DESC:FIELD OF THE INVENTION
The present invention relates to premix of acalabrutinib maleate and process for preparation thereof. Acalabrutinib maleate is represented by following structural formula (IA).

BACKGROUND OF THE INVENTION
Acalabrutinib is a second generation Bruton's tyrosine kinase inhibitor. It blocks an enzyme called Bruton's tyrosine kinase, which helps B cells to survive and grow. By blocking this enzyme, acalabrutinib is expected to slow down the build-up of cancerous B cells in CLL, thereby delaying progression of the cancer.

Acalabrutinib is approved by USFDA as CALQUENCE® capsule for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.

Acalabrutinib is 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 and structurally represented as below.

Acalabrutinib maleate is approved by USFDA as CALQUENCE® tablet for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.

Acalabrutinib maleate is chemically known as 4-{8-Amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (2Z)-2-butenedioic acid hydrate and structurally represented as below.

WO2013010868 discloses acalabrutinib and process for the preparation thereof.

WO2017002095 discloses various crystalline forms I, II, III, IV, V, VI, VII VIII and amorphous form of acalabrutinib. WO’095 also discloses various salt forms fumarate, gentisate, maleate, phosphate, L-tartrate, citrate, oxalate, and sulfate of Acalabrutinib. Amongst the various salts, acalabrutinib maleate crystalline Form A is disclosed in WO’095 and it is characterized by 1H NMR, PXRD, TG-FTIR, DSC and DVS.

WO2018064797 discloses crystalline forms 1, 2, 3 and 4 of Acalabrutinib.

WO2018229613 discloses crystalline forms RSV1, RSV2, RSV3, RSV4 and RSV5 of Acalabrutinib.

WO2021239893A1 discloses amorphous solid dispersion of Acalabrutinib.

WO2018148961A1 discloses crystalline form I of Acalabrutinib Malate and its preparation.

WO2022234602A1 discloses crystalline form M and amorphous form of Acalabrutinib Maleate and its preparation.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability.

Amorphous form prepared in prior art process suffer from many disadvantages like poor yield, purity and stability.

To overcome this problem, it is necessary to develop stable amorphous form of Acalabrutinib Maleate and its process for the preparation.

Thus, the present invention provides premix of acalabrutinib maleate and its process for the preparation.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide premix of acalabrutinib maleate and pharmaceutically acceptable excipient.

Another object of the present invention is to provide process for preparation of premix of acalabrutinib maleate and pharmaceutically acceptable excipient which comprises;
(a) Dissolving Acalabrutinib maleate and pharmaceutically acceptable excipient in suitable solvent
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

Another object of the present invention is to provide process for preparation of premix of acalabrutinib maleate and pharmaceutically acceptable excipient which comprises;
(a) Mixing Acalabrutinib maleate and pharmaceutically acceptable excipient in absence of solvent.
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide premix of acalabrutinib maleate and pharmaceutically acceptable excipient.

Another aspect of the present invention is to provide process for preparation premix of acalabrutinib maleate and pharmaceutically acceptable excipient which comprises;
(a) Dissolving Acalabrutinib maleate and pharmaceutically acceptable excipient in suitable solvent
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.
Another aspect of the present invention is to provide process for preparation of premix of acalabrutinib maleate and pharmaceutically acceptable excipient which comprises;
(a) Mixing Acalabrutinib maleate and pharmaceutically acceptable excipient in absence of solvent.
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE DRAWINGS
Fig.1 shows an XRPD pattern of premix of acalabrutinib maleate as prepared by Example 3.
Fig.2 shows an XRPD pattern of premix of acalabrutinib maleate as prepared by Example 4.

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide premix of acalabrutinib maleate and pharmaceutically acceptable excipient.

Another embodiment of the present invention is to provide process for preparation of premix of acalabrutinib maleate and pharmaceutically acceptable excipient which comprises;
(a) Dissolving Acalabrutinib maleate and pharmaceutically acceptable excipient in suitable solvent
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

Another embodiment of the present invention is to provide process for preparation of premix of acalabrutinib maleate and pharmaceutically acceptable excipient which comprises;
(a) Mixing Acalabrutinib maleate and pharmaceutically acceptable excipient in absence of solvent.
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

Wherein the Acalabrutinib maleate which is used in step (a) may be selected from crystalline or amorphous.

