WO2019105359A1 - Crystal form of acalabrutinib, preparation method therefor and application thereof - Google Patents

Crystal form of acalabrutinib, preparation method therefor and application thereof Download PDF

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Publication number
WO2019105359A1
WO2019105359A1 PCT/CN2018/117808 CN2018117808W WO2019105359A1 WO 2019105359 A1 WO2019105359 A1 WO 2019105359A1 CN 2018117808 W CN2018117808 W CN 2018117808W WO 2019105359 A1 WO2019105359 A1 WO 2019105359A1
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Prior art keywords
csxi
acalabrutinib
crystal form
crystalline form
crystalline
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PCT/CN2018/117808
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
高慧
刘远
张晓宇
张群
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苏州科睿思制药有限公司
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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
    • A61P35/00—Antineoplastic agents
    • 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 invention relates to the field of medicinal chemistry.
  • it relates to the crystalline form of Acalabrutinib and its preparation and use.
  • Mantle Cell Lymphoma is one of the non-Hodgkin's lymphomas and is a difficult to cure lymphoma.
  • BTK is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell development and activation and survival of mature B cells. BTK has been reported to play a role in apoptosis, and thus BTK inhibitors are useful in the treatment of certain B-cell lymphomas and leukemias.
  • Acalabrutinib is a second-generation BTK inhibitor with higher drug selectivity and lower side effects than the first-generation BTK inhibitor, Ibrutinib.
  • the availability of Acalabrutinib provides a new treatment option for patients with relapsed drug-resistant mantle cell lymphoma.
  • Acalabrutinib was developed by Acerta and launched in the US in October 2017.
  • a crystal form is a solid in which a compound molecule is orderedly arranged in a microstructure to form a crystal lattice, and a drug polymorphism phenomenon means that two or more different crystal forms of a drug exist.
  • Patent WO2017002095A1 discloses eight crystal forms of Acalabrutinib, in which the crystal form I is an anhydrate; the crystal form II is a trihydrate, the flowability is poor, the particle size is not uniform, the water content is different under different conditions, and the highest water content can be Up to 10%; Form III is dihydrate, crystal form is unstable, water content is different under different conditions, the highest water content can reach 8%; Form IV, Form V is anhydrate, unstable, respectively Form II is obtained by dehydration and heat dehydration under low moisture conditions; Form VI, Form VII is a methanol solvate; and Form VIII is an acetic acid solvate.
  • the inventors of the present application have unexpectedly discovered the crystalline form CSXI and crystalline form A of Acalabrutinib, which have advantages in physical and chemical properties, formulation processability and bioavailability, such as melting point, solubility, wettability, There is an advantage in at least one of purification, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability.
  • the stability of the drug substance and the preparation is good, the preparation method is simple and reproducible, the compressibility is good, the intrinsic dissolution rate is high, and the dissolution rate of the preparation is high, which provides a new and better preparation for the preparation of the pharmaceutical preparation containing Acalabrutinib. Choice is very important.
  • the main object of the present invention is to provide a novel crystalline form of Acalabrutinib and a process for its preparation and use.
  • the present invention provides the crystalline form CSXI of the compound (I) (hereinafter referred to as "crystalline form CSXI").
  • the X-ray powder diffraction of the crystalline form CSXI has characteristic peaks at diffraction angles 2 ⁇ of 6.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, and 11.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CSXI has a characteristic peak at one or two of the diffraction angle 2 ⁇ of 22.9° ⁇ 0.2° and 25.1° ⁇ 0.2°; preferably, the crystalline form CSXI
  • the X-ray powder diffraction has a characteristic peak at a diffraction angle 2 ⁇ of 22.9° ⁇ 0.2° and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CSXI is 6.0° ⁇ 0.2°, 11.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 25.1° ⁇ 0.2°, 22.9 at the diffraction angle 2 ⁇ .
  • Any 3, or 4, or 5, or 6, or 7, or 8 of ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, 13.4 ° ⁇ 0.2 °, 22.0 ° ⁇ 0.2, 19.8 ° ⁇ 0.2 There are characteristic peaks at or at 9 places.
  • the X-ray powder diffraction of the crystalline form CSXI is 6.0° ⁇ 0.2°, 11.8° ⁇ 0.2°, 17.5° ⁇ 0.2°, 11.0° ⁇ 0.2°, 22.9 at the diffraction angle 2 ⁇ . Any 3, or 4, or 5, or 6 or 7 of ° ⁇ 0.2 °, 8.0 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, 25.1 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2, or There are characteristic peaks at 8 or 9 places.
  • the X-ray powder diffraction pattern of the crystalline form CSXI is substantially as shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CSXI, the preparation method comprising:
  • the temperature is preferably 40 ° C;
  • the humidity is preferably 75% RH ⁇ 5% RH;
  • the rest time is preferably 3 days.
  • the present invention provides a crystal form H of the compound (I) (hereinafter referred to as "crystal form H") which is an acetonitrile solvate.
  • the X-ray powder diffraction pattern of Form H is substantially as shown in FIG.
  • the present invention provides a method for preparing the crystal form H comprising: placing an Acalabrutinib sample in an acetonitrile solvent to form a suspension, and stirring and crystallization at -20 ° C to 10 ° C.
  • the stirring temperature is preferably 5 °C.
  • the crystal form CSXI provided by the present invention has good physical stability. Placed at 25 ° C / 60% relative humidity, the crystal form did not change for at least 1 month. It shows that the crystalline CSXI API has good long-term stability and is beneficial for drug storage. At the same time, under the condition of 40 ° C / 75% relative humidity, the crystal form did not change for at least 1 month, indicating that the crystalline CSXI bulk drug has better acceleration stability.
  • the physical stability of the drug substance under accelerated conditions is critical to the drug. From the bulk drug to the formulation, it is necessary to undergo storage, transportation and formulation processes, which often encounter harsh conditions, most commonly high temperature and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
  • Form CSXI has good physical stability in the formulation.
  • the crystalline form CSXI of the present invention is mixed with an auxiliary material to form a pharmaceutical preparation, and is placed under the conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and the crystal form does not change for at least 3 months.
  • the transformation of the crystal form can lead to changes in the absorption of the drug, affecting the bioavailability, and even causing the toxic side effects of the drug.
  • the crystalline form CSXI has good physical stability, ensuring consistent controllable quality of the drug substance and the preparation, minimizing the quality change caused by the crystal form change of the drug, affecting the bioavailability, and even causing the toxic side effect of the drug.
  • the crystalline form CSXI of the present invention has superior in vitro dissolution rate and dissolution rate.
  • the intrinsic dissolution rate of the crystalline CSXI bulk drug was 1.3 times that of the prior art WO2017002095A1 Form I in a pH 2.5 HCl/NaCl solution.
  • the crystalline CSXI formulation had a dissolution rate of 94% at 15 minutes in a 0.1 N aqueous hydrochloric acid medium.
  • Dissolution and dissolution rates are important prerequisites for drug absorption.
  • Good in vitro dissolution indicates that the drug has a higher level of absorption in the body, better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug; a high dissolution rate enables the drug to reach the highest concentration in plasma quickly after administration. Value, which in turn ensures that the drug works quickly.
  • crystalline form CSXI provided by the present invention has the following beneficial effects:
  • the crystalline form CSXI provided by the present invention has superior compressibility.
  • the good compressibility of the crystalline form CSXI can effectively improve the hardness/friability of the tableting process, such as unqualified, cracked, etc., making the formulation process more reliable, improving the appearance of the product and improving the product quality.
  • Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
  • the present invention provides the crystal form A of the compound (I) (hereinafter referred to as "crystal form A").
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at diffraction angles 2 ⁇ of 9.8° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 8.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 21.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, and 10.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2 ⁇ of 21.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 10.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, and 26.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2 ⁇ of 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, and 26.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A is 9.8° ⁇ 0.2°, 13.9° ⁇ 0.2°, 8.4° ⁇ 0.2°, 21.7° ⁇ 0.2°, 5.9 at the diffraction angle 2 ⁇ . Any 3, or 4, or 5, or 6 or 7 of ° ⁇ 0.2 °, 10.8 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 18.4 ° ⁇ 0.2 °, 26.0 ° ⁇ 0.2 °, Or there are characteristic peaks at 8 or 9 places.
  • the X-ray powder diffraction pattern of Form A is substantially as shown in FIG.
  • the present invention also provides a method for preparing the crystal form A, the preparation method comprising:
  • a sample of Acalabrutinib free base is dissolved in an alcohol solvent at 30 ° C to 70 ° C, and the temperature is lowered to -20 ° C to 10 ° C to obtain crystal form A;
  • a sample of Acalabrutinib free base is stirred in an alcohol solvent or a mixed solvent of an alcohol solvent and water at -20 ° C to 10 ° C to obtain Form A.
  • the alcohol solvent is preferably methanol.
  • the temperature for cooling or stirring is preferably a temperature of -20 °C.
  • the crystal form A provided by the present invention has good physical stability. It was placed under a closed condition of 25 ° C / 60% relative humidity, and the crystal form did not change for at least 1 month. It is indicated that the crystalline form A drug substance has good long-term stability and is beneficial for drug storage. At the same time, it was placed under the closed condition of 40 ° C / 75% relative humidity, and the crystal form did not change for at least 1 month. It is indicated that the crystalline form A drug substance has good acceleration stability.
  • the physical stability of the drug substance under accelerated conditions is critical to the drug. From the bulk drug to the formulation, it is necessary to undergo storage, transportation and formulation processes, which often encounter harsh conditions, most commonly high temperature and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
  • Form A has good physical stability, ensuring consistent controllable quality of the drug substance and preparation, minimizing drug quality changes due to crystal form changes, bioavailability changes, and even toxic side effects.
  • the crystalline form A of the present invention has a higher solubility in different buffer solutions. Compared to WO2017002095A1 Form I, Form A has a higher solubility in a buffer having a pH of 5.1, 7.4, 8.7.
  • Acalabrutinib is a BCS class II compound that is highly permeable but has low solubility, so increasing solubility is critical. Higher solubility is beneficial to improve the absorption of the drug in the human body, thereby improving the bioavailability and making the drug play a better therapeutic effect. In addition, the higher solubility can lower the dosage of the drug while reducing the drug efficacy, thereby lowering the drug. Side effects and improve the safety of the drug.
  • crystal form A provided by the present invention has the following beneficial effects:
  • the crystal form A provided by the present invention has superior compressibility as compared with the prior art.
