WO2019205812A1 - Acalabrutinib的新晶型及其制备方法和用途 - Google Patents

Acalabrutinib的新晶型及其制备方法和用途 Download PDF

Info

Publication number
WO2019205812A1
WO2019205812A1 PCT/CN2019/076944 CN2019076944W WO2019205812A1 WO 2019205812 A1 WO2019205812 A1 WO 2019205812A1 CN 2019076944 W CN2019076944 W CN 2019076944W WO 2019205812 A1 WO2019205812 A1 WO 2019205812A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
crystal
preparation
acalabrutinib
solid
Prior art date
Application number
PCT/CN2019/076944
Other languages
English (en)
French (fr)
Inventor
陈敏华
张炎锋
刘远
张龙
杨朝惠
Original Assignee
苏州科睿思制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Priority to US17/050,329 priority Critical patent/US20210087195A1/en
Priority to CN201980002375.2A priority patent/CN110650960B/zh
Publication of WO2019205812A1 publication Critical patent/WO2019205812A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—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
    • 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

  • 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 crystal form K1 of Acalabrutinib, which has advantages in physical and chemical properties, processing properties and bioavailability, such as melting point, solubility, moisture absorbing property, purification effect, stability, adhesion, and pressure.
  • At least one of the aspects of sex, fluidity, dissolution in vitro and in vivo, and bioavailability have advantages, in particular, the preparation method is simple, the repeatability is good, the physical stability of the drug substance is good, the solubility in the organic solvent is high, and the compressibility is good. Good adhesion, good formulation stability and high dissolution rate provide a new and better choice for the preparation of pharmaceutical preparations containing Acalabrutinib, which is of great significance.
  • 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 crystal form K1 of the compound (I) (hereinafter referred to as "crystal form K1").
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at a diffraction angle 2 ⁇ of 5.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, and 14.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 13.8° ⁇ 0.2°, 12.8° ⁇ 0.2°, and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at a diffraction angle 2 ⁇ of 13.8° ⁇ 0.2°, 12.8° ⁇ 0.2°, and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 16.3° ⁇ 0.2°, 6.9° ⁇ 0.2°, and 11.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at a diffraction angle 2 ⁇ of 16.3° ⁇ 0.2°, 6.9° ⁇ 0.2°, and 11.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 is 5.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 13.8° ⁇ 0.2°, 12.8 at the diffraction angle 2 ⁇ .
  • At any 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13 of 0.2° At any 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13 of 0.2° .
  • the X-ray powder diffraction pattern of Form K1 is substantially as shown in FIG.
  • the present invention also provides a method for preparing the crystal form K1, characterized in that the preparation method comprises:
  • Acalabrutinib free base is added to an acidic solution, stirred, and the obtained solid is separated and dried, and the solid is further transferred to an alkaline solution and stirred to obtain a solid crystal form K1.
  • the acid in the method (1) is maleic acid or fumaric acid;
  • the alkaline solution is an aqueous sodium hydroxide solution;
  • the ketone solvent is acetone, 2-butanone or methyl isobutyl ketone;
  • the acidic solution in the method (2) is an aqueous hydrochloric acid solution; and the alkaline solution is an aqueous sodium hydroxide solution.
  • the crystal form K1 provided by the invention has the following beneficial effects:
  • the crystal form K1 provided by the present invention has good physical stability in water compared to the crystal form I of WO2017002095A1. At room temperature and 5 °C, the crystal form K1 can remain unchanged for at least 7 days under magnetic stirring and shaking dispersion conditions in water, while the crystal form I in WO2017002095A1 is magnetically stirred at room temperature for 4 hours, and the crystallinity has been significantly decreased. It almost becomes amorphous.
  • the physical stability of the crystal form in water is essential for drug production and stable absorption of the drug in the body.
  • solution crystallization is the most important method, and water is a commonly used solvent in solution crystallization.
  • the crystalline form of the drug substance maintains good physical stability in water and is beneficial to the quality control of the product during the production process.
  • the crystalline form of the drug substance can maintain good physical stability during the process of full contact with water, which can reduce the control requirements for water content and humidity during the production process, and reduce the production cost.
  • water is the main component of the biological medium in the human body, and the crystal form of the raw material drug has good physical stability in water, and can avoid the occurrence of crystal transformation of the active ingredient of the drug in the human body. 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 crystal form K1 provided by the present invention is more thermodynamically stable in water at room temperature and 5 ° C than the prior art.
