WO2019159097A1 - Crystalline polymorphic forms of acalabrutinib - Google Patents

Crystalline polymorphic forms of acalabrutinib Download PDF

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WO2019159097A1
WO2019159097A1 PCT/IB2019/051201 IB2019051201W WO2019159097A1 WO 2019159097 A1 WO2019159097 A1 WO 2019159097A1 IB 2019051201 W IB2019051201 W IB 2019051201W WO 2019159097 A1 WO2019159097 A1 WO 2019159097A1
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acalabrutinib
solution
crystalline form
temperature
solvent
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PCT/IB2019/051201
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French (fr)
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Hari Babu MATTA
Ratnakar Mani TRIPATHI
Muddassar Ajij KAZI
Mahavir Singh Khanna
Mohan Prasad
Shakir Shabbir SHAIKH
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Sun Pharmaceutical Industries Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to crystalline Form S and Form S2 of acalabrutinib, processes for their preparation, pharmaceutical composition comprising them, and their use for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
  • MCL mantle cell lymphoma
  • Acalabrutinib is chemically known as 4- ⁇ 8-amino-3-[(2S)-l-(but-2- ynoyl)pyrrolidin-2-yl] imidazo [ 1 ,5 -a]pyrazin- 1 -yl) ⁇ -N-(pyridine-2-yl)benzamide and represented by the structural Formula I.
  • Acalabrutinib is an inhibitor of Bruton tyrosine kinase (BTK) and it is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
  • BTK Bruton tyrosine kinase
  • U.S. Patent No. 9,290,504 discloses 4-imidazopyridazin-l-yl-benzamides and 4- imidazotriazin-l-yl-benzamides as Bruton’s tyrosine kinase (BTK) inhibitors.
  • U.S. Patent No. 9,796,721 allegedly describes anhydrates, hydrates and solvates of Acalabrutinib designated as Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, and amorphous form.
  • The’721 patent further discloses various crystalline acid addition salts of acalabrutinib.
  • the present invention relates to crystalline Form S and Form S2 of acalabrutinib, and processes for their preparation.
  • the present invention also relates to pharmaceutical composition comprising crystalline Form S or Form S2 of acalabrutinib.
  • the present invention also provides use of crystalline Form S and Form S2 of acalabrutinib for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
  • MCL mantle cell lymphoma
  • the crystalline Form S and Form S2 of acalabrutinib of the present invention are stable.
  • Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form
  • Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form S of acalabrutinib.
  • Figure 3 depicts an Infra-red (IR) spectrum of crystalline Form S of Acalabrutinib.
  • Figure 4 depicts a Thermogravimetric analysis (TGA) of crystalline Form S of acalabrutinib.
  • IR Infra-red
  • TGA Thermogravimetric analysis
  • Figure 5 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form S2 of acalabrutinib.
  • Figure 6 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form S2 of acalabrutinib.
  • Figure 7 depicts an Infra-red (IR) spectrum of crystalline Form S2 of acalabrutinib.
  • Figure 8 depicts a Thermogravimetric analysis (TGA) of crystalline Form S2 of acalabrutinib.
  • a first aspect of the present invention provides a crystalline Form S of acalabrutinib.
  • the crystalline Form S of acalabrutinib is characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 7.8 ⁇ 0.2° 2Q, 8.5 ⁇ 0.2° 2Q, 15.5 ⁇ 0.2° 2Q, and 16.9 ⁇ 0.2° 2Q.
  • the crystalline Form S of acalabrutinib is further characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 9.9 ⁇ 0.2° 2Q, 12.1 ⁇ 0.2° 2Q, 13.2 ⁇ 0.2° 2Q, 17.8 ⁇ 0.2° 2Q, 20. l ⁇ 0.2° 2Q, 22.2 ⁇ 0.2° 2Q, and 23.3 ⁇ 0.2° 2Q.
  • the crystalline Form S of acalabrutinib is characterized by an
  • the crystalline Form S of acalabrutinib is characterized by an XRPD peak positions ( ⁇ 0.2° 2Q) and/or d-spacing values (A) substantially as shown in Table 1.
  • Table 1 provides the d-spacing values (A), the corresponding 2Q values, and the relative intensity of crystalline Form S of acalabrutinib.
  • the crystalline Form S of acalabrutinib is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peak at about 158.5°C.
  • DSC differential scanning calorimetry
  • the crystalline Form S of acalabrutinib is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an IR absorption spectrum substantially as depicted in Figure 3, or a TGA substantially as depicted in Figure 4.
  • step b) adding water to the solution of step a) at 20°C to 35°C,
  • step b) heating the solution of step b) at temperature from 40°C to reflux temperature of the solvent
  • step a) dissolving acalabrutinib in a mixture of solvent and water at 20°C to 35°C, b) heating the solution of step a) at temperature from 40°C to reflux temperature of the solvent,
  • step c) optionally seeding the solution of step b) with crystalline acalabrutinib Form S, d) cooling the solution of step c), and
  • the crystalline Form S of acalabrutinib is prepared by dissolving acalabrutinib in a solvent.
  • the solvent is selected from the group consisting of alcohols, sulfoxides, ketones, nitriles, ethers and mixtures thereof.
  • alcohols include methanol, ethanol, n- propanol, iso-propanol, n-butanol, sec-butanol, tert-butanol or n-pentanol.
  • sulfoxides include dimethyl sulfoxide or sulfolane.
  • ketones include acetone, methyl ethyl ketone or methyl isobutyl ketone.
  • An example of nitrile is acetonitrile.
  • ethers examples include tetrahydrofuran, or l,4-dioxane. Wherever necessary, a mixture of solvent and water can be used. Thus, alcohols, sulfoxides, ketones, nitriles, or ethers can be used as solvent along with water.
  • alcohol is selected as a solvent. More preferably, the solvent selected is methanol, or a mixture of methanol and water.
  • acalabrutinib is dissolved in a solvent at temperature of about 20°C to temperature of about 35°C.
  • the temperature range selected to dissolve acalabrutinib in a solvent is about 20°C to about 30°C.
  • the solution of acalabrutinib in a solvent is heated to temperature of about 40°C to reflux temperature of the solvent. If methanol is used as a solvent then the heating of the solution is performed at temperature of about 40°C to temperature of about 85°C.
  • seed crystal of Form S of acalabrutinib may be added to the solution.
  • the seed crystal of Form S of acalabrutinib is added to the solution to obtain pure crystalline Form S of acalabrutinib.
  • crystalline Form S of acalabrutinib having chromatographic purity of more than 99% is obtained by adding the seed crystal of Form S of acalabrutinib into the solution.
  • the solution is cooled (step d) to temperature of about 20°C to temperature of about 35°C.
