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WO2018148961A1 - Acp-196盐的晶型、其制备方法、药物组合物和用途 - Google Patents

Acp-196盐的晶型、其制备方法、药物组合物和用途 Download PDF

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WO2018148961A1
WO2018148961A1 PCT/CN2017/074087 CN2017074087W WO2018148961A1 WO 2018148961 A1 WO2018148961 A1 WO 2018148961A1 CN 2017074087 W CN2017074087 W CN 2017074087W WO 2018148961 A1 WO2018148961 A1 WO 2018148961A1
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acp
solvent
crystalline form
crystal
solution
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French (fr)
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盛晓红
盛晓霞
朱涛
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SOLIPHARMA LLC
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SOLIPHARMA LLC
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Priority to PCT/CN2017/074087 priority Critical patent/WO2018148961A1/zh
Priority to CN201780086288.0A priority patent/CN110312723B/zh
Priority to US16/487,324 priority patent/US10899770B2/en
Publication of WO2018148961A1 publication Critical patent/WO2018148961A1/zh
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    • 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
    • A61K31/4985—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
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B17/00—Sulfur; Compounds thereof
    • C01B17/69—Sulfur trioxide; Sulfuric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • 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 application relates to the field of medicinal chemical crystallization technology.
  • the present application relates to crystalline forms of ACP-196 salts, methods for their preparation, pharmaceutical compositions, and uses.
  • ACP-196 is a second-generation Bruton's tyrosine kinase (BTK) inhibitor that can be used to treat or prevent Bruton's tyrosine kinase-mediated disorders such as chronic lymphocytic leukemia (CLL).
  • BTK Bruton's tyrosine kinase
  • CLL chronic lymphocytic leukemia
  • the drug works by permanently binding to BTK.
  • BTK is part of a chain of protein chains that transmit growth signals from the surface of CLL cells to genes in the nucleus, allowing cancer cells to survive and grow. By blocking BTK, ACP-196 can stop the transmission of this growth signal and thus CLL cells die.
  • ACP-196 is 4-[8-amino-3-[(2S)-(1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5 -a] pyrazin-1-yl]-N-2-pyridinebenzamide, English name Acalabrutinib, CAS No. 1420477-60-6, the chemical structural formula of which is shown in the following (VI).
  • Patent Document CN103889987A reports the preparation of ACP-196 and discloses liquid chromatography mass spectrometry (LCMS) data for ACP-196.
  • LCMS liquid chromatography mass spectrometry
  • crystalline forms of ACP-196 salts as well as processes for their preparation, pharmaceutical compositions comprising the crystalline forms of the salts, and uses.
  • the crystalline form of the ACP-196 salt of the present invention should have one or more improved properties, particularly in higher crystallinity, lower moisture absorption, and better solubility, stability, formulation processability, and the like. aspect.
  • one of the contents of the present invention is to provide a crystalline form 1 of solid ACP-196 malate and a process for the preparation thereof.
  • the crystalline form 1 of the ACP-196 malate of the present invention is a compound formed by a molar ratio of ACP-196 and malic acid of 1:1, and its structural formula is as shown in the following formula (I):
  • the X-ray powder diffraction pattern of Form A of the ACP-196 malate at 2 ⁇ angle has the following characteristic peaks: 6.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 12.0° ⁇ 0.2 °, 12.4 ° ⁇ 0.2 °, 16.9 ° ⁇ 0.2 ° and 22.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 malate at a 2 ⁇ angle has the following characteristic peaks: 6.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 12.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.9° ⁇ 0.2°, 23.8° ⁇ 0.2° and 27.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form 1 of the ACP-196 malate salt expressed in 2 theta angle has the following characteristic peaks and their relative intensities:
  • a typical example of Form 1 of the ACP-196 malate has an XRPD pattern as shown in FIG.
  • TGA profile of Form 1 of the ACP-196 malate salt is shown in FIG.
  • Form 1 of the ACP-196 malate salt of the present invention has the following beneficial properties as compared to the prior art ACP-196 amorphous form:
  • the crystalline form 1 of the ACP-196 malate of the present invention has a plurality of advantageous properties as compared with the prior art ACP-196 amorphous, and is more suitable as an active ingredient of a pharmaceutical preparation.
  • the amorphous form is susceptible to the transformation of the crystal form, which affects the quality and stability of the drug.
  • the crystalline form 1 of ACP-196 malate is a crystalline solid, and the stability of the crystal form is obviously better. Crystalline solids have better fluidity and better processability (such as filtration, drying, weighing, sieving, etc.) in the manufacturing process of the drug, which is beneficial to improve the uniformity of the active ingredients and preparations of the drug.
  • Form A of ACP-196 malate has high solubility and higher bioavailability, and crystal form 1 of ACP-196 malate has lower hygroscopicity, which can better ensure the active ingredients of the drug itself and contain
  • the formulation form of Form 1 of ACP-196 malate prevents or reduces quality, safety and stability issues during the manufacture and/or storage of the drug, such as non-uniform content of active ingredients, impurities and the like. Avoid special and expensive packaging.
  • the invention provides a preparation method of crystal form 1 of ACP-196 malate, which comprises any one of the following methods:
  • ACP-196 and malic acid respectively formed a solution in a solvent, mixed, stirred and crystallized, and then separated crystals, dried to obtain the crystal form 1 of the ACP-196 malate;
  • the ACP-196 and the malic acid are selected from the same solvent to form a solution;
  • the solvent is an alcohol or a ketone, more preferably isopropanol;
  • the mass to volume ratio of the ACP-196 to a solvent to form a solution is 30 to 100 mg / mL, more preferably 30 to 50 mg / mL;
  • the molar ratio of the ACP-196 to malic acid is 1:0.8 to 1:1.1;
  • the stirring time is 1-2 days
  • the operation is carried out at room temperature
  • the good solvent is ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane or chloroform, more preferably tetrahydrofuran;
  • the mass to volume ratio of the ACP-196 to the good solvent is 20 to 100 mg/mL, more preferably 20 to 50 mg/mL;
  • the molar ratio of the ACP-196 to malic acid is 1:0.8 to 1:1.1;
  • the anti-solvent is an ether, an alkane or toluene, more preferably isopropyl ether;
  • the stirring time is 1-3 days
  • the operation is carried out at room temperature.
  • a second aspect of the present invention provides a crystalline form 1 of solid ACP-196 hemi-fumarate and a process for its preparation.
  • the crystalline form 1 of the ACP-196 hemi-fumarate of the present invention is a compound formed by a molar ratio of ACP-196 and fumaric acid of 2:1, and has the structural formula shown in the following formula (II):
  • the X-ray powder diffraction pattern of the crystal form 1 of the ACP-196 hemi-fumarate represented by 2 ⁇ angle has the following characteristic peaks: 4.9° ⁇ 0.2°, 9.8° ⁇ 0.2°, 10.8°. ⁇ 0.2°, 11.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 hemi-fumarate represented by 2 ⁇ angle has the following characteristic peaks: 4.9° ⁇ 0.2°, 7.1° ⁇ 0.2°, 9.8° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.2° ⁇ 0.2°, 16.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.0° ⁇ 0.2°, 23.2° ⁇ 0.2° , 24.9 ° ⁇ 0.2 ° and 28.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 hemi-fumarate represented by the 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • a typical example of the crystalline form 1 of the ACP-196 hemi-fumarate has an XRPD pattern as shown in FIG.
  • TGA profile of Form 1 of the ACP-196 hemifumarate is shown in FIG.
  • the crystalline form 1 of the ACP-196 hemi-fumarate of the present invention has the following beneficial properties:
  • the crystalline form 1 of the ACP-196 hemi-fumarate of the present invention has a plurality of advantageous properties as compared with the prior art ACP-196 amorphous, and is more suitable as an active ingredient of a pharmaceutical preparation.
  • Amorphous materials are susceptible to external crystal growth, which affects the quality and stability of the drug.
  • ACP-196 semi-fumarate crystal form 1 is a crystalline solid, and the crystal form stability is significantly better. Crystalline solids have better fluidity and better processability (such as filtration, drying, weighing, sieving, etc.) in the manufacturing process of the drug, which is beneficial to improve the uniformity of the active ingredients and preparations of the drug.
  • Form A of semi-fumarate of ACP-196 has high solubility and higher bioavailability, and crystal form 1 of ACP-196 hemi-fumarate has lower hygroscopicity and can better ensure drug activity.
  • the formulation itself and the formulation form of the semi-fumarate-containing ACP-196 Form 1 avoid or reduce the quality, safety and stability problems in the manufacture and/or storage of the drug, such as uneven content of active ingredients, impurities, etc. . Avoid special and expensive packaging.
  • the invention provides a preparation method of crystal form 1 of ACP-196 hemi-fumarate, which comprises any one of the following methods:
  • ACP-196 and fumaric acid respectively formed a solution in a solvent, mixed and stirred to crystallize, and then separated crystals, dried to obtain the crystal form 1 of the ACP-196 hemi-fumarate;
  • the ACP-196 and the fumaric acid are selected from the same solvent to form a solution;
  • the solvent is an alcohol or a ketone, more preferably acetone;
  • the mass to volume ratio of the ACP-196 and the solvent to form a solution is 40 to 200 mg / mL, more preferably 40 to 100 mg / mL;
  • the molar ratio of the ACP-196 to fumaric acid is 1:0.5 to 1:1.1;
  • the stirring time is 1-2 days
  • the operation is carried out at room temperature
  • ACP-196 and fumaric acid mixture is formed into a solution in a good solvent, an anti-solvent is added, stirred and crystallized, and then the crystal is separated and dried to obtain the crystal form 1 of the ACP-196 hemi-fumarate;
  • the good solvent is ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane or chloroform, more preferably 1,4-dioxane;
  • the mass to volume ratio of the ACP-196 to the good solvent is 20 to 100 mg/mL, more preferably 50 to 100 mg/mL;
  • the molar ratio of the ACP-196 to fumaric acid is 1:0.5 to 1:1.1;
  • the anti-solvent is an ether, an alkane or toluene, more preferably a diisopropyl ether
  • the stirring time is 1-3 days
  • the operation is carried out at room temperature.
  • a third aspect of the present invention provides a crystalline form 1 of solid ACP-196 maleate salt and a process for the preparation thereof.
  • the crystalline form 1 of the ACP-196 maleate salt of the present invention is a compound formed by a molar ratio of ACP-196 and maleic acid of 1:1, and its structural formula is as shown in the following formula (III):
  • the X-ray powder diffraction pattern of the crystal form 1 of the ACP-196 maleate salt represented by the 2 ⁇ angle has the following characteristic peaks: 5.3° ⁇ 0.2°, 9.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 maleate salt represented by the 2 ⁇ angle has the following characteristic peaks: 5.3° ⁇ 0.2°, 9.8° ⁇ 0.2° 10.5° ⁇ 0.2°, 11.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.3° ⁇ 0.2°, 19.8° ⁇ 0.2°, 22.8° ⁇ 0.2°, 24.4 ° ⁇ 0.2° and 24.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 maleate salt represented by the 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • a typical example of Form 1 of the ACP-196 maleate salt has an XRPD pattern as shown in FIG.
  • TGA profile of Form 1 of the ACP-196 maleate salt is shown in FIG.
  • Form 1 of the ACP-196 maleate salt of the present invention has the following beneficial properties as compared to the prior art ACP-196 amorphous form:
  • the crystalline form 1 of the ACP-196 maleate salt of the present invention has a plurality of advantageous properties as compared with the prior art ACP-196 amorphous, and is more suitable as an active ingredient of a pharmaceutical preparation.
  • Amorphous materials are susceptible to the transformation of crystal forms due to external factors, which in turn affects the quality and stability of the drug.
  • the crystalline form 1 of ACP-196 maleate is crystalline solid, and the crystal form stability is significantly better. Crystalline solids have better fluidity and better processability (such as filtration during drug manufacturing) Characteristics of drying, weighing, sieving, etc., are beneficial to improve the uniformity of the active ingredients and preparations of the drug.
  • Form A of ACP-196 maleate has high solubility and higher bioavailability, and Form 1 of ACP-196 maleate has lower hygroscopicity and better guarantees the active ingredient itself.
  • Formulation dosage forms containing Form 1 of ACP-19 maleate salt avoid or reduce quality, safety and stability issues during the manufacture and/or storage of the drug, such as non-uniform content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the present invention provides a process for the preparation of Form 1 of ACP-196 maleate salt, comprising any of the following methods:
  • ACP-196 and maleic acid are respectively formed into a solution in a solvent, mixed and stirred to crystallize, and then the crystal is separated and dried to obtain the crystal form 1 of the ACP-196 maleate;
  • the ACP-196 and the maleic acid select the same solvent to form a solution
  • the solvent is an alcohol or a ketone, more preferably isopropanol;
  • the mass to volume ratio of the ACP-196 to a solvent to form a solution is 30 to 100 mg / mL, more preferably 30 to 50 mg / mL;
  • the molar ratio of the ACP-196 to maleic acid is 1:0.8 to 1:1.1;
  • the stirring time is 1-2 days
  • the operation is carried out at room temperature
  • the good solvent is ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane or chloroform, more preferably tetrahydrofuran;
  • the mass to volume ratio of the ACP-196 to the good solvent is 20 to 100 mg/mL, more preferably 20 to 50 mg/mL;
  • the molar ratio of the ACP-196 to maleic acid is 1:0.8 to 1:1.1;
  • the anti-solvent is an ether, an alkane or toluene, more preferably n-heptane;
  • the stirring time is 1-3 days
  • the operation is carried out at room temperature.