  • the mixed solid of Form K1 and WO2017002095A1 Form I was stirred in water at room temperature and 5 ° C, and Form I was converted to Form K1 of the present invention.
  • thermodynamically unstable crystal form has a tendency to spontaneously transform into a thermodynamically stable crystal form.
  • Drug preparation and processing such as tableting, milling, wet granulation, and freeze drying, accelerates the transformation of thermodynamically unstable crystal forms.
  • the presence of thermodynamically stable crystalline seeds can induce and accelerate the transition of the crystal from a thermodynamic metastable state to a thermodynamically stable state.
  • a thermodynamically stable crystal form is generally selected as the drug substance.
  • the crystal form K1 of the present invention is more stable in thermodynamics, and can reduce the above risks and more. It is suitable for use as a drug substance.
  • the crystalline K1 drug substance provided by the present invention has good long-term and accelerated stability.
  • the crystalline K1 drug substance was placed at 25 ° C / 60% relative humidity, and the crystal form did not change for at least 1 month. It is indicated that the crystalline K1 drug substance has good long-term stability and is beneficial for drug storage. At the same time, it was left at 40 ° C / 75% relative humidity, and the crystal form did not change for at least 1 month. It is indicated that the crystalline K1 drug substance has good acceleration stability. In the process of storage, transportation and preparation of raw materials, raw materials will encounter harsh conditions caused by seasonal differences, climate differences in different regions and weather factors. The crystalline K1 drug substance has good acceleration stability and is favorable for storage of the drug under special environmental conditions, such as high temperature and high humidity.
  • Form K1 has good long-term and accelerated stability in the formulation. After the crystal form K1 of the present invention is mixed with an auxiliary material to form a pharmaceutical preparation, it is placed under the condition of 25 ° C / 60% RH closed mouth and 40 ° C / 75% RH closed mouth, and the crystal form does not change for at least 6 months.
  • Form K1 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 K1 raw material provided by the present invention has good physical stability after grinding.
  • the grinding and pulverization of the raw material medicine is often required in the processing of the preparation, and the good physical stability after the grinding can reduce the risk of crystallinity change and crystal transformation of the raw material medicine during the processing of the preparation.
  • the crystalline form K1 of the present invention has a higher solubility in different buffer solutions.
  • Form K1 has a higher solubility in a buffer having a pH of 7.0, 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.
  • the crystal form K1 of the present invention has higher solubility in an organic solvent than the prior art.
  • Form K1 is in methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran.
  • the solubility in the organic solvent commonly used for crystallization such as 1,4-dioxane and acetonitrile is higher than that of the crystalline form I.
  • the crystal form K1 of the invention has higher solubility in various organic solvents, so that more solvent selection is possible in the crystallization process, and the use of the solvent in the crystallization process can be reduced, the cost is reduced, and the environment is more environmentally friendly.
  • the Form K1 preparation has a high in vitro dissolution rate and a faster in vitro dissolution rate, and the dissolution rate at 20 minutes is 84% 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.
  • crystal form K1 provided by the present invention has the following beneficial effects:
  • the crystal form K1 provided by the present invention has superior compressibility.
  • the good compressibility of the crystal form K1 can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more reliable, 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 crystal form K1 of the present invention has superior adhesion.
  • the results of the adhesion evaluation showed that the adsorption amount of the crystal form K1 was lower than that of the prior art crystal form.
  • the low adhesion of the crystal form K1 can effectively improve or avoid the phenomenon of sticking wheel and sticking caused by dry granulation and tablet tableting, and is beneficial to improving the appearance and weight difference of the product.
  • the low adhesion of crystal form K1 can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. Content uniformity.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form K1 and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a crystalline form K1 for the preparation of a mantle cell lymphoma and/or chronic lymphocytic leukemia and/or macroglobulinemia and/or follicular lymphoma and/or diffuse large B cell lymphocytes. Use in neoplastic and/or multiple myeloma drugs.
  • the present invention provides the isopropyl acetate solvate crystal form CS10 (hereinafter referred to as "crystal form CS10") of the compound (I).