  • the good compressibility of the crystal form A can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more controllable, improve the appearance of the product, and improve the product quality.
  • Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form CSXI, Form A or any combination thereof and a pharmaceutically acceptable carrier, diluent or formulation Shape agent.
  • the "room temperature” is not a specific temperature value, and refers to a temperature range of 10 to 30 °C.
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction pattern characterization Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CSXI, Form A of the present invention is pure, substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Figure 2 is a DSC diagram of the crystalline form CSXI obtained in Example 3.
  • Figure 3 is a TGA diagram of the crystalline form CSXI obtained in Example 3.
  • Figure 5 is an XRPD pattern of the solvate form H obtained in Example 1.
  • Figure 6 is a DSC chart of the solvate form H obtained in Example 1.
  • Figure 7 is a TGA diagram of the solvate Form H obtained in Example 1.
  • Figure 1 is a 1 H NMR chart of the solvate Form H obtained in Example 1.
  • Figure 1 1 H NMR chart of the crystalline form CSXI obtained in Example 5.
  • Figure 10 is an XRPD pattern of Form A obtained in Example 14.
  • Figure 11 is a DSC chart of Form A obtained in Example 15.
  • Figure 12 is a TGA diagram of Form A obtained in Example 15.
  • Figure 13 is a 1 H NMR chart of Form A obtained in Example 15.
  • Figure 14 XRPD comparison chart of crystal form CSXI stability study (from top to bottom: initial crystal form CSXI, 25 ° C / 60% RH closed condition for 1 month, 25 ° C / 60% RH open condition Place for 1 month, place at 40°C/75% RH for 1 month, and place at 40°C/75% RH for 1 month.
  • Figure 16 XRPD comparison chart during the process of crystalline CSXI preparation (from top to bottom: blank mixed powder, CSXI capsule preparation and CSXI bulk drug)
  • Figure 18 XRPD comparison chart of stability study of crystalline CSXI preparation (from top to bottom: closed at 40 ° C / 75% relative humidity for 1 month after adding 1 g of desiccant, closed at 25 ° C / 60% relative humidity) Add 1 g of desiccant for 1 month, start the preparation sample)
  • Figure 19 XRPD comparison chart of crystal form A stability study (from top to bottom: initial crystal form A, 25 ° C / 60% RH closed condition for 1 month, 40 ° C / 75% RH closed condition 1 month)
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • the Acalabrutinib and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) and/or its salt as a raw material is in the form of a solid powder.
  • Acalabrutinib free base solids used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2017002095A1.
  • the DSC characterization results of the crystal form sample are shown in Fig. 2, which have two endothermic peaks, and the first endothermic peak starts to appear near 63 ° C, and the endothermic peak is a dehydration endothermic peak. A second endothermic peak begins to appear near 125 ° C, which is the melting endotherm. It is indicated that the crystalline form CSXI is a hydrate.
  • the 1 H NMR characterization results of the crystal form sample are shown in Fig. 4.
  • the NMR results are consistent with the structure of the compound (C 26 H 23 N 7 O 2 ), and the nuclear magnetic data are: 1 H NMR (400 MHz, DMSO-d6) ⁇ 10.
  • the crystal form H of 308.3 mg Acalabrutinib was weighed into a 20 mL glass vial, and the opening was statically placed in a stable box at 40 ° C and 75% RH for humidity induction. After standing for 66 hours, the XRPD was tested, and the obtained solid was tested for the crystal form of the present invention.
  • CSXI Its XRPD data is shown in Table 4.
  • Formabrutinib crystal form H 254.4 mg was weighed into a 20 mL glass vial, and the opening was statically placed in a stable box at 40 ° C, 75% RH for humidity induction. After standing for 64 hours, the XRPD was tested. Type CSXI. Its XRPD data is shown in Table 5. The 1 H NMR characterization results of this crystal form are shown in Figure 9. The peak results are consistent with the structure of the compound.
  • the crystal form H sample of 75.0 mg Acalabrutinib was weighed into a 1.5 mL glass vial, the opening was statically placed at 25 ° C, and the humidity was induced under the condition of 73.5% RH. After 5 days, the XRPD was tested, and the obtained crystalline solid was the crystal of the invention.
  • Type CSXI its XRPD data is shown in Table 6.
  • a crystal form H sample of Acalabrutinib was taken to be about 10 mg, and the change in humidity was controlled by a dynamic moisture adsorption analyzer (DVS) to be 20% RH ⁇ 95% ⁇ 0% RH ⁇ 95% RH to obtain white crystals.
  • DVD dynamic moisture adsorption analyzer
  • the obtained solid was the crystalline form CSXI of the present invention, and its XRPD data is shown in Table 7.
  • the crystalline CSXI maintains good stability under both long-term and accelerated conditions.
  • the tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 12.
  • stage step mixing Weigh the material according to the prescription to the LDPE bag, and put it in the LDPE bag for 2 minutes; Capsule filling Weigh 316.45 ⁇ 2mg mixed powder into 0# capsule shell; package One capsule and 1 g of desiccant were placed in a 35 mL HDPE bottle and sealed.
  • Dissolution apparatus Agilent 708DS method Paddle method medium 0.1N hydrochloric acid aqueous solution Media volume 900mL Rotating speed 50rpm Medium temperature 37 ° C Sampling point 5,10,15,20,30 and 45min
  • the CSXI-containing capsules prepared in Example 11 and 1 g of the desiccant were placed under the conditions of 25 ° C / 60% RH closed, 40 ° C / 75% RH closed, and the crystal form was tested by XRPD method. The results are shown in Table 17, and the XRPD comparison chart is shown in Fig. 18.
  • Form A can be stable for at least 1 month at 25 ° C / 60% RH closed and 40 ° C / 75% RH closed. It can be seen that Form A can maintain good stability under long-term and accelerated conditions.
  • Form A has a higher solubility in a buffer having a pH of 5.1, 7.4, 8.7 as compared to Form I of WO2017002095A1.

Abstract

The present invention relates to a new crystal form of Acalabrutinib and a preparation method therefor, a pharmaceutical composition containing the crystal form, and use of the crystal form in preparing a Bruton's tyrosine kinase inhibitor and a pharmaceutical preparation for treating Mantle Cell Lymphoma. Compared with the prior art, the crystal form of Acalabrutinib provided by the present invention has one or more improved features, and is of great value to the future optimization and development of this drug. (I)

Description

Acalabrutinib的晶型及其制备方法和用途Crystal form of Acalabrutinib and preparation method and use thereof 技术领域Technical field
本发明涉及药物化学领域。具体而言，涉及Acalabrutinib的晶型及其制备方法和用途。The invention relates to the field of medicinal chemistry. In particular, it relates to the crystalline form of Acalabrutinib and its preparation and use.
背景技术Background technique
套细胞淋巴瘤(Mantle Cell Lymphoma)是非霍奇金淋巴瘤中的一种，是一种难以治愈的淋巴瘤。BTK是酪氨酸激酶Tec家族的成员，并且显示是早期B细胞发育以及成熟B细胞活化和存活的关键调节剂。已经报道BTK在细胞凋亡中发挥作用，因此BTK抑制剂可用于治疗某些B-细胞淋巴瘤和白血病。Mantle Cell Lymphoma is one of the non-Hodgkin's lymphomas and is a difficult to cure lymphoma. BTK is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell development and activation and survival of mature B cells. BTK has been reported to play a role in apoptosis, and thus BTK inhibitors are useful in the treatment of certain B-cell lymphomas and leukemias.
Acalabrutinib是第二代BTK抑制剂，相比于第一代的BTK抑制剂Ibrutinib，药物选择性更高，副作用更低。Acalabrutinib的上市给复发耐药的套细胞淋巴瘤患者提供了新的治疗选择。Acalabrutinib由Acerta研发，2017年10月于美国上市。Acalabrutinib的化学名称为：(S)-4-(8-氨基-3-(1-丁-2-炔酰基)吡咯烷-2-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺(以下称为“化合物(I)”)，其结构式如下：Acalabrutinib is a second-generation BTK inhibitor with higher drug selectivity and lower side effects than the first-generation BTK inhibitor, Ibrutinib. The availability of Acalabrutinib provides a new treatment option for patients with relapsed drug-resistant mantle cell lymphoma. Acalabrutinib was developed by Acerta and launched in the US in October 2017. The chemical name of Acalabrutinib is: (S)-4-(8-Amino-3-(1-but-2-ynyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazine-1- -N-(pyridin-2-yl)benzamide (hereinafter referred to as "compound (I)"), which has the following structural formula:
Figure PCTCN2018117808-appb-000001
Figure PCTCN2018117808-appb-000001
晶型是化合物分子在微观结构中有序排列而形成晶格的固体,药物多晶型现象是指药物存在两种或两种以上的不同晶型。A crystal form is a solid in which a compound molecule is orderedly arranged in a microstructure to form a crystal lattice, and a drug polymorphism phenomenon means that two or more different crystal forms of a drug exist.
由于理化性质不同，药物的不同晶型可能在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效和安全性；特别是对难溶性固体药物，晶型的影响会更大。因此，药物晶型必然是药物研究的重要内容，也是药物质量控制的重要内容。Due to different physical and chemical properties, different crystal forms of drugs may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent; especially for poorly soluble solid drugs, the crystal form will have greater influence. Therefore, the drug crystal form is inevitably an important part of drug research and an important part of drug quality control.
专利WO2017002095A1公开了Acalabrutinib的8个晶型，文本中披露晶型I为无水合物；晶型II为三水合物，流动性较差，粒度不均一，不同条件下含水量不同，最高含水量可达10％；晶型III为二水合物，晶型不稳定，不同条件下含水量不同，最高含水量可达8％；晶型IV、晶型V为无水合物，不稳定，分别由晶型II在低水分条件下脱水和加热脱水得到；晶型VI、晶型VII为甲醇溶剂合物；晶型VIII为乙酸溶剂合物。Patent WO2017002095A1 discloses eight crystal forms of Acalabrutinib, in which the crystal form I is an anhydrate; the crystal form II is a trihydrate, the flowability is poor, the particle size is not uniform, the water content is different under different conditions, and the highest water content can be Up to 10%; Form III is dihydrate, crystal form is unstable, water content is different under different conditions, the highest water content can reach 8%; Form IV, Form V is anhydrate, unstable, respectively Form II is obtained by dehydration and heat dehydration under low moisture conditions; Form VI, Form VII is a methanol solvate; and Form VIII is an acetic acid solvate.
