avatrombopag.

In an embodiment, the present disclosure is to provide a novel crystalline Form M4 of Avatrombopag, having significant peaks at 2? angle positions of about 3.17, 8.78, 10.15, 13.12, 14.43, 15.15, 15.69, 16.12, 16.87, 17.36, 18.10, 19.16, 20.81, 21.23, 21.85, 22.23, 24.12, 24.75, 25.62, 27.67, 29.46, 34.86, 35.66, 36.95 and 40.91±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M4 of Avatrombopag that is characterized by powdered X-ray diffraction pattern as shown in Figure 4.

Another embodiment of the present invention is to provide a process for the preparation of crystalline Form M4 of Avatrombopag, which comprises:
a) heating Avatrombopag crystalline Form M1 to elevated temperature;
b) slowly cooling to obtain crystalline Form M4 of Avatrombopag.

Within the context of this embodiment of the present invention crystalline Form M1 of Avatrombopag is heating at a temperature about 20°C to about 400°C. In particular useful embodiments of the present invention crystalline Form M1 of Avatrombopag may be heated at about 30°C to 240°C.

Within the context of this embodiment of the present invention, slow cooling about 25°C to about 35°C temperature. In particular useful embodiments of the present invention it is cooled to about 30°C.

In another embodiment, the present invention is to provide a novel crystalline Form M5 of Avatrombopag.
In an embodiment, the present disclosure is to provide a novel crystalline Form M5 of Avatrombopag, having significant peaks at 2? angle positions of about 3.59, 7.52, 7.89, 8.93, 10.37, 11.87, 13.47, 14.64, 15.28, 15.75, 16.94, 19.98, 20.59, 21.12, 21.92, 22.72, 24.41, 25.21, 29.25 and 42.58±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M5 of Avatrombopag is characterized by powdered X-ray diffraction pattern as shown in Figure 5.

Another embodiment of the present invention is to provide a process for the preparation of crystalline Form M5 of Avatrombopag, which comprises:
a) heating Avatrombopag crystalline Form M2 to elevated temperature;
b) slowly cooling to obtain crystalline Form M5 of Avatrombopag.

Within the context of this embodiment of the present invention crystalline Form M2 of Avatrombopag is heating at a temperature about 20°C to about 400°C. In particular useful embodiments of the present invention crystalline Form M2 of Avatrombopag may be heated at about 30°C to 240°C.

Within the context of this embodiment of the present invention, slow cooling about 25°C to about 35°C temperature. In particular useful embodiments of the present invention it is cooled to about 30°C.

In another aspect, the present invention provides a novel crystalline Form M1 of Avatrombopag maleate.

In a specific aspect, the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 11.48, 17.67,18.85, 22.00 and 23.55 ±0.2°.

Within the context of the present invention, crystalline Form M1 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 5.14, 8.01, 8.46, 8.91, 9.67, 10.32, 10.90, 11.48, 12.27, 12.92, 13.67, 14.11, 14.55, 15.14, 15.99, 16.77, 17.23, 17.67, 18.06, 18.42, 18.85, 19.41, 20.19, 20.63, 21.34, 22.00, 22.80, 23.55, 23.87, 24.69, 26.25, 26.89, 27.58, 27.98, 28.99, 30.22, 30.77, 31.29, 32.57, 32.97, 33.66, 34.35, 35.15, 36.18, 37.98, 39.10, 39.87 and 40.71±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M1 of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 6.

Another aspect of the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethylsulfoxide at elevated temperature;
b) cooling the solution to 20-30°C;
c) adding to an anti-solvent, optionally containing a seed of avatrombopag maleate crystalline form M1;
d) isolating the crystalline Form M1 of Avatrombopag maleate.

Within the context of this embodiment, Avatrombopag maleate may be dissolved in dimethyl sulfoxide at a temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in dimethyl sulfoxide (DMSO) at about 85°C.

