DESC:FIELD OF THE INVENTION
The present invention relates to an amorphous solid dispersion of Acalabrutinib maleate and processes for preparation thereof. The invention also relates to pharmaceutical compositions comprising amorphous solid dipsersion of Acalabrutinib maleate.

BACKGROUND OF THE INVENTION:

Acalabrutinib (coded as ACP-196) is an inhibitor of Bruton tyrosine kinase, chemically known as 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)
benzamide represented by structural Formula I as below:

-

Formula I

Acalabrutinib is a selective, covalent Bruton Tyrosine Kinase (“BTK”) inhibitor indicated for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and mantle cell lymphoma. Acalabrutinib was approved by USFDA and market by Astrazeneca under the brand name Calquence® in the form of oral capsule having dosage strength 100mg. The prescribing information for Calquence® recommends avoiding co-administration with gastric acid reducing agents because such agents can decrease Acalabrutinib maleate plasma concentrations.

The bioavailability of BCS Class II drug substances, including Acalabrutinib, generally is limited by their dissolution rate and/or solvation. In addition, Acalabrutinib free base exhibits pH-dependent solubility with solubility decreasing as pH increases up to the maximum basic pKa, (i.e., around pH 6 where Acalabrutinib is largely un-ionized). Increasing the stomach pH of a subject taking Calquence® (e.g., in a subject also taking a proton pump inhibitor or other gastric acid reducing agent) can reduce the solubility of Acalabrutinib in the stomach and potentially result in lower bioavailability and/or greater intra- and inter-subject variability in Acalabrutinib pharmacokinetics.

To circumvent above problem, thereafter a new dosage form i.e. tablet dosage form containing 100 mg of Acalabrutinib maleate has been approved and marketed in USA.

US 9,290,504 discloses Acalabrutinib and its physiologically acceptable salts. US ‘504 disclose the process for preparation of Acalabrutinib as follows:

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).

WO 2017002095 A1, IN 201641037734, IN 201841040898, WO2018229613 A1, IN 201811034524, IN 201841038090, WO2019041026 A1, WO2019105359 A1, WO2019134455 A1, WO2019159097 A1, WO2019205812 A1, WO2020141562 A1, WO2020198429 A1, WO2022078122 A1, WO2021135346 A1, WO2021239893 A1, WO2020225831 A1, WO2018064797 A1, WO2020065667 A1, WO 2021168561 A1, WO 2020053795 A2, IN 201921008530 discloses various polymorphs of Acalabrutinib free base such as crystalline forms, amorphous forms, amorphous solid dispersions and solvates.

WO 2019041026 A1 and WO 2021168561 disclose Acalabrutinib Co-crystals.

WO2017002095 A1, WO2018148961, WO2021255246 and EP3587421A1 discloses various salts of Acalabrutinib such as fumarate, maleate, phosphate, L-tartrate, citrate, gentisate, oxalate, sulfate, hemi-fumarate, L-pyroglutamate salts and their crystalline forms.

WO2017002095 A1 discloses processes for the preparation of Acalabrutinib maleate from Acalabrutinib free base by treating with maleic acid in acetone and water as solvents to provides Acalabrutinib maleate crystalline Form A as hydrate.

WO2018148961 A1 (herein after referred as ‘961) discloses processes for the preparation of Acalabrutinib maleate from Acalabrutinib free base by treating with maleic acid in a solvent selected from isopropanol, acetone, ethanol, sec-butanol, butanone, methanol or mixtures thereof to provide Acalabrutinib maleate crystalline Form 1 as anhydrate.

WO ‘961 also discloses an alternate process for preparation of Acalabrutinib maleate anhydrate crystalline Form 1 from Acalabrutinib free base by treating with maleic acid in solvent and followed by addition of anti-solvent.

WO 2021255246 discloses processes for the preparation of Acalabrutinib maleate from Acalabrutinib free base by treating with maleic acid in tetrahydrofuran and water as solvents to provide Acalabrutinib maleate as monohydrate.

WO 2022234602 discloses crystalline Form-M of Acalabrutinib maleate from Amorphous Acalabrutinib by treating with maleic acid in ethyl formate.