  • a fourth aspect of the present invention provides a crystalline form 1 of solid ACP-196 phosphate and a process for its preparation.
  • the crystalline form 1 of the ACP-196 phosphate of the present invention is a compound formed by ACP-196, phosphoric acid and water at a molar ratio of 1:1:1.5, and has the structural formula shown in the following formula (IV):
  • the line powder diffraction pattern has the following characteristic peaks: 4.5 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 12.0 ° ⁇ 0.2 °, 14.3 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, and 21.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 phosphate represented by the 2 ⁇ angle has the following characteristic peaks: 4.5° ⁇ 0.2°, 6.0° ⁇ 0.2°, 10.4. ° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.5° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.9° ⁇ 0.2° and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form 1 of the ACP-196 phosphate in the 2 theta angle has the following characteristic peaks and their relative intensities:
  • a typical example of Form 1 of the ACP-196 phosphate has an XRPD pattern as shown in FIG.
  • TGA profile of Form 1 of the ACP-196 phosphate is shown in FIG.
  • Form 1 of the ACP-196 phosphate of the present invention has the following beneficial properties as compared to the prior art ACP-196 amorphous:
  • the crystalline form 1 of the ACP-196 phosphate of the present invention has various advantageous properties as compared with the prior art ACP-196 amorphous, and is more suitable as an active ingredient of a pharmaceutical preparation.
  • Amorphous materials are susceptible to external crystal growth, which affects the quality and stability of the drug.
  • ACP-196 phosphate crystal form 1 is a crystalline solid, and the crystal form stability is significantly better. Crystalline solids have better fluidity and better processability (such as filtration, drying, weighing, sieving, etc.) in the manufacturing process of the drug, which is beneficial to improve the uniformity of the active ingredients and preparations of the drug.
  • Form 1 of ACP-196 phosphate has high solubility and higher bioavailability, and crystal form 1 of ACP-196 phosphate has lower hygroscopicity, which can better ensure the active ingredients of the drug and contain ACP-
  • the formulation form of crystalline form 1 of 196 phosphate avoids or reduces problems in quality, safety and stability during the manufacture and/or storage of the drug, such as non-uniform content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the invention provides a preparation method of crystal form 1 of ACP-196 phosphate, which comprises any one of the following methods:
  • ACP-196 and phosphoric acid were respectively formed into a solution in a solvent, mixed and stirred to crystallize, and then the crystal was separated and dried to obtain crystal form 1 of the ACP-196 phosphate;
  • the ACP-196 and the phosphoric acid are selected from the same solvent to form a solution;
  • the solvent is an alcohol or a ketone, more preferably isopropanol;
  • the mass to volume ratio of the ACP-196 to a solvent to form a solution is 30 to 100 mg / mL, more preferably 30 to 50 mg / mL;
  • the molar ratio of the ACP-196 to phosphoric acid is 1:0.8 to 1:1.1;
  • the stirring time is 1-2 days
  • the operation is carried out at room temperature
  • ACP-196 is formed into a solution in a good solvent, added with phosphoric acid, added with anti-solvent, stirred and crystallized, and then separated crystals, dried to obtain crystal form 1 of the ACP-196 phosphate;
  • the good solvent is ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane or chloroform, more preferably dichloromethane;
  • the mass to volume ratio of the ACP-196 to the good solvent is 50 to 150 mg / mL, more preferably 50 to 100 mg / mL;
  • the molar ratio of the ACP-196 to phosphoric acid is 1:0.8 to 1:1.1;
  • the anti-solvent is an ether, an alkane or toluene, more preferably methylcyclohexane;
  • the stirring time is 1-3 days
  • the operation is carried out at room temperature.
  • a fifth aspect of the present invention provides a crystalline form 1 of solid ACP-196 sulfate and a process for its preparation.
  • the crystal form 1 of the ACP-196 sulfate of the present invention is a compound formed by a molar ratio of ACP-196 and sulfuric acid of 1:1, and its structural formula is as shown in the following formula (V):
  • the X-ray powder diffraction pattern of Form 1 of the ACP-196 sulfate in terms of 2 ⁇ angle has the following characteristic peaks: 8.9° ⁇ 0.2°, 9.7° ⁇ 0.2°, 17.5° ⁇ 0.2°. 19.6° ⁇ 0.2°, 21.9° ⁇ 0.2° and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form 1 of the ACP-196 sulfate represented by the 2 ⁇ angle has the following characteristic peaks: 4.6° ⁇ 0.2°, 7.9° ⁇ 0.2°, 8.9. ° ⁇ 0.2°, 9.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.9° ⁇ 0.2°, 23.6° ⁇ 0.2° and 25.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form 1 of the ACP-196 sulfate in the 2 theta angle has the following characteristic peaks and their relative intensities:
  • a typical example of Form 1 of the ACP-196 sulfate has an XRPD pattern as shown in FIG.
  • Form 1 of ACP-196 sulfate of the present invention has the following beneficial properties as compared to prior art ACP-196 amorphouss:
  • the crystalline form 1 of the ACP-196 sulfate of the present invention has various advantageous properties as compared with the prior art ACP-196 amorphous, and is more suitable as an active ingredient of a pharmaceutical preparation.
  • Amorphous materials are susceptible to external crystal growth, which affects the quality and stability of the drug.
  • ACP-196 sulfate crystal form 1 is a crystalline solid, and the crystal form stability is significantly better. Crystalline solids have better fluidity and better processability (such as filtration, drying, weighing, sieving, etc.) in the manufacturing process of the drug, which is beneficial to improve the uniformity of the active ingredients and preparations of the drug.
  • Form 1 of ACP-196 sulphate has a high solubility and a higher bioavailability.
  • the invention provides a preparation method of crystal form 1 of ACP-196 sulfate, which comprises any one of the following methods:
  • the ACP-196 and the sulfuric acid are selected from the same solvent to form a solution;
  • the solvent is an alcohol or a ketone, more preferably isopropanol;
  • the mass to volume ratio of the ACP-196 to a solvent to form a solution is 30 to 100 mg / mL, more preferably 30 to 50 mg / mL;
  • the molar ratio of the ACP-196 to sulfuric acid is 1:0.8 to 1:1.1;
  • the stirring time is 1-2 days
  • the operation is carried out at room temperature
  • ACP-196 is formed into a solution in a good solvent, added with sulfuric acid, added with an anti-solvent, stirred and crystallized, and then the crystal is separated and dried to obtain the crystal form 1 of the ACP-196 sulfate;
  • the good solvent is ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane or chloroform, more preferably ethyl acetate;
  • the mass to volume ratio of the ACP-196 to the good solvent is 10 to 50 mg/mL, more preferably 25 to 50 mg/mL;
  • the molar ratio of the ACP-196 to sulfuric acid is 1:0.8 to 1:1.1;
  • the anti-solvent is an ether, an alkane or toluene, more preferably n-hexane;
  • the stirring time is 1-3 days
  • the operation is carried out at room temperature.
  • the raw material "ACP-196 solid" may be a disclosed ACP-196 compound including an amorphous substance thereof, for example, but not limited to, any one of the reference patent documents CN103889987A. ACP-196 obtained by the preparation method. These patent documents are incorporated herein by reference in their entirety.
  • the "room temperature” means 10 to 30 °C.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation” can be carried out by conventional methods in the art, such as concentration under reduced pressure, evaporation, centrifugation or filtration. It is preferably filtered under reduced pressure or concentrated under reduced pressure, and is generally subjected to suction filtration or concentration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the "drying" can be accomplished by conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying; it can be reduced or at atmospheric pressure, preferably at a pressure of less than 0.09 MPa.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; it may be carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09 MPa.
  • crystalline means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRD pattern will typically vary slightly from instrument to sample. The difference in peak angle may vary by 1°, 0.8°, 0.5°, 03°, 0.1°, etc. depending on the instrument, and the error is usually ⁇ 0.2°, so the difference in peak angle cannot be the sole criterion.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows a certain offset.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present invention is within the scope of the present invention.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • the crystalline form of the ACP-196 salt of the present invention is substantially pure, unitary, and substantially free of any other crystalline or amorphous form.
  • substantially pure when used in reference to a new crystalline form means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% ( Weight), especially at least 99% by weight.
  • a sixth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the crystalline form of the ACP-196 salt of the present invention or by the present invention.
  • ACP-196 semi-fumarate crystal form 1, ACP-196 maleate salt form 1, ACP-196 phosphate form 1 and ACP-196 sulfate form 1.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable salts or crystal forms of ACP-196 and amorphous.
  • the dosage form of the compound used in the methods of the invention can be determined by the particular compound selected, the type of pharmacokinetic profile desired for the route of administration, and the condition of the patient.
  • the compounds of the present invention may be formulated for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, topical or rectal administration according to recognized methods in the pharmaceutical arts, and the formulations contain at least one active compound, preferably It is administered in unit dosage form for administration.
  • the human dose preferably contains 0.001 to 25 mg/kg body weight.
  • the pharmaceutical combination may be prepared into a certain dosage form depending on the route of administration or need, and may be solid or liquid.
  • Solid oral dosage forms including, for example, tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including, for example, solutions, syrups, suspensions, dispersions, and emulsions; injectable preparations including, for example, solutions, dispersions And lyophilizate.
  • the formulation may be suitable for immediate, sustained or controlled release of the active ingredient of the drug. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation.
  • Excipients in the pharmaceutical compositions are well known to those skilled in the art, and the choice of species, usage, and amount is well known to those skilled in the art.
  • examples include sugars, cellulose and its derivatives, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semi-solids such as lipids or paraffins, Mixtures such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, light anhydrous silicic acid, Crystalline cellulose, talc or magnesium stearate, disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry cornstarch, lubricants such as stearin Acid, magnesium stearate, sodium stearyl fumarate, polyethylene glyco
  • Suitable carriers include lactose, starch, sucrose, glucose, methylcellulose, and the like, or mixtures thereof, for use in suitable amounts.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmaceutically acceptable dispersing and/or wetting agents, such as propylene glycol or butylene glycol may be employed.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the crystalline form of the ACP-196 salt of the present invention (form of ACP-196 malate, crystal form of ACP-196 hemi-fumarate 1, ACP-196 maleate) Form 1, Form 1 of ACP-196 Phosphate and Form 1 of ACP-196 Sulfate are mixed with one or more pharmaceutically acceptable excipients, optionally with pharmaceutically acceptable ACP
  • Other crystalline forms, salt forms, amorphous forms of -196 are mixed, optionally in admixture with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the active ingredient may be presented in discrete units such as tablets, capsules, powders, granules, solutions, suspensions and the like.
  • compositions of the invention may be presented in unit or multi-dose containers, such as a predetermined amount of injectable liquid, such as in a sealed vial or ampule, or in lyophilized (frozen) Dry) conditions.
  • a seventh aspect of the present invention provides a crystalline form of the ACP-196 salt of the present invention or a crystalline form of the ACP-196 salt obtained by the process of the present invention for the preparation or treatment of a tyrosine kinase such as Bruce Use of a tyrosine kinase (BTK) mediated drug in a disease or condition.
  • the crystal form of the ACP-196 salt of the present invention includes the crystal form of ACP-196 malate, the crystal form of ACP-196 hemi-fumarate, and the crystal form of ACP-196 maleate. Form 1 of ACP-196 phosphate and Form 1 of ACP-196 sulfate.
  • the BTK-mediated disease or condition refers to any disease state or other deleterious condition that is primarily responsible for B cells, mast cells, bone marrow cells, or osteoclasts. These diseases include, but are not limited to, immune, autoimmune and inflammatory diseases, allergies, infectious diseases, bone resorption disorders, and proliferative diseases.
  • the immune, autoimmune and inflammatory diseases include, but are not limited to, for example, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, infectious arthritis, progressive chronic arthritis, teratogenicity Arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, traumatic arthritis, gouty arthritis, Reiter syndrome, autoimmune Addison's disease, polychondritis, acute synovitis and spondylitis, etc.
