This application claims the benefit of priority of our Indian patent application numbers 202141020855 filed on 07 May 2021; 202241000790 filed on 06 January 2022 and 202241015010 filed on 18 March 2022 which are incorporated herein by reference.

Field of the Invention:

The present invention relates to a process for the preparation of crystalline Form-S of 4- {8-amino-3-[(2S)-l-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[l,5- a]pyrazin-l-yl)}-N-(pyridine-2- yl)benzamide represented by the following structural formula- 1, which is referred to as Acalabrutinib.

Formula- 1

The present invention also relates to a process for the preparation of amorphous form of Acalabrutinib.

Background of the Invention:

Acalabrutinib is an orally bioavailable and a small chiral molecule inhibiter of Bruton tyrosine kinase (BTK). Acalabmtinib is classified as BCS class 2 that exhibits BCS class 1 characteristics under in vivo conditions.

Acalabrutinib is approved by United States Federal Drug Administration (USFDA) as CALQUENCE capsule for oral administration for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. U.S patent 7459554 B2 discloses Acalabrutinib or a pharmaceutically acceptable salt and not reported any of the crystalline forms.

International PCT publication WO2017/002095 A1 (hereinafter referred as WO Ό95) describes various crystalline Forms I, II, III, IV, V, VI, VII, VIII and amorphous forms of Acalabrutinib.

WO'095 also describes various salt forms fumarate, maleate, phosphate, L-tartrate, citrate, oxalate and sulfate of Acalabrutinib.

International PCT publication of WO2018/064797 A1 describes crystalline Forms 1, 2, 3 and 4 of Acalabrutinib.

International PCT publication of WO2020/198429 A1 discloses a process for the preparation of amorphous Acalabrutinib, which comprises Acalabrutinib, was dissolved in methanol at a temperature of about 20-25 °C and a clear solution formed. The solvent was distilled of at a temperature of about 40-45 °C (Tj) afforded a solid, which was dried under vacuum at a temperature of about 40-45 °C (Tj) to afford amorphous Acalabrutinib.

The inventors of the present invention have also repeated the reaction by utilize the same solvents and same reaction conditions. It was observed that formation of impurities due to distillation of the mixture at a temperature of about 40-45°C.

The present invention involves a process for the preparation of amorphous Acalabrutinib by distillation of the mixture at a temperature below 35°C, which controls the formation of impurities such as diamide impurity and increased the productivity.

Brief description of the Invention:

The present invention relates to a process for the preparation of crystalline Form-S of Acalabrutinib.

The present invention also relates to a process for the preparation of amorphous form of Acalabrutinib.

The present invention also relates to an amorphous form of Acalabrutinib maleate and process for its preparation thereof.

The present invention also relates to a novel crystalline form of Acalabrutinib maleate, hereinafter designated as Form-M. The present invention also relates to a process for the preparation of a novel crystalline Form-M of Acalabrutinib maleate.

Brief description of Drawings:

Figure-1: Illustrates the PXRD pattern of crystalline Form-S of Acalabrutinib.

Figure-2: Illustrates the PXRD pattern of amorphous form of Acalabrutinib.

Figure-3: Illustrates the PXRD pattern of co-crystal of Acalabrutinib and adipic acid.

Figure-4: Illustrates the PXRD pattern of amorphous form of Acalabrutinib maleate.

Figure-5: Illustrates the PXRD pattern of crystalline Form-M of Acalabrutinib maleate.

Detailed description of the Invention:

In first embodiment, the present invention provides a process for the preparation of crystalline Form-S of Acalabrutinib of formula- 1, which comprises: a) dissolving Acalabrutinib ethylene glycol in a suitable solvent, b) providing crystalline Form-S of Acalabrutinib.

In the process of the first embodiment, dissolving Acalabrutinib ethylene glycol in step-a) in a solvent selected from dichloromethane and water or mixture thereof.

In the process of the first embodiment, dissolving Acalabrutinib ethylene glycol in a solvent at a suitable temperature of about 25°C and above to provide a solution of Acalabrutinib.

In the process of the first embodiment, treating the obtained solution with carbon and filtering through hyflow bed and distilling off the solvent from the filtrate.

In the process of the first embodiment, dissolving the obtained compound in a suitable solvent selected from methanol and water or mixture thereof.

In the process of the first embodiment, further heating the obtained solution to a temperature ranging from 30°C to 50°C or above. Optionally, filtering the solution to make it particle free.

