FIELD OF THE INVENTION
The present invention relates to solid forms of 4-{8-amino-3-[(2S)-l-(but-2-ynoyl) pyrrolidin-2-yl] imidazo [1,5-a] pyrazin-l-yl)}-N-(pyridine-2-yl) benzamide (Acalabrutinib). More specifically it relates to the process for the preparation of novel crystalline form Bl, solid dispersions and amorphous form of Acalabrutinib (1) with purity more than 99.0% (w/w).
BACKGROUND OF THE INVENTION
Acalabrutinib (1) is a second generation Bruton's tyrosine kinase (BTK) inhibitor with potential antineoplastic activity. It is used for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and was approved by USFDA on 31 October 2017. It is marketed in United States as Calquence by AstraZeneca. Chemically, it is 4-{8-amino-3-[(2S)-l-(but-2-ynoyl) pyrrolidin-2-yl] imidazo [1,5-a] pyrazin-l-yl)}-N-(pyridine-2-yl) benzamide.
The following patents and applications describe the different polymorphic forms of Acalabrutinib (1) and its different salts.
US9796721 patent discloses crystalline form I, II, III, IV, V, VI, VII and VIII of Acalabrutinib (1) free base. Further, it discloses amorphous free base of Acalabrutinib (1), different salts and co-crystals of Acalabrutinib (1)
IN201641037734 application discusses about the process for preparing amorphous Acalabrutinib (1) and solid dispersions of Acalabrutinib (1) by suitable methods.
Accordingly, to the FDA label, Acalabrutinib (1) has pH-dependent solubility. It is freely soluble below pH of 3 and practically insoluble at pH above 6. Not much information is available for the stable form of Acalabrutinib (1). So, there is still a need

to develop stable forms of Acalabrutinib (1) with better physiochemical properties. This could be achieved by preparing different polymorphic forms. Hence, the present inventors hereby report new solid forms of Acalabrutinib (1) and the process to prepare the same.
OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide solid forms of Acalabrutinib (1)
Another objective of the present invention is to provide novel crystalline forms Bl of Acalabrutinib (1) and process for preparation thereof.
In another objective, the present invention provides solid dispersions of Acalabrutinib (1) using suitable pharmaceutical acceptable excipients and process for the preparation thereof.
In another objective, the present invention provides amorphous form of Acalabrutinib (1) and process for the preparation thereof.
Yet, another objective of the present invention is to provide solid forms of Acalabrutinib (1) with more than 99.0% of purity by HPLC (High-performance liquid chromatography).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel solid forms of Acalabrutinib (1)

In one embodiment, the present invention provides novel crystalline form Bl of Acalabrutinib (1) and process for preparation thereof, which comprises of the following steps:
a) providing Acalabrutinib (1) in a suitable protic solvent at 25-30 °C;
b) heating the reaction mixture at 50-100 °C;
c) filtering and cooling the reaction mixture to 25-30 °C; and
d) isolating crystalline form of Acalabrutinib (1), using a suitable technique.
In another embodiment, the present invention provides solid dispersions of Acalabrutinib (1) and process for the preparation thereof comprising of the following steps:
a) providing Acalabrutinib (1) in a suitable aprotic solvent;
b) adding a suitable pharmaceutically acceptable excipient;
c) stirring and filtering the reaction mixture;
d) heating the reaction mixture to a suitable temperature; and
e) isolating amorphous solid dispersion of Acalabrutinib (1).
In yet another embodiment, the present invention provides amorphous form of Acalabrutinib (1) and process for the preparation thereof comprising of the following steps:
a) providing Acalabrutinib (1) in a suitable aprotic solvent;
b) stirring the reaction mixture and filtering;
c) heating the reaction mixture to a suitable temperature; and
d) isolating amorphous forms of Acalabrutinib (1).
Yet, another objective of the present invention is to provide solid forms of Acalabrutinib (1) with more than 99.0% of purity by HPLC (High-performance liquid chromatography).