  • the crystalline Form S of acalabrutinib may be isolated by any conventional techniques, for example, precipitation, crystallization, etc.
  • the crystalline Form S of acalabrutinib may be dried using conventional techniques, for example, drying under vacuum, spray drying, suck drying, air drying, or agitated thin fdm drying.
  • the dried material may optionally be micronized.
  • micronization is carried out using technique selected from the group consisting of ball milling, colloid milling, grinding milling, air jet milling, roller milling, and impact milling.
  • the crystalline Form S of acalabrutinib is obtained by adding acalabrutinib in methanol, or methanol-water mixture at temperature of about 20°C to temperature of about 35°C. If necessary, water may be added to the methanol solution at temperature of about 20°C to temperature of about 35°C. The obtained solution is then heated at temperature from 40°C to reflux temperature of the methanol, or methanol-water solution. Whenever necessary during the process, the solution may be filtered. The seed crystals of Form S of acalabrutinib may be added to the heated solution, or else the solution is allowed to cool and then seed crystals may be added.
  • the solution is then cooled to temperature of about 20°C to temperature of about 35°C.
  • the cooling of the solution may be performed slowly, for example, over a time period of about 1 hour to 4 hours.
  • the crystalline Form S of acalabrutinib, so obtained, may be isolated from the solution by any of the conventional isolation techniques.
  • the crystalline Form S of acalabrutinib is found to be stable upon exposure at different temperatures (°C ) and relative humidity (RH) conditions, for example, at 25°C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days. At these temperatures and relative humidity conditions, there is no change found in the X-ray powder differaction pattern (XRPD) of the crystalline Form S of acalabrutinib with the initial XRPD Figure 1.
  • XRPD X-ray powder differaction pattern
  • the crystalline Form S of acalabrutinib can be converted to the crystalline Form S2 of acalabrutinib by exposing the crystalline Form S of acalabrutinib to temperature of l05°C for 4 days.
  • the XRPD pattern after exposure to temperature of l05°C for 4 days is found to comply with the Figure 5.
  • the crystalline Form S of acalabrutinib is found to be stable upon exposure to temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 1 month, and 2 months.
  • RH relative humidity
  • XRPD X-ray powder differaction pattern
  • the crystalline Form S of acalabrutinib can be converted to the crystalline Form S2 of acalabrutinib by exposing the crystalline Form S of acalabrutinib to temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 3 months.
  • the XRPD pattern after the exposure to temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 3 months is found to comply with the Figure 5.
  • a second aspect of the present invention provides a crystalline Form S2 of acalabrutinib.
  • the crystalline Form S2 of acalabrutinib is characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 8.4 ⁇ 0.2° 2Q, 9.9 ⁇ 0.2° 2Q, 16.9 ⁇ 0.2° 2Q, and 2l.6 ⁇ 0.2° 2Q; wherein the Form S2 of acalabrutinib is further characterized by absence of any peak at 7.8 ⁇ 0.2° 2Q.
  • the crystalline Form S2 of acalabrutinib is further characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 15.9 ⁇ 0.2° 2Q, 17.7 ⁇ 0.2° 2Q, 19.9 ⁇ 0.2° 2Q, 2l.l ⁇ 0.2° 2Q, 25.8 ⁇ 0.2° 2Q and 30.2 ⁇ 0.2° 2Q.
  • the crystalline Form S2 of acalabrutinib is characterized by an XRPD pattern substantially as shown in Figure 5.
  • the crystalline Form S2 of acalabrutinib is characterized by an
  • Table 2 provides the d-spacing values (A), the corresponding 2Q values, and the relative intensity of crystalline Form S2 of acalabrutinib.
  • the crystalline Form S2 of acalabrutinib is characterized by a differential scanning calorimetry (DSC) thermogram as shown in Figure 6 and having endothermic peaks at about l6l°C-l65°C.
  • DSC differential scanning calorimetry
  • the crystalline Form S2 of acalabrutinib is characterized by an XRPD pattern substantially as depicted in Figure 5, a DSC thermogram substantially as depicted in Figure 6, an IR absorption spectrum substantially as depicted in Figure 7, or a TGA substantially as depicted in Figure 8.
  • step b) optionally treating the solution of step a) with activated carbon and filtering the solution,
  • step c) heating the solution obtained from step a) or step b) at temperature from 40°C to reflux temperature of the solvent, d) slowly adding water to the solution of step c) maintaining temperature from 40°C to reflux temperature of the solvent,
  • step a) optionally treating the solution of step a) with activated carbon and filtering the solution while maintaining the temperature from 40°C to reflux temperature of the solvent,
  • the solvent is selected from the group consisting of alcohols, sulfoxides, ketones, nitriles, ethers, and mixtures thereof.
  • alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec- butanol, tert-butanol or n-pentanol.
  • sulfoxides include dimethylsulfoxide or sulfolane.
  • ketones include acetone, methyl ethyl ketone or methyl isobutyl ketone.
  • An example of nitrile is acetonitrile.
  • ethers examples include tetrahydrofuran, or l,4-dioxane. Wherever necessary, a mixture of solvent and water can be used. Thus, alcohols, sulfoxides, ketones, nitriles, or ethers can be used as solvent along with water.
  • alcohol is selected as a solvent. More preferably, the solvent selected is methanol, or a mixture of methanol and water.
  • the present invention provides a process for the preparation of crystalline acalabrutinib Form S2 comprising
  • step b) optionally treating the solution of step a) with activated carbon and filtering the solution,
  • step c) heating the solution obtained from step a) or step b) at temperature from 40°C to reflux temperature of methanol d) slowly adding water to the solution of step c) maintaining temperature from 40°C to reflux temperature of the methanol,
  • the present invention provides a process for the preparation of crystalline acalabrutinib Form S2 comprising
  • step a) dissolving acalabrutinib in a mixture of methanol and water by heating the solution at temperature from 40°C to reflux temperature of the solvent mixture b) optionally treating the solution of step a) with activated carbon and filtering the solution while maintaining the temperature from 40°C to reflux temperature of the solvent mixture,
  • acalabrutinib is contacted with a solvent at temperature of about
  • the temperature range selected is about 20°C to about 30°C.
  • the reaction solution of acalabrutinib in a solvent is heated to temperature of about 40°C to reflux temperature of the solvent.
  • temperature of about 40°C to reflux temperature of the solvent For example, if methanol is used as a solvent then the heating of the solution is performed at temperature of about 40°C to temperature of about 85°C.
  • de-ionized water is slowly added to the heated solution maintaining temperature of about 40°C to reflux temperature of the solvent.
  • temperature of about 40°C to reflux temperature of the solvent For example, if methanol is used as a solvent then the addition of water is performed at temperature of about 40°C to temperature of about 85°C.