Within the context of this embodiment, the solution is added to an anti-solvent at room temperature. The anti-solvent employed may include water and methyl tertiary-butyl ether. In particular useful embodiments of the present invention, the solution is added to an anti-solvent at room temperature containing a seed of avatrombopag maleate crystalline form M1.

In one embodiment, the present invention is to provide novel crystalline Form M2 of Avatrombopag maleate.

In an embodiment, the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 6.90, 7.69, 8.69, 11.33, 11.69, 12.63, 13.65, 15.31, 17.55, 18.49, 19.50, 20.68, 21.76, 22.43, 22.85, 23.35, 25.74, 28.03, 28.82, 30.63, 32.65 and 40.38±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag maleate is characterized by powder X-ray diffraction pattern as shown in Figure 7.

In an embodiment, the present invention is to provide a process for the preparation of crystalline Form M2 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethylsulfoxide at elevated temperature;
b) cooling the solution to 20-30°C;
c) adding an anti-solvent to the solution of step (b) or vice-versa;
d) isolating the crystalline Form M2 of Avatrombopag maleate.

Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in dimethylsulfoxide at elevated temperature. Within the context of this embodiment, Avatrombopag maleate may be dissolved at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved at about 85°C.

Within the context of this embodiment, solution of Avatrombopag maleate may be treated with an anti-solvent or vice-versa at room temperature to obtain crystalline form M2 of Avatrombopag maleate. The anti-solvent employed for this embodiment may include ethyl acetate.

Within the context of this embodiment, the product is isolated by filtration, evaporation, centrifuge, suck drying and distillation.

In another aspect, the present invention is to provide novel crystalline Form M3 of Avatrombopag maleate.
In a specific aspect, the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 4.94, 8.47, 9.75 and 17.95±0.2°.

Within the context of the present invention, crystalline Form M3 of Avatrombopag maleate, having significant peaks at 2? angle positions of about 4.94, 8.47, 9.75, 9.72, 10.13, 11.02, 12.82, 13.08, 13.35, 14.59, 15.91, 16.07, 16.51, 17.08, 17.52, 17.95, 18.68, 18.95, 19.28, 19.85, 20.21, 20.65, 21.09, 21.74, 22.49, 23.31, 23.76, 24.10, 24.30, 24.85, 25.33, 26.50, 27.45, 28.29, 29.42, 30.72, 31.66, 32.45, 33.60, 34.24, 36.11,37.14, 38.30, 39.72, 40.85, and 41.46±0.2°.

In an embodiment, the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag maleate is characterized by powder X-ray diffraction pattern as shown in Figure 8.

Another aspect of the present invention is to provide a process for the preparation of crystalline Form M3 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethyl acetamide or a mixture of dimethyl acetamide and 2-ethoxyethanol at elevated temperature;
b) cooling the solution to 20°C -30°C;
c) optionally treating with an anti-solvent;
d) isolating the crystalline Form M3 of Avatrombopag maleate.

Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in dimethyl acetamide and 2-ethoxy ethanol or mixture thereof. Within the context of this embodiment, Avatrombopag maleate may be dissolved at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved at about 85°C.

Within the context of this embodiment, the product is isolated by filtration, evaporation, centrifuge, suck drying and distillation.

Within the context of this embodiment, solution of Avatrombopag maleate may be treated with an anti-solvent or vice-versa at room temperature to obtain crystalline form M3 of Avatrombopag maleate. The anti-solvent employed for this embodiment may include isobutyl acetate, ethyl acetate, anisole, methyl isobutyl ketone, 2-butanol, 2-propanol and 2-methyl-1-propanol.
Within the context of this embodiment, the product is isolated by filtration, evaporation, centrifuge, suck drying and distillation.

In another embodiment, the present invention is to provide amorphous Avatrombopag.
In an embodiment, the present disclosure is to provide amorphous Avatrombopag is characterized by powdered X-ray diffraction pattern as shown in Figure 9.

Another embodiment of the present invention is to provide a process for the preparation of amorphous Avatrombopag, which comprises drying Avatrombopag crystalline form M3 at about 80°C to about 120°C under reduced pressure.
Within the context of this embodiment, crystalline Form M3 of Avatrombopag may be dried at about 100°C.