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 illustrates X-Ray powder diffraction (XPRD) pattern of crystalline form Bl
of Acalabrutinib (1) prepared by example-1
Figure 2 illustrates X-Ray powder diffraction (XPRD) pattern of amorphous solid
dispersion of Acalabrutinib (1) prepared by example-2
Figure 3 illustrates X-Ray powder diffraction (XPRD) pattern of amorphous solid
dispersion of Acalabrutinib (1) prepared by example-3
Figure 4 illustrates X-Ray powder diffraction (XPRD) pattern of amorphous solid
dispersion of Acalabrutinib (1) prepared by example-4
Figure 5 illustrates X-Ray powder diffraction (XPRD) pattern of amorphous solid
dispersion of Acalabrutinib (1) prepared by example-5
Figure 6 illustrates X-Ray powder diffraction (XPRD) pattern of amorphous solid
dispersion of Acalabrutinib (1) prepared by example-6
Figure 7 illustrates X-Ray powder diffraction (XPRD) pattern of amorphous form of
Acalabrutinib (1) prepared by example-7
DETAILED DESCRIPTION
Accordingly, in one embodiment, the present invention provides the solid forms of Acalabrutinib (1)
Acalabrutinib (1) used herein can be prepared by any prior art methods.
In one embodiment, the present invention provides novel crystalline form Bl of Acalabrutinib (1) and process for preparation thereof, comprising of the following steps:
a) providing Acalabrutinib (1) in a suitable protic solvent at 25-30 °C;
b) heating the reaction mixture at 50-100 °C;
c) filtering and cooling the reaction mixture to 25-30 °C; and
d) isolating crystalline form of Acalabrutinib (1), using a suitable technique.

In one embodiment, the Acalabrutinib (1) was added to a suitable protic solvent and heated at 50-100 °C, preferably 60-65 °C. The reaction mixture was filtered, and the filtrate was cooled to 25-35 °C. The solid formed was filtered and dried under vacuum, then loaded in in air try dryer (ATD) at 50-55 °C to obtain crystalline form Bl of Acalabrutinib (1), characterized by X-ray diffraction (XRD) pattern as illustrated in figure 1 with two theta values at 44.63, 44.22 ,43.12 ,41.75, 41.44, 39.97,38.42, 36.66 , 35.54, 33.12, 32.43, 31.10, 30.64, 30.19, 29.60, 29.05, 28.10, 27.60, 26.83, 26.49, 25.30, 24.22, 23.51, 21.84, 21.3 ,20.62, 19.80, 18.87,18.37, 17.88, 17.6, 17.25, 16.50, 15.65, 14.97, 13.16, 12.16, 11.63, 10.64, 10.22, 9.58,9.10,8.88 ,7.48 ,5.52 and 4.97.
In some embodiment the protic solvent used in the present invention may be selected from a group comprising of water, methanol, ethanol, formamide, ethylene glycol, isopropyl alcohol, benzyl alcohol or the like, preferably formamide was used in the present invention.
The isolated solid may be dried to form crystalline form Bl of Acalabrutinib (1). Drying may be carried out using suitable drying technique which may comprise of but not limited to an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer or the like. Preferably, air tray dryer was used in the present invention. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 80°C, preferably less than about 55 °C.
In another embodiment, the present invention provides solid dispersions of Acalabrutinib (1) and process for the preparation thereof comprising the following steps:
a) providing Acalabrutinib (1) in a suitable aprotic solvent at 25-30 °C;
b) adding a suitable pharmaceutical^ acceptable excipient;
c) stirring and filtering the reaction mixture;