  • Glomerulonephritis autoimmune blood system disorders such as autoimmune hemolytic anemia, aplastic anemia, autoimmune thrombocytopenic purpura (ATP), autoimmune lymphocytosis syndrome (ALPS), and neutrophils Reduced, autoimmune hepatitis, autoimmune gastritis and autoimmune inflammatory bowel disease (eg ulcerative colitis and Crohn's disease), graft versus host disease, allograft rejection, thyroid dysfunction, bridge This thyroiditis, Graves'disease, scleroderma, diabetes (types I and II), active hepatitis (acute and chronic), pancreatitis, primary bile Juice cirrhosis, acquired immunodeficiency syndrome (AIDS), endometriosis, myasthenia gravis, chronic fatigue immune syndrome (CFIDS), pernicious anemia, nodular polyarteritis, polychondritis, multiple Glandular syndrome, rheumatic polymyopathy, polymyositis and dermatomy
  • Allergies that can be treated or prevented include, for example, allergies to food, food additives, insect toxins, mold, dust mites, pollen, animal materials, drugs and metals, type I hypersensitivity, allergic asthma, allergic rhinitis, allergies Conjunctivitis or specific dermatitis.
  • Infectious diseases that can be treated or prevented include, but are not limited to, for example, sepsis, septic shock, endotoxic shock, sepsis caused by Gram-negative bacteria, Shigella, meningitis, pleura Inflammation, malaria, pneumonia, bronchitis, tuberculosis, endocarditis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), nephritis, HIV infection, tendinitis, retinitis, influenza, Herpes, measles, whooping cough, enteritis, infections associated with severe burns, myalgia caused by infection, cachexia secondary to infection, and infections caused by animal viruses.
  • Bone resorption conditions that can be treated or prevented include, for example, osteoporosis, osteoarthritis, traumatic arthritis, gouty arthritis, and bone disorders associated with multiple myeloma.
  • Proliferative diseases that can be treated or prevented include, for example, B cell proliferative diseases such as diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular cell lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia , B-cell pro-lymphocytic leukemia, acute lymphocytic leukemia (ALL), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, marginal lymphoma, hairy cell leukemia, plasma cell myeloma, plasmacytoma, Extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, diffuse mixed cell and large cell lymphoma, mediastinal (thymus) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudation Lymphoma, Burkitt's lymphoma/leukemia or lymphomatoid granulomatosis
  • a method of treating and/or preventing a Bruton's tyrosine kinase (BTK) mediated disease comprising administering to a patient in need thereof a prophylactic, inhibitory and/or therapeutically effective amount selected from the invention Crystalline form of ACP-196 malate, crystal form of ACP-196 hemi-fumarate 1, crystal form of ACP-196 maleate 1, crystal form 1 of ACP-196 phosphate and ACP-196 sulfuric acid Form 1 of the salt or crystal form containing the ACP-196 malate of the present invention 1, crystal form of ACP-196 hemifumarate, crystal form of ACP-196 maleate 1, and phosphate of ACP-196
  • the aforementioned pharmaceutical composition of Form 1 of crystal form 1 and ACP-196 sulfate; the disease is as described above in the present specification.
  • the effective amount such as a human dose for parenteral administration, preferably contains from 0.001 to 25 mg/kg body weight.
  • the desired dose can be
  • Figure 2 is a TGA map of ACP-196 amorphous material prepared by reference to CN103889987A
  • Figure 3 is a reference to the PLM map of ACP-196 amorphous form prepared by CN103889987A
  • Figure 4 is an isotherm adsorption curve of ACP-196 amorphous material prepared by reference to CN103889987A
  • Figure 5 is an XRPD pattern of Form 1 of ACP-196 malate prepared by the present invention.
  • Figure 7 is a DSC spectrum of Form 1 of ACP-196 malate prepared by the present invention.
  • Figure 8 is a PLM map of Form 1 of ACP-196 malate prepared by the present invention.
  • Figure 12 is a DSC spectrum of Form 1 of ACP-196 hemifumarate prepared by the present invention.
  • Figure 13 is a PLM map of Form 1 of ACP-196 hemi-fumarate prepared by the present invention.
  • Figure 14 isotherm adsorption curve of crystal form 1 of ACP-196 hemi-fumarate prepared by the present invention
  • Figure 16 is a TGA map of Form 1 of ACP-196 maleate salt prepared by the present invention.
  • Figure 17 is a DSC spectrum of Form 1 of ACP-196 maleate salt prepared by the present invention.
  • Figure 18 is a PLM map of Form 1 of ACP-196 maleate salt prepared by the present invention.
  • Figure 19 isotherm adsorption curve of crystal form 1 of ACP-196 maleate prepared by the present invention
  • Figure 22 is a DSC spectrum of Form 1 of ACP-196 phosphate prepared by the present invention.
  • Figure 23 is a PLM map of Form 1 of ACP-196 phosphate prepared by the present invention.
  • Figure 24 isotherm adsorption curve of crystal form 1 of ACP-196 phosphate prepared by the present invention
  • Figure 25 is an XRPD pattern of Form 1 of ACP-196 sulfate prepared by the present invention.
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • Polarized light microscopy (PLM) spectra were taken from XP-500E polarized light microscopy. Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to disperse the sample, cover the cover glass, place it on the stage for observation and take a picture.
  • PLM Polarized light microscopy
  • Differential thermal analysis data was taken from a TA Instruments Q200 DSC.
  • the detection method is as follows: 1 to 10 mg of the sample is placed in a small-pore aluminum crucible, and the sample is raised from room temperature to 200 ° C under the protection of 40 mL/min dry N 2 at a heating rate of 10 ° C/min.
  • Thermogravimetric analysis data was taken from the TA Instruments Q500 TGA.
  • the detection method is as follows: 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to a temperature of 10 ° C/min under the protection of 40 mL/min dry N 2 by means of segmented high-resolution detection. 350 ° C.
  • Dynamic moisture adsorption analysis data and isothermal adsorption analysis data were taken from the TA Instruments Q5000 TGA.
  • the detection method is as follows: 1 to 10 mg of the sample is placed in a platinum crucible, and the change in weight during the change of relative humidity from 0% to 80% to 0% is detected.
  • Nuclear magnetic resonance spectroscopy ( 1 H-NMR) data was obtained from a Bruker Avance II DMX 500 MHZ NMR spectrometer. A sample of 1 to 10 mg was weighed and dissolved in a nuclear magnetic sample tube with about 0.5 mL of deuterated reagent for detection.
  • ion chromatograph (IC) data was taken from Dionex ICS-900, and the workstation and analysis software were all Chromeleon Console.
  • the external standard method was used for ion content detection.
  • ACP-196 solid was prepared according to the method of Example 6 in CN103889987A. Data: LCMS (B) Rt: 2.08 min; m/z 466.1 (M+H) + .
  • ACP-196 is mixed with malic acid at a molar ratio of about 1:1.
  • Form 1 of ACP-196 malate was obtained by replacing the solvent of Example 3 with the following table.
  • Form 1 of ACP-196 malate was obtained by replacing the solvent in Example 7 with the following table.
  • the samples prepared in Examples 2 to 8 had the same or similar 1 H-NMR data (not shown), an XRPD pattern (not shown), a PLM map (not shown), and a TGA map (the sample of Example 1). Not shown), DSC pattern (not shown), isothermal adsorption pattern (not shown), indicating that the samples of Examples 2-8 are the same crystalline form of the same compound as the sample of Example 1.
  • ACP-196 is mixed with fumaric acid at a molar ratio of about 2:1.
  • the TGA spectrum is shown in Figure 11 and is shown as an anhydride with a decomposition temperature of about 170 °C.
  • the isothermal adsorption curve is shown in Fig. 14, showing a weight change of 1.2% in the range of 30% to 80% relative humidity.
  • Form 1 of ACP-196 hemi-fumarate was obtained by replacing the solvent in Example 11 with the following table.
  • ACP-196 of Preparation Example 1 Take 200 mg of ACP-196 of Preparation Example 1 and 24.9 mg of fumaric acid, add 4 mL of 1,4-dioxane to form a solution, add 6 mL of isopropyl ether, stir and crystallize, and after 1 day, filter, and vacuum dry at room temperature for 24 hours. 198 mg of ACP-196 hemi-fumarate salt form 1 was obtained in a yield of 88%.
  • Form 1 of ACP-196 hemi-fumarate was obtained by replacing the solvent of Example 15 with the following table.
  • the samples prepared in Examples 10 to 16 had the same or similar 1 H-NMR data (not shown), an XRPD pattern (not shown), a PLM map (not shown), and a TGA map (the sample of Example 9). Not shown), DSC pattern (not shown), isothermal adsorption profile (not shown), indicating that the samples of Examples 10-16 and the sample of Example 9 are the same crystalline form of the same compound.
  • the TGA spectrum is shown in Figure 16 and is shown as an anhydride with a decomposition temperature of about 125 °C.
  • the isothermal adsorption curve is shown in Fig. 19, showing a weight change of 0.4% in the range of 30% to 80% relative humidity.
  • Form 1 of ACP-196 maleate salt was obtained by replacing the solvent of Example 19 with the following table.
  • Form 1 of ACP-196 maleate salt was obtained by replacing the solvent in Example 23 with the following table.
  • the samples prepared in Examples 18 to 24 had the same or similar 1 H-NMR data (not shown), an XRPD pattern (not shown), a PLM map (not shown), and a TGA map (the sample of Example 17). Not shown), DSC pattern (not shown), isothermal adsorption profile (not shown), indicating that the samples of Examples 18-24 were the same crystalline form of the same compound as Example 17.
  • the phosphate content of ACP-196 phosphate is 20.1%
  • the theoretical content of monophosphate phosphate is 16.9%
  • the theoretical content of bisphosphonate phosphate is 28.7%. Therefore, the molar ratio of ACP-196 to phosphoric acid is about 1:1 salt.
  • the TGA spectrum is shown in Figure 21, combined with a 4.3% step weight loss as a sesquihydrate, and a decomposition temperature of about 198 °C.
  • the isothermal adsorption curve is shown in Fig. 24, showing a weight change of 4.2% in the range of 30% to 80% relative humidity.
  • Form 1 of ACP-196 phosphate was obtained by replacing the solvent in Example 27 with the following table.
  • Form 1 of ACP-196 phosphate can be obtained by replacing the solvent in Example 31 with the following table.
  • the samples prepared in Examples 26 to 32 had the same or similar IC data (not shown), XRPD pattern (not shown), PLM map (not shown), TGA map (not shown). ), DSC pattern (not shown), isothermal adsorption pattern (not shown), indicating that the samples of Examples 26 to 32 and the sample of Example 25 were the same crystalline form of the same compound.
  • the sulfate content of ACP-196 sulfate is 18.2%
  • the theoretical content of monosulfate sulfate is 17.0%
  • the theoretical content of disulfate sulfate is 29.0%. Therefore, the molar ratio of ACP-196 to sulfuric acid is about 1:1 salt.
  • Form 1 of ACP-196 sulfate was obtained by replacing the solvent in Example 35 with the following table.
  • ACP-196 of Preparation Example 1 50 mg was added, 2 mL of ethyl acetate was added to form a solution, 8.6 mg of concentrated sulfuric acid was added dropwise, 3 mL of n-hexane was added thereto, and the mixture was stirred and crystallized. After 1 day, it was filtered, and dried under vacuum at room temperature for 24 hours to obtain 40 mg of ACP- Form 1 of 196 sulfate, yield 81%.
  • Form 1 of ACP-196 sulfate was obtained by replacing the solvent in Example 39 with the following table.
  • the samples prepared in Examples 34 to 40 had the same or similar IC data (not shown) and XRPD patterns (not shown) as the samples of Example 33, indicating that the samples of Examples 34 to 40 and Example 33 were The same crystalline form of the same compound.
  • Compressible starch The microcrystalline cellulose and the crospovidone are mixed, then the mixture is lubricated by silica, and finally compressed into tablets.
  • Ethyl fiber Mix ethyl cellulose, hydroxypropylmethylcellulose, lactose and microcrystalline cellulose, granulate with 75% ethanol, dry, pulverize, pass through 80 mesh sieve, then add magnesium stearate and talc to mix , filled into the capsule.
  • Apparent solubility test 20 mg of ACP-196 of Preparation Example 1, crystal form of ACP-196 malate of the present invention, and crystal form of ACP-196 hemifumarate of the present invention were respectively taken under a 25 ° C water bath condition. 1.
  • the test results are shown in the table below.