本申请的发明人意外发现了Acalabrutinib的晶型CSXI和晶型A，晶型CSXI和晶型A在理化性质，制剂加工性能及生物利用度方面具有优势，例如其在熔点，溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶 出，生物有效性方面中的至少一方面上存在优势。特别是原料药和制剂中的稳定性好，制备方法简单且重复性好，可压性好，固有溶出速率高，制剂溶出度高，为含Acalabrutinib的药物制剂的制备提供了新的更好的选择，具有非常重要的意义。The inventors of the present application have unexpectedly discovered the crystalline form CSXI and crystalline form A of Acalabrutinib, which have advantages in physical and chemical properties, formulation processability and bioavailability, such as melting point, solubility, wettability, There is an advantage in at least one of purification, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability. In particular, the stability of the drug substance and the preparation is good, the preparation method is simple and reproducible, the compressibility is good, the intrinsic dissolution rate is high, and the dissolution rate of the preparation is high, which provides a new and better preparation for the preparation of the pharmaceutical preparation containing Acalabrutinib. Choice is very important.
发明内容Summary of the invention
本发明的主要目的是提供Acalabrutinib的新晶型及其制备方法和用途。The main object of the present invention is to provide a novel crystalline form of Acalabrutinib and a process for its preparation and use.
根据本发明的目的，本发明提供化合物(I)的晶型CSXI(以下称作“晶型CSXI”)。According to the purpose of the present invention, the present invention provides the crystalline form CSXI of the compound (I) (hereinafter referred to as "crystalline form CSXI").
一方面，使用Cu-Kα辐射，所述晶型CSXI的X射线粉末衍射在衍射角2θ为6.0°±0.2°、11.0°±0.2°、11.8°±0.2°处有特征峰。In one aspect, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSXI has characteristic peaks at diffraction angles 2θ of 6.0°±0.2°, 11.0°±0.2°, and 11.8°±0.2°.
进一步地，所述晶型CSXI的X射线粉末衍射在衍射角2θ为22.9°±0.2°、25.1°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CSXI的X射线粉末衍射在衍射角2θ为22.9°±0.2°、25.1°±0.2°处有特征峰。Further, the X-ray powder diffraction of the crystalline form CSXI has a characteristic peak at one or two of the diffraction angle 2θ of 22.9°±0.2° and 25.1°±0.2°; preferably, the crystalline form CSXI The X-ray powder diffraction has a characteristic peak at a diffraction angle 2θ of 22.9°±0.2° and 25.1°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型CSXI的X射线粉末衍射在衍射角2θ为6.0°±0.2°、11.8°±0.2°、15.1°±0.2°、25.1°±0.2°、22.9°±0.2°、11.0°±0.2°、13.4°±0.2°、22.0°±0.2、19.8°±0.2中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSXI is 6.0°±0.2°, 11.8°±0.2°, 15.1°±0.2°, 25.1°±0.2°, 22.9 at the diffraction angle 2θ. Any 3, or 4, or 5, or 6, or 7, or 8 of ° ± 0.2 °, 11.0 ° ± 0.2 °, 13.4 ° ± 0.2 °, 22.0 ° ± 0.2, 19.8 ° ± 0.2 There are characteristic peaks at or at 9 places.
另一方面，使用Cu-Kα辐射，所述晶型CSXI的X射线粉末衍射在衍射角2θ为6.0°±0.2°、11.8°±0.2°、17.5°±0.2°、11.0°±0.2°、22.9°±0.2°、8.0°±0.2°、21.4°±0.2°、25.1°±0.2°、10.4°±0.2中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSXI is 6.0°±0.2°, 11.8°±0.2°, 17.5°±0.2°, 11.0°±0.2°, 22.9 at the diffraction angle 2θ. Any 3, or 4, or 5, or 6 or 7 of ° ± 0.2 °, 8.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 25.1 ° ± 0.2 °, 10.4 ° ± 0.2, or There are characteristic peaks at 8 or 9 places.
非限制性地，晶型CSXI的X射线粉末衍射谱图基本如图1所示。Without limitation, the X-ray powder diffraction pattern of the crystalline form CSXI is substantially as shown in FIG.
根据本发明的目的，本发明还提供所述晶型CSXI的制备方法，所述制备方法包括：According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSXI, the preparation method comprising:
1)将Acalabrutinib的晶型H在4℃-60℃、22％-97％相对湿度(RH)条件下静置1-10天，得到白色晶体；或1) The Form H of Acalabrutinib is allowed to stand at 4 ° C - 60 ° C, 22% - 97% relative humidity (RH) for 1-10 days to obtain white crystals; or
2)将Acalabrutinib的晶型H控制湿度循环为：10％RH-95％-0％RH-95％RH，得到白色晶体。2) The crystal form H controlled humidity of Acalabrutinib was cycled to: 10% RH-95%-0% RH-95% RH to obtain white crystals.
其中，方法1)中：Among them, in method 1):
所述温度优选为40℃；The temperature is preferably 40 ° C;
所述湿度优选为75％RH±5％RH；The humidity is preferably 75% RH ± 5% RH;
所述静置时间优选为3天。The rest time is preferably 3 days.
根据本发明的目的，本发明提供化合物(I)的晶型H(以下称作“晶型H”)，所述晶型H是乙腈溶剂合物。According to an object of the present invention, the present invention provides a crystal form H of the compound (I) (hereinafter referred to as "crystal form H") which is an acetonitrile solvate.
非限制性地，所述晶型H的X射线粉末衍射图基本如图5所示。Without limitation, the X-ray powder diffraction pattern of Form H is substantially as shown in FIG.
进一步地，本发明还提供所述晶型H的制备方法包括：将Acalabrutinib样 品置于乙腈溶剂中形成悬浮液，在-20℃～10℃下搅拌析晶。Further, the present invention provides a method for preparing the crystal form H comprising: placing an Acalabrutinib sample in an acetonitrile solvent to form a suspension, and stirring and crystallization at -20 ° C to 10 ° C.
其中，搅拌温度优选5℃。Among them, the stirring temperature is preferably 5 °C.
本发明提供的晶型CSXI具有以下有益效果：The crystal form CSXI provided by the invention has the following beneficial effects:
(1)本发明提供的晶型CSXI物理稳定性好。在25℃/60％相对湿度条件下放置，至少1个月晶型未发生变化。说明晶型CSXI原料药具有较好的长期稳定性，有利于药物的储存。同时，在40℃/75％相对湿度条件下放置，至少1个月晶型未发生变化，说明晶型CSXI原料药具有较好的加速稳定性。原料药在加速条件下物理稳定性对于药物至关重要。从原料药到制剂需要经历储存、运输和制剂工艺过程，这些过程往往会遇到苛刻的条件，最常见为高温高湿。如原料药在储存和运输过程中的碰撞、制剂生产中的湿法制粒过程、季节和不同地区气候差异、及天气因素等带来的苛刻条件。(1) The crystal form CSXI provided by the present invention has good physical stability. Placed at 25 ° C / 60% relative humidity, the crystal form did not change for at least 1 month. It shows that the crystalline CSXI API has good long-term stability and is beneficial for drug storage. At the same time, under the condition of 40 ° C / 75% relative humidity, the crystal form did not change for at least 1 month, indicating that the crystalline CSXI bulk drug has better acceleration stability. The physical stability of the drug substance under accelerated conditions is critical to the drug. From the bulk drug to the formulation, it is necessary to undergo storage, transportation and formulation processes, which often encounter harsh conditions, most commonly high temperature and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
晶型CSXI在制剂中具有良好的物理稳定性。本发明晶型CSXI与辅料混合做成药物制剂后，在25℃/60％相对湿度和40℃/75％相对湿度条件下放置，至少3个月晶型未发生变化。Form CSXI has good physical stability in the formulation. The crystalline form CSXI of the present invention is mixed with an auxiliary material to form a pharmaceutical preparation, and is placed under the conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and the crystal form does not change for at least 3 months.
晶型的转变会导致药物的吸收发生变化，影响生物利用度，甚至引起药物的毒副作用。晶型CSXI具有良好的物理稳定性，保证原料药和制剂质量一致可控，最大程度地减少药物由于晶型改变引起的质量变化，影响生物利用度，甚至引起药物的毒副作用。The transformation of the crystal form can lead to changes in the absorption of the drug, affecting the bioavailability, and even causing the toxic side effects of the drug. The crystalline form CSXI has good physical stability, ensuring consistent controllable quality of the drug substance and the preparation, minimizing the quality change caused by the crystal form change of the drug, affecting the bioavailability, and even causing the toxic side effect of the drug.
(2)与现有技术相比，本发明晶型CSXI具有更优的体外溶出度与溶出速率。在pH2.5的HCl/NaCl溶液中，晶型CSXI原料药的固有溶出速率是现有技术WO2017002095A1晶型I的1.3倍。晶型CSXI制剂在0.1N盐酸水溶液介质中，15分钟时的溶出度达94％。(2) Compared with the prior art, the crystalline form CSXI of the present invention has superior in vitro dissolution rate and dissolution rate. The intrinsic dissolution rate of the crystalline CSXI bulk drug was 1.3 times that of the prior art WO2017002095A1 Form I in a pH 2.5 HCl/NaCl solution. The crystalline CSXI formulation had a dissolution rate of 94% at 15 minutes in a 0.1 N aqueous hydrochloric acid medium.
不同的晶型可能导致制剂在体内有不同的溶出速率，直接影响制剂在体内的吸收、分布、***、代谢，最终因其生物利用度不同而导致临床药效的差异。溶出度和溶出速率是药物被吸收的重要前提。良好的体外溶出度预示药物的体内吸收程度较高，在体内暴露特性更好，从而提高生物利用度，提高药物的疗效；高的溶出速率使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability. Dissolution and dissolution rates are important prerequisites for drug absorption. Good in vitro dissolution indicates that the drug has a higher level of absorption in the body, better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug; a high dissolution rate enables the drug to reach the highest concentration in plasma quickly after administration. Value, which in turn ensures that the drug works quickly.
