DESC:FIELD OF THE INVENTION
The present invention relates to polymorphic forms of Acalabrutinib and process of preparation thereof.
BACKGROUND OF THE INVENTION
Acalabrutinib, has a chemical name 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)benzamide. Acalabrutinib is represented by the following chemical structure according to Formula (I).

Formula I
Acalabrutinib is an orally-available, small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTKmediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.
US 9,290,504 first discloses Acalabrutinib, its process for preparation and its method of use. US 9,796,721 (herein after referred to as the ‘721 patent) discloses crystalline forms I-VIII of a Acalabrutinib base, further, US’721 also discloses crystalline form of Acalabrutinib salts. This patent teaches that Form I is difficult to crystallize but may be prepared from a very limited set of solvents, in particular certain mixtures with n-heptane.
WO2018/064797 also discloses solid crystalline forms 1-4 of Acalabrutinib. WO2018/229613 discloses RSV1-RSV5 crystalline form of Acalabrutinib, which are solvated Forms.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Acalabrutinib, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point (mp), thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
Discovering new solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of Acalabrutinib.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide novel crystalline polymorph Form AL-1 of Acalabrutinib and process of preparation thereof.
Yet another aspect the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Acalabrutinib obtained according to present invention, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of Form AL-1 of Acalabrutinib.
Fig 2 shows the Differential scanning calorimetry ("DSC") pattern of Form AL-1 of Acalabrutinib.
Fig 3 shows the thermal gravimetric analysis ("TGA") pattern of Form AL-1 of Acalabrutinib.
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention relates to crystalline Form AL-1 of Acalabrutinib.
In an embodiment of the invention, crystalline Form AL-1 of Acalabrutinib is characterized by 2-theta peak(s) (XRPD) selected from the 2-theta (XRPD) peaks 6.29, 6.59, 10.32, 10.87, 11.58, 11.69, 13.17, 14.45, 15.13, 16.29, 17.66, 18.37, 19.49, 19.65, 20.23, 20.39, 20.53, 20.67, 21.52, 23.88, 24.16, 25.62, 26.09, 26.59, 27.74, 28.34, 28.79, 29.75, 30.84, 31.94, 32.79, 34.21, 35.85 and 37.16 (+0.2O).
In another embodiment of the present invention, the crystalline form AL-1 of Acalabrutinib is characterized by having PXRD peaks as shown in Fig-1.
In an embodiment of the invention, crystalline Form AL-1 of Acalabrutinib is characterized by having DSC as shown in Fig-2 with thermal events at 182oC and 211oC. TGA as shown in Fig.-3 shows a loss of approximately 0.5% mass over the temperature range of 40-130oC.
Another aspect of the invention relates to a process of preparation of novel crystalline form AL-1 of Acalabrutinib comprising;
a. providing solution of Acalabrutinib in a suitable solvent;
b. isolating crystalline form AL-1 of Acalabrutinib.
In an embodiment of the invention, providing a solution of Acalabrutinib in a suitable solvent is achieved by dissolving Acalabrutinib (of any polymorphic form) in a solvent, or preparing Acalabrutinib by treating Acalabrutinib salt with base in suitable solvent or any such a solution may be obtained in the course of its synthesis as a residue or in a solid form. Providing a solution of Acalabrutinib optionally involves use of other suitable solvents capable of dissolving Acalabrutinib. Then optionally, filtering the solvent solution to remove any extraneous matter; and finally isolating Acalabrutinib by filtration. Before filtration the solvent removed partially so as to increase the yield of the product or cooled to lower temperature.
In another embodiment the solution of Acalabrutinib is suitable solvent is stirred or stored at a temperature in the range of 5-35oC, preferably at 25 oC for a duration varied from 1-24 hours, preferably more than 3 - 15 before the isolation of the product.
In some other embodiment the present invention the solvent system may be dried to remove any moisture content by a conventional method so as to get pure polymorphic form according to the invention. For example, the Acalabrutinib of any Form, including hydrated form, is dissolved in a water miscible solvent and distilled several times under vacuum or atmospheric pressure so as to reduce the moisture content of the system and then solvent system is completely removed and the residue is dissolved using solvent system of the present invention. The crystalline Form of Acalabrutinib thus obtained can be characterized by XRPD pattern having peaks selected from 6.29, 10.32, 10.87, 11.58, 11.69, 13.17, 14.45, 15.13, 16.29, 17.66, 18.37, 19.49, 19.65, 20.23, 20.39, 20.53, 20.67, 21.52, 23.88, 24.16, 25.62, 26.09, 26.59, 27.74, 28.34, 28.79, 29.75, 30.84, 31.94, 32.79, 34.21, 35.85 and 37.16 o two-theta +0.2O.