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Abstract

本发明涉及ACP-196（Acalabrutinib）盐的晶型，与已知的ACP-196固体形式相比，本发明盐的晶型在结晶度、溶解度、吸湿性等方面具有优势。本发明还涉及所述ACP-196盐的晶型的制备方法，其药物组合物及其在制备用于治疗和/或预防布鲁顿酪氨酸激酶（BTK）介导的病症如自身免疫性疾病或病症、异种免疫性疾病或病症、癌症包括淋巴瘤以及炎性疾病或病症的方法中的用途。

Description

ACP-196盐的晶型、其制备方法、药物组合物和用途 技术领域
本申请涉及药物化学结晶技术领域。具体而言，本申请涉及ACP-196盐的晶型、其制备方法、药物组合物和用途。
背景技术
ACP-196是第二代布鲁顿氏酪氨酸激酶(BTK)抑制剂，可用于治疗或预防布鲁顿酪氨酸激酶介导的病症如慢性淋巴细胞白血病(CLL)。该药物通过持久地结合BTK而发挥作用。BTK是一连串蛋白链的一部分，该蛋白链将生长信号从CLL细胞表面传播到细胞核内的基因，使得癌症细胞得以生存和生长。通过阻断BTK，ACP-196可以使该生长信号的传递停止因而CLL细胞死亡。
ACP-196化学名称为4-[8-氨基-3-[(2S)-(1-(1-氧-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶苯甲酰胺，英文名为Acalabrutinib，CAS号1420477-60-6，其化学结构式如下(VI)所示。
Figure PCTCN2017074087-appb-000001
专利文献CN103889987A报道了ACP-196的制备方法，并公开了ACP-196的液相色谱质谱联用(LCMS)数据。本发明人研究发现，按照CN103889987A中实施例6的制备方法得到的ACP-196为黄色无定型物，其具有晶型不稳定、易吸湿、流动性差、溶解度低的缺点。专利文献CN103889987A中还提及无定型、多种晶型和盐型等物理形式都在其保护范围之内，但该专利并没有提供任何这些物理形式的特征性数据，因此不能作为充分的公开内容。
鉴于现有技术尚存不足，本领域仍需要开发具有更多改进性能的结晶态的ACP-196盐及其晶型，以满足药物制剂对于活性物质的形态、溶解度、稳定性等物化性质的严格要求。
发明内容
针对现有技术的不足，本发明的目的是提供ACP-196盐的晶型以及它们的制备方法、包含所述盐的晶型的药物组合物和用途。本发明的ACP-196盐的晶型应具有一种或多种改进的特性，特别是表现在更高的结晶度、更低地吸湿性、以及更好地溶解度、稳定性、制剂可加工性等方面。
根据本发明目的，本发明的内容之一是提供固态的ACP-196苹果酸盐的晶型1及其制备方法。
本发明的ACP-196苹果酸盐的晶型1，是由ACP-196和苹果酸以摩尔比为1:1形成的化合物，其结构式如下式(I)所示：
Figure PCTCN2017074087-appb-000002
使用Cu-Kα辐射，所述ACP-196苹果酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.2°±0.2°、8.9°±0.2°、12.0°±0.2°、12.4°±0.2°、16.9°±0.2°和22.9°±0.2°。
在本发明优选的一个实施方案中，所述ACP-196苹果酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.2°±0.2°、8.9°±0.2°、12.0°±0.2°、12.4°±0.2°、15.6°±0.2°、16.9°±0.2°、19.6°±0.2°、20.3°±0.2°、20.7°±0.2°、22.9°±0.2°、23.8°±0.2°和27.6°±0.2°。
在本发明进一步优选的一个实施方案中，所述ACP-196苹果酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2017074087-appb-000003
非限制性地，所述ACP-196苹果酸盐的晶型1的一个典型实例具有如图5所示的XRPD图谱。
非限制性地，所述ACP-196苹果酸盐的晶型1的TGA图谱如图6所示。
非限制性地，所述ACP-196苹果酸盐的晶型1的DSC图谱如图7所示。
非限制性地，所述ACP-196苹果酸盐的晶型1的PLM图谱如图8所示。
非限制性地，所述ACP-196苹果酸盐的晶型1的等温吸附曲线如图9所示。
与现有技术的ACP-196无定型物相比，本发明的ACP-196苹果酸盐的晶型1具有以下有益性质：
1)由XRPD图谱和PLM图谱可知，ACP-196苹果酸盐的晶型1为结晶态固体，结晶度高、稳定性好；
2)由等温吸附曲线可知，ACP-196苹果酸盐的晶型1和ACP-196无定型物在30％～80％相对湿度范围内重量变化分别为1.5％和5.5％，本发明的ACP-196苹果酸盐的晶型1更不易吸湿。
3)由对比例1可知，ACP-196苹果酸盐的晶型1比ACP-196无定型物具有更高的溶解度。
上述有益性质表明：与现有技术的ACP-196无定型物相比，本发明的ACP-196苹果酸盐的晶型1具有多种优势性能，更适合作为药物制剂的活性成分。无定型物易受外来因素影响发生晶型转化，进而影响药物的质量和稳定性，而ACP-196苹果酸盐的晶型1为结晶态固体，晶型稳定性明显更优。结晶态固体具有更好的流动性和更优良的可加工性(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高药物活性成分和制剂的均一性。ACP-196苹果酸盐的晶型1溶解度大，具有更高的生物利用率，且ACP-196苹果酸盐的晶型1具有更低的吸湿性，能够更好地保证药物活性成分自身和含有ACP-196苹果酸盐的晶型1的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
本发明提供ACP-196苹果酸盐的晶型1的制备方法，包括以下方法中的任意一种：
1)分别将ACP-196和苹果酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196苹果酸盐的晶型1；
优选地，所述ACP-196与苹果酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
优选地，所述ACP-196与苹果酸的摩尔比为1:0.8～1:1.1；
优选地，所述搅拌时间为1～2天；
优选地，所述操作过程在室温下进行；
2)将ACP-196和苹果酸的混合物在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196苹果酸盐的晶型1；
优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为四氢呋喃；
优选地，所述ACP-196与良溶剂的质量体积比为20～100mg/mL，更优选为20～50mg/mL；
优选地，所述ACP-196与苹果酸的摩尔比为1:0.8～1:1.1；
优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为异丙醚；
优选地，所述搅拌时间为1～3天；
优选地，所述操作过程在室温下进行。
根据本发明目的，本发明的内容之二是提供固态的ACP-196半富马酸盐的晶型1及其制备方法。
本发明的ACP-196半富马酸盐的晶型1，是由ACP-196和富马酸以摩尔比为2:1形成的化合物，其结构式如下式(II)所示：
Figure PCTCN2017074087-appb-000004
使用Cu-Kα辐射，所述ACP-196半富马酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.9°±0.2°、9.8°±0.2°、10.8°±0.2°、11.6°±0.2°、16.1°±0.2°和24.9°±0.2°。
在本发明优选的一个实施方案中，所述的ACP-196半富马酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.9°±0.2°、7.1°±0.2°、9.8°±0.2°、10.8°±0.2°、11.6°±0.2°、12.2°±0.2°、16.1°±0.2°、20.2°±0.2°、22.0°±0.2°、23.2°±0.2°、24.9°±0.2°和28.2°±0.2°。
在本发明进一步优选的一个实施方案中，所述ACP-196半富马酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2017074087-appb-000005
Figure PCTCN2017074087-appb-000006
非限制性地，所述ACP-196半富马酸盐的晶型1的一个典型实例具有如图10所示的XRPD图谱。
非限制性地，所述ACP-196半富马酸盐的晶型1的TGA图谱如图11所示。
非限制性地，所述ACP-196半富马酸盐的晶型1的DSC图谱如图12所示。
非限制性地，所述ACP-196半富马酸盐的晶型1的PLM图谱如图13所示。
非限制性地，所述ACP-196半富马酸盐的晶型1的等温吸附曲线如图14所示。
与现有技术的ACP-196无定型物相比，本发明的ACP-196半富马酸盐的晶型1具有以下有益性质：
1)由XRPD图谱和PLM图谱可知，ACP-196半富马酸盐的晶型1为结晶态固体，结晶度高、稳定性好。
2)由等温吸附曲线可知，ACP-196半富马酸盐的晶型1和ACP-196无定型物在30％～80％相对湿度范围内重量变化分别为1.2％和5.5％，本发明的ACP-196半富马酸盐的晶型1更不易吸湿。
3)由对比例1可知，ACP-196半富马酸盐的晶型1比ACP-196无定型物具有更高的溶解度。
上述有益性质表明：与现有技术的ACP-196无定型物相比，本发明的ACP-196半富马酸盐的晶型1具有多种优势性能，更适合作为药物制剂的活性成分。无定型物易受外来因素影响发生晶型转化，进而影响药物的质量和稳定性，而ACP-196半富马酸盐的晶型1为结晶态固体，晶型稳定性明显更优。结晶态固体具有更好的流动性和更优良的可加工性(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高药物活性成分和制剂的均一性。ACP-196半富马酸盐的晶型1溶解度大，具有更高的生物利用率，且ACP-196半富马酸盐的晶型1具有更低的吸湿性，能够更好地保证药物活性成分自身和含有半富马酸盐的ACP-196晶型1的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
本发明提供ACP-196半富马酸盐的晶型1的制备方法，包括以下方法中的任意一种：
1)分别将ACP-196和富马酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196半富马酸盐的晶型1；
优选地，所述ACP-196与富马酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为丙酮；
优选地，所述ACP-196与溶剂形成溶液时的质量体积比为40～200mg/mL，更优选为40～100mg/mL；
优选地，所述ACP-196与富马酸的摩尔比为1:0.5～1:1.1；
优选地，所述搅拌时间为1～2天；
优选地，所述操作过程在室温下进行；
2)将ACP-196和富马酸的混合物在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196半富马酸盐的晶型1；
优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为1,4-二氧六环；
优选地，所述ACP-196与良溶剂的质量体积比为20～100mg/mL，更优选为50～100mg/mL；
优选地，所述ACP-196与富马酸的摩尔比为1:0.5～1:1.1；
优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为异丙醚
优选地，所述搅拌时间为1～3天；
优选地，所述操作过程在室温下进行。
根据本发明目的，本发明的内容之三是提供固态的ACP-196马来酸盐的晶型1及其制备方法。
本发明的ACP-196马来酸盐的晶型1，是由ACP-196和马来酸以摩尔比为1:1形成的化合物，其结构式如下式(III)所示：
Figure PCTCN2017074087-appb-000007
使用Cu-Kα辐射，所述ACP-196马来酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.3°±0.2°、9.8°±0.2°、10.5°±0.2°、11.7°±0.2°、17.4°±0.2°和24.4°±0.2°。
在本发明优选的一个实施方案中，所述ACP-196马来酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.3°±0.2°、9.8°±0.2°、10.5°±0.2°、11.7°±0.2°、15.7°±0.2°、17.4°±0.2°、18.8°±0.2°、19.3°±0.2°、19.8°±0.2°、22.8°±0.2°、24.4°±0.2°和24.7°±0.2°。
在本发明进一步优选的一个实施方案中，所述ACP-196马来酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2017074087-appb-000008
Figure PCTCN2017074087-appb-000009
非限制性地，所述ACP-196马来酸盐的晶型1的一个典型实例具有如图15所示的XRPD图谱。
非限制性地，所述ACP-196马来酸盐的晶型1的TGA图谱如图16所示。
非限制性地，所述ACP-196马来酸盐的晶型1的DSC图谱如图17所示。
非限制性地，所述ACP-196马来酸盐的晶型1的PLM图谱如图18所示。
非限制性地，所述ACP-196马来酸盐的晶型1的等温吸附曲线如图19所示。
与现有技术的ACP-196无定型物相比，本发明的ACP-196马来酸盐的晶型1具有以下有益性质：
1)由XRPD图谱和PLM图谱可知，ACP-196马来酸盐的晶型1为结晶态固体，结晶度高、稳定性好；
2)由等温吸附曲线可知，ACP-196马来酸盐的晶型1和ACP-196无定型物在30％～80％相对湿度范围内重量变化分别为0.4％和5.5％，本发明的ACP-196马来酸盐的晶型1更不易吸湿。
3)由对比例1可知，ACP-196马来酸盐的晶型1比ACP-196无定型物具有更高的溶解度。