WO ‘602 also discloses the process for the preparation of amorphous Acalabrutinib maleate from Acalabrutinib maleate in a mixture of dichloromethane and methanol.

The prior-arts disclose various crystalline forms and amorphous form of Acalabrutinib maleate. There is no disclosure of amorphous solid dispersion of Acalabrutinib maleate in the art.

The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising the said API.

Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form, such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized. The presence of the high energy form of the API in a pharmaceutical composition usually improves the dissolution rate

In view of the above art, there is provided an amorphous solid dispersion of Acalabrutinib maleate together with one or more pharmaceutically acceptable excipients and process for preparation thereof.

OBJECTIVES OF THE INVENTION

The object of the present invention to provide an amorphous solid dispersion of Acalabrutinib maleate.
Another object of the present invention is to provide a process for preparing the amorphous solid dispersion of Acalabrutinib maleate and pharmaceutical composition comprising it.

SUMMARY OF THE INVENTION
The present invention relates to amorphous solid dispersion of Acalabrutinib maleate with a suitable pharmaceutically acceptable excipient selected from a group consisting of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), povidone and co-povidone.
In another embodiment of the present invention provides a process for the preparation of amorphous
solid dispersion of Acalabrutinib maleate, which comprises:
a. treating Acalabrutinib, maleic acid, and a suitable pharmaceutically acceptable excipient in a solvent or mixture of solvents;
b. isolating amorphous solid dispersion of Acalabrutinib maleate.

In another embodiment of the present invention provides a process for the preparation of amorphous
solid dispersion of Acalabrutinib maleate, which comprises:
a. treating Acalabrutinib maleate and a suitable pharmaceutically acceptable excipient in a solvent or mixture of solvents;
b. isolating amorphous solid dispersion of Acalabrutinib maleate.

In another embodiment of the present invention provides a pharmaceutical composition comprising amorphous solid dispersion of Acalabrutinib maleate.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows powder X-ray diffractogram pattern of the amorphous solid dispersion of Acalabrutinib maleate with povidone K-30 obtained according to example -1.
FIG. 2 shows powder X-ray diffractogram pattern of the amorphous solid dispersion of Acalabrutinib maleate with povidone K-30 obtained according to example -2.
FIG. 3 shows powder X-ray diffractogram pattern of the amorphous solid dispersion of Acalabrutinib maleate with HPMC obtained according to example -3.
FIG. 4 shows powder X-ray diffractogram pattern of the amorphous solid dispersion of Acalabrutinib maleate with povidone K30 obtained according to example -4.
FIG. 5 shows powder X-ray diffractogram pattern of the amorphous solid dispersion of Acalabrutinib maleate with povidone K30 obtained according to example -5.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-a radiation. Adequate sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 increment and scan speed of 0.2 sec/step. The sample was placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to amorphous solid dispersion of Acalabrutinib maleate with a suitable pharmaceutically acceptable excipient selected from a group consisting of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), povidone and co-povidone.
In another aspect of the present invention the amount of Acalabrutinib maleate in amorphous solid dispersion with a suitable pharmaceutically acceptable excipient may be about 5% w/w to about 95% w/w, or about 10% w/w to about 80% w/w, or about 20% w/w to about 50% w/w, or about 30% w/w to about 70% w/w, or about 40% w/w to about 60% w/w, or about 50% w/w.
In another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Acalabrutinib maleate, which comprises treating Acalabrutinib with maleic acid and a pharmaceutically acceptable excipient in solvent or mixture of solvents, wherein solvent selected from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; and alcohol solvent such as methanol, ethanol isopropanol, propanol and n-butanol; and isolating amorphous solid dispersion of Acalabrutinib maleate.