  • the X-ray powder diffraction of the crystal form CS10 has characteristic peaks at diffraction angles 2 ⁇ of 8.5° ⁇ 0.2°, 6.0° ⁇ 0.2°, and 18.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS10 has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 20.1° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 15.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at a diffraction angle 2 ⁇ of 20.1° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 15.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS10 has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 15.9° ⁇ 0.2°, 26.0° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K1 has a characteristic peak at a diffraction angle 2 ⁇ of 15.9° ⁇ 0.2°, 26.0° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS10 is 8.5° ⁇ 0.2°, 6.0° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.1° ⁇ 0.2°, 14.9 at the diffraction angle 2 ⁇ . Any 3, or 4, or 5, or 6 or 7 of ° ⁇ 0.2 °, 15.3 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 26.0 ° ⁇ 0.2 °, 26.6 ° ⁇ 0.2 °, Or there are characteristic peaks at 8 or 9 places.
  • the X-ray powder diffraction pattern of Form CS10 is substantially as shown in FIG.
  • the present invention further provides a method for preparing the crystalline form CS10, characterized in that the preparation method comprises: adding Acalabrutinib free base to a mixed solvent of acetonitrile and an alcohol, and the temperature is from 10 ° C to 60 ° C. The resulting solid was separated by stirring. The solid is added to isopropyl acetate or a mixed solvent of isopropyl acetate and halogenated alkane, and the mixture is suspended and stirred at 0 ° C to 40 ° C to obtain a crystal form of CS10.
  • 10 ° C - 60 ° C is preferably 50 ° C; the 0 ° C - 40 ° C is preferably 5 ° C; the volume ratio of the isopropyl acetate and halogenated alkane is preferably 99: 1 ⁇ 90: 10, more Preferably, it is 95:5; the volume ratio of the acetonitrile to the alcohol is preferably from 99:1 to 80:20, more preferably 90:10.
  • the alcohol solvent in the above method is preferably methanol; and the halogenated alkane solvent is preferably dichloromethane.
  • the "room temperature” is not a specific temperature value, and refers to a temperature range of 10 to 30 °C.
  • Isolation as described herein is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the "centrifugation” operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern (XRPD pattern).
  • XRPD pattern X-ray powder diffraction pattern
  • XRPD patterns typically vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the XRPD pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensities of the peaks in the XRPD pattern are related to the preferred orientation of the crystal.
  • the peak intensities shown herein are illustrative and not absolute.
  • the experimental error of the peak position (2 ⁇ ) is usually 5% or less, and the error of these peak positions 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 the same or similar pattern as the characteristic peaks in these XRPD patterns is within the scope of the present invention.
  • One skilled in the art will be able to compare the XRPD pattern listed herein with an XRPD pattern of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form K1 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 chart of the crystal form K1 obtained in Example 1.
  • Figure 3 is a TGA diagram of the crystal form K1 obtained in Example 1.
  • Figure 1 1 H NMR chart of the crystal form K1 obtained in Example 2.
  • Fig. 5 XRPD comparison chart of physical stability study of crystal form K1 under magnetic stirring at room temperature (from bottom to top: initial crystal form K1, stirring for 4 hours, 1 day, 2 days, 7 days)
  • Fig. 6 XRPD comparison chart of physical stability study of crystal form K1 under magnetic stirring conditions at 5 ° C (from bottom to top: initial crystal form K1, stirring for 4 hours, 1 day, 2 days, 7 days)
  • Figure 7 XRPD comparison chart of physical stability study of crystal form K1 under shaking and dispersion conditions at room temperature (from bottom to top: initial crystal form K1, shock 4 hours, 1 day, 2 days, 7 days)
  • Fig. 8 XRPD comparison chart of physical stability study of crystal form K1 under shaking and dispersion conditions at 5 °C (from bottom to top: initial crystal form K1, shock 4 hours, 1 day, 2 days, 7 days)
  • Fig. 9 XRPD comparison chart of physical stability study of Form I of WO2017002095A1 under room temperature magnetic stirring conditions (from bottom to top: starting form I, stirring at room temperature for 4 hours)
  • Fig. 10 XRPD comparison chart of the physical stability study of the crystal form I of WO2017002095A1 under magnetic stirring conditions at 5 °C (from bottom to top: initial crystal form I, 5 ° C stirring for 4 hours, 1 day)