上述有益性质表明：与现有技术的ACP-196无定型物相比，本发明的ACP-196马来酸盐的晶型1具有多种优势性能，更适合作为药物制剂的活性成分。无定型物易受外来因素影响发生晶型转化，进而影响药物的质量和稳定性，而ACP-196马来酸盐的晶型1为结晶态固体，晶型稳定性明显更优。结晶态固体具有更好的流动性和更优良的可加工性(如药物制造过程中的过滤、 干燥、称量、过筛等操作)特性，有利于提高药物活性成分和制剂的均一性。ACP-196马来酸盐的晶型1溶解度大，具有更高的生物利用率，且ACP-196马来酸盐的晶型1具有更低的吸湿性，能够更好地保证药物活性成分自身和含有ACP-19马来酸盐的晶型1的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
本发明提供ACP-196马来酸盐的晶型1的制备方法，包括以下方法中的任意一种：
1)分别将ACP-196和马来酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196马来酸盐的晶型1；
优选地，所述ACP-196与马来酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
优选地，所述ACP-196与马来酸的摩尔比为1:0.8～1:1.1；
优选地，所述搅拌时间为1～2天；
优选地，所述操作过程在室温下进行；
2)将ACP-196和马来酸的混合物在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196马来酸盐的晶型1；
优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为四氢呋喃；
优选地，所述ACP-196与良溶剂的质量体积比为20～100mg/mL，更优选为20～50mg/mL；
优选地，所述ACP-196与马来酸的摩尔比为1:0.8～1:1.1；
优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为正庚烷；
优选地，所述搅拌时间为1～3天；
优选地，所述操作过程在室温下进行。
根据本发明目的，本发明的内容之四是提供固态的ACP-196磷酸盐的晶型1及其制备方法。
本发明的ACP-196磷酸盐的晶型1，是由ACP-196、磷酸和水以摩尔比为1:1:1.5形成的化合物，其结构式如下式(IV)所示：
Figure PCTCN2017074087-appb-000010
使用Cu-Kα辐射，所述ACP-196磷酸盐的晶型1以2θ角度表示的X-射 线粉末衍射图具有以下特征峰：4.5°±0.2°、10.4°±0.2°、12.0°±0.2°、14.3°±0.2°、18.0°±0.2°和21.9°±0.2°。
在本发明优选的一个实施方案中，所述ACP-196磷酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.5°±0.2°、6.0°±0.2°、10.4°±0.2°、12.0°±0.2°、14.3°±0.2°、15.5°±0.2°、18.0°±0.2°、19.3°±0.2°、20.5°±0.2°、20.9°±0.2°、21.9°±0.2°和25.1°±0.2°。
在本发明进一步优选的一个实施方案中，所述ACP-196磷酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2017074087-appb-000011
非限制性地，所述ACP-196磷酸盐的晶型1的一个典型实例具有如图20所示的XRPD图谱。
非限制性地，所述ACP-196磷酸盐的晶型1的TGA图谱如图21所示。
非限制性地，所述ACP-196磷酸盐的晶型1的DSC图谱如图22所示。
非限制性地，所述ACP-196磷酸盐的晶型1的PLM图谱如图23所示。
非限制性地，所述ACP-196磷酸盐的晶型1的等温吸附曲线如图24所示。
与现有技术的ACP-196无定型物相比，本发明的ACP-196磷酸盐的晶型1具有以下有益性质：
1)由XRPD图谱和PLM图谱可知，ACP-196磷酸盐的晶型1为结晶态固体，结晶度高、稳定性好；
2)由等温吸附曲线可知，ACP-196磷酸盐的晶型1和ACP-196无定型物在30％～80％相对湿度范围内重量变化分别为4.2％和5.5％，本发明的ACP-196磷酸盐的晶型1更不易吸湿。
3)由对比例1可知，ACP-196磷酸盐的晶型1比ACP-196无定型物具有更高的溶解度。
上述有益性质表明：与现有技术的ACP-196无定型物相比，本发明的ACP-196磷酸盐的晶型1具有多种优势性能，更适合作为药物制剂的活性成分。无定型物易受外来因素影响发生晶型转化，进而影响药物的质量和稳定性，而ACP-196磷酸盐的晶型1为结晶态固体，晶型稳定性明显更优。结晶态固体具有更好的流动性和更优良的可加工性(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高药物活性成分和制剂的均一性。ACP-196磷酸盐的晶型1溶解度大，具有更高的生物利用率，且ACP-196磷酸盐的晶型1具有更低的吸湿性，能够更好地保证药物活性成分自身和含有ACP-196磷酸盐的晶型1的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
本发明提供ACP-196磷酸盐的晶型1的制备方法，包括以下方法中的任意一种：
1)分别将ACP-196和磷酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196磷酸盐的晶型1；
优选地，所述ACP-196与磷酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
优选地，所述ACP-196与磷酸的摩尔比为1:0.8～1:1.1；
优选地，所述搅拌时间为1～2天；
优选地，所述操作过程在室温下进行；
2)将ACP-196在良溶剂中形成溶液，滴加磷酸后加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196磷酸盐的晶型1；
优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为二氯甲烷；
优选地，所述ACP-196与良溶剂的质量体积比为50～150mg/mL，更优选为50～100mg/mL；
优选地，所述ACP-196与磷酸的摩尔比为1:0.8～1:1.1；
优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为甲基环己烷；
优选地，所述搅拌时间为1～3天；
优选地，所述操作过程在室温下进行。
根据本发明目的，本发明的内容之五是提供固态的ACP-196硫酸盐的晶型1及其制备方法。
本发明的ACP-196硫酸盐的晶型1，是由ACP-196和硫酸以摩尔比为1:1形成的化合物，其结构式如下式(V)所示：
Figure PCTCN2017074087-appb-000012
使用Cu-Kα辐射，所述ACP-196硫酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：8.9°±0.2°、9.7°±0.2°、17.5°±0.2°、19.6°±0.2°、21.9°±0.2°和23.6°±0.2°。
在本发明优选的一个实施方案中，所述ACP-196硫酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6°±0.2°、7.9°±0.2°、8.9°±0.2°、9.7°±0.2°、14.6°±0.2°、15.0°±0.2°、17.5°±0.2°、19.6°±0.2°、20.0°±0.2°、21.9°±0.2°、23.6°±0.2°和25.9°±0.2°。
在本发明进一步优选的一个实施方案中，所述ACP-196硫酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2017074087-appb-000013
Figure PCTCN2017074087-appb-000014
非限制性地，所述ACP-196硫酸盐的晶型1的一个典型实例具有如图25所示的XRPD图谱。
与现有技术的ACP-196无定型物相比，本发明的ACP-196硫酸盐的晶型1具有以下有益性质：
1)由XRPD图谱可知，ACP-196硫酸盐的晶型1为结晶态固体，结晶度高、稳定性好；
2)由对比例1可知，ACP-196硫酸盐的晶型1比ACP-196无定型物具有更高的溶解度。
上述有益性质表明：与现有技术的ACP-196无定型物相比，本发明的ACP-196硫酸盐的晶型1具有多种优势性能，更适合作为药物制剂的活性成分。无定型物易受外来因素影响发生晶型转化，进而影响药物的质量和稳定性，而ACP-196硫酸盐的晶型1为结晶态固体，晶型稳定性明显更优。结晶态固体具有更好的流动性和更优良的可加工性(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高药物活性成分和制剂的均一性，能够更好地保证药物活性成分自身和含有ACP-196硫酸盐的晶型1的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。ACP-196硫酸盐的晶型1溶解度大，具有更高的生物利用率。
本发明提供ACP-196硫酸盐的晶型1的制备方法，包括以下方法中的任意一种：
1)分别将ACP-196和硫酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196硫酸盐的晶型1；
优选地，所述ACP-196与硫酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
优选地，所述ACP-196与硫酸的摩尔比为1:0.8～1:1.1；
优选地，所述搅拌时间为1～2天；
优选地，所述操作过程在室温下进行；
2)将ACP-196在良溶剂中形成溶液，滴加硫酸后加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196硫酸盐的晶型1；
优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为乙酸乙酯；
优选地，所述ACP-196与良溶剂的质量体积比为10～50mg/mL，更优选为25～50mg/mL；
优选地，所述ACP-196与硫酸的摩尔比为1:0.8～1:1.1；
优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为正己烷；
优选地，所述搅拌时间为1～3天；
优选地，所述操作过程在室温下进行。
本发明的ACP-196盐的晶型的各制备方法中：原料“ACP-196固体”可以为已公开的ACP-196化合物包括其无定型物，例如包括但不限于参照专利文献CN103889987A中任意一种制备方法得到的ACP-196。这些专利文献通过引用其全文的方式并入到本申请中。
本发明中使用的术语有：
所述“室温”，是指10～30℃。
所述“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选300～900转/分。
所述“分离”可以采用本领域的常规方法，例如减压浓缩、挥发、离心或过滤。优选减压过滤或减压浓缩，一般是在室温下以小于大气压的压力进行抽滤或浓缩，优选压力小于0.09MPa。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥；可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。
本发明中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。XRD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°，03°，0.1°等，通常允许误差±0.2°，所以峰角度的差别不能作为唯一标准。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本发明所述ACP-196盐的晶型是基本纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本纯的”当用来指新晶型时，指这个新晶型占所存在的化合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。
本发明的内容之六是提供一种药物组合物，所述药物组合物含有治疗和/或预防有效量的药物活性成分选自本发明的ACP-196盐的晶型或者由本发明制 备方法制备得到的ACP-196盐的晶型，以及至少一种药学上可接受的载体或助剂，其中所述本发明的ACP-196盐的晶型包括ACP-196苹果酸盐的晶型1、ACP-196半富马酸盐的晶型1、ACP-196马来酸盐的晶型1、ACP-196磷酸盐的晶型1和ACP-196硫酸盐的晶型1。此外，所述药物组合物还可以包含ACP-196的其它可药用盐或晶型及无定型。本发明方法中使用的化合物的给药剂型可以通过所选择的特定化合物、给药途径要求的药物动力学分布类型及患者的状态来确定。
本发明的化合物可按制药领域的公认方法制备适合于口服、舌下、皮下、静脉内、肌内、经鼻、局部或直肠给药的制剂，并且所述制剂含有至少一种活性化合物，优选以单位剂型的形式用于给药。人用剂量优选含有0.001～25mg/kg体重。
所述药物组合可以根据给药途径或需要，制备成一定的剂型，可为固态或液态。固体口服剂型，例如包括片剂、颗粒剂、散剂、丸剂和胶囊剂；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，例如包括溶液剂、分散剂和冻干剂。配方可适于药物活性成分的速释、缓释或可控释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。
所述药物组合物中的赋形剂，是本领域技术人员公知的，其种类、用法、用量的选择也是本领域技术人员公知的。例如包括糖类，纤维素及其衍生物，淀粉或改性淀粉，固体无机物如磷酸钙、磷酸氢二钙、羟基磷灰石、硫酸钙、碳酸钙，半固体如脂质或石蜡，粘合剂如微晶纤维素、乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素，助流剂如胶态二氧化硅、轻质无水硅酸、结晶纤维素、滑石粉或硬脂酸镁，崩解剂如乙醇酸淀粉钠、交聚维酮、交联羧甲基纤维素、羧甲基纤维素钠、干玉米淀粉，润滑剂如硬脂酸、硬脂酸镁、硬脂酰富马酸钠、聚乙二醇。