Isolating crystalline Form AL-1 of Acalabrutinib can preferably be carried out by optionally cooling the step a) solution to lower temperature followed by filtering off the solid. Alternatively, the isolation can be effected by addition of an anti-solvent to the solution obtained in step a) and then filtering the solid.
In some embodiments of the present invention, clear solution obtained in step (a) may be optionally seeded to promote nucleation.
In few embodiments of the present invention, involves dissolving Acalabrutinib in a suitable solvent, if needed involves stirring, heating and the combination thereof.
In few embodiments of the present invention, the isolation is performed by any conventional methods such as cooling, filtration or combination thereof.
In few embodiments of the present invention, the isolation further comprises optionally washing with a suitable solvent and drying.
In few embodiments of the invention, the novel solid form of Acalabrutinib according to the present invention includes pure crystalline forms, amorphous form, mixture of crystalline forms, or mixture of crystalline and amorphous forms.
In some embodiments of the present invention, the suitable solvent used in present invention, is/are selected from acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like or mixtures thereof , preferably acetone.
In some embodiments of the invention, the excipients or pharmaceutically acceptable excipients includes but not limited to diluents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof.
In another aspect the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Acalabrutinib obtained according to present invention, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
The “at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient” can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
In an embodiment the disease includes include, but not limited to a further subject of the present invention is a method for treating and/or preventing hyperproliferative disease is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disease, ? cell acute lymphoblastic leukemia, Waldenstrom’s macroglobulinemia, Burkitt’s leukemia, Hodgkin’s
disease, multiple myeloma, acute myeloid leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, mast cell leukemia, mastocytosis, myeloproliferative disorders, (MPDs), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (??), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABLl-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, primary central nervous system (CNS) lymphoma, primary multifocal lymphoma of peripheral nervous system (PNS), thymus cancer,
brain cancer, glioblastoma, lung cancer, squamous cell cancer, skin cancer (e.g., melanoma), eye cancer, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal cancers, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head and
neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (e.g., metastatic bone cancer), esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, epidermoid cancer, AIDS-related cancer (e.g., lymphoma), viral-induced
cervical carcinoma (human papillomavirus), nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi’s sarcoma, primary effusion lymphoma (Kaposi’s sarcoma herpesvirus), hepatocellular carcinoma (hepatitis ? and hepatitis C viruses), T-cell leukemias (Human T-cell leukemia virus-1), benign hyperplasia of the skin, restenosis, benign prostatic hypertrophy, tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of
prematurity, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet’s disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren’s syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, lupus, and lupus nephritis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to the present invention or the pharmaceutical composition according to the present invention.
The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PANalytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree.
The pattern of differential scanning calorimetry (DSC) in the present invention was
acquired by a TA Q2000. The parameters of the differential scanning calorimetry (DSC)
method of the present invention were as follow: Heating rate: 10° C./min and Purge gas:
nitrogen.
Thermo gravimetric analysis (TGA) used for estimation of solvent/water content
of dried material is performed using a TA-instruments TGA-Q500 about 10 mg sample
is heated 10°/min in an open pan under nitrogen flow.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Preparation of Form AL-1 of Acalabrutinib
Acalabrutinib residue (obtained from distilling dichloromethane layer containing the Acalabrutinib) (47.0 g) and acetone (120 ml) were added into a stirring apparatus. The reaction mixture was heated at 55 ± 5°C and stirred till clear solution. Reaction mass was cooled to 25 ± 3°C and then stirred for 12 hours at the same temperature. The solid obtained was filtered at room temperature and dried under vacuum at 60 ± 3°C. XRPD: Fig.1
The obtained solid was kept open in petri dish for 5 days at room temperature which shows no change in XRPD pattern.
,CLAIMS:We Claim:
1. A process for preparation of crystalline Acalabrutinib Form AL-1, characterized by Figure 1, comprising;
a. providing solution of Acalabrutinib in the suitable solvent;
b. isolating crystalline form AL-1 of Acalabrutinib.
2. The process of claim 1, wherein suitable solvent is selected from acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like or mixtures thereof.
3. A crystalline Acalabrutinib Form AL-1, characterized by Figure 1.
4. A crystalline Acalabrutinib Form AL-1, characterized by DSC having thermal event at 182oC.