In another aspect of the present invention is to provide amorphous Avatrombopag maleate.

In an embodiment, the present disclosure is to provide amorphous Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 10.

Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in a mixture of organic solvent or organic solvent and water at elevated temperature,
b) cooling the solution to room temperature,
c) isolating the amorphous Avatrombopag maleate.
Within the context of this embodiment of the present invention, dissolving Avatrombopag maleate in a mixture of organic solvent and water. The solvent employed may include, ether solvents such as 1,4-dioxane and tetrahydrofuran (THF) and nitrile solvents such as acetonitrile, dimethyl sulfoxide (DMSO), anisole, methanol, ethanol, isopropyl alcohol, acetone, acetonitrile and dimethylformamide. In particular useful embodiments of the present invention solvent employed is a mixture of 1,4-dioxane/ water, tetrahydrofuran/water and dimethyl sulfoxide/anisole.

In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in mixture of tetrahydrofuran (THF) and water at about 85°C. Within the context of this embodiment, Avatrombopag maleate may be dissolved in mixture of mixture of 1,4-dioxane and water at about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in mixture of 1,4-dioxane and water at about 85°C.

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

Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in organic solvent,
b) adding an anti-solvent,
c) isolating the amorphous Avatrombopag maleate.
Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in dimethyl sulfoxide (DMSO).

Within the context of this embodiment, Avatrombopag maleate may be dissolved in mixture of dimethyl sulfoxide (DMSO) at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in dimethyl sulfoxide at about 80°C.

Within the context of this embodiment, solution of Avatrombopag maleate may be combined with an anti- solvent at room temperature to obtain amorphous product. Suitable anti-solvent employed for this embodiment is water.

Within the context of this embodiment of the present invention, removing of solvent can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, ATFD, lyophilization and spray-drying. In particular useful embodiments of the present invention the solvent is removed by spray-drying.
Yet another embodiment of the present invention is to provide amorphous solid dispersion of avatrombopag maleate with pharmaceutically acceptable carriers.
In an embodiment, the present disclosure is to provide amorphous solid dispersion of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 11.

Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Avatrombopag maleate with pharmaceutically acceptable carriers, which comprises:
a) dissolving Avatrombopag maleate in a mixture of organic solvent and water at elevated temperature,
b) cooling the solution to room temperature,
c) adding pharmaceutically acceptable carrier to the solution obtained in step (b),
d) removing the solvent and isolating the amorphous solid dispersion of Avatrombopag maleate.

Within the context of this embodiment of the present invention, dissolving Avatrombopag maleate in a mixture of organic solvent and water. The solvent employed may include, ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane and nitrile solvents such as acetonitrile. In particular useful embodiments of the present invention solvent employed is a mixture of tetrahydrofuran (THF), and water.

Within the context of this embodiment, Avatrombopag maleate may be dissolved in mixture of tetrahydrofuran (THF) and water at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved in mixture of tetrahydrofuran (THF) and water at about 85°C.

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

Within the context of this embodiment of the present invention, pharmaceutically acceptable carrier employed may include, PLASDONETM S-630, polyvinyl pyrrolidine K-30 (PVP-K30), silicon dioxide, microcrystalline cellulose, lactose monohydrate, HPMC or mixtures thereof. In particular useful embodiments of the present invention pharmaceutically acceptable carrier selected is silicon dioxide or polyvinyl pyrrolidine K-30 (PVP-K30).

Within the context of this embodiment of the present invention, Avatrombopag maleate with pharmaceutically acceptable carrier employed in the ratio of 1:99 to 99:1, preferably 1:1 ratio.

In another embodiment, the present invention is to provide amorphous solid dispersion of Avatrombopag maleate.

In an embodiment, the present disclosure is to provide amorphous solid dispersion of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 10.

Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Avatrombopag maleate with pharmaceutically acceptable carriers, which comprises:
a) dissolving Avatrombopag maleate in a mixture of organic solvent and water at elevated temperature;
b) adding pharmaceutically acceptable carrier;
c) removing the solvent to obtain amorphous solid dispersion of Avatrombopag maleate.

Within the context of this embodiment of the present invention, Avatrombopag maleate is dissolved in a mixture of organic solvent and water. The solvent employed may include tetrahydrofuran (THF) and 1,4-dioxane. In particular useful embodiments of the present invention solvent employed is a mixture of tetrahydrofuran (THF) and water.

Within the context of this embodiment, Avatrombopag maleate may be dissolved in solvent at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved at about 85°C.

Within the context of this embodiment of the present invention, pharmaceutically acceptable carrier employed may include, PLASDONETM S-630, polyvinyl pyrrolidine K-30 (PVP-K30), silicon dioxide, microcrystalline cellulose (MCC), lactose monohydrate, HPMC or mixtures thereof. In particular useful embodiments of the present invention pharmaceutically acceptable carrier selected is microcrystalline cellulose (MCC).

Within the context of this embodiment of the present invention, Avatrombopag maleate with pharmaceutically acceptable carrier employed in the ratio of 1:99 to 99:1, preferably 1:1 ratio.

Within the context of this embodiment of the present invention, the solvent is removed by lyophilization, spray-drying, evaporation and filtration.
Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Avatrombopag maleate with pharmaceutically acceptable carrier, which comprises:
a) dissolving Avatrombopag maleate and pharmaceutically acceptable carrier in a mixture of organic solvent and water at elevated temperature;
b) removing the solvent to obtain amorphous solid dispersion of Avatrombopag maleate.

Within the context of this embodiment of the present invention, Avatrombopag maleate and pharmaceutically acceptable carrier is dissolved in a mixture of organic solvent and water. The solvent employed may include ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane. In particular useful embodiments of the present invention solvent employed is a mixture of tetrahydrofuran (THF) and water.

Within the context of this embodiment of the present invention, pharmaceutically acceptable carrier employed may include, PLASDONE S-630, polyvinyl pyrrolidine K-30 (PVP-K30), silicon dioxide, microcrystalline cellulose (MCC), lactose monohydrate, HPMC or mixtures thereof.
In particular useful embodiments of the present invention pharmaceutically acceptable carrier selected is PLASDONE S-630 or lactose monohydrate.

Within the context of this embodiment, Avatrombopag maleate and pharmaceutical carrier may be dissolved in mixture of tetrahydrofuran (THF) and water at a temperature about 60°C to about 95°C. In particular useful embodiments it may be dissolved at about 85°C.

Within the context of this embodiment of the present invention, the solvent is removed by lyophilization, spray-drying, evaporation and filtration.

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.

Indicative stability:
In yet another embodiment, physical and chemical stability of Avatrombopag maleate Amorphous form sample was determined by storing the sample at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for 6 months and analyzed by PXRD. The results are shown in Table 1.
In yet another embodiment, physical stability of Avatrombopag maleate Form M1 sample was determined by storing the sample at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for 1 month and analyzed by PXRD. The results are shown in Table 2.

In yet another embodiment, physical stability of Avatrombopag maleate Form M3 sample was determined by storing the sample at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for 1 month and analyzed by PXRD. The results are shown in Table 2.

The indicative stability data shows Avatrombopag maleate Amorphous, Form M1 and Form M3 are physically stable and shows no change in PXRD pattern when stored at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for 6 months, 1 month and 1 month respectively.
Table 1
Conditions/ Polymorph Avatrombopag maleate Amorphous form
PXRD
at 40°C/75% RH
Initial Amorphous
1 months Stable
3 months Stable
6 months Stable
at 25°C/60% RH
Initial Amorphous
1 months Stable
3 months Stable
6 months Stable

Table 2
Conditions/ Polymorph Avatrombopag maleate
Form M1 Form M3
PXRD PXRD
at 40°C/75% RH
Initial Form M1 Form M3
1 months Stable Stable
at 25°C/60% RH
Initial Form M1 Form M3
1 months Stable Stable
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
EXAMPLES
Example 1: Preparation of crystalline Form M1 of Avatrombopag.