In another aspect of the present invention the suitable pharmaceutically acceptable excipient is selected from a group consisting of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), povidone and co-povidone.
In another aspect of the present invention treating Acalabrutinib, maleic acid and pharmaceutically acceptable excipient in a solvent or mixture of solvents is carried out at a temperature in the range of 25°C to 35°C.
In another aspect of the present invention treating Acalabrutinib, maleic acid and pharmaceutically acceptable excipient in a solvent or mixture of solvents is stirred for 15 minutes to 1 hour.
In another aspect of the present invention any physical form of Acalabrutinib may be used for the preparation of solid dispersion of Acalabrutinib maleate.
In another aspect of the present invention the isolation of amorphous solid dispersion of Acalabrutinib maleate is carried out by removing the solvent, wherein removal is carried out by distillation, spray drying, freeze drying (lyophilisation), turbo drying, evaporation under reduced pressure, agitated thin film drying, flash evaporation, Buchi® Rotavapor and vacuum distillation.
In another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Acalabrutinib maleate, which comprises treating Acalabrutinib maleate and a pharmaceutically acceptable excipient in solvent or mixture of solvents, wherein solvent selected from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; and alcohol solvent such as methanol, ethanol isopropanol, propanol and n-butanol; and isolating amorphous solid dispersion of Acalabrutinib maleate.

In another aspect of the present invention the suitable pharmaceutically acceptable excipient is selected from a group consisting of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), povidone and co-povidone.
In another aspect of the present invention treating Acalabrutinib maleate and pharmaceutically acceptable excipient in a solvent or mixture of solvents is carried out at a temperature in the range of 25°C to 35°C.
In another aspect of the present invention treating Acalabrutinib maleate and pharmaceutically acceptable excipient in a solvent or mixture of solvents is stirred for 15 minutes to 1 hour.
In another aspect of the present invention any physical form of Acalabrutinib maleate may be used for the preparation of solid dispersion of Acalabrutinib maleate.
In another aspect of the present invention the isolation of amorphous solid dispersion of Acalabrutinib maleate is carried out by removing the solvent, wherein removal is carried out by distillation, spray drying, freeze drying (lyophilisation), turbo drying, evaporation under reduced pressure, agitated thin film drying, flash evaporation, Buchi® Rotavapor and vacuum distillation.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous solid dispersion of Acalabrutinib maleate and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. Acalabrutinib maleate amorphous solid dispersion may preferably be formulated into tablets.
The details of the invention are given in the examples provided-below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Examples:
Reference example 1:
(S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide
(a) (S)-Benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl) pyrrolidine-1-carboxylate
(S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (98.5 mg) and 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid (63.0 mg) were suspended in a mixture of 2N aqueous potassium carbonate solution (1.18 ml) and dioxane (2.96 ml). Nitrogen was bubbled through the mixture, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene palladium (ii) chloride (47.8 mg). The reaction mixture was heated for 20 minutes at 140° C. in the microwave. water was added to the reaction mixture, followed by an extraction with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using silica gel and dichloromethane/methanol=9/1 v/v % as eluent to afford (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate. Yield: 97.1 mg.
(b) (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide
To (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl) pyrrolidine-1-carboxylate (78 mg) was added a 33% hydrobromic acid/acetic acid solution (2 ml) and the mixture was left at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized using 2N sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to give (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide. Yield: 34 mg.
(c) (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (Acalabrutinib)
To a solution of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl) benzamide (19.7 mg), triethylamine (20 mg, 0.027 ml) and 2-butynoic acid (9.45 mg) in dichloromethane (2 ml) was added HATU (18.75 mg). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford (S)-4-(8-amino-3-(1-but-2-ynoyl pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide. Yield: 10.5 mg.

Reference example 2: Preparation of crystalline form A of (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide maleate (Acalabrutinib maleate)

16.296 g of Acalabrutinib free base was dissolved in a 350 ml of acetone and 35 ml of water mixture. The mixture was subsequently heated to 50°C, which led to a clear solution. Thereafter, 20 ml of an aqueous solution containing 4.043 g of maleic acid was added. Moreover, the vessel and pipette holding the aqueous maleic acid solution were washed with 1.0 ml of water and the wash solution was also included in the mixture. The solution was allowed to cool while stirring at about 300 rpm at about 45°C, the solution was seeded with about 20 mg of Acalabrutinib maleate and further cooled to approximately 20°C. After about 24 hours, the suspension was filtered to obtain a solid which was dried in air at 40°C for about 20 hours to get Acalabrutinib maleate crystalline form A.
Yield: 14.1 grams.

