Classifications

• • 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
• • 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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• This invention relates to a novel crystalline form of ibrutinib, and pharmaceutical compositions, methods of preparation, and method of uses thereof.
• Bruton's tyrosine kinase is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells and a key regulator of B-cell development, activation, signaling, and survival. It plays an essential role in the
• B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.
• BCR cell surface B-cell receptor
• BTK contributes to the proliferation and survival of B cells, which are the white blood cells that turn malignant in mantle cell lymphoma.
• Ibrutinib is the first BTK inhibitor approved by the U.S. Food and Drug
• Ibrutinib has a structure of formula (I), with a chemical name as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-
• ibrutinib Polymorphism of ibrutinib has been reported in WO2013184572, which discloses six crystalline forms of ibrutinib, including 3 anhydrous forms and 3 solvates (i.e., methyl isobutyl ketone solvate, toluene solvate, and methanol solvate, respectively), obtained through screening a large number of solvent systems, including their mixtures.
• the solvate forms are not suitable for use directly in dosage forms.
• the present invention provides a surprisingly discovered new crystalline form of ibrutinib having desired pharmacological properties, for example, higher stability and solubility and low hygroscopicity, which make it more suitable for use in dosage forms to achieve desired bioavailability and therapeutic effects.
• the crystalline form can also be prepared using simple process in a low cost.
• the present invention provides a crystalline form of ibrutinib, designated as Form I.
• the present invention provides process for preparation of ibrutinib
• the present invention provides pharmaceutical compositions comprising the crystalline Form I of ibrutinib and a pharmaceutically acceptable carrier.
• the present invention provides a method of using crystalline Form I of ibrutinib in the manufacture of a medicament for treatment of a disease or disorder in connection with BTK activities.
• the present invention provides a method of treating a disease or disorder in connection with BTK activities, comprising administering to a subject in need thereof a pharmaceutical composition comprising crystalline Form I of ibrutinib.
• FIG. 1 shows a representative X-ray powder diffraction (XRPD) pattern of crystalline Form I.
• FIG. 2 shows a representative differential scanning calorimetric (DSC) thermogram of crystalline Form I.
• FIG. 3 shows a representative thermal gravimetric analysis (TGA) thermogram of crystalline Form I.
• FIG 4 shows a representative dynamic vapor sorption (DVS) isotherm plot of crystalline Form I.
• FIG. 5 shows the change in the XRPD pattern of Form I when stored at 25 °C/60%
• the present invention provides a new crystalline form of ibrutinib, which has a higher solubility under physiological conditions than crystalline Form A of WO2013184572, and thus provides various advantages, such as enhanced bioavailability and reduced drug loading.
• the new crystalline form is physically and chemically stable, is not hygroscopic and does not become deliquescent at a high humidity, and is therefore convenient for long-term storage.
• the new crystalline form can be prepared using a simple process in a low cost, which is also highly valuable for further optimization and development of the drug in the future.
• the present invention provides a crystalline form of ibrutinib, designated as Form I.
• the crystalline Form I is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa radiation: 5.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• the crystalline Form I is characterized by an X-ray powder diffraction pattern further comprising the following 2 ⁇ values measured using CuKa radiation: 19.3° ⁇ 0.2°, 20.8° ⁇ 0.2°, and 22.4° ⁇ 0.2°.
• the crystalline Form I is characterized by an X-ray powder diffraction pattern further comprising the following 2 ⁇ values measured using CuKa radiation: 16.2° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 23.0° ⁇ 0.2°.
• the crystalline Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
• the crystalline Form I has a differential scanning calorimetric thermogram substantially as shown in FIG. 2, which exhibits an endothermic peak at about 135.1 °C.
• the crystalline Form I has a thermal gravimetric analysis thermogram substantially as shown in FIG. 3, which exhibits about 0.5% weight loss up to 120 °C, suggesting that the crystalline form is substantially unsolvated and anhydrous.
• the present invention provides a process for preparation of ibrutinib Form I, comprising: dissolving ibrutinib in alcohol, ether, or ketone, or a mixture or alcohol, ether, or ketone with an alkane; and crystallizing said Form I from the solution, either by equilibration under ambient conditions or by controlled cooling.
• said dissolving is conducted in a mixed solvent system comprising an alcohol and an alkane.
• said mixed solvent system comprises 2-propanol and n-heptane.
• the present invention provides solid pharmaceutical compositions comprising ibrutinib Form I.
• Form I of ibrutinib together with one or more pharmaceutically acceptable excipients of the present invention may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.
• the present invention provides a method for treating cancer in a mammal, comprising administering a therapeutically effective amount of ibrutinib Form I.
• the cancer is a B cell malignancy.
• the cancer is a B cell malignancy selected from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
• the present invention provides use of ibrutinib Form I in the manufacture of a medicament for the treatment of a disease or disorder related to BTK activities.
• the disease or disorder is a B cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• MCL mantle cell lymphoma
• DLBCL diffuse large B Cell lymphoma
• multiple myeloma multiple myeloma
• X-ray Powder diffraction Analytical Instrument: Panalytical Empyrean.
• the X-ray powder diffraction was conducted by mounting a sample of the crystalline material on a Si single crystal low-background holder and spreading out the sample into a thin layer with the aid of a microscope slide. The 2 ⁇ position was calibrated against Panalytical 640 Si powder standard.
• the collimated X-ray source was passed through a programmed divergence slit set at 10 mm and the reflected radiation directed through a 5.5 mm anti-scatter slit.
• the sample was exposed for 16.3 seconds per 0.013° 2-theta increment (continuous scan mode) over the range 3 degrees to 40 degrees 2-theta in theta-theta mode.
• the running time was 3 minutes and 57 seconds.
• the instrument was equipped with a RTMS detector (X'Celerator). Control and data capture was by means of a Dell Optiplex 780 XP operating with data collector software.
• Heating rate 10 °C per minute.
• Heating rate 10 °C per minute.
• Purge gas nitrogen.
• Dynamic Vapor Sorption was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C were calibrated against deliquescence point of LiCl, Mg(N0 3 )2 and KC1. Typical Parameters for DVS test are listed below.
• RH range 0% RH to 95% RH
• Hygroscopicity criteria applied in this example refer to the standard in European pharmacopoeia:
• deliquescent sufficient water is absorbed to form a liquid

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Hematology (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2013
  • 2013-11-27 CN CN201310616065.4A patent/CN103694241A/zh active Pending
• 2014
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