  • the inventors of the present invention observed that addition of de-ionized water into the solution is crucial for obtaining the desired crystalline Form of acalabrutinib.
  • the inventors observed that if the addition of de-ionized water into the solution is performed at temperature of about 20°C to temperature of about 35°C, then the Form S of acalabrutinib is obtained. In case, if the addition of de-ionized water into the solution is performed at temperature from 40°C to reflux temperature of the solvent, then the Form S2 of acalabrutinib is obtained.
  • the reaction solution may be treated with activated carbon followed by filteration, before or after the heating step.
  • seed crystal of Form S2 of acalabrutinib may be added to the reaction solution.
  • the inventors of the present invention also observed that final polymorphic form of acalabrutinib depends upon the polymorphic form of the seed crystal added during the process, for example, if seed crystal of Form S2 of acalabrutinib is added into the solution (at cooling step) at temperature of about 20°C to temperature of about 35°C, then the final polymorphic form obtained is crystalline Form S2 of acalabrutinib.
  • the solution is cooled to temperature of about 20°C to temperature of about 35°C.
  • the crystalline Form S2 of acalabrutinib may be isolated by using any of the conventional techniques, for example, precipitation, crystallization, etc.
  • the crystalline Form S2 of acalabrutinib may be dried using any of the
  • drying is carried out at elevated temparature. In another embodiment, drying is carried out at temparature of about 25°C to about l00°C. In another embodiment, drying is carried out at temparature of about 30°C to about 80°C. In another embodiment, drying is carried out at temparature of about 40°C to about 60°C.
  • the dried material may optionally be micronized.
  • micronization is carried out using technique selected from the group consisting of ball milling, colloid milling, grinding milling, air jet milling, roller milling, and impact milling.
  • the crystalline Form S2 of acalabrutinib is found to be stable upon exposure at different temperatures (°C ) and relative humidity (RH) conditions, for example, at 25°C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days. At these temperatures and relative humidity conditions, there is no change found in the X-ray powder differaction pattern (XRPD) of the crystalline Form S2 of acalabrutinib with the initial XRPD Figure 5.
  • XRPD X-ray powder differaction pattern
  • the crystalline Form S2 of acalabrutinib is found to be stable upon exposure to temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 1 month, 2 months, and 3 months.
  • RH relative humidity
  • XRPD X-ray powder differaction pattern
  • the crystalline Form S and Form S2 of acalabrutinib of the present invention are highly pure, easy to filter, free-flowing solid having good thermodynamic stability, good solubility, residual solvent content in compliance with the ICH guidelines and prolonged shelf life.
  • Acalabrutinib used as a starting material in the present invention for the preparation of crystalline Form S and Form S2 may be prepared by methods known in the literature such as those described in U.S. Patent No. 9,290,504.
  • a third aspect of the present invention provides a pharmaceutical composition comprising crystalline Form S or Form S2 of acalabrutinib, and one or more
  • a fourth aspect of the present invention provides a method of treating mantle cell lymphoma (MCL) who have received at least one prior therapy, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising crystalline Form S or Form S2 of acalabrutinib.
  • MCL mantle cell lymphoma
  • XRPD of the samples were determined by using a PANalytical ® instrument; Model X’pert PRO; Detector: X’celerator ® .
  • DSC of the sample was recorded using a Mettler-Toledo ® 82 le instrument (for Form S of acalabrutinib), and Shimadzu DTG60A model instrument (for Form S2 of acalabrutinib).
  • IR of the samples were recorded using a PerkinElmer ® instrument, Model:
  • TGA was recorded using TA Q-500 instrument (for Form S of acalabrutinib), and Shimadzu DTG60A model instrument (for Form S2 of acalabrutinib).
  • Acalabrutinib (17 g) was added to methanol (170 mL) at 20-25 °C and stirred for 5 minutes to get a solution.
  • DI (deionized) water (68 mL) was added slowly at 20-25°C to the solution, followed by methanol (34 mL).
  • the reaction mass was heated to reflux and then stirred at 60-65 °C for 1 hour.
  • the reaction mass was filtered while hot, through filter paper to remove any foreign particles.
  • the filtrate was cooled at 20-25°C and then stirred for 3 hours to obtain a solid.
  • the solid obtained was collected by filtration and then washed with 25% aq. methanol (17 mL).
  • the wet solid was dried under vacuum at 40-45°C for 24 hours to obtain the titled compound.
  • Acalabrutinib (2 g) was added to 20% (v/v) aq. methanol (30 mL) at 20-25°C. The resulting mixture was stirred at 20-25°C for 0.5 hour and then heated at 60-65°C for 0.5 hour. The reaction mass was filtered while hot, to remove any foreign particles. The filtrate was cooled to a temperature of 45-50°C and then seeded with crystalline Form S (10 mg) obtained in example 1. The reaction mass was slowly cooled to a temperature of 20-25°C over a period of 2 hours. The reaction mass was further stirred for 3 hours to obtain a solid. The solid obtained was collected by filtration and then washed with ⁇ 20 % aq. methanol (2 mL). The wet solid was dried under vacuum at 40-45°C for 20 hours to obtain the titled compound.
  • Acalabrutinib (2g) was added to 20% Aq. Methanol (10 mL) at 20-25°C.
  • the resulting mixture was heated at temparature of 60-65°C for 0.5 hour to get clear solution.
  • the hot solution was filtered through filter paper, while hot to remove any foreign particles.
  • the filtrate was cooled slowly to a temparature of 20-25 °C over a period of 2 hours.
  • the reaction mass was stirred at 20-25 °C for further 3 hours to obtain a solid.
  • the solid obtained was filtered under vacuum to obtain a wet cake and the cake was washed with ⁇ 20% Aq. methanol (4 mL).
  • the wet solid was dried under vacuum at a temparature of 40- 45°C for 15 hours to obtain the titled compound.
  • Acalabrutinib (16 g) was added to aq. methanol (20 % v/v; 160 mL) at 20°C-25°C. The resulting mixture was heated to reflux at 60°C-65°C for 15 minutes - 20 minutes to get clear solution. Activated carbon (1.0 g) was added to the resulting and stirred at 60°C-
  • the reaction mass was filtered while hot, through hyflo- bed to remove foreign particle.
  • the filtrate was cooled to a temperature of 45°C-50°C and then stirred for 1.0 hour.
  • the reaction mass was slowly cooled to a temperature of 20°C- 25°C over a period of 2 hours and then further stirred for 2 hours to obtain a solid.
  • the solid obtained was collected by filtration under vacuum and washed with aq. methanol ( ⁇ 20 %; 2 mL). The wet solid was dried under vacuum at 40°C-45°C for 12 hours to obtain the titled compound.