进一步地，本发明提供的晶型CSXI还具有以下有益效果：Further, the crystalline form CSXI provided by the present invention has the following beneficial effects:
与现有技术相比，本发明提供的晶型CSXI具有更优的可压性。晶型CSXI好的可压性好可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可靠，改善产品外观，提升产品质量。更优的可压性亦可提升压片速度进而提升生产效率，同时可减少用于改善可压性的辅料的成本支出。Compared with the prior art, the crystalline form CSXI provided by the present invention has superior compressibility. The good compressibility of the crystalline form CSXI can effectively improve the hardness/friability of the tableting process, such as unqualified, cracked, etc., making the formulation process more reliable, improving the appearance of the product and improving the product quality. Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
根据本发明的目的，本发明提供化合物(I)的晶型A(以下称作“晶型A”)。According to the purpose of the present invention, the present invention provides the crystal form A of the compound (I) (hereinafter referred to as "crystal form A").
一方面，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在衍射角2θ为9.8°±0.2°、13.9°±0.2°、8.4°±0.2°处有特征峰。On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has characteristic peaks at diffraction angles 2θ of 9.8°±0.2°, 13.9°±0.2°, and 8.4°±0.2°.
进一步地，所述晶型A的X射线粉末衍射在衍射角2θ为21.7°±0.2°、5.9°±0.2°、 10.8°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型A的X射线粉末衍射在衍射角2θ为21.7°±0.2°、5.9°±0.2°、10.8°±0.2°处有特征峰。Further, the X-ray powder diffraction of the crystal form A has a characteristic peak at one, or two, or three of the diffraction angles 2θ of 21.7°±0.2°, 5.9°±0.2°, and 10.8°±0.2°. Preferably, the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2θ of 21.7°±0.2°, 5.9°±0.2°, 10.8°±0.2°.
进一步地，所述晶型A的X射线粉末衍射在衍射角2θ为18.0°±0.2°、18.4°±0.2°、26.0°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型A的X射线粉末衍射在衍射角2θ为18.0°±0.2°、18.4°±0.2°、26.0°±0.2°处有特征峰。Further, the X-ray powder diffraction of the crystal form A has a characteristic peak at one, or two, or three of the diffraction angles 2θ of 18.0°±0.2°, 18.4°±0.2°, and 26.0°±0.2°. Preferably, the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2θ of 18.0°±0.2°, 18.4°±0.2°, and 26.0°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在衍射角2θ为9.8°±0.2°、13.9°±0.2°、8.4°±0.2°、21.7°±0.2°、5.9°±0.2°、10.8°±0.2°、18.0°±0.2°、18.4°±0.2°、26.0°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A is 9.8°±0.2°, 13.9°±0.2°, 8.4°±0.2°, 21.7°±0.2°, 5.9 at the diffraction angle 2θ. Any 3, or 4, or 5, or 6 or 7 of ° ± 0.2 °, 10.8 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.4 ° ± 0.2 °, 26.0 ° ± 0.2 °, Or there are characteristic peaks at 8 or 9 places.
非限制性地，晶型A的X射线粉末衍射谱图基本如图10所示。Without limitation, the X-ray powder diffraction pattern of Form A is substantially as shown in FIG.
根据本发明的目的，本发明还提供所述晶型A的制备方法，所述制备方法包括:According to the purpose of the present invention, the present invention also provides a method for preparing the crystal form A, the preparation method comprising:
1)将Acalabrutinib游离碱样品在醇类溶剂中30℃～70℃下溶解，降温至-20℃～10℃，得到晶型A；或1) A sample of Acalabrutinib free base is dissolved in an alcohol solvent at 30 ° C to 70 ° C, and the temperature is lowered to -20 ° C to 10 ° C to obtain crystal form A;
2)将Acalabrutinib游离碱样品在醇类溶剂或者醇类溶剂和水的混合溶剂中-20℃～10℃下搅拌，得到晶型A。2) A sample of Acalabrutinib free base is stirred in an alcohol solvent or a mixed solvent of an alcohol solvent and water at -20 ° C to 10 ° C to obtain Form A.
在本发明的晶型A的制备方法中：In the preparation method of the crystal form A of the present invention:
所述醇类溶剂优选为甲醇。The alcohol solvent is preferably methanol.
所述降温或搅拌的温度优选为-20℃温度。The temperature for cooling or stirring is preferably a temperature of -20 °C.
本发明提供的晶型A具有以下有益效果：The crystal form A provided by the invention has the following beneficial effects:
(1)本发明提供的晶型A物理稳定性好。在25℃/60％相对湿度闭口条件下放置，至少1个月晶型未发生变化。说明晶型A原料药具有较好的长期稳定性，有利于药物的储存。同时，在40℃/75％相对湿度闭口条件下放置，至少1个月晶型未发生变化。说明晶型A原料药具有较好的加速稳定性。原料药在加速条件下物理稳定性对于药物至关重要。从原料药到制剂需要经历储存、运输和制剂工艺过程，这些过程往往会遇到苛刻的条件，最常见为高温高湿。如原料药在储存和运输过程中的碰撞、制剂生产中的湿法制粒过程、季节和不同地区气候差异、及天气因素等带来的苛刻条件。(1) The crystal form A provided by the present invention has good physical stability. It was placed under a closed condition of 25 ° C / 60% relative humidity, and the crystal form did not change for at least 1 month. It is indicated that the crystalline form A drug substance has good long-term stability and is beneficial for drug storage. At the same time, it was placed under the closed condition of 40 ° C / 75% relative humidity, and the crystal form did not change for at least 1 month. It is indicated that the crystalline form A drug substance has good acceleration stability. The physical stability of the drug substance under accelerated conditions is critical to the drug. From the bulk drug to the formulation, it is necessary to undergo storage, transportation and formulation processes, which often encounter harsh conditions, most commonly high temperature and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
晶型的转变会导致药物的吸收发生变化，影响生物利用度，甚至引起药物的毒副作用。晶型A具有良好的物理稳定性，保证原料药和制剂质量一致可控，最大程度地减少药物由于晶型改变引起的药物质量变化，生物利用度改变，甚至毒副作用。The transformation of the crystal form can lead to changes in the absorption of the drug, affecting the bioavailability, and even causing the toxic side effects of the drug. Form A has good physical stability, ensuring consistent controllable quality of the drug substance and preparation, minimizing drug quality changes due to crystal form changes, bioavailability changes, and even toxic side effects.
(2)与现有技术相比，本发明晶型A在不同缓冲溶液中的溶解度更高。与WO2017002095A1晶型I相比，晶型A在pH为5.1，7.4，8.7的缓冲液中具有更高的溶解度。(2) Compared with the prior art, the crystalline form A of the present invention has a higher solubility in different buffer solutions. Compared to WO2017002095A1 Form I, Form A has a higher solubility in a buffer having a pH of 5.1, 7.4, 8.7.
Acalabrutinib为BCS II类化合物，该类化合物渗透性高，但溶解性低，因此 提高溶解度非常关键。更高的溶解度有利于提高药物在人体内的吸收，从而提高生物利用度使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Acalabrutinib is a BCS class II compound that is highly permeable but has low solubility, so increasing solubility is critical. Higher solubility is beneficial to improve the absorption of the drug in the human body, thereby improving the bioavailability and making the drug play a better therapeutic effect. In addition, the higher solubility can lower the dosage of the drug while reducing the drug efficacy, thereby lowering the drug. Side effects and improve the safety of the drug.
进一步地，本发明提供的晶型A还具有以下有益效果：Further, the crystal form A provided by the present invention has the following beneficial effects:
与现有技术相比，本发明提供的晶型A具有更优的可压性。晶型A可压性好可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可控，改善产品外观，提升产品质量。更优的可压性亦可提升压片速度进而提升生产效率，同时可减少用于改善可压性的辅料的成本支出。The crystal form A provided by the present invention has superior compressibility as compared with the prior art. The good compressibility of the crystal form A can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more controllable, improve the appearance of the product, and improve the product quality. Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSXI、晶型A或它们的任意组合及药学上可接受的载体、稀释剂或赋形剂。In accordance with the purpose of the present invention, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of Form CSXI, Form A or any combination thereof and a pharmaceutically acceptable carrier, diluent or formulation Shape agent.
进一步地，本发明提的晶型CSXI、晶型A或它们的任意组合在制备布鲁顿酪氨酸激酶抑制剂药物中的用途。Further, the use of the crystalline form CSXI, Form A or any combination thereof of the present invention for the preparation of a Bruton's tyrosine kinase inhibitor drug.
更进一步地，本发明提供的晶型CSXI、晶型A或它们的任意组合在制备治疗套细胞淋巴癌药物中的用途。Further, the use of the crystalline form CSXI, Form A or any combination thereof provided by the present invention for the preparation of a medicament for treating a mantle cell lymphoma.
本发明中，所述“室温”不是特定的温度值，是指10-30℃温度范围。In the present invention, the "room temperature" is not a specific temperature value, and refers to a temperature range of 10 to 30 °C.
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线粉末衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystal" or "polymorph" means confirmed by X-ray powder diffraction pattern characterization. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal. The peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample thickness, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray powder diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray powder diffraction pattern in the examples referred to herein, and the "XRPD pattern is the same" as described herein. Absolutely the same, the same peak position can differ by ±0.2° and the peak intensity allows for some variability. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
在一些实施方案中，本发明的晶型CSXI、晶型A是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, the crystalline form CSXI, Form A of the present invention is pure, substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不 背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。It should be noted that the numerical values and numerical ranges recited in the present invention are not to be construed as narrowly construed as a numerical value or a numerical range per se. It will be understood by those skilled in the art that they may vary depending on the specific technical environment without departing from the spirit of the invention. On the basis of the principle, there are fluctuations around specific numerical values. In the present invention, such a floating range which can be foreseen by those skilled in the art is often expressed by the term "about".
附图说明DRAWINGS
图1实施例3得到的晶型CSXI的XRPD图Figure 1 XRPD pattern of the crystalline form CSXI obtained in Example 3.
图2实施例3得到的晶型CSXI的DSC图Figure 2 is a DSC diagram of the crystalline form CSXI obtained in Example 3.
图3实施例3得到的晶型CSXI的TGA图Figure 3 is a TGA diagram of the crystalline form CSXI obtained in Example 3.
图4实施例3得到的晶型CSXI的 1H NMR图 Figure 1 1 H NMR chart of the crystalline form CSXI obtained in Example 3.
图5实施例1得到的溶剂合物晶型H的XRPD图Figure 5 is an XRPD pattern of the solvate form H obtained in Example 1.