In the process of the first embodiment, further adding water to the obtained solution at a suitable temperature about 45°C and above. Further, cooling the mixture to 0-5°C and isolating to provide crystalline Form-S of Acalabrutinib of formula- 1. In the process of the first embodiment, isolating the crystalline Form-S of Acalabmtinib of formula- 1 can be carried out by any methods known in the art or isolating the crystalline Form-S of Acalabmtinib of formula- 1 by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, distillation, centrifugation, adding anti-solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In second embodiment, the present invention provides a process for the preparation of amorphous form of Acalabmtinib of formula- 1, which comprises: a) dissolving Acalabmtinib ethylene glycol in dichloromethane and water, b) adding methanol to the mixture, c) isolating to provide amorphous form of Acalabmtinib of formula- 1.

In the process of the second embodiment, treating the solution obtained in step-a) with carbon and filtering through hyflow bed and distilling off the solvent from the filtrate.

In the process of the second embodiment, distilling off the solvent from the mixture of step-b) at below 35°C.

In the process of the second embodiment, adding methyl tert-butyl ether to the mixture obtained in step-b).

In the process of the second embodiment, isolating the amorphous form of Acalabmtinib of formula- 1 by any methods known in the art or isolating amorphous form of Acalabmtinib of formula- 1 by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, distillation, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In third embodiment, the present invention provides a co-crystal of Acalabmtinib and adipic acid, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 4.2, 6.0 and 20.2 ± 0.2 degrees of 2-theta. The co-crystal of Acalabrutinib and adipic acid is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure-3.

In fourth embodiment, the present invention provides a process for the preparation of co crystal of Acalabrutinib and adipic acid, which comprises: a) suspending Acalabrutinib with a adipic acid in methanol; and b) isolating to provide co-crystal of Acalabrutinib and adipic acid.

In the process of the fourth embodiment, isolation of co-crystal of Acalabrutinib and adipic acid can be carried out by any methods known in the art or co-crystal of Acalabrutinib and adipic acid can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, distillation, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the fourth embodiment, drying of the co-crystal of Acalabrutinib and adipic acid can be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the fifth embodiment, the present invention provides an amorphous form of Acalabrutinib maleate of formula- 1 a.

In the sixth embodiment, the present invention provides an amorphous form of Acalabrutinib maleate, which characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-4.

In the seventh embodiment, the present invention provides a process for the preparation of amorphous form of Acalabrutinib maleate of formula- la, which comprises: a) providing a solution of Acalabrutinib maleate of formula- 1 a in a suitable solvent or a mixture of solvents; and b) isolating the amorphous form of Acalabrutinib maleate of formula- 1 a.

In the process of the seventh embodiment, the suitable solvent used in step-a) is selected from alcohol solvents, chloro solvents or mixtures thereof.

In the process of the seventh embodiment, Acalabrutinib maleate of formula- la dissolved in a suitable solvent at a suitable temperature of about 30°C and above. Optionally, the resulting solution may be filtered to make it particle free.

Alternatively, a solution of Acalabrutinib maleate can be prepared by dissolving Acalabrutinib and maleic acid in a suitable solvent at a suitable temperature of about 30°C and above. Optionally, the resulting solution may be filtered to make it particle free.

In the first aspect of the seventh embodiment, the present invention provides a process for the preparation of amorphous form of Acalabrutinib maleate of formula- la, which comprises: a) providing a solution of Acalabrutinib maleate of formula- la in a mixture of dichloromethane and methanol; and b) isolating the amorphous form of Acalabrutinib maleate of formula- 1 a.

In the process of the seventh embodiment, isolation of amorphous form of Acalabrutinib maleate of formula- 1 a can be carried out by any methods known in the art or amorphous form of Acalabrutinib maleate of formula- la can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, evaporation or distillation with or without vacuum, aqueous thin film drying, spray drying, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the seventh embodiment, drying of the amorphous form of Acalabrutinib maleate of formula- la can be carried out in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the eighth embodiment, the present invention provides a novel crystalline Form-M of Acalabrutinib maleate of formula- la, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-5.

In the ninth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Acalabrutinib maleate of formula- la, which comprises: a) providing a solution of Acalabrutinib of formula- 1 with maleic acid in ethyl formate; and b) isolating crystalline Form-M of Acalabrutinib maleate of formula- 1 a.

In the process of ninth embodiment in step-a) dissolving Acalabrutinib in ethyl formate and further adding a solution of maleic acid and ethyl formate to the mixture at suitable temperature.