  • Acalabrutinib (20.0 g) was added to methanol (120 mL) at 25°C-30°C and the mixture was stirred for 10 minutes at 25°C-30°C.
  • Activated carbon 2.0 g was added to the resulting mixture and stirred for another 30 minutes.
  • the contents were filtered through hyflo-bed to remove foreign particle and bed was washed with methanol (40 mL).
  • the filterate was heated to 50°C-55°C and DI (deionized) water (40 mL) was added slowly.
  • the reaction mass was stirred at 50°C-55°C for 30 minutes and then slowly cooled to 25°C-30°C.
  • the reaction mass was further stirred for 4 hours at 25°C-30°C to obtain a solid.
  • the solid obtained was collected by filtration and then washed with aq. methanol (-20% v/v; 20 mL) to afford a wet solid.
  • the wet solid obtained was divided into three equal parts and dried under varied temparature and atmospheric conditions as provided below.
  • the crystalline Form S of acalabrutinib was kept at different temperatures (°C) and relative humidity (RH) conditions, for example, at 25°C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
  • °C temperatures
  • RH relative humidity
  • the crystalline Form S of acalabrutinib was converted to the crystalline Form S2 of acalabrutinib when the crystalline Form S of acalabrutinib was exposed to temperature of l05°C for 4 days.
  • the crystalline Form S of acalabrutinib was kept at temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 1 month, and 2 months, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
  • the crystalline Form S of acalabrutinib was converted to the crystalline Form S2 of acalabrutinib when the crystalline Form S of acalabrutinib was kept at temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 3 months
  • the crystalline Form S2 of acalabrutinib was kept at temperature of 40 ⁇ 2°C at 75 ⁇ 5% relative humidity (RH) for 1 month, 2 months, and 3 months, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
  • RH relative humidity

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Abstract

The present invention relates to crystalline Form S and Form S2 of acalabrutinib, processes for their preparation, pharmaceutical composition comprising them, and their use for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Description

CRYSTALLINE POLYMORPHIC FORMS OF ACALABRUTINIB
Field of the Invention
The present invention relates to crystalline Form S and Form S2 of acalabrutinib, processes for their preparation, pharmaceutical composition comprising them, and their use for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
Background of the Invention
Acalabrutinib is chemically known as 4-{8-amino-3-[(2S)-l-(but-2- ynoyl)pyrrolidin-2-yl] imidazo [ 1 ,5 -a]pyrazin- 1 -yl) } -N-(pyridine-2-yl)benzamide and represented by the structural Formula I.
Figure imgf000002_0001
Formula I
Acalabrutinib is an inhibitor of Bruton tyrosine kinase (BTK) and it is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
U.S. Patent No. 9,290,504 discloses 4-imidazopyridazin-l-yl-benzamides and 4- imidazotriazin-l-yl-benzamides as Bruton’s tyrosine kinase (BTK) inhibitors.
U.S. Patent No. 9,796,721 allegedly describes anhydrates, hydrates and solvates of Acalabrutinib designated as Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, and amorphous form. The’721 patent further discloses various crystalline acid addition salts of acalabrutinib.
There is a need in the art to develop novel and stable polymorphic forms of acalabrutinib. Summary of the Invention
The present invention relates to crystalline Form S and Form S2 of acalabrutinib, and processes for their preparation. The present invention also relates to pharmaceutical composition comprising crystalline Form S or Form S2 of acalabrutinib. The present invention also provides use of crystalline Form S and Form S2 of acalabrutinib for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The crystalline Form S and Form S2 of acalabrutinib of the present invention are stable.
Brief Description of the Drawings
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form
S of acalabrutinib.
Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form S of acalabrutinib.
Figure 3 depicts an Infra-red (IR) spectrum of crystalline Form S of Acalabrutinib. Figure 4 depicts a Thermogravimetric analysis (TGA) of crystalline Form S of acalabrutinib.
Figure 5 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form S2 of acalabrutinib.
Figure 6 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form S2 of acalabrutinib.
Figure 7 depicts an Infra-red (IR) spectrum of crystalline Form S2 of acalabrutinib.
Figure 8 depicts a Thermogravimetric analysis (TGA) of crystalline Form S2 of acalabrutinib.
Detailed Description of the Invention
The term“about,” as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term“contacting,” as used herein, refers to dissolving, slurrying, stirring, suspending, or combinations thereof. A first aspect of the present invention provides a crystalline Form S of acalabrutinib.
In an embodiment, the crystalline Form S of acalabrutinib is characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 7.8±0.2° 2Q, 8.5±0.2° 2Q, 15.5±0.2° 2Q, and 16.9±0.2° 2Q.
In another embodiment, the crystalline Form S of acalabrutinib is further characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 9.9±0.2° 2Q, 12.1±0.2° 2Q, 13.2±0.2° 2Q, 17.8±0.2° 2Q, 20. l±0.2° 2Q, 22.2±0.2° 2Q, and 23.3±0.2° 2Q.
In an embodiment, the crystalline Form S of acalabrutinib is characterized by an
XRPD pattern substantially as shown in Figure 1.
In an embodiment, the crystalline Form S of acalabrutinib is characterized by an XRPD peak positions (±0.2° 2Q) and/or d-spacing values (A) substantially as shown in Table 1.
Table 1 provides the d-spacing values (A), the corresponding 2Q values, and the relative intensity of crystalline Form S of acalabrutinib.
Table 1
Figure imgf000004_0001
Figure imgf000005_0001
In an embodiment, the crystalline Form S of acalabrutinib is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peak at about 158.5°C.
The crystalline Form S of acalabrutinib is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an IR absorption spectrum substantially as depicted in Figure 3, or a TGA substantially as depicted in Figure 4.
Further embodiment provides a process for the preparation of crystalline acalabrutinib Form S comprising
a) dissolving acalabrutinib in a solvent,
b) adding water to the solution of step a) at 20°C to 35°C,
c) heating the solution of step b) at temperature from 40°C to reflux temperature of the solvent,
d) cooling the solution of step c), and
e) isolating crystalline acalabrutinib Form S from step d).
Further embodiment provides a process for the preparation of crystalline acalabrutinib Form S comprising
a) dissolving acalabrutinib in a mixture of solvent and water at 20°C to 35°C, b) heating the solution of step a) at temperature from 40°C to reflux temperature of the solvent,
c) optionally seeding the solution of step b) with crystalline acalabrutinib Form S, d) cooling the solution of step c), and
e) isolating crystalline acalabrutinib Form S from step d).
The crystalline Form S of acalabrutinib is prepared by dissolving acalabrutinib in a solvent.