图6实施例1得到的溶剂合物晶型H的DSC图Figure 6 is a DSC chart of the solvate form H obtained in Example 1.
图7实施例1得到的溶剂合物晶型H的TGA图Figure 7 is a TGA diagram of the solvate Form H obtained in Example 1.
图8实施例1得到的溶剂合物晶型H的 1H NMR图 Figure 1 is a 1 H NMR chart of the solvate Form H obtained in Example 1.
图9实施例5得到的晶型CSXI的 1H NMR图 Figure 1 1 H NMR chart of the crystalline form CSXI obtained in Example 5.
图10实施例14得到的晶型A的XRPD图Figure 10 is an XRPD pattern of Form A obtained in Example 14.
图11实施例15得到的晶型A的DSC图Figure 11 is a DSC chart of Form A obtained in Example 15.
图12实施例15得到的晶型A的TGA图Figure 12 is a TGA diagram of Form A obtained in Example 15.
图13实施例15得到的晶型A的 1H NMR图 Figure 13 is a 1 H NMR chart of Form A obtained in Example 15.
图14晶型CSXI稳定性研究的XRPD对比图(由上至下分别为：起始晶型CSXI，25℃/60％RH闭口条件下放置1个月，25℃/60％RH敞口条件下放置1个月，40℃/75％RH闭口条件下放置1个月，40℃/75％RH敞口条件下放置1个月)Figure 14 XRPD comparison chart of crystal form CSXI stability study (from top to bottom: initial crystal form CSXI, 25 ° C / 60% RH closed condition for 1 month, 25 ° C / 60% RH open condition Place for 1 month, place at 40°C/75% RH for 1 month, and place at 40°C/75% RH for 1 month.
图15晶型CSXI的固有溶出曲线Figure 15 Intrinsic dissolution curve of crystalline CSXI
图16晶型CSXI制剂工艺过程中的XRPD对比图(从上到下依次为：空白混粉、CSXI胶囊制剂以及CSXI原料药)Figure 16 XRPD comparison chart during the process of crystalline CSXI preparation (from top to bottom: blank mixed powder, CSXI capsule preparation and CSXI bulk drug)
图17晶型CSXI制剂的溶出曲线Figure 17 Dissolution curve of crystalline CSXI preparation
图18晶型CSXI制剂的稳定性研究的XRPD对比图(从上到下分别为：在40℃/75％相对湿度闭口加1g干燥剂放置1个月后、在25℃/60％相对湿度闭口加1g干燥剂放置1个月后、起始制剂样品)Figure 18 XRPD comparison chart of stability study of crystalline CSXI preparation (from top to bottom: closed at 40 ° C / 75% relative humidity for 1 month after adding 1 g of desiccant, closed at 25 ° C / 60% relative humidity) Add 1 g of desiccant for 1 month, start the preparation sample)
图19晶型A稳定性研究的XRPD对比图(由上至下分别为：起始晶型A，25℃/60％RH闭口条件下放置1个月，40℃/75％RH闭口条件下放置1个月)Figure 19 XRPD comparison chart of crystal form A stability study (from top to bottom: initial crystal form A, 25 ° C / 60% RH closed condition for 1 month, 40 ° C / 75% RH closed condition 1 month)
具体实施方式Detailed ways
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。The invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric analysis
1H NMR：液态核磁氢谱 1 H NMR: liquid NMR
HPLC：高效液相色谱HPLC: high performance liquid chromatography
采集数据所用的仪器及方法：Instruments and methods used to collect data:
本发明所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:
X射线光源：Cu,KαX-ray source: Cu, Kα
Figure PCTCN2018117808-appb-000002
1.54060；
Figure PCTCN2018117808-appb-000003
1.54439
Figure PCTCN2018117808-appb-000002
1.54060;
Figure PCTCN2018117808-appb-000003
1.54439
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：30仟伏特(kV)Voltage: 30 volts (kV)
电流：10毫安培(mA)Current: 10 milliamperes (mA)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。 Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，测试纯度的方法参数如下：The high performance liquid chromatography (HPLC) data of the present invention was taken from Agilent 1260, and the method parameters for testing purity are as follows:
1、色谱柱：Ultimate LP-C18,250×4.6mm,5μm1. Column: Ultimate LP-C18, 250×4.6mm, 5μm
2、流动相：A:0.1％H 3PO 4水溶液(pH＝3.5,TEA) 2. Mobile phase: A: 0.1% H 3 PO 4 aqueous solution (pH=3.5, TEA)
B:乙腈B: acetonitrile
洗脱梯度如下：The elution gradient is as follows:
时间(min)Time (min) ％B%B
0.00.0 2020
9.09.0 3434
11.011.0 4040
18.018.0 5050
22.022.0 7070
30.030.0 7070
31.031.0 2020
40.040.0 2020
3、流速：1.0mL/min3. Flow rate: 1.0mL/min
4、进样量：10μL4, injection volume: 10μL
5、检测波长：230nm5, detection wavelength: 230nm
6、柱温：40℃6, column temperature: 40 ° C
7、稀释剂：乙腈7, thinner: acetonitrile
根据本发明，作为原料的所述Acalabrutinib和/或其盐指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物(I)和/或其盐为固体粉末形式。According to the present invention, the Acalabrutinib and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compound (I) and/or its salt as a raw material is in the form of a solid powder.
以下实施例中所使用的Acalabrutinib游离碱固体可根据现有技术制备得到，例如根据WO2017002095A1文献所记载的方法制备获得。The Acalabrutinib free base solids used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2017002095A1.
具体实施方式Detailed ways
实施例1溶剂合物晶型H的制备方法Example 1 Preparation method of solvate crystal form H
称取2.50g的Acalabrutinib游离碱至100mL结晶釜中，加入25mL的L-乳酸乙酯，升温至40℃，搅拌8h后降温至20℃，继续搅拌过夜，分离得到固体，称取535.2mg该固体样品于20mL玻璃瓶中，加入20mL乙腈于形成悬浮液，于5℃搅拌三天后将样品离心，滤饼于室温下敞口干燥过夜，所得固体为本发明晶型H。其XRPD如附图5所示，其XRPD数据如表1所示。其DSC图如附图6，加热至133℃附近出现第一个吸热峰，为脱溶剂吸热峰。其TGA图如附图7，加热至150℃时，具有约7.7％的质量损失。该晶型的 1H NMR表征结果如图8所示，核磁结果与该化合物结构一致，核磁数据为：δH(400MHz,DMSO)10.87(1H,s),8.46–8.38(m,1H),8.23(d,J＝8.4Hz,1H),8.16(dd,J＝8.4,2.5Hz,2H),7.85(ddd,J＝21.8,12.2,3.5Hz,2H),7.74(t,J＝7.8Hz,2H),7.23–7.09(m,2H),6.18(d,J＝24.7Hz,2H),5.60(ddd,J＝96.3,7.6,4.3Hz,1H),3.83(t,J＝6.5Hz,1H),3.68–3.54(m,1H),2.45–2.18(m,2H),2.17–2.10(m,1H),2.08(s,2H),2.04–1.92(m,3H),1.63(s,1H).根据核磁数据可知， 1HNMR在2.08处的明显单峰对应乙腈上氢的核磁峰位置，晶型H为乙腈溶剂合物。 2.50 g of Acalabrutinib free base was weighed into a 100 mL crystallization kettle, 25 mL of L-lactate was added, and the temperature was raised to 40 ° C. After stirring for 8 h, the temperature was lowered to 20 ° C, stirring was continued overnight, and a solid was isolated, and 535.2 mg of the solid was weighed. The sample was placed in a 20 mL glass vial, 20 mL of acetonitrile was added to form a suspension, and after stirring at 5 ° C for three days, the sample was centrifuged, and the filter cake was dried overnight at room temperature, and the obtained solid was the crystalline form H of the present invention. Its XRPD is shown in Figure 5, and its XRPD data is shown in Table 1. Its DSC chart is as shown in Fig. 6, and the first endothermic peak appears near the temperature of 133 ° C, which is the desolvation endothermic peak. Its TGA pattern is as shown in Figure 7, with a mass loss of about 7.7% when heated to 150 °C. The 1 H NMR characterization results of this crystal form are shown in Fig. 8. The NMR results are consistent with the structure of the compound. The NMR data are: δH (400 MHz, DMSO) 10.87 (1H, s), 8.46–8.38 (m, 1H), 8.23. (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 8.4, 2.5 Hz, 2H), 7.85 (ddd, J = 21.8, 12.2, 3.5 Hz, 2H), 7.74 (t, J = 7.8 Hz, 2H), 7.23–7.09 (m, 2H), 6.18 (d, J=24.7 Hz, 2H), 5.60 (ddd, J=96.3, 7.6, 4.3 Hz, 1H), 3.83 (t, J=6.5 Hz, 1H) ), 3.68–3.54 (m, 1H), 2.45–2.18 (m, 2H), 2.17–2.10 (m, 1H), 2.08 (s, 2H), 2.04–1.92 (m, 3H), 1.63 (s, 1H) According to the nuclear magnetic data, a distinct single peak at 1 H NMR at 2.08 corresponds to the nuclear magnetic peak position of hydrogen on acetonitrile, and Form H is an acetonitrile solvate.
表1Table 1
Figure PCTCN2018117808-appb-000004
Figure PCTCN2018117808-appb-000004
Figure PCTCN2018117808-appb-000005
Figure PCTCN2018117808-appb-000005
实施例2溶剂合物晶型H的制备方法Example 2 Preparation method of solvate crystal form H
称取3.508g Acalabrutinib游离碱样品于100mL结晶反应瓶中，加入44mL在4℃预冷过的乙腈溶剂形成悬浮液，置于4℃下搅拌6天后离心得到固体。经检测，本实施例得到的固体为本发明晶型H。其XRPD数据如表2所示。A sample of 3.508 g of Acalabrutinib free base was weighed into a 100 mL crystallization reaction flask, and 44 mL of a pre-cooled acetonitrile solvent at 4 ° C was added to form a suspension, which was stirred at 4 ° C for 6 days and then centrifuged to obtain a solid. Upon examination, the solid obtained in this example was the crystalline form H of the present invention. Its XRPD data is shown in Table 2.