对于制备固体剂量单位，预期使用常规载体如填充剂、着色剂、粘合剂等。一般而言，可使用惰性的任何药学上可接受的载体。本发明的活性成分可与其一起给药作为固体组合物。适宜的载体包括乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素等，或其混合物，以适宜的量使用。对于肠胃外给药，可使用含有药学上可接受的分散剂和/或润湿剂，如丙二醇或丁二醇的水性悬浮液、等渗盐水溶液或无菌注射溶液。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，将本发明的ACP-196盐的晶型(ACP-196苹果酸盐的晶型1、ACP-196半富马酸盐的晶型1、ACP-196马来酸盐的晶型1、ACP-196磷酸盐的晶型1和ACP-196硫酸盐的晶型1)与一种或多种药学上可接受的赋形剂相混合，任选地与可药用的ACP-196的其它晶型、盐型、无定型物相混合，任选地与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
对于口服给药，活性成分可呈现为离散单位，如片剂、胶囊、散剂、颗粒剂、溶液、混悬剂等。
对于肠胃外给药，本发明的药物组合物可存在于单位剂量或多剂量容器内，例如预定量的注射液体，例如在密封小瓶或安瓿内，也可储存在冷冻干燥(冻 干)条件下。
根据本发明目的，本发明的内容之七是提供本发明的ACP-196盐的晶型或者由本发明制备方法得到的ACP-196盐的晶型在制备用治疗或预防酪氨酸激酶例如布鲁顿酪氨酸激酶(BTK)介导的疾病或病况的药物中的用途。其中所述本发明的ACP-196盐的晶型包括ACP-196苹果酸盐的晶型1、ACP-196半富马酸盐的晶型1、ACP-196马来酸盐的晶型1、ACP-196磷酸盐的晶型1和ACP-196硫酸盐的晶型1。所述BTK介导的疾病或病况是指由B细胞、肥大细胞、骨髓细胞或破骨细胞起主要作用的任何疾病状态或其它有害病况。这些疾病包括但不限于免疫、自身免疫和炎性疾病、过敏症、感染性疾病、骨吸收病症和增生性疾病。所述免疫、自身免疫和炎性疾病包括但不限于，例如关节炎、类风湿性关节炎、银屑病性关节炎、骨关节炎、感染性关节炎、进行性慢性关节炎、致畸性关节炎、关节强直性脊椎炎、青少年类风湿性关节炎、创伤性关节炎、痛风性关节炎、Reiter综合症、自身免疫阿狄森病、多软骨炎、急性滑膜炎和脊椎炎等、肾小球肾炎、自身免疫性血液系统病症例如自身免疫性溶血性贫血、再生障碍性贫血、自身免疫性血小板减少紫癜(ATP)、自身免疫性淋巴细胞增生综合征(ALPS)和嗜中性白血球减少症、自身免疫性肝炎、自身免疫性胃炎和自身免疫性炎性肠病(例如溃疡性结肠炎和Crohn氏病)、移植物抗宿主病、同种异体移植物排斥、甲状腺机能异常、桥本甲状腺炎、格雷夫斯氏病(Graves’disease)、硬皮病、糖尿病(I型和II型)、活动性肝炎(急性和慢性)、胰腺炎、原发性胆汁性肝硬化、获得性免疫缺陷综合症(AIDS)、子宫内膜异位、重症肌无力、慢性疲劳免疫异常综合征(CFIDS)、恶性贫血、结节性多动脉炎、多软骨炎、多腺体综合征、风湿性多肌病、多发性肌炎和皮肤肌炎、原发性无丙种球蛋白血症、自身免疫性内耳病(AIED)、多发性硬化症、狼疮、银屑病、牛皮癣、牛皮癣性关节炎、特应性皮炎、接触性皮炎、湿疹、丘疹、风湿热、皮肤晒伤、血管炎(例如Behcet氏病)、慢性肾功能不全、Stevens-Johnson综合症、炎性痛、特发性脂肪泻(idiopathic sprue)、恶病质、结节病、少年皮肌炎、传染性神经元炎(Guillain-Barré综合症)、葡萄膜炎、白癜风、肉芽肿、结膜炎、角膜结膜炎、中耳炎、纤维肌炎、牙周病、肺间质性纤维化、哮喘、阑尾炎、细支气管炎、支气管炎、鼻炎、窦炎、尘肺病、肺功能不全综合症、肺气肿、肺纤维化、矽肺、慢性炎性肺病(例如慢性阻塞性肺病)和呼吸道的其他炎性或阻塞性疾病。
可治疗或预防的过敏症包括，例如对食物、食品添加剂、昆虫毒素、霉菌、尘螨、花粉、动物材料、药物和金属等过敏、I型超敏反应、过敏性哮喘、过敏性鼻炎、过敏性结膜炎或特异性皮炎。
可治疗或预防的感染性疾病包括但不限于，例如败血症、感染性休克、内毒素性休克、由革兰氏阴性菌引起的败血症、志贺杆菌病、脑膜炎、胸膜 炎、疟疾、肺炎、支气管炎、结核、心内膜炎、病毒性心肌炎、病毒性肝炎(甲型肝炎、乙型肝炎和丙型肝炎)、肾炎、HIV感染、睑炎、视网膜炎、流感、疱疹、麻疹、百日咳、肠炎、与严重烧伤相关的感染、由感染引起的肌痛、继发于感染的恶病质、和动物病毒引起的感染。
可治疗或预防的骨吸收病症包括例如骨质疏松症、骨关节炎、创伤性关节炎、痛风性关节炎和与多发性骨髓瘤相关的骨病症。
可治疗或预防的增生性疾病包括，例如B细胞增生性疾病，例如弥漫性大B细胞淋巴瘤、套细胞淋巴瘤(MCL)、滤泡细胞淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、急性淋巴细胞性白血病(ALL)、淋巴浆细胞淋巴瘤/Waldenstrom巨球蛋白血症、缘区淋巴瘤、多毛细胞白血病、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、弥散性混合细胞和大细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、Burkitt氏淋巴瘤/白血病或淋巴瘤样肉芽肿病、和AIDS-相关淋巴瘤。本发明所述化合物晶型尤其可用于治疗由慢性活动型B细胞受体信号传导引起的B细胞淋巴瘤。
根据本发明目的，治疗和/或预防布鲁顿酪氨酸激酶(BTK)介导的疾病的方法，所述方法包括给予需要的患者预防、抑制和/或治疗有效量的选自本发明的ACP-196苹果酸盐的晶型1、ACP-196半富马酸盐的晶型1、ACP-196马来酸盐的晶型1、ACP-196磷酸盐的晶型1和ACP-196硫酸盐的晶型1或者含有本发明ACP-196苹果酸盐的晶型1、ACP-196半富马酸盐的晶型1、ACP-196马来酸盐的晶型1、ACP-196磷酸盐的晶型1和ACP-196硫酸盐的晶型1的前述药物组合物；所述疾病同本说明书的前述内容。所述有效量如肠胃外给药的人用剂量优选含有0.001～25mg/kg体重。所需剂量可呈现为单剂量或在一天内以适当间隔给药的多个亚剂量。。
附图说明
图1参照CN103889987A制备得到的ACP-196无定型物的XRPD图谱
图2参照CN103889987A制备得到的ACP-196无定型物的TGA图谱
图3参照CN103889987A制备得到的ACP-196无定型物PLM图谱
图4参照CN103889987A制备得到的ACP-196无定型物等温吸附曲线
图5本发明制备得到的ACP-196苹果酸盐的晶型1的XRPD图谱
图6本发明制备得到的ACP-196苹果酸盐的晶型1的TGA图谱
图7本发明制备得到的ACP-196苹果酸盐的晶型1的DSC图谱
图8本发明制备得到的ACP-196苹果酸盐的晶型1的PLM图谱
图9本发明制备得到的ACP-196苹果酸盐的晶型1的等温吸附曲线
图10本发明制备得到的ACP-196半富马酸盐的晶型1的XRPD图谱
图11本发明制备得到的ACP-196半富马酸盐的晶型1的TGA图谱
图12本发明制备得到的ACP-196半富马酸盐的晶型1的DSC图谱
图13本发明制备得到的ACP-196半富马酸盐的晶型1的PLM图谱
图14本发明制备得到的ACP-196半富马酸盐的晶型1的等温吸附曲线
图15本发明制备得到的ACP-196马来酸盐的晶型1的XRPD图谱
图16本发明制备得到的ACP-196马来酸盐的晶型1的TGA图谱
图17本发明制备得到的ACP-196马来酸盐的晶型1的DSC图谱
图18本发明制备得到的ACP-196马来酸盐的晶型1的PLM图谱
图19本发明制备得到的ACP-196马来酸盐的晶型1的等温吸附曲线
图20本发明制备得到的ACP-196磷酸盐的晶型1的XRPD图谱
图21本发明制备得到的ACP-196磷酸盐的晶型1的TGA图谱
图22本发明制备得到的ACP-196磷酸盐的晶型1的DSC图谱
图23本发明制备得到的ACP-196磷酸盐的晶型1的PLM图谱
图24本发明制备得到的ACP-196磷酸盐的晶型1的等温吸附曲线
图25本发明制备得到的ACP-196硫酸盐的晶型1的XRPD图谱
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8 Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
偏振光显微镜(PLM)图谱采自于XP～500E偏振光显微镜。取少量粉末样品置于载玻片上，滴加少量矿物油分散样品，盖上盖玻片，放置在载物台上进行观测并拍照。
差热分析数据采自于TA Instruments Q200 DSC。检测方法为：取1～10mg的样品放置于小孔铝坩埚内，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至200℃。
热重分析数据采自于TA Instruments Q500 TGA。检测方法为：取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至350℃。
动态水份吸附分析数据和等温吸附分析数据采自于TA Instruments Q5000 TGA。检测方法为：取1～10mg的样品放置于白金坩埚内，检测相对湿度从0％到80％到0％变化过程中的重量变化。
核磁氢谱(1H-NMR)数据采自于Bruker Avance II DMX 500MHZ核磁共振波谱仪。称量1～10mg样品，用约0.5mL氘代试剂溶解到核磁样品管中进行检测。
离子色谱仪(IC)数据采自于Dionex ICS-900，工作站和分析软件均为Chromeleon Console，采用外标法进行离子含量检测。
实施例中所用的各种试剂如无特别说明均为市售购买。
实施例中如无特别说明均为室温操作。
制备例1 ACP-196的制备
参照CN103889987A中实例6方法制备得到ACP-196固体，数据： LCMS(B)Rt：2.08min；m/z 466.1(M+H)+。
其XRPD图谱如图1所示，显示无特征衍射峰。
其TGA图谱如图2所示，显示含有超过10％的表面溶剂。
其PLM图谱如图3所示，显示为不规则无偏光颗粒。
其等温吸附曲线如图4所示，显示在30％～80％相对湿度范围内重量变化为5.5％。
以上表征结果表明：参照CN100352817A实施例6制备方法得到的ACP-196为无定型物。
实施例1
取3g制备例1的ACP-196，加100mL异丙醇形成溶液，缓慢滴加50mL含有苹果酸(1.1倍摩尔量)的异丙醇溶液，搅拌析晶，2天后，过滤，室温下真空干燥24小时，得到3.3g ACP-196苹果酸盐的晶型1，产率为85％。
1H-NMR(d6-DMSO,500MHz)：10.84(s,1H),8.50–8.34(m,1H),8.32–8.08(m,2H),7.87(td,3H),7.26–7.04(m,2H),6.22(s,2H),5.73(dd,1H),5.49(dd,1H),4.26(s,1H),3.84(t,1H),3.62(dtt,1H),2.62(dd,1H),2.48–2.18(m,3H),2.15(dt,1H),2.08–1.92(m,2H),1.64(s,1H)。
显示ACP-196与苹果酸以摩尔比约为1:1成盐。
其XRPD图谱如图5所示，显示为结晶态。
其TGA图谱如图6所示，显示为无水物，分解温度约为181℃。
其DSC图谱如图7所示，显示熔点约为177℃。
其PLM图谱如图8所示，显示为规则块状颗粒。
其等温吸附曲线如图9所示，显示在30％～80％相对湿度范围内重量变化为1.5％。
实施例2
取200mg制备例1的ACP-196，加4mL异丙醇形成溶液，缓慢滴加3mL含有苹果酸(0.8倍摩尔量)的异丙醇溶液，搅拌析晶，1天后，过滤，室温下真空干燥20小时，得到170mg ACP-196苹果酸盐的晶型1，产率为82％。
实施例3
取200mg制备例1的ACP-196，加2mL丙酮形成溶液，缓慢滴加1mL含有苹果酸(1倍摩尔量)的丙酮溶液，搅拌析晶，1天后，过滤，室温下真空干燥10小时，得到150mg ACP-196苹果酸盐的晶型1，产率为58％。
实施例4
对实施例3中的溶剂按以下表格进行替换均可获得ACP-196苹果酸盐的晶型1。
Figure PCTCN2017074087-appb-000015
Figure PCTCN2017074087-appb-000016
实施例5
取30mg制备例1的ACP-196和6.9mg苹果酸，加1.5mL四氢呋喃形成溶液，加入5mL异丙醚，搅拌析晶，1天后，过滤，室温下真空干燥24小时，得到26mg ACP-196苹果酸盐的晶型1，产率为84％。
实施例6
取50mg制备例1的ACP-196和15.8mg苹果酸，加1mL四氢呋喃形成溶液，加入4mL异丙醚，搅拌析晶，3天后，过滤，室温下真空干燥48小时，得到53mg ACP-196苹果酸盐的晶型1，产率为82％。
实施例7
取40mg制备例1的ACP-196和11.5mg苹果酸，加0.4mL二氯甲烷形成溶液，加入2.5mL正庚烷，搅拌析晶，2天后，过滤，室温下真空干燥30小时，得到37mg ACP-196苹果酸盐的晶型1，产率为72％。
实施例8
对实施例7中的溶剂按以下表格进行替换均可获得ACP-196苹果酸盐的晶型1。
Figure PCTCN2017074087-appb-000017
实施例2～8制备得到的样品与实施例1的样品具有相同或相似的1H-NMR数据(未示出)、XRPD图谱(未示出)、PLM图谱(未示出)、TGA图谱(未示出)、DSC图谱(未示出)、等温吸附图谱(未示出)，说明实施例2～8样品与实施例1的样品是相同化合物的同一晶型。
实施例9
取3g制备例1的ACP-196，加75mL丙酮形成溶液，缓慢滴加60mL含有富马酸(1.1倍摩尔量)的丙酮溶液，搅拌析晶，2天后，过滤，室温真空干燥24小时，得到3g ACP-196半富马酸盐的晶型1，产率为89％。
1H-NMR(d6-DMSO,500MHz)：10.84(d,1H),8.51–8.32(m,1H),8.28–8.11(m,2H),7.94–7.68(m,2H),7.26–7.08(m,1H),6.64(s,1H),6.17(d,1H), 5.73(dd,1H),5.49(dd,1H),3.84(t,1H),3.71–3.52(m,1H),2.45–1.88(m,5H),1.63(s,1H).。
显示ACP-196与富马酸以摩尔比约为2:1成盐。
其XRPD图谱如图10所示，显示为结晶态。
其TGA图谱如图11所示，显示为无水物，分解温度约为170℃。
其DSC图谱如图12所示，显示熔点约为153℃。
其PLM图谱如图13所示，显示为粒状细小颗粒。
其等温吸附曲线如图14所示，显示在30％～80％相对湿度范围内重量变化为1.2％。
实施例10
取200mg制备例1的ACP-196，加2mL丙酮形成溶液，缓慢滴加3mL含有富马酸(0.5倍摩尔量)的丙酮溶液，搅拌析晶，1天后，过滤，室温真空干燥10小时，得到183mg ACP-196半富马酸盐的晶型1，产率为81％。
实施例11