Avatrombopag maleate (50mg) was dissolved in pyridine (2mL) at 80±5°C. The resulting clear solution was cooled to 25±5°C and allowed for slow solvent evaporation for 15h at 25±5°C. Then added water (2mL) and stirred for 30min. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
Example 2: Preparation of crystalline Form M1 of Avatrombopag.
Avatrombopag maleate (0.5g) was dissolved in a mixture of pyridine (5mL) and water (3mL) at 80±5°C. The resulting clear solution was cooled to 25±5°C, added seeds of Form M1 and maintained under stirring for 15h at 25±5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
Example 3: Preparation of crystalline Form M1 of Avatrombopag.

Avatrombopag maleate (50mg) was dissolved in a mixture of 2-methoxy ethanol (2mL), 1,4-dioxane (1mL) and DMSO (0.5mL) at 80±5°C. The resulting clear solution was cooled to 25±5°C and allowed for slow solvent evaporation for 15h at 25±5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
Example 4: Preparation of crystalline Form M1 of Avatrombopag.
Avatrombopag maleate (50mg) was dissolved in a mixture of Formamide (2mL), DMF (2mL) and DMSO (0.5mL) at 80±5°C. The resulting clear solution was cooled to 25±5°C and allowed for slow solvent evaporation for 15h at 25±5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
Example 5: Preparation of crystalline Form M1 of Avatrombopag.
Avatrombopag maleate (50mg) was dissolved in DMF (2mL) at 80±5°C. The resulting clear solution was cooled to 25±5°C and allowed for slow solvent evaporation for 15h at 25±5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
Example 6: Preparation of crystalline Form M2 of Avatrombopag.
Avatrombopag maleate (200mg) was dissolved in a mixture of acetonitrile (10mL), water (3mL) and DMF (2.5mL) at 80±5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield crystalline Form M2 of Avatrombopag.
Example 7: Preparation of crystalline Form M3 of Avatrombopag.

Avatrombopag maleate (50mg) was dissolved in a mixture of morpholine (2.5mL) and isobutyl acetate (3mL) at 80±5°C. The resulting clear solution was cooled to 25±5°C and maintained under stirring for 5h at 25±5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M3 of Avatrombopag.
Example 8: Preparation of crystalline Form M4 of Avatrombopag.
Avatrombopag crystalline Form M1 (200mg) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-240°C and followed by slow cooling to 30°C. The resulting solid was identified as crystalline Form M4 of Avatrombopag.
Example 9: Preparation of crystalline Form M5 of Avatrombopag.
Avatrombopag Form M2 (200mg) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-240°C and followed by slow cooling to 30°C. The resulting solid was identified as crystalline Form M5 of Avatrombopag.
Example 10: Preparation of crystalline Form M1 of Avatrombopag maleate.

Avatrombopag maleate (1g) was dissolved in DMSO (3mL) at 80±5°C. The resulting clear solution was filtered to remove any undissolved particulate, added to water (16mL) at 25±5°C and maintained for 4h at 25±5°C. The solid precipitated was filtered, washed with 4mL of water and dried the material at 70±5°C under vacuum for 2h. The solid obtained is identified as crystalline Form M1 of Avatrombopag maleate.
Example 11: Preparation of crystalline Form M1 of Avatrombopag maleate.