表2Table 2
Figure PCTCN2018117808-appb-000006
Figure PCTCN2018117808-appb-000006
Figure PCTCN2018117808-appb-000007
Figure PCTCN2018117808-appb-000007
实施例3晶型CSXI的制备方法Example 3 Preparation method of crystalline form CSXI
称取1.2g的Acalabrutinib游离碱至玻璃小瓶中，加入20mL的乳酸乙酯形成悬浮液，室温下磁力搅拌大约30分钟后过滤，将滤饼转移至50℃烘箱中干燥1天。干燥后的样品加入10mL的乙腈中形成悬浮液，室温下磁力搅拌1天，再次过滤分离固体，并在50℃烘箱中干燥1天。将得到的固体转移至5℃冰箱(湿度：～90％RH)中放置3天。经检测，本实施例中最后得到的固体为晶型CSXI，其XRPD如图1和表。1.2 g of Acalabrutinib free base was weighed into a glass vial, 20 mL of ethyl lactate was added to form a suspension, magnetically stirred at room temperature for about 30 minutes, and then filtered, and the filter cake was transferred to an oven at 50 ° C for 1 day. The dried sample was added to 10 mL of acetonitrile to form a suspension, and magnetically stirred at room temperature for 1 day, and the solid was separated again by filtration and dried in an oven at 50 ° C for 1 day. The obtained solid was transferred to a refrigerator (humidity: -90% RH) at 5 ° C for 3 days. Upon examination, the solid obtained in the present example was the crystalline form CSXI, and its XRPD is shown in Table 1 and Table.
该晶型样品的DSC表征结果如图2所示，其有两个吸热峰，在63℃附近开始出现第一个吸热峰，该吸热峰为脱水吸热峰。在125℃附近开始出现第二个吸热峰，该吸热峰为熔化吸热峰。表明晶型CSXI为水合物。The DSC characterization results of the crystal form sample are shown in Fig. 2, which have two endothermic peaks, and the first endothermic peak starts to appear near 63 ° C, and the endothermic peak is a dehydration endothermic peak. A second endothermic peak begins to appear near 125 ° C, which is the melting endotherm. It is indicated that the crystalline form CSXI is a hydrate.
该晶型样品的TGA表征结果如图3所示，加热至100℃时，具有约9.8％的质量损失梯度，对应加热过程中脱水。The TGA characterization results for this crystalline sample are shown in Figure 3. When heated to 100 ° C, there is a mass loss gradient of about 9.8%, corresponding to dehydration during heating.
该晶型样品的 1H NMR表征结果如图4所示，核磁结果与该化合物结构(C 26H 23N 7O 2)一致，核磁数据为： 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.41(dd,J＝4.8,1.1Hz,1H),8.27–8.10(m,3H),7.91–7.66(m,4H),7.23–7.07(m,2H),6.15(d,J＝25.0Hz,2H),5.60(ddd,J＝94.6,7.6,4.2Hz,1H),3.82(t,J＝6.6Hz,1H),3.70–3.50(m,1H),2.45–2.19(m,2H),2.18–1.77(m,4H),1.62(s,1H)。 The 1 H NMR characterization results of the crystal form sample are shown in Fig. 4. The NMR results are consistent with the structure of the compound (C 26 H 23 N 7 O 2 ), and the nuclear magnetic data are: 1 H NMR (400 MHz, DMSO-d6) δ 10. 83(s,1H), 8.41 (dd, J=4.8, 1.1 Hz, 1H), 8.27–8.10 (m, 3H), 7.91–7.66 (m, 4H), 7.23–7.07 (m, 2H), 6.15 ( d, J = 25.0 Hz, 2H), 5.60 (ddd, J = 94.6, 7.6, 4.2 Hz, 1H), 3.82 (t, J = 6.6 Hz, 1H), 3.70 - 3.50 (m, 1H), 2.45 - 2.19 (m, 2H), 2.18 - 1.77 (m, 4H), 1.62 (s, 1H).
表3table 3
Figure PCTCN2018117808-appb-000008
Figure PCTCN2018117808-appb-000008
Figure PCTCN2018117808-appb-000009
Figure PCTCN2018117808-appb-000009
实施例4晶型CSXI的制备方法Example 4 Preparation method of crystalline form CSXI
称取308.3mg Acalabrutinib的晶型H于20mL玻璃小瓶中，开口静置于40℃，75％RH的稳定箱中进行湿度诱导，放置66小时后测试XRPD，经检测，所得固体为本发明晶型CSXI。其XRPD数据如表4所示。The crystal form H of 308.3 mg Acalabrutinib was weighed into a 20 mL glass vial, and the opening was statically placed in a stable box at 40 ° C and 75% RH for humidity induction. After standing for 66 hours, the XRPD was tested, and the obtained solid was tested for the crystal form of the present invention. CSXI. Its XRPD data is shown in Table 4.
表4Table 4
Figure PCTCN2018117808-appb-000010
Figure PCTCN2018117808-appb-000010
Figure PCTCN2018117808-appb-000011
Figure PCTCN2018117808-appb-000011
实施例5晶型CSXI的制备方法Example 5 Preparation method of crystalline form CSXI
称取254.4mg的Acalabrutinib的晶型H于20mL玻璃小瓶中，开口静置于40℃，75％RH的稳定箱中进行湿度诱导，放置64小时后测试XRPD，经检测，所得固体为本发明晶型CSXI。其XRPD数据如表5所示。该晶型的 1H NMR表征结果如图9所示，出峰结果与该化合物结构一致，核磁数据为： 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.47–8.35(m,1H),8.22(d,J＝8.4Hz,1H),8.16(dd,J＝8.4,2.6Hz,2H),7.91–7.78(m,2H),7.74(t,J＝7.6Hz,2H),7.24–7.07(m,2H),6.14(d,J＝25.3Hz,2H),5.60(ddd,J＝93.3,7.6,4.2Hz,1H),3.83(t,J＝6.6Hz,1H),3.69–3.50(m,1H),2.45–2.20(m,2H),2.18–2.09(m,1H),2.08–1.92(m,3H),1.62(s,1H)。 254.4 mg of Formabrutinib crystal form H was weighed into a 20 mL glass vial, and the opening was statically placed in a stable box at 40 ° C, 75% RH for humidity induction. After standing for 64 hours, the XRPD was tested. Type CSXI. Its XRPD data is shown in Table 5. The 1 H NMR characterization results of this crystal form are shown in Figure 9. The peak results are consistent with the structure of the compound. The nuclear magnetic data are: 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.47–8.35 (m, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 8.4, 2.6 Hz, 2H), 7.91 - 7.78 (m, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.24–7.07 (m, 2H), 6.14 (d, J=25.3 Hz, 2H), 5.60 (ddd, J=93.3, 7.6, 4.2 Hz, 1H), 3.83 (t, J=6.6 Hz, 1H) ), 3.69 - 3.50 (m, 1H), 2.45 - 2.20 (m, 2H), 2.18 - 2.09 (m, 1H), 2.08 - 1.92 (m, 3H), 1.62 (s, 1H).
表5table 5
Figure PCTCN2018117808-appb-000012
Figure PCTCN2018117808-appb-000012
Figure PCTCN2018117808-appb-000013
Figure PCTCN2018117808-appb-000013
实施例6晶型CSXI的制备方法Example 6 Preparation method of crystalline form CSXI
称取75.0mg Acalabrutinib的晶型H样品于1.5mL玻璃小瓶中，开口静置于25℃，73.5％RH的条件下进行湿度诱导，放置5天后测试XRPD，经检测，所得结晶固体为本发明晶型CSXI，其XRPD数据如表6所示。The crystal form H sample of 75.0 mg Acalabrutinib was weighed into a 1.5 mL glass vial, the opening was statically placed at 25 ° C, and the humidity was induced under the condition of 73.5% RH. After 5 days, the XRPD was tested, and the obtained crystalline solid was the crystal of the invention. Type CSXI, its XRPD data is shown in Table 6.
表6Table 6
Figure PCTCN2018117808-appb-000014
Figure PCTCN2018117808-appb-000014
Figure PCTCN2018117808-appb-000015
Figure PCTCN2018117808-appb-000015
实施例7晶型CSXI的制备方法Example 7 Preparation method of crystalline form CSXI
取Acalabrutinib的晶型H样品约10mg，通过动态水分吸附分析仪(DVS)控制湿度变化为：20％RH→95％→0％RH→95％RH，得到白色晶体。经检测，所得固体为本发明晶型CSXI，其XRPD数据如表7所示。A crystal form H sample of Acalabrutinib was taken to be about 10 mg, and the change in humidity was controlled by a dynamic moisture adsorption analyzer (DVS) to be 20% RH → 95% → 0% RH → 95% RH to obtain white crystals. Upon examination, the obtained solid was the crystalline form CSXI of the present invention, and its XRPD data is shown in Table 7.
表7Table 7
Figure PCTCN2018117808-appb-000016
Figure PCTCN2018117808-appb-000016
实施例8晶型CSXI的稳定性Example 8 Stability of Form CSXI
称取4份本发明晶型CSXI，各约10mg，分别放置在25℃/60％RH敞口、25℃/60％RH闭口、40℃/75％RH敞口、40℃/75％RH闭口条件下，采用XRPD法测定晶型。结果如表8所示，XRPD对比图如图14所示。Weigh 4 parts of the crystalline form CSXI of the present invention, each about 10 mg, placed at 25 ° C / 60% RH open, 25 ° C / 60% RH closed, 40 ° C / 75% RH open, 40 ° C / 75% RH closed Under the conditions, the crystal form was determined by the XRPD method. The results are shown in Table 8, and the XRPD comparison chart is shown in Fig. 14.
表8Table 8
Figure PCTCN2018117808-appb-000017
Figure PCTCN2018117808-appb-000017
结果表明，晶型CSXI在25℃/60％RH敞口、25℃/60％RH闭口、40℃/75％RH敞口、40℃/75％RH闭口条件下至少可稳定1个月，可见，晶型CSXI在长期和加速条件下均可保持良好的稳定性。The results show that the crystalline CSXI can be stabilized for at least 1 month at 25 ° C / 60% RH open, 25 ° C / 60% RH closed, 40 ° C / 75% RH open, 40 ° C / 75% RH closed condition. The crystalline CSXI maintains good stability under both long-term and accelerated conditions.