Example 1: Preparation of amorphous solid dispersion of Acalabrutinib maleate
Acalabrutinib (3 g), maleic acid (0.74 g), povidone K30 (0.6 g) were taken in mixture of methylene dichloride (15 ml) and methanol (15 ml) at 25-35° and stirred for 20 minutes. Filtered the reaction mixture through hi-flow and the filtrate was distilled under reduced pressure at 45-50°C and then dried at 50-55°C for 48 hours to get amorphous solid dispersion of Acalabrutinib maleate. Yield: 3.6 grams; Purity by HPLC: 99.85 %.
The PXRD pattern of the obtained compound is represented as Figure-1.
Example 2: Preparation of amorphous solid dispersion of Acalabrutinib Maleate
Acalabrutinib (3 g), maleic acid (0.748 g), povidone K30 (1.2 g) were taken in mixture of methylene dichloride (15 ml) and methanol (15 ml) at 25-35° and stirred for 20 minutes. Filtered the reaction mixture through hi-flow and the filtrate was distilled under reduced pressure at 45-50°C and then dried at 50-55°C for 48 hours to get amorphous solid dispersion of Acalabrutinib maleate.
Yield: 4.0 grams; Purity by HPLC: 99.82 %.
The PXRD pattern of the obtained compound is represented as Figure-2.
Example 3: Preparation of amorphous solid dispersion of Acalabrutinib maleate
Acalabrutinib (3 g), Maleic acid (0.748 g), HPMC (0.45 g) were taken in mixture of methylene dichloride (15 ml) and methanol (15 ml) at 25-35° and stirred for 20 minutes. Filtered the reaction mixture through hiflow and the filtrate was distilled under reduced pressure at 45-50°C and then dried at 50-55°C for 48 hours to get amorphous solid dispersion of Acalabrutinib maleate. Yield: 3.6 g ; Purity by HPLC: 99.78 %.
The PXRD pattern of the obtained compound is represented as Figure-3.
Example 4: Preparation of amorphous solid dispersion of Acalabrutinib maleate

Acalabrutinib maleate (2.55 g), povidone K30 (0.45 g) were taken in mixture of methylene dichloride (13 ml) and methanol (13 ml) at 25-35° and stirred for 20 minutes. Filtered the reaction mixture through hiflow and the filtrate was distilled under reduced pressure at 45-50°C and then dried at 50-55°C for 48 hours to get amorphous solid dispersion of Acalabrutinib maleate.
Yield: 2.44 g. Purity by HPLC: 99.88 %.
The PXRD pattern of the obtained compound is represented as Figure-4.
Example 5: Preparation of Amorphous solid dispersion of Acalabrutinib maleate

Acalabrutinib maleate (2.25 g), povidone K30 (0.75 g) were taken in mixture of methylene dichloride (11.5 ml) and methanol (11.5 ml) at 25-35° and stirred for 20 minutes. Filtered the reaction mixture through hiflow and the filtrate was distilled under reduced pressure at 45-50°C and then dried at 50-55°C for 48 hours to get amorphous solid dispersion of Acalabrutinib maleate. Yield: 2.6 grams; Purity by HPLC: 99.81 %.

The PXRD pattern of obtained compound is represented as Figure-5.

,CLAIMS:We claim:

1. An amorphous solid dispersion of Acalabrutinib maleate with a suitable pharmaceutically acceptable excipient selected from a group consisting of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), povidone and co-povidone.

2. A process for preparation of amorphous solid dispersion of Acalabrutinib maleate, which comprises:
a. treating Acalabrutinib, maleic acid, and a suitable pharmaceutically acceptable excipient in a solvent or mixture of solvents;
b. isolating amorphous solid dispersion of Acalabrutinib maleate.

3. A process for the preparation of amorphous solid dispersion of Acalabrutinib maleate, which comprises:
a. treating Acalabrutinib maleate and a suitable pharmaceutically acceptable excipient in a solvent or mixture of solvents;
b. isolating amorphous solid dispersion of Acalabrutinib maleate.

4. The process as claimed in claims 2 & 3, wherein suitable pharmaceutically acceptable excipient is povidone K30 or HPMC.

5. The process as claimed in claims 2 & 3, wherein solvent is selected from methylene dichloride, methanol or mixtures thereof.

6. A pharmaceutical composition comprising amorphous solid dispersion of Acalabrutinib maleate.