The solvent is selected from the group consisting of alcohols, sulfoxides, ketones, nitriles, ethers and mixtures thereof. Examples of alcohols include methanol, ethanol, n- propanol, iso-propanol, n-butanol, sec-butanol, tert-butanol or n-pentanol. Examples of sulfoxides include dimethyl sulfoxide or sulfolane. Examples of ketones include acetone, methyl ethyl ketone or methyl isobutyl ketone. An example of nitrile is acetonitrile.
Examples of ethers include tetrahydrofuran, or l,4-dioxane. Wherever necessary, a mixture of solvent and water can be used. Thus, alcohols, sulfoxides, ketones, nitriles, or ethers can be used as solvent along with water. Preferably, alcohol is selected as a solvent. More preferably, the solvent selected is methanol, or a mixture of methanol and water.
In an embodiment, acalabrutinib is dissolved in a solvent at temperature of about 20°C to temperature of about 35°C. Preferably, the temperature range selected to dissolve acalabrutinib in a solvent is about 20°C to about 30°C.
In an embodiment, the solution of acalabrutinib in a solvent is heated to temperature of about 40°C to reflux temperature of the solvent. If methanol is used as a solvent then the heating of the solution is performed at temperature of about 40°C to temperature of about 85°C.
In an embodiment, seed crystal of Form S of acalabrutinib may be added to the solution. Preferably, the seed crystal of Form S of acalabrutinib is added to the solution to obtain pure crystalline Form S of acalabrutinib. More preferably, crystalline Form S of acalabrutinib having chromatographic purity of more than 99% is obtained by adding the seed crystal of Form S of acalabrutinib into the solution.
In an embodiment, the solution is cooled (step d) to temperature of about 20°C to temperature of about 35°C. The crystalline Form S of acalabrutinib may be isolated by any conventional techniques, for example, precipitation, crystallization, etc.
The crystalline Form S of acalabrutinib may be dried using conventional techniques, for example, drying under vacuum, spray drying, suck drying, air drying, or agitated thin fdm drying.
The dried material may optionally be micronized. In one embodiment, micronization is carried out using technique selected from the group consisting of ball milling, colloid milling, grinding milling, air jet milling, roller milling, and impact milling.
In an embodiment, the crystalline Form S of acalabrutinib is obtained by adding acalabrutinib in methanol, or methanol-water mixture at temperature of about 20°C to temperature of about 35°C. If necessary, water may be added to the methanol solution at temperature of about 20°C to temperature of about 35°C. The obtained solution is then heated at temperature from 40°C to reflux temperature of the methanol, or methanol-water solution. Whenever necessary during the process, the solution may be filtered. The seed crystals of Form S of acalabrutinib may be added to the heated solution, or else the solution is allowed to cool and then seed crystals may be added. The solution is then cooled to temperature of about 20°C to temperature of about 35°C. The cooling of the solution may be performed slowly, for example, over a time period of about 1 hour to 4 hours. The crystalline Form S of acalabrutinib, so obtained, may be isolated from the solution by any of the conventional isolation techniques.
The crystalline Form S of acalabrutinib is found to be stable upon exposure at different temperatures (°C ) and relative humidity (RH) conditions, for example, at 25°C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days. At these temperatures and relative humidity conditions, there is no change found in the X-ray powder differaction pattern (XRPD) of the crystalline Form S of acalabrutinib with the initial XRPD Figure 1.
The crystalline Form S of acalabrutinib can be converted to the crystalline Form S2 of acalabrutinib by exposing the crystalline Form S of acalabrutinib to temperature of l05°C for 4 days. The XRPD pattern after exposure to temperature of l05°C for 4 days is found to comply with the Figure 5.
Upon accelerated stability conditions, the crystalline Form S of acalabrutinib is found to be stable upon exposure to temperature of 40±2°C at 75±5% relative humidity (RH) for 1 month, and 2 months. At this temperature and relative humidity condition, there is no change found in the X-ray powder differaction pattern (XRPD) with the initial XRPD Figure 1.
The crystalline Form S of acalabrutinib can be converted to the crystalline Form S2 of acalabrutinib by exposing the crystalline Form S of acalabrutinib to temperature of 40±2°C at 75±5% relative humidity (RH) for 3 months. The XRPD pattern after the exposure to temperature of 40±2°C at 75±5% relative humidity (RH) for 3 months is found to comply with the Figure 5.
A second aspect of the present invention provides a crystalline Form S2 of acalabrutinib.
In another embodiment, the crystalline Form S2 of acalabrutinib is characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 8.4±0.2° 2Q, 9.9±0.2° 2Q, 16.9±0.2° 2Q, and 2l.6±0.2° 2Q; wherein the Form S2 of acalabrutinib is further characterized by absence of any peak at 7.8±0.2° 2Q.
In another embodiment, the crystalline Form S2 of acalabrutinib is further characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 15.9±0.2° 2Q, 17.7±0.2° 2Q, 19.9±0.2° 2Q, 2l.l±0.2° 2Q, 25.8±0.2° 2Q and 30.2±0.2° 2Q.
In an embodiment, the crystalline Form S2 of acalabrutinib is characterized by an XRPD pattern substantially as shown in Figure 5.
In an embodiment, the crystalline Form S2 of acalabrutinib is characterized by an
XRPD peak positions (±0.2° 2Q) and/or d-spacing values (A) substantially as shown in Table 2.
Table 2 provides the d-spacing values (A), the corresponding 2Q values, and the relative intensity of crystalline Form S2 of acalabrutinib.
Table 2
Figure imgf000008_0001
Figure imgf000009_0001
In an embodiment, the crystalline Form S2 of acalabrutinib is characterized by a differential scanning calorimetry (DSC) thermogram as shown in Figure 6 and having endothermic peaks at about l6l°C-l65°C.
The crystalline Form S2 of acalabrutinib is characterized by an XRPD pattern substantially as depicted in Figure 5, a DSC thermogram substantially as depicted in Figure 6, an IR absorption spectrum substantially as depicted in Figure 7, or a TGA substantially as depicted in Figure 8.
Further embodiment provides a process for the preparation of crystalline acalabrutinib Form S2 comprising
a) dissolving acalabrutinib in a solvent,
b) optionally treating the solution of step a) with activated carbon and filtering the solution,
c) heating the solution obtained from step a) or step b) at temperature from 40°C to reflux temperature of the solvent, d) slowly adding water to the solution of step c) maintaining temperature from 40°C to reflux temperature of the solvent,
e) cooling the solution of step d), and
f) isolating crystalline Form S2 of acalabrutinib from step e).