实施例9晶型CSXI的固有溶出速率Example 9 Intrinsic dissolution rate of crystalline CSXI
分别称取约200mg的晶型CSXI与WO2017002095A1晶型I，倒入固有溶出模具，在10kN压力下持续1min，制成表面积为0.5cm 2的薄片，确保薄片完整后将固有溶出模具转移至溶出仪测试固有溶出速率，测试条件如表9所示，测得的溶出曲线如图15所示，溶出数据如表10所示。根据0-35min之间的测定点计算斜率，以mg/min表示，由斜率进一步计算固有溶出速率(IDR)，以mg/min/cm 2表示，IDR结果如表11所示。 About 200 mg of crystalline form CSXI and WO2017002095A1 crystalline form I were weighed separately, poured into an intrinsic dissolution mold, and kept at a pressure of 10 kN for 1 min to prepare a sheet having a surface area of 0.5 cm 2 to ensure that the intrinsic dissolution mold was transferred to the dissolution apparatus after the sheet was completed. The intrinsic dissolution rate was tested. The test conditions are shown in Table 9, the measured dissolution profile is shown in Figure 15, and the dissolution data is shown in Table 10. The slope was calculated from the measurement points between 0 and 35 min, expressed in mg/min, and the intrinsic dissolution rate (IDR) was further calculated from the slope, expressed in mg/min/cm 2 , and the IDR results are shown in Table 11.
表9Table 9
溶出仪Dissolution apparatus Agilent 708DSAgilent 708DS
介质medium pH＝2.5盐酸/氯化钠水溶液pH=2.5 hydrochloric acid/sodium chloride aqueous solution
介质体积Media volume 500mL500mL
转速Rotating speed 100rpm100rpm
介质温度Medium temperature 37℃37 ° C
取样点Sampling point 5,10,15,20,25,30,35min5,10,15,20,25,30,35min
补充介质Supplementary medium 不补充(每个时间点取样1.0mL)Not added (sample 1.0mL at each time point)
表10Table 10
Figure PCTCN2018117808-appb-000018
Figure PCTCN2018117808-appb-000018
表11Table 11
晶型Crystal form IDR(mg/min/cm 2) IDR (mg/min/cm 2 )
WO2017002095A1晶型IWO2017002095A1 Crystal Form I 0.36760.3676
晶型CSXICrystal CSXI 0.46200.4620
结果表明，晶型CSXI的溶出速率约是WO2017002095A1晶型I的1.3倍。The results showed that the dissolution rate of the crystalline form CSXI was about 1.3 times that of the crystal form I of WO2017002095A1.
实施例10晶型CSXI的可压性Example 10 Compressibility of Form CSXI
称取晶型CSXI与WO2017002095A1晶型I各约80mg，采用手动压片机进行压片，选择6mm圆形平冲，在10kN的压力下压制成圆形片剂，放置于干燥器中24小时，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)，同时采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好，实验结果如表12所示。The crystal form CSXI and the WO2017002095A1 crystal form I were each weighed about 80 mg, and were pressed by a manual tableting machine. A 6 mm round flat punch was selected, and a round tablet was pressed under a pressure of 10 kN, and placed in a desiccator for 24 hours. After full elastic recovery, the radial crushing force (hardness, H) was measured by a tablet hardness tester, and the diameter (D) and thickness (L) of the tablet were measured using a vernier caliper, and the difference was calculated by the formula T=2H/πDL. The tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 12.
表12Table 12
晶型Crystal form 抗张强度(MPa)Tensile strength (MPa)
WO2017002095A1晶型IWO2017002095A1 Crystal Form I 无法压制成片Unable to compress into tablets
晶型CSXICrystal CSXI 1.891.89
结果表明，晶型CSXI较WO2017002095A1晶型I抗张强度更大，具有更优的可压性。The results show that the crystalline form CSXI has higher tensile strength than the WO2017002095A1 crystal form I, and has better compressibility.
实施例11晶型CSXI的制剂处方工艺Example 11 Formulation Process for Forming Form of CSXI
使用本发明中的晶型CSXI，根据表13中所列的制剂配方，按照表14所述的制剂步骤，制备成相应的胶囊，并分别检测制成胶囊后药物晶型的变化，测试结果如图16所示。Using the crystalline form CSXI of the present invention, according to the formulation formulas listed in Table 13, according to the formulation steps described in Table 14, the corresponding capsules were prepared, and the changes in the crystalline form of the drug after the capsules were respectively measured, and the test results were as follows. Figure 16 shows.
表13Table 13
Figure PCTCN2018117808-appb-000019
Figure PCTCN2018117808-appb-000019
表14Table 14
阶段stage 步骤step
混合mixing 根据处方称取物料至LDPE袋，置LDPE袋混合2min；Weigh the material according to the prescription to the LDPE bag, and put it in the LDPE bag for 2 minutes;
胶囊填装Capsule filling 称量316.45±2mg混粉装入0#胶囊壳；Weigh 316.45±2mg mixed powder into 0# capsule shell;
包装package 将1粒胶囊与1g干燥剂装入35mL HDPE瓶中，封口。One capsule and 1 g of desiccant were placed in a 35 mL HDPE bottle and sealed.
结果表明，晶型CSXI在胶囊制剂的工艺中，固体晶型保持不变。The results show that the crystalline form of CSXI remains unchanged in the process of capsule preparation.
实施例12晶型CSXI制剂的溶出度Example 12 Dissolution of Formal CSXI Formulations
使用实施例11中制备的含晶型CSXI的胶囊，测试在0.1当量盐酸的水溶液中的溶出度。测试方法如表15所示，测试结果如表16和图17所示。The dissolution rate in an aqueous solution of 0.1 equivalent of hydrochloric acid was tested using the CSXI-containing capsule prepared in Example 11. The test methods are shown in Table 15, and the test results are shown in Table 16 and Figure 17.
表15Table 15
溶出仪Dissolution apparatus Agilent 708DSAgilent 708DS
方法method 桨法Paddle method
介质medium 0.1N盐酸水溶液0.1N hydrochloric acid aqueous solution
介质体积Media volume 900mL900mL
转速Rotating speed 50rpm50rpm
介质温度Medium temperature 37℃37 ° C
取样点Sampling point 5,10,15,20,30和45min5,10,15,20,30 and 45min
表16Table 16
时间(min)Time (min) 累积溶出度(％)Cumulative dissolution (%)
00 0.00.0
55 92.192.1
1010 93.893.8
1515 94.194.1
2020 94.194.1
3030 94.794.7
4545 94.794.7
结果表明，晶型CSXI的胶囊制剂在0.1当量盐酸的水溶液中具有较高的体外溶出度。The results showed that the capsule preparation of the crystalline form CSXI had a high in vitro dissolution in an aqueous solution of 0.1 equivalent of hydrochloric acid.
实施例13晶型CSXI制剂的稳定性Example 13 Stability of Formal CSXI Formulations
将实施例11中制备的含CSXI的胶囊加1g干燥剂分别放置在25℃/60％RH闭口、40℃/75％RH闭口条件下放置，采用XRPD法测试晶型。结果如表17所示，其XRPD对比图如图18所示。The CSXI-containing capsules prepared in Example 11 and 1 g of the desiccant were placed under the conditions of 25 ° C / 60% RH closed, 40 ° C / 75% RH closed, and the crystal form was tested by XRPD method. The results are shown in Table 17, and the XRPD comparison chart is shown in Fig. 18.
表17Table 17
Figure PCTCN2018117808-appb-000020
Figure PCTCN2018117808-appb-000020
结果表明，晶型CSXI制剂在25℃/60％RH、40℃/75％RH闭口条件下可以至少保持1个月稳定。The results showed that the crystalline CSXI formulation was stable for at least one month at 25 ° C / 60% RH, 40 ° C / 75% RH closed conditions.
实施例14晶型A的制备方法Example 14 Preparation Method of Form A
称取54.5mg Acalabrutinib游离碱固体于3mL玻璃小瓶中，加入0.5mL甲醇与水的混合溶剂(v:v,95:5)，于5℃下搅拌2天后离心得到固体。经检测，本实施例得到的固体为晶型A。其XRPD如附图10，表18所示。54.5 mg of Acalabrutinib free base solid was weighed into a 3 mL glass vial, and 0.5 mL of a mixed solvent of methanol and water (v:v, 95:5) was added thereto, and the mixture was stirred at 5 ° C for 2 days, and then centrifuged to obtain a solid. Upon examination, the solid obtained in this example was Form A. Its XRPD is shown in Figure 10 and Table 18.
表18Table 18
Figure PCTCN2018117808-appb-000021
Figure PCTCN2018117808-appb-000021
Figure PCTCN2018117808-appb-000022
Figure PCTCN2018117808-appb-000022
实施例15晶型A的制备方法Example 15 Preparation Method of Form A
称取64.1mg Acalabrutinib游离碱固体于1.5mL玻璃小瓶中，加入1mL甲醇于50℃搅拌确保得到饱和溶液，过滤饱和溶液并将滤液于50℃保温1小时，然后将滤液降温至-20℃，静置得到固体。经检测，本实施例得到的固体为晶型A。其XRPD数据如表19所示，其DSC图如附图11，加热至37℃附近出现第一个吸热峰，为脱水的吸热峰；在207℃附近出现第二个吸热峰为熔化吸热峰随后伴随放热分解。其TGA图如附图12，加热至150℃时，具有约3.8％的质量损失。晶型A为水合物。该晶型的 1H NMR表征结果如图13所示。核磁数据为： 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.41(d,J＝3.9Hz,1H),8.22(d,J＝8.4Hz,1H),8.16(dd,J＝8.3,2.4Hz,2H),7.84(ddd,J＝22.7,14.2,3.4Hz,2H),7.73(t,J＝7.7Hz,2H),7.24–7.08(m,2H),6.16(d,J＝25.0Hz,2H),5.60(ddd,J＝94.8,7.6,4.3Hz,1H),3.83(t,J＝6.6Hz,1H),3.67–3.54(m,1H),2.44–2.22(m,2H),2.12(ddd,J＝23.8,15.7,6.4Hz,1H),2.05–1.95(m,3H),1.62(s,1H)。 64.1 mg of Acalabrutinib free base solid was weighed into a 1.5 mL glass vial, and 1 mL of methanol was added to stir at 50 ° C to ensure a saturated solution. The saturated solution was filtered and the filtrate was incubated at 50 ° C for 1 hour, then the filtrate was cooled to -20 ° C. Set a solid. Upon examination, the solid obtained in this example was Form A. The XRPD data is shown in Table 19, and its DSC chart is as shown in Fig. 11. The first endothermic peak appears near 37 °C, which is the endothermic peak of dehydration; the second endothermic peak near the 207 °C is melted. The endothermic peak is then accompanied by an exothermic decomposition. Its TGA pattern is as shown in Figure 12, with a mass loss of about 3.8% when heated to 150 °C. Form A is a hydrate. The results of 1 H NMR characterization of this crystal form are shown in FIG. The NMR data are: 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.41 (d, J = 3.9 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.16 (dd) , J = 8.3, 2.4 Hz, 2H), 7.84 (ddd, J = 22.7, 14.2, 3.4 Hz, 2H), 7.73 (t, J = 7.7 Hz, 2H), 7.24 - 7.08 (m, 2H), 6.16 ( d, J = 25.0 Hz, 2H), 5.60 (ddd, J = 94.8, 7.6, 4.3 Hz, 1H), 3.83 (t, J = 6.6 Hz, 1H), 3.67 - 3.54 (m, 1H), 2.44 - 2.22 (m, 2H), 2.12 (ddd, J = 23.8, 15.7, 6.4 Hz, 1H), 2.05 - 1.95 (m, 3H), 1.62 (s, 1H).