Wherein pharmaceutically acceptable excipient which is used in step (a) may be selected from methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, microcrystalline cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinyl alcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), silicon dioxide (syloid), copovidone, mannitol, sorbitol, cyclodextrins, methacrylic acid, polymethacrylate or mixtures thereof.

wherein the suitable solvents which is used in step (a) may be selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, methyl tertiary butyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides such as dimethyl formamide, dialkylsulfoxides such as dimethyl sulfoxide, dialkylacetamides such as N, N-dimethyl acetamide, alkylpyrrolidone such as N-methyl pyrrolidone, nitriles such as acetonitrile, propionitrile; water or mixtures thereof.

Isolation of premix of Acalabrutinib Maleate is carried out by employing any of the techniques, but not limited to cooling, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, solvent evaporation, solvent-anti solvent system, rotational distillation using a device such as buchi rotavapor, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), rotary cone vacuum dryer (RVPD), melt crystallization, sieving, grinding, milling, drying and the like.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of premix of acalabrutinib maleate and MCC
Dissolved Acalabrutinib maleate amorphous form (2.0 gm) in 20% Methanol in MDC (20:80) (30 ml). Microcrystalline cellulose (2.0 gm) was added to the above mixture and stirred for 15-20 minutes. Reaction mass distill out under vacuum below 50°C to obtained powder (3.8 gm).

Example 2: Preparation of premix of acalabrutinib maleate and MCC
Charged Acalabrutinib maleate amorphous form (2.0 gm) and Microcrystalline cellulose (2.0 gm) mix it well. Prepared a physical mixture of it.

Example 3: Preparation of premix of acalabrutinib maleate and Hypromellose
Dissolved Acalabrutinib maleate amorphous form (2.0 gm) in 20% Methanol in MDC (20:80) (30 ml). HPMC (2.0 gm) was added to the above mixture and stirred for 15-20 minutes. Reaction mass distill out under vacuum below 50°C to obtained powder (3.8 gm).

Example 4: Preparation of premix of acalabrutinib maleate and Copovidone
Dissolved Acalabrutinib maleate amorphous form (2.0 gm) in 20% Methanol in MDC (20:80) (30 ml). Copovidone (2.0 gm) was added to the above mixture and stirred for 15-20 minutes. Reaction mass distill out under vacuum below 50°C to obtained powder (3.8 gm).
,CLAIMS:We Claim:

1. Premix of Acalabrutinib Maleate and pharmaceutically acceptable excipient.

2. Process for preparation premix of Acalabrutinib Maleate and pharmaceutically acceptable excipient which comprises;
(a) Dissolving Acalabrutinib maleate and pharmaceutically acceptable excipient in suitable solvent,
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

3. Process for preparation of premix of Acalabrutinib Maleate and pharmaceutically acceptable excipient which comprises;
(a) Mixing Acalabrutinib maleate and pharmaceutically acceptable excipient in absence of solvent,
(b) Isolating premix of Acalabrutinib maleate and pharmaceutically acceptable excipient.

3. The process as claimed in claim 2 and 3, wherein the Acalabrutinib maleate which is used in step (a) is selected from crystalline or amorphous.

4. The process as claimed in claims 2 and 3, wherein pharmaceutically acceptable excipient which is used in step (a) is selected from methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, microcrystalline cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinyl alcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), silicon dioxide (syloid), copovidone, mannitol, sorbitol, cyclodextrins, methacrylic acid, polymethacrylate or mixtures thereof.

5. The process as claimed in claim 2, wherein the suitable solvents which is used in step (a) is selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, methyl tertiary butyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides such as dimethyl formamide, dialkylsulfoxides such as dimethyl sulfoxide, dialkylacetamides such as N, N-dimethyl acetamide, alkylpyrrolidone such as N-methyl pyrrolidone, nitriles such as acetonitrile, propionitrile; water or mixtures thereof.

6. The process as claimed in claims 2 and 3, wherein isolation of premix of Acalabrutinib Maleate is carried out by employing technique is selected from cooling, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, solvent evaporation, solvent-anti solvent system, rotational distillation using a device such as buchi rotavapor, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), rotary cone vacuum dryer (RVPD), melt crystallization, sieving, grinding, milling and drying.