In the process of ninth embodiment, a solution of Acalabrutinib of formula- 1 is prepared by a suitable temperature, such as about 0°C to about the reflux temperature of the ethyl formate used. Stirring and heating the mixture is used to reduce the time required for the dissolution process.

In the process of ninth embodiment, a solution of Acalabrutinib of formula- 1 is dissolved in ethyl formate and optionally the solution is filtered to make it particle free.

In the process of ninth embodiment, isolating the crystalline Form-M of Acalabrutinib maleate may be carried out by any methods known in the art or may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the ninth embodiment, the crystalline Form-M of Acalabrutinib maleate of formula- la resulting is dried using suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressure at temperature of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

Amorphous form of Acalabmtinib of formula- 1 obtained according to the present invention is having (S)-4-(3-(l-(but-2-ynoyl)pyrrolidin-2-yl)-8-hydroxyimidazo[l ,5-a] pyrazin- l-yl)-N-(pyridin-2-yl)benzamide (8-Hydroxy impurity), (S)-4-(3-(l-acetylpyrrolidin-2-yl)-8- aminoimidazo[l,5-a]pyrazin-l-yl)-N-(pyridin-2-yl)benzamide (Acetyl impurity), and (S)-4-(8- amino-3-(pyrrolidin-2-yl)imidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(pyridin-2-yl)benzamide (Pyrrolidine impurity) less than 0.05% as measured by HPLC.

8-Hydroxy impurity Acetyl impurity Pyrrolidine impurity

Amorphous form of Acalabmtinib of formula- 1 obtained according to the present invention is having (R)-4-(8-amino-3-(l-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l,5 -a]pyrazin-l- yl)-N-(pyridin-2-yl)benzamide (Enantiomer impurity) less than 0.01% as measured by HPLC.

Amorphous form of Acalabmtinib of formula- 1 obtained according to the present invention is having (S)-4-(9-(l-(but-2-ynoyl)pyrrolidin-2-yl)-4-methyl-2-oxo-2H- imidazo [5',l':3,4]pyrazino[l,2-a]pyrimidin-ll-yl)-N-(pyridin-2-yl)b enzamide (Diamide impurity) less than 0.1% as measured by HPLC.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline Form-S of Acalabmtinib of formula- 1 and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides pharmaceutical composition comprising amorphous form of Acalabmtinib of formula- 1 and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides pharmaceutical composition comprising amorphous form of Acalabmtinib maleate of formula- la and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline Form-M of Acalabmtinib maleate of formula- la and one or more pharmaceutically acceptable excipients. wherein the excipient can be selected from Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2.006.

In yet another embodiment, pharmaceutical composition comprising crystalline Form-S of Acalabmtinib of formula- 1 and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

In yet another embodiment, pharmaceutical composition comprising amorphous form of Acalabmtinib of formula- 1 and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

In yet another embodiment, pharmaceutical composition comprising amorphous form of Acalabmtinib maleate of formula- la and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

In yet another embodiment, pharmaceutical composition comprising crystalline Form-M of Acalabmtinib maleate of formula- la and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The Acalabrutinib ethylene glycol used in the present invention can be prepared by methods reported in WO2020/225831 Al.

The starting material Acalabrutinib or Acalabrutinib maleate used in the present invention can be prepared from any of the known processes.

Crystalline Form-S or amorphous form of Acalabrutinib or amorphous form of Acalabrutinib maleate or crystalline Form-M of Acalabrutinib maleate prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.

P-XRD Method of Analysis:

PXRD analysis of compound of formula- 1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of crystalline Form-S of Acalabrutinib.

Dichloromethane (1050 ml) was added to Acalabrutinib ethylene glycol (105 gms) at 25- 30°C and stirred for 30 minutes. Cooled the mixture to 20-25°C. Water (1050 ml) was added to mixture at 20-25°C and stirred for 90 minutes. Layers were separated and aqueous layer was extracted with dichloromethane. Combined the total organic layers. Water was added to the organic layer at 20-25°C and stirred for 30 minutes. Layers were separated. Activated carbon was added to organic layer at 20-25°C and stirred for 2 hours. Filtered the mixture through hyflow bed and washed with dichlorome thane. Distilled off the solvent completely from the filtrate under vacuum and co-distilled with dichloromethane. To the obtained compound, methanol (473 ml) was added at 25-30°C and stirred for 15 minutes. Filtered the mixture through 0.2 micron filter and washed with methanol. Raised the temperature of the mixture to 45-50°C and stirred for 15 minutes. Water (263 ml) was slowly added to the mixture at 45-50°C and stirred for 30 minutes. Cooled the mixture to 0-5°C. Filtered the solid, washed with water and dried to get the title compound. Yield: 68 gms; DSC: 166°C.