d) heating the reaction mixture to a suitable temperature; and
e) isolating amorphous solid dispersion of Acalabrutinib (1).
In another embodiment, Acalabrutinib (1) was added to suitable protic, aprotic solvent or mixtures thereof. A suitable pharmaceutically acceptable excipient was then added to the above reaction mass and stirred for 15-20 min. The reaction mixture so obtained was filtered, and the clear filtrate was heated at 50-100 °C, preferably to 55-60 °C in some instances and to 35-40 °C in other instances. The solvent of the filtrate was removed by distillation under vacuum below 60 °C. The solid formed was dried under vacuum to afford amorphous solid dispersions of Acalabrutinib (1) with a suitable pharmaceutically acceptable excipients and characterized by X-ray diffraction (XRD) pattern as illustrated in figure 2, figure 3, figure 4, figure 5 and figure 6.
The suitable pharmaceutically acceptable excipients used in the present invention were selected from a group comprising of lactose, sorbitol, mannitol, saccharose, cellulose, methyl cellulose, ethyl cellulose, macrocrystalline cellulose, polyethylene glycol(PEG), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), Y-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-f}-cyclodextrin (SBCED) , Soluplus , Eudragit or the like; preferably hydroxypropyl beta cyclodextrin (HPBCD), polyvinylpyrrolidone K-30, (PVP K-30) , Soluplus , Eudragit and sulfobutylether-P-cyclodextrin (SBCED) was used in the present invention.
In some embodiment the solvents used in the present invention may be selected from a group comprising of protic, aprotic or mixtures thereof but not limited to a group of protic solvents comprising of water, methanol, ethanol, ethylene glycol, isopropyl alcohol, benzyl alcohol or the like, or aprotic solvents selected from a group comprising of acetone, methyl ethyl ketone , acetonitrile, nitromethane, 1,4-dioxane, diethyl ether,

dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, N, N-dimethylformamide, N,N-dimethyl acetamide, methyl tertiary butyl ether, hexane, cyclohexane, n-heptane, toulene, xylene, tetrahydrofuran or the like, preferably, preferably methanol, dichloromethane or mixtures thereof were used in the present invention.
The solid dispersion of Acalabrutinib (1) formed was isolated by methods which include but not limited to cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin-film drying, freeze-drying or the like. Preferably evaporation and more preferably fast solvent evaporation was used in the present invention.
In another embodiment, the isolated solid dispersion of Acalabrutinib (1) obtained was dried using a suitable technique which may be selected but not limited to distillation, vacuum drying, tray drying, agitated thin film drying ("ATFD") or the like. Preferably, vacuum drying was used in the present invention.
In yet another embodiment, the present invention provides amorphous form of Acalabrutinib (1) and process for the preparation thereof comprising of the following steps:
a) providing Acalabrutmib (1) in a suitable aprotic solvent at 25-30 °C;
b) stirring the reaction mixture and filtering;
c) heating the reaction mixture to a suitable temperature; and
d) isolating amorphous forms of Acalabrutinib (1).
In some embodiment, Acalabrutinib (1) was added to a suitable aprotic solvent at 25-30 °C and filtered. The filtrate was distilled off at 30-60 °C, preferably at 35-40 °C using high vacuum. The solid formed was further dried under vacuum to afford

amorphous Acalabrutinib (1) characterized by an X-ray diffraction (XRD) pattern as illustrated in figure 7.
In some embodiment the aprotic solvents used were selected but not limited to acetone, methyl ethyl ketone , acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, N, N-dimethylformamide, N,N-dimethyl acetamide, methyl tertiary butyl ether, hexane, cyclohexane, n-heptane, toulene, xylene, tetrahydrofuran or the like, preferably, dichloromethane was used in the present invention.
In some embodiment, the amorphous form of Acalabrutinib (1) may be isolated using one or more methods known in the art comprising of cooling, filtration, evaporation, distillation, concentrating the reaction mass, stirring or the like, may also be employed for the isolation. Preferably, distillation and stirring were used in the present invention.
The resulting solid dispersion or amorphous forms may be collected by using suitable techniques such as by scraping, scratching or by shaking the container, or other techniques specific to the equipment used. Preferably, scratching was used in the present invention.
In yet, another embodiment, the suitable techniques which may be used for drying the isolated amorphous form of Acalabrutinib (1) may be selected but not limited to distillation, vacuum drying, pray drying, agitated thin film drying ("ATFD") or the like. Preferably, distillation was used in the present invention.
Yet, another embodiment of the present invention is to provide solid forms of Acalabrutinib (1) with more than 99.0% of purity by HPLC (High-performance liquid chromatography).