Further embodiment provides a process for the preparation of crystalline acalabrutinib Form S2 comprising
a) dissolving acalabrutinib in a mixture of solvent and water by heating the
solution at temperature from 40°C to reflux temperature of the solvent, b) optionally treating the solution of step a) with activated carbon and filtering the solution while maintaining the temperature from 40°C to reflux temperature of the solvent,
c) cooling the solution of step b), and
d) isolating crystalline Form S2 of acalabrutinib from step c).
In an embodiment, for the dissolution of acalabrutinib, the solvent is selected from the group consisting of alcohols, sulfoxides, ketones, nitriles, ethers, and mixtures thereof. Examples of alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec- butanol, tert-butanol or n-pentanol. Examples of sulfoxides include dimethylsulfoxide or sulfolane. Examples of ketones include acetone, methyl ethyl ketone or methyl isobutyl ketone. An example of nitrile is acetonitrile. Examples of ethers include tetrahydrofuran, or l,4-dioxane. Wherever necessary, a mixture of solvent and water can be used. Thus, alcohols, sulfoxides, ketones, nitriles, or ethers can be used as solvent along with water. Preferably, alcohol is selected as a solvent. More preferably, the solvent selected is methanol, or a mixture of methanol and water.
In a preferred embodiment, the present invention provides a process for the preparation of crystalline acalabrutinib Form S2 comprising
a) dissolving acalabrutinib in a methanol,
b) optionally treating the solution of step a) with activated carbon and filtering the solution,
c) heating the solution obtained from step a) or step b) at temperature from 40°C to reflux temperature of methanol d) slowly adding water to the solution of step c) maintaining temperature from 40°C to reflux temperature of the methanol,
e) cooling the solution of step d), and
f) isolating crystalline Form S2 of acalabrutinib from step e).
In another preferred embodiment, the present invention provides a process for the preparation of crystalline acalabrutinib Form S2 comprising
a) dissolving acalabrutinib in a mixture of methanol and water by heating the solution at temperature from 40°C to reflux temperature of the solvent mixture b) optionally treating the solution of step a) with activated carbon and filtering the solution while maintaining the temperature from 40°C to reflux temperature of the solvent mixture,
c) cooling the solution of step b), and
d) isolating crystalline Form S2 of acalabrutinib from step c).
In an embodiment, acalabrutinib is contacted with a solvent at temperature of about
20°C to temperature of about 35°C. Preferably, the temperature range selected is about 20°C to about 30°C.
In an embodiment, the reaction solution of acalabrutinib in a solvent is heated to temperature of about 40°C to reflux temperature of the solvent. For example, if methanol is used as a solvent then the heating of the solution is performed at temperature of about 40°C to temperature of about 85°C.
In an embodiment, de-ionized water is slowly added to the heated solution maintaining temperature of about 40°C to reflux temperature of the solvent. For example, if methanol is used as a solvent then the addition of water is performed at temperature of about 40°C to temperature of about 85°C.
The inventors of the present invention observed that addition of de-ionized water into the solution is crucial for obtaining the desired crystalline Form of acalabrutinib. The inventors observed that if the addition of de-ionized water into the solution is performed at temperature of about 20°C to temperature of about 35°C, then the Form S of acalabrutinib is obtained. In case, if the addition of de-ionized water into the solution is performed at temperature from 40°C to reflux temperature of the solvent, then the Form S2 of acalabrutinib is obtained. In an embodiment, the reaction solution may be treated with activated carbon followed by filteration, before or after the heating step.
In an embodiment, seed crystal of Form S2 of acalabrutinib may be added to the reaction solution.
The inventors of the present invention also observed that final polymorphic form of acalabrutinib depends upon the polymorphic form of the seed crystal added during the process, for example, if seed crystal of Form S2 of acalabrutinib is added into the solution (at cooling step) at temperature of about 20°C to temperature of about 35°C, then the final polymorphic form obtained is crystalline Form S2 of acalabrutinib.
In an embodiment, the solution is cooled to temperature of about 20°C to temperature of about 35°C.
The crystalline Form S2 of acalabrutinib may be isolated by using any of the conventional techniques, for example, precipitation, crystallization, etc.
The crystalline Form S2 of acalabrutinib may be dried using any of the
conventional techniques, for example, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
In an embodiment, drying is carried out at elevated temparature. In another embodiment, drying is carried out at temparature of about 25°C to about l00°C. In another embodiment, drying is carried out at temparature of about 30°C to about 80°C. In another embodiment, drying is carried out at temparature of about 40°C to about 60°C.
The dried material may optionally be micronized. In one embodiment, micronization is carried out using technique selected from the group consisting of ball milling, colloid milling, grinding milling, air jet milling, roller milling, and impact milling.
The crystalline Form S2 of acalabrutinib is found to be stable upon exposure at different temperatures (°C ) and relative humidity (RH) conditions, for example, at 25°C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days. At these temperatures and relative humidity conditions, there is no change found in the X-ray powder differaction pattern (XRPD) of the crystalline Form S2 of acalabrutinib with the initial XRPD Figure 5.
Upon accelerated stability conditions, the crystalline Form S2 of acalabrutinib is found to be stable upon exposure to temperature of 40±2°C at 75±5% relative humidity (RH) for 1 month, 2 months, and 3 months. There is no change in the X-ray powder differaction pattern (XRPD) found with the initial XRPD pattern Figure 5.
The crystalline Form S and Form S2 of acalabrutinib of the present invention are highly pure, easy to filter, free-flowing solid having good thermodynamic stability, good solubility, residual solvent content in compliance with the ICH guidelines and prolonged shelf life.
Acalabrutinib, used as a starting material in the present invention for the preparation of crystalline Form S and Form S2 may be prepared by methods known in the literature such as those described in U.S. Patent No. 9,290,504.
A third aspect of the present invention provides a pharmaceutical composition comprising crystalline Form S or Form S2 of acalabrutinib, and one or more
pharmaceutically acceptable carriers, diluents, or excipients.
A fourth aspect of the present invention provides a method of treating mantle cell lymphoma (MCL) who have received at least one prior therapy, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising crystalline Form S or Form S2 of acalabrutinib.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
Methods
Chromatographic purity was determined using Agilent 1200 series HPLC instrument with G1314B variable wavelength detector on Kromasil column C18
(250x4.60)mm, 5pm (for Form S of acalabrutinib), and Waters Alliance 2695 Separation module with 2487 Dual wavelength detector on Kromasil column C18 (250x4.60)mm,
5 pm HPLC instrument (for Form S2 of acalabrutinib).
XRPD of the samples were determined by using a PANalytical® instrument; Model X’pert PRO; Detector: X’celerator®.
DSC of the sample was recorded using a Mettler-Toledo® 82 le instrument (for Form S of acalabrutinib), and Shimadzu DTG60A model instrument (for Form S2 of acalabrutinib). IR of the samples were recorded using a PerkinElmer® instrument, Model:
Spectrum One potassium bromide pellet method.