Avatrombopag maleate (100mg) was dissolved in DMSO (0.3mL) at 80±5°C. The resulting clear solution was filtered to remove any undissolved particulate and then added to MTBE solution (3mL) maintained at 25±5°C containing seeds of Avatrombopag maleate Form M1. The reaction mass was maintained for 4h under stirring at 25±5°C, filtered and washed with MTBE (1mL). The solid obtained is identified as crystalline Form M1 of Avatrombopag maleate.
Example 12: Preparation of crystalline Form M2 of Avatrombopag maleate.
Avatrombopag maleate (500mg) was dissolved in DMSO (2mL) at 80±5°C, cooled to 25±5°C and filtered using hyflo to remove any undissolved particulate matter. The resulting clear solution was added to Ethyl acetate (10mL) at 25±5°C and the suspension was maintained for 4h at 25±5°C. The resulting reaction mass was filtered, suck-dried for 30min and further dried under vacuum at 80±5°C for 15h. The solid obtained was identified as crystalline Form M2 of Avatrombopag maleate.
Example 13: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (1g) was dissolved in a mixture of Dimethyl acetamide (2.5mL) and 2-Ethoxy ethanol (5mL) at 80±5°C and filtered at same temperature to remove any undissolved particulate. The resulting clear solution was slowly cooled to 25±5°C and maintained under stirring at same temperature for 15h. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 14: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to isobutyl acetate (2mL) at 25±5°C and the reaction mass was stirred for 15h at 25±5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 15: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to ethyl acetate (2mL) at 25±5°C and the reaction mass was stirred for 15h at 25±5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 16: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to anisole (2mL) at 25±5°C and the reaction mass was stirred for 15h at 25±5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 17: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to methyl isobutyl ketone (2mL) at 25±5°C and the reaction mass was stirred for 15h at 25±5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 18: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to 2-butanol (2mL) at 25±5°C and the reaction mass was stirred for 15h at 25±5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example19: Preparation of crystalline Form M3 of Avatrombopag maleate.
Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to 2-Propanol (2mL) at 25±5°C and the reaction mass was stirred for 15h at 25±5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 20: Preparation of crystalline Form M3 of Avatrombopag maleate.

Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60±5°C and allowed to cool to 25±5°C. The clear solution was slowly added to 2-methyl-1-propanol (2mL) at 27±2°C and the reaction mass was stirred for 15h at 27±2°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
Example 21: Preparation of Amorphous Avatrombopag.

Avatrombopag crystalline Form M3 was heated at 100°C under vacuum for 4h, the resulting solid was identified as Amorphous Avatrombopag
Example 22: Preparation of amorphous Avatrombopag maleate

Avatrombopag maleate (0.2g) was dissolved in a mixture of tetrahydrofuran (12mL) and water (3mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulates and subjected to lyophilization using labocon lyophilizer (Model: LFD-BT104) to yield Avatrombopag maleate amorphous form.
Example 23: Preparation of amorphous Avatrombopag maleate

Avatrombopag maleate (0.2g) was dissolved in a mixture of 1,4-dioxane (15mL) and water (3mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulates and subjected to lyophilization using labocon lyophilizer (Model: LFD-BT104) to yield Avatrombopag maleate amorphous form.
Example 24: Preparation of amorphous Avatrombopag maleate

Avatrombopag maleate (5g) was dissolved in a mixture of tetrahydrofuran (300 mL) and water (75 ml) at 85±5°C. Filtered the clear solution through hyflo to remove any undissolved particulate. The clear solution was cooled to 25±5°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 80°C with 100% aspiration to yield Avatrombopag maleate amorphous form.
Example 25: Preparation of amorphous Avatrombopag maleate

Avatrombopag maleate (0.5g) was dissolved in dimethyl sulfoxide (1.5mL) at 80±5°C and cooled to 25±5°C. The resulting clear solution was added to water (6mL) at 25±5°C and the reaction mass was maintained under stirring at 25±5°C for 4h. The solid obtained was filtered, washed with water (4 mL), suck-dried for 4h. The product obtained is identified as Avatrombopag maleate amorphous form.
Example 26: Preparation of amorphous Avatrombopag maleate
Avatrombopag maleate (10g) was dissolved in a mixture of DMSO (30 mL) and Anisole (100 mL) at 65±5°C. Filtered the clear solution through hyflo to remove any undissolved particulate, 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 140°C with 100% aspiration to yield Avatrombopag maleate amorphous form.
Example 27: Preparation of amorphous Avatrombopag maleate
Avatrombopag maleate (2g) was dissolved in a mixture of DMSO (4 mL) and Anisole (20 mL) at 65±5°C. Filtered the clear solution through hyflo to remove any undissolved particulate, 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 120°C with 100% aspiration to yield Avatrombopag maleate amorphous form.
Example 28: Preparation of amorphous solid dispersion of Avatrombopag maleate:

Avatrombopag maleate (0.5g) was dissolved in a mixture of tetrahydrofuran (30mL) and water (7.5mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulates and added silicon dioxide (0.5g) and subjected to lyophilization using labocon lyophilizer (Model: FD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
Example 29: Preparation of amorphous solid dispersion of Avatrombopag maleate:

Avatrombopag maleate (0.5g) was dissolved in a mixture of tetrahydrofuran (30mL) and water (7.5mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulates and added PVP-K-30 (0.5g) and subjected to lyophilization using labocon lyophilizer (Model: FD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
Example 30: Preparation of amorphous solid dispersions of Avatrombopag maleate.

Avatrombopag maleate (0.5g) and Plasdone S-630 (0.5g) were dissolved in a mixture of tetrahydrofuran (30mL) and water (9.5mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
Example 31: Preparation of amorphous solid dispersions of Avatrombopag maleate.

Avatrombopag maleate (0.5g) was dissolved in a mixture of tetrahydrofuran (30mL) and water (7.5mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulate and added Microcrystalline cellulose (MCC, 0.5g) and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
Example 32: Preparation of amorphous solid dispersions of Avatrombopag maleate.

Avatrombopag maleate (0.5g) and Lactose monohydrate (0.5g) were dissolved in a mixture of tetrahydrofuran (30mL) and water (9.5mL) at 85±5°C. The resulting clear solution was filtered to remove any undissolved particulates and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.

,CLAIMS:1. Amorphous Avatrombopag maleate.
2. A process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in a mixture of organic solvent or organic solvent and water at elevated temperature,
b) cooling the solution to room temperature,
c) isolating the amorphous Avatrombopag maleate.
3. The process as claimed in claim 2, wherein the organic solvent is selected from the group consisting of 1,4-dioxane, tetrahydrofuran (THF), anisole, dimethyl sulfoxide (DMSO) and the elevated temperature is at about 60°C to 95°C.
4. A process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethyl sulfoxide,
b) adding water as an anti-solvent,
c) isolating the amorphous Avatrombopag maleate.
5. Crystalline Form M1 of Avatrombopag maleate, characterized by a PXRD pattern having significant peaks at 2? angles of 11.48, 14.55, 17.67, 18.42, 18.85, 19.41, 22.00, 23.55, 23.87 and 24.69±0.2°.
6. A process for the preparation of crystalline Form M1 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethylsulfoxide at elevated temperature,
b) cooling the solution to 20°C-30°C,
c) adding to an anti-solvent, optionally containing a seed of avatrombopag maleate crystalline form M1, and
d) isolating the crystalline Form M1 of Avatrombopag maleate.
7. The process as claimed in claim 6, wherein the anti-solvent is selected from water, methyl tertiary-butyl ether and the elevated temperature is at about 60°C to 95°C.
8. Crystalline Form M3 of Avatrombopag maleate, characterized by a PXRD pattern having significant peaks at 2? angles of 4.94, 8.47, 9.75, 15.91, 16.07,17.95, 21.74, 24.10 and 24.30±0.2°.
9. A process for the preparation of crystalline Form M3 of Avatrombopag maleate, which comprises:
a) dissolving Avatrombopag maleate in dimethyl acetamide or a mixture of dimethyl acetamide and 2-ethoxyethanol at elevated temperature;
b) cooling the solution to 20°C -30°C;
c) optionally treating with an anti-solvent;
d) isolating the crystalline Form M3 of Avatrombopag maleate.
10. The process as claimed in claim 9, wherein the anti-solvent is selected from isobutyl acetate, ethyl acetate, anisole, methyl isobutyl ketone, 2-butanol, 2-propanol, 2-methyl-1-propanol and the elevated temperature is at about 60°C to 95°C.