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE-1: Process for the preparation of crystalline form Bl of Acalabrutinib
(1)
lg of Acalabrutinib (1) was added to 40mL of formamide at 25-35 °C. The reaction
mass was heated and stirred for 10-15min at 60-65 °C. The hot reaction mixture was then filtered, and the filtrate was cooled to 25-35 °C. The solid so formed was dried under vacuum and further loaded in the air tray dryer (ATD) at 50-55 °C to obtain crystalline form Bl of Acalabrutinib (1). Yield: 93%; XRD: Figure 1
EXAMPLE 2: Process for the preparation of solid dispersions of Acalabrutinib (1) with Hydroxypropyl beta cyclodextrin (HPBCD).
lg of Acalabrutinib (1) was added to 50mL of a mixture of methanol and dichloromethane at 25-35 °C. lg of Hydroxypropyl beta cyclodextrin (HPBCD) was added to the reaction mass and stirred for 15-30 mins. The reaction mixture was filtered, and the filtrate heated to 55-60 °C. The solvent of the filtrate was removed by distillation. The solid so formed was dried under vacuum below 60 °C to obtain amorphous solid dispersions of Acalabrutinib (1) with Hydroxypropyl beta cyclodextrin (HPBCD). Yield: 81%; XRD: Figure 2
EXAMPLE 3: Process for the preparation of solid dispersions of Acalabrutinib (1) with Polyvinylpyrrolidone K 30 (PVP-K-30)
lg of Acalabrutinib (1) added to 40mL of dichloromethane at 25-35 °C. lg of polyvinylpyrrolidone K 30 (PVP-K-30) was then added to the reaction mass and stirred for 15-30mins at 25-35 °C. The reaction mixture was filtered, and the filtrate heated to

35-40 °C. The total solvent of the filtrate was removed by distillation. The solid so formed was dried under vacuum below 60 °C to obtain amorphous solid dispersions of Acalabrutinib (1) with Polyvinylpyrrolidone K 30 (PVP-K-30). Yield: 82.5%; XRD: Figure 3
EXAMPLE 4: Process for the preparation of solid dispersions of Acalabrutinib (1) with Soluplus
lg of Acalabrutinib (1) added to 40mL of dichloromethane at 25-35 °C. lg of Soluplus was then added to the reaction mass and stirred for 15-30 mins at 25-35 °C. The reaction mixture was filtered, and the filtrate heated to 35-40 °C. The total solvent of the filtrate was removed by distillation. The solid so formed was dried under vacuum below 60 °C to obtain amorphous solid dispersions of Acalabrutinib (1) with Soluplus. Yield: 82.5%; XRD: Figure 4
EXAMPLE 5: Process for the preparation of solid dispersions of Acalabrutinib (1) with Eudragit
lg of Acalabrutinib (1) added to 40mL of dichloromethane at 25-35 °C. lg of Eudragit was then added to the reaction mass and stirred for 15-30 mins at 25-35 °C. The reaction mixture was filtered, and the filtrate heated to 35-40 °C. The total solvent of the filtrate was removed by distillation. The solid so formed was dried under vacuum below 60 °C to obtain amorphous solid dispersions of Acalabrutinib (1) with Eudragit. Yield: 81.5%; XRD: Figure 5
EXAMPLE 6: Process for the preparation of solid dispersions of Acalabrutinib (1) with sulfobutylether-p-cyclodextrin (SBECD)
lg of Acalabrutinib (1) added to 40mL mixture of dichloromethane and methanol at 25-35 °C. lg of sulfobutylether-p-cyclodextrin (SBECD) was then added to the reaction mass and stirred for 15-30 mins at 25-35 °C. The reaction mixture was filtered,

and the filtrate heated to 35-40 °C. The total solvent of the filtrate was removed by distillation. The solid so formed was dried under vacuum below 60 °C to obtain amorphous solid dispersions of Acalabrutinib (1) with sulfobutylether-P-cyclodextrin (SBECD). Yield: 82 %; XRD: Figure 6
EXAMPLE 7: Process for the preparation of amorphous Acalabrutinib (1)
lg of Acalabrutinib (1) added to 40mL of dichloromethane and stirred for 15-30 mins at 25-35 °C. The reaction mixture was filtered, and the filtrate heated to 35-40 °C. The total solvent of the filtrate was removed by distillation below 40 °C. The solid so formed was dried under vacuum below 60 °C to obtain amorphous Acalabrutinib (1). Yield: 84%; XRD: Figure 7