The P-XRD pattern of the obtained compound is illustrated in figure- 1.

Example-2: Preparation of amorphous form of Acalabrutinib.

Dichloromethane (1100 ml) was added to Acalabrutinib ethylene glycol (110 gms) at 25- 30°C and stirred for 30 minutes. Cooled the mixture to 20-25°C. Water (1100 ml) was added to mixture at 20-25°C and stirred for 90 minutes. Layers were separated and aqueous layer was extracted with dichloromethane. Combined the total organic layers. Water was added to the organic layer at 20-25°C and stirred for 30 minutes. Layers were separated. Activated carbon was added to organic layer at 20-25°C and stirred for 2 hours. Filtered the mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under vacuum and co-distilled with dichloromethane. To the obtained compound, methanol (4400 ml) was added at 25-30°C and stirred for 15 minutes. Filtered the mixture through 0.2 micron filter and washed with methanol. Distilled off the solvent completely from the filtrate below 35°C under vacuum and co-distilled with methyl tert-butyl ether. To the obtained compound, methyl tert-butyl ether (1100 ml) was added at 25-30°C and stirred for 2 hours. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound.

Yield: 75.0 gms. Purity by HPLC: 99.93%; Diamide impurity: 0.04%; Acetyl impurity: 0.01%; Pyrrolidine impurity: 0.02%; Enantiomer impurity (Not detected) and 8-Hydroxy impurity (Not detected). The PXRD pattern of the obtained compound is illustrated in Figure-2.

Example-3: Preparation of amorphous form of Acalabrutinib.

Dichloromethane (140 ml) was added to Acalabrutinib ethylene glycol (14.0 gms) at 25- 30°C and stirred for 10 minutes. Water (70 ml) was added to mixture at 25-30°C and stirred for 15 minutes. Layers were separated and washed the organic layer with water. Distilled off the organic layer at 42°C. To the obtained compound, methanol (470 ml) was added at 25-30°C and stirred for 20 minutes. Activated carbon was added to the mixture at 25-30C and stirred for 20 minutes. Filtered the mixture through hyflow bed and washed with methanol. Distilled off the solvent completely at 42°C. To the obtained compound, methyl tert-butyl ether (70 ml) was added at 25-30° and stirred for 20 minutes. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound. Yield: 10.2 gms.

Purity by HPLC: 99.16%; Diamide impurity: 0.14%; Acetyl impurity: 0.07%; Pyrrolidine impurity: 0.07% and 8-Hydroxy impurity: 0.08%.

The PXRD pattern of the obtained compound is illustrated in Figure-2.

Example-4: Preparation of co-crystal of Acalabrutinib and adipic acid.

Acalabrutinib (100 mg) was suspended together with adipic acid (31.3 mg) in methanol (5.0 ml) at 25-30°C. The suspension was heated to 40°C and stirred for 10 minutes. A clear solution was obtained. The obtained clear solution was kept aside for 25 hours at 25-30°C. Filtered the precipitated solid and dried to get the title compound. Yield: 112 mg;

The PXRD pattern of the obtained compound is illustrated in Figure-3.

Example-5: Preparation of amorphous form of Acalabrutinib maleate of Formula-la.

Acalabrutinib maleate (350.0 mg) was dissolved in a mixture of dichloromethane (5.0 ml) and methanol (5.0 ml) at 25-30°C and stirred for 10 minutes. Distilled off the solvent completely from the mixture and dried to get the title compound.

Yield: 200.0 mg; Purity by HPLC: 99.94%.

The P-XRD pattern of the obtained compound is illustrated in figure-4.

Example-6: Preparation of crystalline Form-M of Acalabrutinib maleate.

Amorphous Acalabrutinib (5.0 gm) was dissolved in ethyl formate (100.0 ml) at 25-30°C and stirred for 10 minutes. A solution of maleic acid (1.249 gm) and ethyl formate (5.0 ml) was added to the mixture at 25-30°C and stirred for 2 hours. Filtered the solid, washed with ethyl formate and dried to get the title compound. Yield: 4.8 gm.

The PXRD pattern of the obtained compound is shown in figure-5.