TGA was recorded using TA Q-500 instrument (for Form S of acalabrutinib), and Shimadzu DTG60A model instrument (for Form S2 of acalabrutinib).
Water content of the samples were determined using Metrohm 795 KFT Titrino instrument.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPFES
Example 1 : Preparation of crystalline Form S of acalabrutinib
Acalabrutinib (17 g) was added to methanol (170 mL) at 20-25 °C and stirred for 5 minutes to get a solution. DI (deionized) water (68 mL) was added slowly at 20-25°C to the solution, followed by methanol (34 mL). The reaction mass was heated to reflux and then stirred at 60-65 °C for 1 hour. The reaction mass was filtered while hot, through filter paper to remove any foreign particles. The filtrate was cooled at 20-25°C and then stirred for 3 hours to obtain a solid. The solid obtained was collected by filtration and then washed with 25% aq. methanol (17 mL). The wet solid was dried under vacuum at 40-45°C for 24 hours to obtain the titled compound.
Yield: 77%
Chromatographic purity: 98.82%
Water content (KF): 4.99%
Example 2: Preparation of crystalline Form S of acalabrutinib
Acalabrutinib (2 g) was added to 20% (v/v) aq. methanol (30 mL) at 20-25°C. The resulting mixture was stirred at 20-25°C for 0.5 hour and then heated at 60-65°C for 0.5 hour. The reaction mass was filtered while hot, to remove any foreign particles. The filtrate was cooled to a temperature of 45-50°C and then seeded with crystalline Form S (10 mg) obtained in example 1. The reaction mass was slowly cooled to a temperature of 20-25°C over a period of 2 hours. The reaction mass was further stirred for 3 hours to obtain a solid. The solid obtained was collected by filtration and then washed with ~20 % aq. methanol (2 mL). The wet solid was dried under vacuum at 40-45°C for 20 hours to obtain the titled compound.
Yield: 70 %
Chromatographic purity: 99.60%
Water content (KF): 6.48%
Example 3: Preparation of crystalline Form S of acalabrutinib
Acalabrutinib (2g) was added to 20% Aq. Methanol (10 mL) at 20-25°C. The resulting mixture was heated at temparature of 60-65°C for 0.5 hour to get clear solution. The hot solution was filtered through filter paper, while hot to remove any foreign particles. The filtrate was cooled slowly to a temparature of 20-25 °C over a period of 2 hours. The reaction mass was stirred at 20-25 °C for further 3 hours to obtain a solid. The solid obtained was filtered under vacuum to obtain a wet cake and the cake was washed with ~ 20% Aq. methanol (4 mL). The wet solid was dried under vacuum at a temparature of 40- 45°C for 15 hours to obtain the titled compound.
Yield: 80 %
Chromatographic purity: 99.87%
Example 4: Preparation of crystalline Form S2 of acalabrutinib
Acalabrutinib (16 g) was added to aq. methanol (20 % v/v; 160 mL) at 20°C-25°C. The resulting mixture was heated to reflux at 60°C-65°C for 15 minutes - 20 minutes to get clear solution. Activated carbon (1.0 g) was added to the resulting and stirred at 60°C-
65 °C for 30 minutes - 40 minutes. The reaction mass was filtered while hot, through hyflo- bed to remove foreign particle. The filtrate was cooled to a temperature of 45°C-50°C and then stirred for 1.0 hour. The reaction mass was slowly cooled to a temperature of 20°C- 25°C over a period of 2 hours and then further stirred for 2 hours to obtain a solid. The solid obtained was collected by filtration under vacuum and washed with aq. methanol (~20 %; 2 mL). The wet solid was dried under vacuum at 40°C-45°C for 12 hours to obtain the titled compound.
Yield: 81%
Chromatographic purity: 99.63% Example 5: Preparation of crystalline Form S2 of acalabrutinib
Acalabrutinib (20.0 g) was added to methanol (120 mL) at 25°C-30°C and the mixture was stirred for 10 minutes at 25°C-30°C. Activated carbon (2.0 g) was added to the resulting mixture and stirred for another 30 minutes. The contents were filtered through hyflo-bed to remove foreign particle and bed was washed with methanol (40 mL). The filterate was heated to 50°C-55°C and DI (deionized) water (40 mL) was added slowly. The reaction mass was stirred at 50°C-55°C for 30 minutes and then slowly cooled to 25°C-30°C. The reaction mass was further stirred for 4 hours at 25°C-30°C to obtain a solid. The solid obtained was collected by filtration and then washed with aq. methanol (-20% v/v; 20 mL) to afford a wet solid. The wet solid obtained was divided into three equal parts and dried under varied temparature and atmospheric conditions as provided below.
a) The one part of wet solid (equal to 6.7g crude) was dried under vacuum at 40°C for 15 hours to obtain a dry solid.
Yield:78. l l%
HPLC Purity:99.77%
b) The second part of wet solid (equal to 6.7g crude) was dried under vacuum at 55°C for 15 hours to obtain a dry solid.
Yield: 70.75%
HPLC Purity:99.78%
c) The third part of wet solid (equal to 6.7g crude) was dried in air oven at 40°C for 15 hours to obtain a dried solid.
Yield: 70.90%
HPLC Purity: 99.79%
Stability Studies:
a) Exposure study of the crystalline Form S of acalabrutinib at different
temperatures and humidity conditions:
The crystalline Form S of acalabrutinib was kept at different temperatures (°C) and relative humidity (RH) conditions, for example, at 25°C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
The crystalline Form S of acalabrutinib was converted to the crystalline Form S2 of acalabrutinib when the crystalline Form S of acalabrutinib was exposed to temperature of l05°C for 4 days.
The results of the exposure study were tabulated below in Table 3.
Table 3
Figure imgf000017_0001
b) Stability study of the crystalline Form S of acalabrutinib at accelerated condition:
The crystalline Form S of acalabrutinib was kept at temperature of 40±2°C at 75±5% relative humidity (RH) for 1 month, and 2 months, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
The crystalline Form S of acalabrutinib was converted to the crystalline Form S2 of acalabrutinib when the crystalline Form S of acalabrutinib was kept at temperature of 40±2°C at 75±5% relative humidity (RH) for 3 months
The results of the accelerated study were tabulated below in Table 4.
Table 4
Figure imgf000017_0002
c) Exposure study of the crystalline Form S2 of acalabrutinib at different temperatures and humidity conditions: The crystalline Form S2 of acalabrutinib was kept at different temperatures (°C) and relative humidity (RH) conditions, for example, at 25 °C and 60% RH for 7 days, at 25°C and 80% RH for 7 days, at 40°C and 75% RH for 7 days, at 60°C for 7 days, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
The results of the exposure study were tabulated below in Table 5.