表19Table 19
Figure PCTCN2018117808-appb-000023
Figure PCTCN2018117808-appb-000023
Figure PCTCN2018117808-appb-000024
Figure PCTCN2018117808-appb-000024
实施例16晶型A的制备方法Example 16 Preparation Method of Form A
称取51.6mg Acalabrutinib游离碱固体于1.5mL玻璃小瓶中，加入0.5mL甲醇溶剂，于5℃下搅拌1天后离心得到固体。经检测，得到的固体为晶型A。其XRPD数据如表20所示。51.6 mg of Acalabrutinib free base solid was weighed into a 1.5 mL glass vial, 0.5 mL of methanol solvent was added, and the mixture was stirred at 5 ° C for 1 day and then centrifuged to obtain a solid. Upon examination, the obtained solid was Form A. Its XRPD data is shown in Table 20.
表20Table 20
Figure PCTCN2018117808-appb-000025
Figure PCTCN2018117808-appb-000025
实施例17晶型A的稳定性Example 17 Stability of Form A
称取2份本发明晶型A，各约10mg，分别放置在25℃/60％RH、40℃/75％RH闭口条件下，采用XRPD法测定晶型。结果如表21所示，XRPD对比图如图19所示。Two parts of Form A of the present invention, about 10 mg each, were weighed and placed under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH, respectively, and the crystal form was determined by XRPD method. The results are shown in Table 21, and the XRPD comparison chart is shown in FIG.
表21Table 21
Figure PCTCN2018117808-appb-000026
Figure PCTCN2018117808-appb-000026
结果表明，晶型A在25℃/60％RH闭口、40℃/75％RH闭口条件下至少可稳定1个月，可见，晶型A在长期和加速条件下均可保持良好的稳定性。The results show that Form A can be stable for at least 1 month at 25 ° C / 60% RH closed and 40 ° C / 75% RH closed. It can be seen that Form A can maintain good stability under long-term and accelerated conditions.
实施例18晶型A在不同缓冲溶液中的溶解度Example 18 Solubility of Form A in Different Buffer Solutions
分别称取足量的晶型A与WO2017002095A1晶型I样品悬浮分散在pH为5.1，7.4，8.7的缓冲溶液中，室温下搅拌平衡2小时，后离心分离上层清液，使用高效液相色谱法测试清液中样品的含量(mg/mL)，实验结果如表22所示。Weigh a sufficient amount of Form A and WO2017002095A1 Form I sample suspended and dispersed in a buffer solution of pH 5.1, 7.4, 8.7, stirred at room temperature for 2 hours, then centrifuged to separate the supernatant, using high performance liquid chromatography The content of the sample in the serum (mg/mL) was tested, and the experimental results are shown in Table 22.
表22Table 22
Figure PCTCN2018117808-appb-000027
Figure PCTCN2018117808-appb-000027
结果表明，与WO2017002095A1晶型I相比，晶型A在pH为5.1，7.4，8.7的缓冲液中具有更高的溶解度。The results show that Form A has a higher solubility in a buffer having a pH of 5.1, 7.4, 8.7 as compared to Form I of WO2017002095A1.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (11)

  1. 一种Acalabrutinib的晶型CSXI，其特征在于，使用Cu-Kа辐射，其X射线粉末衍射图在2θ值为6.0°±0.2°、11.0°±0.2°、11.8°±0.2°处具有特征峰。A crystal form CSXI of Acalabrutinib characterized in that, using Cu-Kа radiation, the X-ray powder diffraction pattern has characteristic peaks at 2θ values of 6.0 ° ± 0.2 °, 11.0 ° ± 0.2 °, and 11.8 ° ± 0.2 °.
  2. 根据权利要求1所述的晶型CSXI，其特征在于，使用Cu-Kа辐射，其X射线粉末衍射图在2θ值为22.9°±0.2°、25.1°±0.2°中的一处或两处具有特征峰。The crystalline form CSXI according to claim 1, wherein the X-ray powder diffraction pattern having Cu-Kа radiation has one or two of 2θ values of 22.9°±0.2° and 25.1°±0.2°. Characteristic peaks.
  3. 一种根据权利要求1所述的晶型CSXI的制备方法，其特征在于：A method for preparing a crystalline form CSXI according to claim 1, wherein:
    1)将Acalabrutinib的晶型H在4℃-60℃、22％-97％相对湿度(RH)条件下静置1-10天，得到白色晶体；或1) The Form H of Acalabrutinib is allowed to stand at 4 ° C - 60 ° C, 22% - 97% relative humidity (RH) for 1-10 days to obtain white crystals; or
    2)将Acalabrutinib的晶型H控制湿度循环为：10％RH-95％-0％RH-95％RH，得到白色晶体。2) The crystal form H controlled humidity of Acalabrutinib was cycled to: 10% RH-95%-0% RH-95% RH to obtain white crystals.
  4. 一种Acalabrutinib的晶型A，其特征在于，使用Cu-Kа辐射，其X射线粉末衍射图在2θ值为9.8°±0.2°、13.9°±0.2°、8.4°±0.2°处具有特征峰。A crystal form A of Acalabrutinib characterized in that, using Cu-Kа radiation, the X-ray powder diffraction pattern has characteristic peaks at 2θ values of 9.8 ° ± 0.2 °, 13.9 ° ± 0.2 °, and 8.4 ° ± 0.2 °.
  5. 根据权利要求4所述的晶型A，其特征在于，使用Cu-Kа辐射，其X射线粉末衍射图在2θ值为21.7°±0.2°、5.9°±0.2°、10.8°±0.2°中的一处、或两处、或三处具有特征峰。The crystal form A according to claim 4, wherein the X-ray powder diffraction pattern of Cu-Kа radiation is used in a 2θ value of 21.7°±0.2°, 5.9°±0.2°, 10.8°±0.2°. One, two or three have characteristic peaks.
  6. 根据权利要求4所述的晶型A，其特征还在于，使用Cu-Kа辐射，其X射线粉末衍射图在2θ值为18.0°±0.2°、18.4°±0.2°、26.0°±0.2°中的一处、或两处、或三处具有特征峰。The crystal form A according to claim 4, wherein the X-ray powder diffraction pattern of Cu-Kа radiation is used in a 2θ value of 18.0 ° ± 0.2 °, 18.4 ° ± 0.2 °, and 26.0 ° ± 0.2 °. One, or two, or three have characteristic peaks.
  7. 一种根据权利要求4所述的Acalabrutinib晶型A的制备方法，其特征在于：A method for preparing Acalabrutinib crystal form A according to claim 4, wherein:
    1)将Acalabrutinib游离碱样品在醇类溶剂中30℃-70℃下溶解，降温至-20℃-10℃，得到晶型A；或1) A sample of Acalabrutinib free base is dissolved in an alcohol solvent at 30 ° C - 70 ° C, and the temperature is lowered to -20 ° C - 10 ° C to obtain Form A;
    2)将Acalabrutinib游离碱样品在醇类溶剂或者醇类溶剂和水的混合溶剂中-20℃-10℃下搅拌，得到晶型A。2) A sample of Acalabrutinib free base is stirred in an alcohol solvent or a mixed solvent of an alcohol solvent and water at -20 ° C to 10 ° C to obtain Form A.
  8. 根据权利要求7所述的制备方法，所述醇类溶剂为甲醇。The process according to claim 7, wherein the alcohol solvent is methanol.
  9. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型CSXI、或权利要求4所述的晶型A、或它们的任意组合及药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CSXI of claim 1, or the crystalline form A of claim 4, or any combination thereof, and a pharmaceutically acceptable carrier , diluent or excipient.
  10. 权利要求1中所述的晶型CSXI、或权利要求4所述的晶型A、或它们的任意组合在制备布鲁顿酪氨酸激酶抑制剂药物中的用途。Use of the crystalline form CSXI as claimed in claim 1, or the crystalline form A of claim 4, or any combination thereof, in the manufacture of a Bruton's tyrosine kinase inhibitor drug.
  11. 权利要求1中所述的晶型CSXI、或权利要求4所述的晶型A、或它们的任意组合在制备治疗套细胞淋巴癌药物中的用途。Use of the crystalline form CSXI as claimed in claim 1, or the crystalline form A of claim 4, or any combination thereof, for the manufacture of a medicament for treating a mantle cell lymphoma.
PCT/CN2018/117808 2017-11-30 2018-11-28 Crystal form of acalabrutinib, preparation method therefor and application thereof WO2019105359A1 (en)

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WO2015181633A2 (en) * 2014-04-11 2015-12-03 Acerta Pharma B.V. Methods of blocking the cxcr-4/sdf-1 signaling pathway with inhibitors of bruton's tyrosine kinase
WO2017002095A1 (en) * 2015-07-02 2017-01-05 Acerta Pharma B.V. Solid forms and formulations of (s)-4-(8-amino-3-(1 -(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-n-(pyridin-2-yl)benzamide
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WO2015181633A2 (en) * 2014-04-11 2015-12-03 Acerta Pharma B.V. Methods of blocking the cxcr-4/sdf-1 signaling pathway with inhibitors of bruton's tyrosine kinase
WO2017002095A1 (en) * 2015-07-02 2017-01-05 Acerta Pharma B.V. Solid forms and formulations of (s)-4-(8-amino-3-(1 -(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-n-(pyridin-2-yl)benzamide
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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