We claim:
1. A process for the preparation of crystalline form Bl of Acalabrutinib (1),
comprising:
a) providing Acalabrutinib (1) in a suitable protic solvent at a suitable temperature;
b) heating the reaction mixture at a suitable temperature;
c) filtering and cooling the reaction mixture to a suitable temperature; and
d) isolating crystalline form Bl of Acalabrutinib (1) using a suitable technique.

2. The process, as claimed in claim 1, wherein the protic solvent used is selected from a group comprising of water, methanol, ethanol, formamide, ethylene glycol, isopropyl alcohol, benzyl alcohol or mixtures thereof.
3. The process, as claimed in claim 1, wherein the solid dried by using air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, under atmospheric pressure or under vacuum.
4. A process for the preparation of solid dispersions of Acalabrutinib (1) comprising:

a) providing Acalabrutinib (1) in a suitable solvent at a suitable temperature;
b) adding a suitable pharmaceutically acceptable excipient;
c) stirring the reaction mixture;
d) heating the reaction mixture to a suitable temperature; and
e) isolating amorphous solid dispersion of Acalabrutinib (1).
5. The process, as claimed in claim 3, wherein the solvent is selected from water,
methanol, ethanol, ethylene glycol, isopropyl alcohol, benzyl alcohol, acetone,
methyl ethyl ketone , acetonitrile, nitromethane, 1,4-dioxane, diethyl ether,
dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, N, N-
dimethylformamide, N,N-dimethyl acetamide, methyl tertiary butyl ether,

hexane, cyclohexane, n-heptane, toulene, xylene, tetrahydrofuran or mixtures
thereof.
The process, as claimed in claim 3, wherein the suitable pharmaceutically
acceptable excipients used is selected from a group comprising of lactose,
sorbitol, mannitol, saccharose, cellulose, methyl cellulose, ethyl cellulose,
microcrystalline cellulose, polyethylene glycol(PEG), polyvinylpyrrolidone
(PVP), polyvinylpyrrolidone K-30, (PVP K-30), polyvinyl acetate
hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC),
hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate
succinate (HPMC-AS), Y-cyclodextrin, hydroxypropyl beta cyclodextrin
(HPBCD), sulfobutylether-p-cyclodextrin (SBCED), Soluplus, Eudragit or the
like.
The process, as claimed in claim 3, wherein the solid is isolated by cooling,
evaporation under vacuum, flash evaporation, fast solvent evaporation,
rotational drying, spray drying, thin-film drying, agitated thin-film drying,
freeze-drying.
A process for the preparation of amorphous form of Acalabrutinib (1),
comprising:
a) providing Acalabrutinib (1) in a suitable aprotic solvent;
b) stirring the reaction mixture;
c) heating the reaction mixture to a suitable temperature; and
d) isolating amorphous form of Acalabrutinib (1).
The process, as claimed in claim 3, wherein the suitable aprotic solvents used is selected from a group comprising of acetone, methyl ethyl ketone , acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, N, N-dimethylformamide, N,N-dimethyl

acetamide, methyl tertiary butyl ether, hexane, cyclohexane, n-heptane, toulene, xylene, tetrahydrofuran mixtures thereof. 10. The process, as claimed in claim 8, wherein the reaction mixture is heated to a suitable temperature ranging from 30-60 °C, to afford amorphous Acalabrutinib (1) characterized by an X-ray diffraction (XRD) pattern as illustrated in figure 7.
IS