取200mg制备例1的ACP-196，加1mL甲醇形成溶液，缓慢滴加6mL含有富马酸(0.8倍摩尔量)的甲醇溶液，搅拌析晶，1天后，过滤，室温真空干燥24小时，得到165mg ACP-196半富马酸盐的晶型1，产率为73％。
实施例12
对实施例11中的溶剂按以下表格进行替换均可获得ACP-196半富马酸盐的晶型1。
Figure PCTCN2017074087-appb-000018
实施例13
取200mg制备例1的ACP-196和24.9mg富马酸，加4mL 1,4-二氧六环形成溶液，加入6mL异丙醚，搅拌析晶，1天后，过滤，室温下真空干燥24小时，得到198mg ACP-196半富马酸盐的晶型1，产率为88％。
实施例14
取300mg制备例1的ACP-196和82.3mg富马酸，加3mL 1,4-二氧六环形成溶液，加入5mL异丙醚，搅拌析晶，3天后，过滤，室温下真空干燥48小时，得到287mg ACP-196半富马酸盐的晶型1，产率为85％。
实施例15
取40mg制备例1的ACP-196和8.0mg富马酸，加2mL四氢呋喃形成溶液，加入6mL异丙醚，搅拌析晶，2天后，过滤，室温下真空干燥30小时，得到36mg ACP-196半富马酸盐的晶型1，产率为80％。
实施例16
对实施例15中的溶剂按以下表格进行替换均可获得ACP-196半富马酸盐的晶型1。
Figure PCTCN2017074087-appb-000019
实施例10～16制备得到的样品与实施例9的样品具有相同或相似的1H-NMR数据(未示出)、XRPD图谱(未示出)、PLM图谱(未示出)、TGA图谱(未示出)、DSC图谱(未示出)、等温吸附图谱(未示出)，说明实施例10～16样品与实施例9的样品是相同化合物的同一晶型。
实施例17
取3g制备例1的ACP-196，加100mL异丙醇形成溶液，缓慢滴加50mL含有马来酸(1.1倍摩尔量)的异丙醇溶液，搅拌析晶，2天后，过滤，室温真空干燥24小时，得到3.15g ACP-196马来酸盐的晶型1，产率为84％。
1H NMR(d6-DMSO,500MHz)：10.88(d,1H),8.42(d,1H),8.22(dd,2H),8.11–7.69(m,3H),7.64–6.88(m,3H),6.16(s,2H),5.77(dd,1H),5.52(dd,1H),3.94–3.54(m,3H),2.45–1.89(m,5H),1.69(s,1H),1.05(d,1H).。显示ACP-196与马来酸以摩尔比约为1:1成盐。
其XRPD图谱如图15所示，显示为结晶态。
其TGA图谱如图16所示，显示为无水物，分解温度约为125℃。
其DSC图谱如图17所示，显示熔点约为132℃。
其PLM图谱如图18所示，显示为粒状细小颗粒。
其等温吸附曲线如图19所示，显示在30％～80％相对湿度范围内重量变化为0.4％。
实施例18
取100mg制备例1的ACP-196，加2mL异丙醇形成溶液，缓慢滴加2mL含有马来酸(0.8倍摩尔量)的异丙醇溶液，搅拌析晶，1天后，过滤，室温真空干燥18小时，得到79mg ACP-196马来酸盐的晶型1，产率为79％。
实施例19
取100mg制备例1的ACP-196，加1mL丙酮形成溶液，缓慢滴加1mL含有马来酸(1.0倍摩尔量)的丙酮溶液，搅拌析晶，1天后，过滤，室温真空干燥48小时，得到95mg ACP-196马来酸盐的晶型1，产率为76％。
实施例20
对实施例19中的溶剂按以下表格进行替换均可获得ACP-196马来酸盐的晶型1。
Figure PCTCN2017074087-appb-000020
实施例21
取30mg制备例1的ACP-196和6.0mg马来酸，加1.5mL四氢呋喃形成溶液，加入6mL正庚烷，搅拌析晶，1天后，过滤，室温下真空干燥24小时，得到25mg ACP-196马来酸盐的晶型1，产率为83％。
实施例22
取50mg制备例1的ACP-196和13.7mg马来酸，加1mL四氢呋喃形成溶液，加入5mL正庚烷，搅拌析晶，3天后，过滤，室温下真空干燥48小时，得到49mg ACP-196马来酸盐的晶型1，产率为78％。
实施例23
取100mg制备例1的ACP-196和24.9mg马来酸，加1mL二氯甲烷形成溶液，加入5mL正庚烷，搅拌析晶，2天后，过滤，室温下真空干燥30小时，得到96mg ACP-196马来酸盐的晶型1，产率为77％。
实施例24
对实施例23中的溶剂按以下表格进行替换均可获得ACP-196马来酸盐的晶型1。
Figure PCTCN2017074087-appb-000021
实施例18～24制备得到的样品与实施例17的样品具有相同或相似的1H-NMR数据(未示出)、XRPD图谱(未示出)、PLM图谱(未示出)、TGA图谱(未示出)、DSC图谱(未示出)、等温吸附图谱(未示出)，说明实施例18～24样品与实施例17的样品是相同化合物的同一晶型。
实施例25
取3g制备例1的ACP-196，加100mL异丙醇形成溶液，缓慢滴加20mL 含有磷酸(1.1倍摩尔量)的异丙醇溶液，搅拌析晶，2天后，过滤，室温真空干燥24小时，得到285mg ACP-196磷酸盐的晶型1，产率为75％。
经IC测定，ACP-196磷酸盐中磷酸根含量为20.1％，一磷酸盐磷酸根理论含量为16.9％，二磷酸盐磷酸根理论含量为28.7％，故ACP-196与磷酸以摩尔比约为1:1成盐。
其XRPD图谱如图20所示，显示为结晶态。
其TGA图谱如图21所示，结合4.3％的台阶失重显示为倍半水合物，分解温度约为198℃。
其DSC图谱如图22所示，显示熔点约为170℃。
其PLM图谱如图23所示，显示为粒状细小颗粒。
其等温吸附曲线如图24所示，显示在30％～80％相对湿度范围内重量变化为4.2％。
实施例26
取100mg制备例1的ACP-196，加2mL异丙醇形成溶液，缓慢滴加1mL含有磷酸(0.8倍摩尔量)的异丙醇溶液，搅拌析晶，1天后，过滤，室温真空干燥40小时，得到70mg ACP-196磷酸盐的晶型1，产率为69％。
实施例27
取100mg制备例1的ACP-196，加1mL丙酮形成溶液，缓慢滴加1mL含有磷酸(1.0倍摩尔量)的丙酮溶液，搅拌析晶，1天后，过滤，室温真空干燥36小时，得到80mg ACP-196磷酸盐的晶型1，产率为63％。
实施例28
对实施例27中的溶剂按以下表格进行替换均可获得ACP-196磷酸盐的晶型1。
Figure PCTCN2017074087-appb-000022
实施例29
取100mg制备例1的ACP-196，加2mL二氯甲烷形成溶液，滴加19.8mg磷酸(85％)后，加入5mL甲基环己烷，搅拌析晶，1天后，过滤，室温下真空干燥24小时，得到87mg ACP-196磷酸盐的晶型1，产率为86％。
实施例30
取100mg制备例1的ACP-196，加1mL二氯甲烷形成溶液，滴加27.2mg磷酸(85％)后，加入2.5mL甲基环己烷，搅拌析晶，3天后，过滤，室温下真空干燥30小时，得到105mg ACP-196磷酸盐的晶型1，产率为83％。
实施例31
取300mg制备例1的ACP-196，加2mL氯仿形成溶液，滴加66.9mg磷酸(85％)后，加入6mL正庚烷，搅拌析晶，3天后，过滤，室温下真空干燥36小时，得到276mg ACP-196磷酸盐的晶型1，产率为81％。
实施例32
对实施例31中的溶剂按以下表格进行替换均可获得ACP-196磷酸盐的晶型1。
Figure PCTCN2017074087-appb-000023
实施例26～32制备得到的样品与实施例25的样品具有相同或相似的IC数据(未示出)、XRPD图谱(未示出)、PLM图谱(未示出)、TGA图谱(未示出)、DSC图谱(未示出)、等温吸附图谱(未示出)，说明实施例26～32样品与实施例25的样品是相同化合物的同一晶型。
实施例33
取3g制备例1的ACP-196，加100mL异丙醇形成溶液，缓慢滴加20mL含有硫酸(1.1倍摩尔量)的异丙醇溶液，搅拌析晶，2天后，过滤，室温真空干燥16小时，得到2.8g ACP-196硫酸盐的晶型1，产率为77％。
经IC测定，ACP-196硫酸盐中硫酸根含量为18.2％，一硫酸盐硫酸根理论含量为17.0％，二硫酸盐硫酸根理论含量为29.0％，故ACP-196与硫酸以摩尔比约为1:1成盐。
其XRPD图谱如图25所示。
实施例34
取300mg制备例1的ACP-196，加6mL异丙醇形成溶液，缓慢滴加2mL含有硫酸(0.8倍摩尔量)的丙酮溶液，搅拌析晶，1天后，过滤，室温真空干燥20小时，得到220mg ACP-196硫酸盐的晶型1，产率为76％。
实施例35
取300mg制备例1的ACP-196，加3mL丙酮形成溶液，缓慢滴加1mL含有硫酸(1.0倍摩尔量)的丙酮溶液，搅拌析晶，1天后，过滤，室温真空干燥20小时，得到250mg ACP-196硫酸盐的晶型1，产率为69％。
实施例36
对实施例35中的溶剂按以下表格进行替换均可获得ACP-196硫酸盐的晶型1。
Figure PCTCN2017074087-appb-000024
实施例37
取50mg制备例1的ACP-196，加2mL乙酸乙酯形成溶液，滴加8.6mg浓硫酸，加入3mL正己烷，搅拌析晶，1天后，过滤，室温下真空干燥24小时，得到40mg ACP-196硫酸盐的晶型1，产率为81％。
实施例38
取200mg制备例1的ACP-196，加4mL乙酸乙酯形成溶液，滴加47.3mg浓硫酸，加入6mL正己烷，搅拌析晶，3天后，过滤，室温下真空干燥48小时，得到192mg ACP-196硫酸盐的晶型1，产率为79％。
实施例39
取300mg制备例1的ACP-196，加30mL四氢呋喃形成溶液，滴加58.0mg浓硫酸，加入30mL乙醚，搅拌析晶，2天后，过滤，室温下真空干燥20小时，得到210mg ACP-196硫酸盐的晶型1，产率为63％。
实施例40
对实施例39中的溶剂按以下表格进行替换均可获得ACP-196硫酸盐的晶型1。
Figure PCTCN2017074087-appb-000025
实施例34～40制备得到的样品与实施例33的样品具有相同或相似的IC数据(未示出)和XRPD图谱(未示出)，说明实施例34～40样品与实施例33的样品是相同化合物的同一晶型。
实施例41
Figure PCTCN2017074087-appb-000026
Figure PCTCN2017074087-appb-000027
将ACP-196苹果酸盐的晶型1或ACP-196半富马酸盐的晶型1或ACP-196马来酸盐的晶型1或ACP-196磷酸盐的晶型1、可压淀粉、微晶纤维素和交联聚维酮混合，然后通过二氧化硅润滑混合物，最后将其压制成片剂。
实施例42
Figure PCTCN2017074087-appb-000028
将ACP-196苹果酸盐的晶型1或ACP-196半富马酸盐的晶型1或ACP-196马来酸盐的晶型1或ACP-196磷酸盐的晶型1、乙基纤维素、乙基纤维素、羟丙甲基纤维素、乳糖和微晶纤维素混合，用75％乙醇制粒，烘干，粉碎，过80目筛，然后加入硬脂酸镁和滑石粉混匀，填充到胶囊中。
对比例1
表观溶解度测试：25℃水浴条件下，分别取20mg制备例1的ACP-196、本发明的ACP-196苹果酸盐的晶型1、本发明的ACP-196半富马酸盐的晶型1、本发明的ACP-196马来酸盐的晶型1、本发明的ACP-196磷酸盐的晶型1、本发明的ACP-196硫酸盐的晶型1于烧杯中，加入1mL水，搅拌1～2分钟，观察溶解情况，若未溶，则增加溶剂量至完全溶清，最大加水量为200mL。检测结果见下表。
Figure PCTCN2017074087-appb-000029
结果显示：本发明的ACP-196苹果酸盐的晶型1、本发明的ACP-196半富马酸盐的晶型1、本发明的ACP-196马来酸盐的晶型1、本发明的ACP-196磷酸盐的晶型1和本发明的ACP-196硫酸盐的晶型1在水中的溶解度均大于制备例1的ACP-196。

Claims (24)

  1. 结构式如下式(I)所示的ACP-196苹果酸盐的晶型1，
    Figure PCTCN2017074087-appb-100001
    其特征在于，使用Cu-Kα辐射，所述ACP-196苹果酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.2°±0.2°、8.9°±0.2°、12.0°±0.2°、12.4°±0.2°、16.9°±0.2°和22.9°±0.2°。
  2. 根据权利要求1所述的ACP-196苹果酸盐的晶型1，其特征在于，所述ACP-196苹果酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.2°±0.2°、8.9°±0.2°、12.0°±0.2°、12.4°±0.2°、15.6°±0.2°、16.9°±0.2°、19.6°±0.2°、20.3°±0.2°、20.7°±0.2°、22.9°±0.2°、23.8°±0.2°和27.6°±0.2°。
  3. 根据权利要求2所述的ACP-196苹果酸盐的晶型1，其特征在于，所述ACP-196苹果酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2017074087-appb-100002
    Figure PCTCN2017074087-appb-100003
  4. 根据权利要求1～3任一项所述的ACP-196苹果酸盐的晶型1的制备方法，其特征在于，所述制备方法包括以下方法中的任意一种：
    1)分别将ACP-196和苹果酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196苹果酸盐的晶型1；
    优选地，所述ACP-196与苹果酸选择同一种溶剂形成溶液；
    优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
    优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
    优选地，所述ACP-196与苹果酸的摩尔比为1:0.8～1:1.1；
    优选地，所述搅拌时间为1～2天；
    优选地，所述操作过程在室温下进行；
    2)将ACP-196和苹果酸的混合物在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196苹果酸盐的晶型1；
    优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为四氢呋喃；
    优选地，所述ACP-196与良溶剂的质量体积比为20～100mg/mL，更优选为20～50mg/mL；
    优选地，所述ACP-196与苹果酸的摩尔比为1:0.8～1:1.1；
    优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为异丙醚；