Table 5
Figure imgf000018_0001
d) Stability study of the crystalline Form S2 of acalabrutinib at accelerated
condition:
The crystalline Form S2 of acalabrutinib was kept at temperature of 40±2°C at 75±5% relative humidity (RH) for 1 month, 2 months, and 3 months, and found to have no change in the X-ray powder differaction pattern (XRPD) with the initial XRPD.
The results of the accelerated study were tabulated below in Table 6.
Table 6
Figure imgf000018_0002

Claims

Claims
1. A crystalline Form S of acalabrutinib characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 7.8±0.2° 2Q, 8.5±0.2° 2Q, 15.5±0.2° 2Q, and 16.9±0.2° 2Q.
2. The crystalline Form S of acalabrutinib of claim 1 further characterized by an X- ray powder diffraction pattern comprising peaks having 2Q values at 9.9±0.2° 2Q,
12.1±0.2° 2Q, 13.2±0.2° 2Q, 17.8±0.2° 2Q, 20. l±0.2° 2Q, 22.2±0.2° 2Q, and 23.3±0.2° 2Q.
3. The crystalline Form S of acalabrutinib of claim 1 characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peak at about 158.5 °C.
4. The crystalline Form S of acalabrutinib of claim 1 prepared by a process comprising
a) dissolving acalabrutinib in a solvent,
b) adding water to the solution of step a) at 20°C to 35°C,
c) heating the solution of step b) at temperature from 40°C to reflux temperature of the solvent,
d) cooling the solution of step c), and
e) isolating crystalline acalabrutinib Form S from step d).
5. The crystalline Form S of acalabrutinib of claim 1 prepared by a process
comprising
a) dissolving acalabrutinib in a mixture of solvent and water at 20°C to 35°C, b) heating the solution of step a) at temperature from 40°C to reflux temperature of the solvent,
c) optionally seeding the solution of step b) with crystalline acalabrutinib Form S, d) cooling the solution of step c), and
e) isolating crystalline acalabrutinib Form S from step d).
6. A crystalline Form S2 of acalabrutinib is characterized by an X-ray powder diffraction pattern comprising peaks having 2Q values at 8.4±0.2° 2Q, 9.9±0.2° 2Q, 16.9±0.2° 2Q, and 2l .6±0.2° 2Q; wherein the Form S2 of acalabrutinib is further characterized by absence of any peak at 7.8±0.2° 2Q.
7. The crystalline Form S2 of acalabrutinib of claim 6 further characterized by an X- ray powder diffraction pattern comprising peaks having 2Q values at 15.9±0.2° 2Q, 17.7±0.2° 2Q, 19.9±0.2° 2Q, 2l . l±0.2° 2Q, 25.8±0.2° 2Q and 30.2±0.2° 2Q.
8. The crystalline Form S2 of acalabrutinib of claim 6 characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about l6l°C- l65°C.
9. The crystalline acalabrutinib Form S2 of claim 6 prepared by a process comprising a) dissolving acalabrutinib in a solvent,
b) optionally treating the solution of step a) with activated carbon and filtering the solution,
c) heating the solution obtained from step a) or step b) at temperature from 40°C to reflux temperature of the solvent,
d) slowly adding water to the solution of step c) maintaining temperature from 40°C to reflux temperature of the solvent,
e) cooling the solution of step d), and
f) isolating crystalline Form S2 of acalabrutinib from step e).
10. The crystalline acalabrutinib Form S2 of claim 6 prepared by a process comprising a) dissolving acalabrutinib in a mixture of solvent and water by heating the solution at temperature from 40°C to reflux temperature of the solvent, b) optionally treating the solution of step a) with activated carbon and filtering the solution while maintaining the temperature from 40°C to reflux temperature of the solvent,
c) cooling the solution of step c), and
d) isolating crystalline Form S2 of acalabrutinib from step c).
PCT/IB2019/051201 2018-02-14 2019-02-14 Crystalline polymorphic forms of acalabrutinib WO2019159097A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020065667A1 (en) 2018-09-25 2020-04-02 Cipla Limited Novel polymorphs of acalabrutinib, a bruton's tyrosine kinase inhibitor
CN112028896A (en) * 2020-10-14 2020-12-04 奥锐特药业(天津)有限公司 Novel crystal form of acatinib and preparation method thereof
WO2021135346A1 (en) * 2019-12-31 2021-07-08 苏州科睿思制药有限公司 New crystal form of acalabrutinib, preparation method therefor and use thereof
WO2022234602A1 (en) * 2021-05-07 2022-11-10 Msn Laboratories Private Limited, R&D Center A process for the preparation of solid state forms of 4-{8-amino-3-[(2s)-1-(but-2-ynoyl) pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150174124A1 (en) * 2013-03-15 2015-06-25 Vm Pharma Llc Crystalline forms of tryosine kinase inhibitors and their salts
US20170029428A1 (en) * 2015-07-02 2017-02-02 Acerta Pharma B.V. Solid Forms and Formulations of Imidazopyrazine Compound
WO2017040304A1 (en) * 2015-08-28 2017-03-09 Cornell University Malt1 inhibitors and uses thereof
WO2018064797A1 (en) * 2016-10-05 2018-04-12 杭州领业医药科技有限公司 Crystal form of acp-196, preparation method therefor and pharmaceutical composition thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150174124A1 (en) * 2013-03-15 2015-06-25 Vm Pharma Llc Crystalline forms of tryosine kinase inhibitors and their salts
US20170029428A1 (en) * 2015-07-02 2017-02-02 Acerta Pharma B.V. Solid Forms and Formulations of Imidazopyrazine Compound
WO2017040304A1 (en) * 2015-08-28 2017-03-09 Cornell University Malt1 inhibitors and uses thereof
WO2018064797A1 (en) * 2016-10-05 2018-04-12 杭州领业医药科技有限公司 Crystal form of acp-196, preparation method therefor and pharmaceutical composition thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020065667A1 (en) 2018-09-25 2020-04-02 Cipla Limited Novel polymorphs of acalabrutinib, a bruton's tyrosine kinase inhibitor
WO2021135346A1 (en) * 2019-12-31 2021-07-08 苏州科睿思制药有限公司 New crystal form of acalabrutinib, preparation method therefor and use thereof
CN112028896A (en) * 2020-10-14 2020-12-04 奥锐特药业(天津)有限公司 Novel crystal form of acatinib and preparation method thereof
WO2022234602A1 (en) * 2021-05-07 2022-11-10 Msn Laboratories Private Limited, R&D Center A process for the preparation of solid state forms of 4-{8-amino-3-[(2s)-1-(but-2-ynoyl) pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide

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