    优选地，所述搅拌时间为1～3天；
    优选地，所述操作过程在室温下进行。
  5. 结构式如下式(II)所示的ACP-196半富马酸盐的晶型1，
    Figure PCTCN2017074087-appb-100004
    其特征在于，使用Cu-Kα辐射，所述ACP-196半富马酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.9°±0.2°、9.8°±0.2°、10.8°±0.2°、11.6°±0.2°、16.1°±0.2°和24.9°±0.2°。
  6. 根据权利要求5所述的ACP-196半富马酸盐的晶型1，其特征在于，所 述ACP-196半富马酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.9°±0.2°、7.1°±0.2°、9.8°±0.2°、10.8°±0.2°、11.6°±0.2°、12.2°±0.2°、16.1°±0.2°、20.2°±0.2°、22.0°±0.2°、23.2°±0.2°、24.9°±0.2°和28.2°±0.2°。
  7. 根据权利要求6所述的ACP-196半富马酸盐的晶型1，其特征在于，所述ACP-196半富马酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2017074087-appb-100005
  8. 根据权利要求5～7任一项所述的ACP-196半富马酸盐的晶型1的制备方法，其特征在于，所述制备方法包括以下方法中的任意一种：
    1)分别将ACP-196和富马酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196半富马酸盐的晶型1；
    优选地，所述ACP-196与富马酸选择同一种溶剂形成溶液；
    优选地，所述溶剂为醇类或酮类，更优选为丙酮；
    优选地，所述ACP-196与溶剂形成溶液时的质量体积比为40～200mg/mL，更优选为40～100mg/mL；
    优选地，所述ACP-196与富马酸的摩尔比为1:0.5～1:1.1；
    优选地，所述搅拌时间为1～2天；
    优选地，所述操作过程在室温下进行；
    2)将ACP-196和富马酸的混合物在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196半富马酸盐的晶型1；
    优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为1,4-二氧六环；
    优选地，所述ACP-196与良溶剂的质量体积比为20～100mg/mL，更优选 为50～100mg/mL；
    优选地，所述ACP-196与富马酸的摩尔比为1:0.5～1:1.1；
    优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为异丙醚；
    优选地，所述搅拌时间为1～3天；
    优选地，所述操作过程在室温下进行。
  9. 结构式如下式(III)所示的ACP-196马来酸盐的晶型1，
    Figure PCTCN2017074087-appb-100006
    其特征在于，使用Cu-Kα辐射，所述ACP-196马来酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.3°±0.2°、9.8°±0.2°、10.5°±0.2°、11.7°±0.2°、17.4°±0.2°和24.4°±0.2°。
  10. 根据权利要求9所述的ACP-196马来酸盐的晶型1，其特征在于，所述ACP-196马来酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.3°±0.2°、9.8°±0.2°、10.5°±0.2°、11.7°±0.2°、15.7°±0.2°、17.4°±0.2°、18.8°±0.2°、19.3°±0.2°、19.8°±0.2°、22.8°±0.2°、24.4°±0.2°和24.7°±0.2°。
  11. 根据权利要求10所述的ACP-196马来酸盐的晶型1，其特征在于，所述ACP-196马来酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2017074087-appb-100007
    Figure PCTCN2017074087-appb-100008
  12. 根据权利要求9～11任一项所述的ACP-196马来酸盐的晶型1的制备方法，其特征在于，所述制备方法包括以下方法中的任意一种：
    1)分别将ACP-196和马来酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196马来酸盐的晶型1；
    优选地，所述ACP-196与马来酸选择同一种溶剂形成溶液；
    优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
    优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
    优选地，所述ACP-196与马来酸的摩尔比为1:0.8～1:1.1；
    优选地，所述搅拌时间为1～2天；
    优选地，所述操作过程在室温下进行；
    2)将ACP-196和马来酸的混合物在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196马来酸盐的晶型1；
    优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为四氢呋喃；
    优选地，所述ACP-196与良溶剂的质量体积比为20～100mg/mL，更优选为20～50mg/mL；
    优选地，所述ACP-196与马来酸的摩尔比为1:0.8～1:1.1；
    优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为正庚烷；
    优选地，所述搅拌时间为1～3天；
    优选地，所述操作过程在室温下进行。
  13. 结构式如下式(IV)所示的ACP-196磷酸盐的晶型1，
    Figure PCTCN2017074087-appb-100009
    其特征在于，所述ACP-196磷酸盐的晶型1为倍半水合物，使用Cu-Kα辐射，所述ACP-196磷酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下 特征峰：4.5°±0.2°、10.4°±0.2°、12.0°±0.2°、14.3°±0.2°、18.0°±0.2°和21.9°±0.2°。
  14. 根据权利要求13所述的ACP-196磷酸盐的晶型1，其特征在于，所述ACP-196磷酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.5°±0.2°、6.0°±0.2°、10.4°±0.2°、12.0°±0.2°、14.3°±0.2°、15.5°±0.2°、18.0°±0.2°、19.3°±0.2°、20.5°±0.2°、20.9°±0.2°、21.9°±0.2°和25.1°±0.2°。
  15. 根据权利要求14所述的ACP-196磷酸盐的晶型1，其特征在于，所述ACP-196磷酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2017074087-appb-100010
  16. 根据权利要求13～15任一项所述的ACP-196磷酸盐的晶型1的制备方法，其特征在于，所述制备方法包含下述方法中的任意一种：
    1)分别将ACP-196和磷酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196磷酸盐的晶型1；
    优选地，所述ACP-196与磷酸选择同一种溶剂形成溶液；
    优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
    优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL， 更优选为30～50mg/mL；
    优选地，所述ACP-196与磷酸的摩尔比为1:0.8～1:1.1；
    优选地，所述搅拌时间为1～2天；
    优选地，所述操作过程在室温下进行；
    2)将ACP-196在良溶剂中形成溶液，滴加磷酸后加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196磷酸盐的晶型1；
    优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为二氯甲烷；
    优选地，所述ACP-196与良溶剂的质量体积比为50～150mg/mL，更优选为50～100mg/mL；
    优选地，所述ACP-196与磷酸的摩尔比为1:0.8～1:1.1；
    优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为甲基环己烷；
    优选地，所述搅拌时间为1～3天；
    优选地，所述操作过程在室温下进行。
  17. 结构式如下式(V)所示的ACP-196硫酸盐的晶型1，
    Figure PCTCN2017074087-appb-100011
    其特征在于，使用Cu-Kα辐射，所述ACP-196硫酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：8.9°±0.2°、9.7°±0.2°、17.5°±0.2°、19.6°±0.2°、21.9°±0.2°和23.6°±0.2°。
  18. 根据权利要求17所述的ACP-196硫酸盐的晶型1，其特征在于，所述ACP-196硫酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6°±0.2°、7.9°±0.2°、8.9°±0.2°、9.7°±0.2°、14.6°±0.2°、15.0°±0.2°、17.5°±0.2°、19.6°±0.2°、20.0°±0.2°、21.9°±0.2°、23.6°±0.2°和25.9°±0.2°。
  19. 根据权利要求18所述的ACP-196硫酸盐的晶型1，其特征在于，所述ACP-196硫酸盐的晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2017074087-appb-100012
    Figure PCTCN2017074087-appb-100013
  20. 根据权利要求17～19任一项所述的ACP-196硫酸盐的晶型1的制备方法，其特征在于，所述制备方法包含以下方法中的任意一种：
    1)分别将ACP-196和硫酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述ACP-196硫酸盐的晶型1；
    优选地，所述ACP-196与硫酸选择同一种溶剂形成溶液；
    优选地，所述溶剂为醇类或酮类，更优选为异丙醇；
    优选地，所述ACP-196与溶剂形成溶液时的质量体积比为30～100mg/mL，更优选为30～50mg/mL；
    优选地，所述ACP-196与硫酸的摩尔比为1:0.8～1:1.1；
    优选地，所述搅拌时间为1～2天；
    优选地，所述操作过程在室温下进行；
    2)将ACP-196在良溶剂中形成溶液，滴加硫酸后加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述ACP-196硫酸盐的晶型1；
    优选地，所述良溶剂为乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷或氯仿，更优选为乙酸乙酯；
    优选地，所述ACP-196与良溶剂的质量体积比为10～50mg/mL，更优选为25～50mg/mL；
    优选地，所述ACP-196与硫酸的摩尔比为1:0.8～1:1.1；
    优选地，所述抗溶剂为醚类、烷烃类或甲苯，更优选为正己烷；
    优选地，所述搅拌时间为1～3天；
    优选地，所述操作过程在室温下进行。
  21. 一种药物组合物，其包含治疗和/或预防有效量一种或多种选自权利要求1～4中任一项所述的ACP-196苹果酸盐的晶型1、权利要求5～8中任一项所述的ACP-196半富马酸盐的晶型1、权利要求9～12中任一项所述的ACP-196马来酸盐的晶型1、权利要求13～16中任一项所述的ACP-196磷酸盐的晶型1、权利要求17～20中任一项所述的ACP-196硫酸盐的晶型1，以及至少一种药学上可接受的载体或助剂。
  22. 根据权利要求21所述的药物组合物，其特征在于，所述药物组合物选自适合口服、舌下、皮下、静脉内、肌内、经鼻、局部或直肠给药的制剂。
  23. 权利要求1～4中任一项所述的ACP-196苹果酸盐的晶型1、权利要求5～8中任一项所述的ACP-196半富马酸盐的晶型1、权利要求9～12中任一项所述的ACP-196马来酸盐的晶型1、权利要求13～16中任一项所述的ACP-196磷酸盐的晶型1、权利要求17～20中任一项所述的ACP-196硫酸盐的晶型1在制备用于治疗和/或预防布鲁顿酪氨酸激酶(BTK)介导的疾病或病况的药物中的用途；所述BTK介导的疾病或病况是指由B细胞、肥大细胞、骨髓细胞或破骨细胞起主要作用的任何疾病状态或其它有害病况，包括但不限于，免疫、自身免疫和炎性疾病、过敏症、感染性疾病、骨吸收病症和增生性疾病。
  24. 一种治疗和/或预防布鲁顿酪氨酸激酶(BTK)介导的疾病或病况的方法，所述方法包括给予需要的患者治疗和/或预防有效量的一种或多种选自权利要求1～4中任一项所述的ACP-196苹果酸盐的晶型1、权利要求5～8中任一项所述的ACP-196半富马酸盐的晶型1、权利要求9～12中任一项所述的ACP-196马来酸盐的晶型1、权利要求13～16中任一项所述的ACP-196磷酸盐的晶型1、权利要求17～20中任一项所述的ACP-196硫酸盐的晶型1或权利要求21～22中任一项所述的药物组合物；所述BTK介导的疾病或病况是指由B细胞、肥大细胞、骨髓细胞或破骨细胞起主要作用的任何疾病状态或其它有害病况，包括但不限于，免疫、自身免疫和炎性疾病、过敏症、感染性疾病、骨吸收病症和增生性疾病。
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