  • Fig. 11 XRPD comparison chart of the physical stability study of the crystal form I of WO2017002095A1 under room temperature shaking dispersion conditions (from bottom to top: initial crystal form I, room temperature oscillation for 4 hours, 1 day)
  • Fig. 12 XRPD comparison chart of the physical stability study of the crystal form I of WO2017002095A1 under the condition of 5 ° C shock dispersion (from bottom to top: initial crystal form I, 5 ° C shock 4 hours, 1 day, 2 days, 7 days)
  • Fig. 13 Results of suspension competition of crystal form K1 and WO2017002095A1 form I at 5 ° C (top to bottom are: XRPD pattern of starting form K1 + form I, XRPD pattern after stirring for 6 days, form K1 XRPD pattern, XRPD pattern of Form I)
  • Fig. 14 Results of suspension competition of crystal form K1 and WO2017002095A1 form I at room temperature (top to bottom are: XRPD pattern of starting form K1 + form I, XRPD pattern after stirring for 24 days, XRPD of form K1 Figure, XRPD pattern of Form I)
  • Figure 15 XRPD comparison chart of crystal form K1 stability study (from top to bottom: initial crystal form K1, 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 is a comparison of the mechanical stability XRPD of the crystal form K1 (the figure above is before grinding, the figure below is after grinding)
  • Figure 17 XRPD comparison chart during the process of crystal form K1 preparation (from top to bottom, in order, crystal form K1 capsule preparation, blank adjuvant control, crystal form K1 drug substance)
  • Figure 19 XRPD comparison chart of the stability study of the Form K1 preparation (from top to bottom: starting sample, at 25 ° C / 60% relative humidity, adding 1 g of desiccant for 6 months, at 40 ° C / 75% relative humidity closed with 1g desiccant for 6 months)
  • Figure 20 is an XRPD pattern of the crystalline form CS10 obtained according to Example 14 of the present invention.
  • Figure 21 is an XRPD pattern of the crystalline form CS10 obtained according to Example 15 of the present invention.
  • 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:
  • H NMR data (1 HNMR) collected 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 above solid 118.1 mg to 3 mL glass vial was weighed out, 2 mL of water was added, and stirred at room temperature to form a suspension.
  • 22.3 mg of NaOH was dissolved in 1 mL of water to obtain an aqueous NaOH solution, and the aqueous NaOH solution was added to the above suspension at room temperature, stirred, and separated to give a solid.
  • the solid obtained in this example was a crystalline form K1, and its XRPD pattern is shown in Fig. 1, and its XRPD data is shown in Table 1.
  • the DSC starts to show a dehydration endotherm when heated to around 69 °C; its TGA pattern is shown in Fig. 3, and when it is heated to around 100 °C, it has a mass loss of about 14.2%.
  • Form K1 is a hydrate.
  • the 1 H NMR spectrum of this crystal form sample is shown in Fig. 4, and the nuclear magnetic data is identical to the structure of the compound (C 26 H 23 N 7 O 2 ).
  • the following experiment was conducted to compare the physical stability of the crystalline form K1 of the present invention and the crystalline form I of WO2017002095A1 in water. Approximately 10 mg of a solid sample of a different crystal form was weighed separately, and 1.0 mL of pure water was added to form a suspension, which was allowed to stand at room temperature and 5 ° C to disperse.
  • the physical stability of crystal form K1 and WO2017002095A1 crystal form I in water was evaluated by means of magnetic stirring and oscillating dispersion. The results show that under the conditions of room temperature and 5 °C, the crystal form K1 of the present invention does not change under the magnetic stirring and shaking, and the crystallinity of the crystal form I decreases, and almost changes to amorphous. The results show that the crystalline form K1 of the present invention has superior physical stability in water.
  • Form K1 has a higher solubility in a buffer of pH 7.0, 7.4, 8.7 compared to Form I of WO2017002095A1.
  • the small intestine is the main site of oral drug absorption. It is known that the small intestine is a neutral environment, and the crystal form K1 of the present invention has higher solubility in the neutral or weakly alkaline medium than the crystalline form I, on the one hand, the drug is successfully delivered to the intestine, and on the other hand, the drug is in the intestine. Dissolution and absorption in the channel.
  • a certain mass of crystal form K1 and WO2017002095A1 form I were weighed into a glass vial, respectively.
  • the organic solvent was gradually added to the vial, and 100 ⁇ L was added each time.
  • the solid is rapidly dispersed in the solvent by shaking or ultrasonication, and it is observed whether the solid is completely dissolved. When it was observed that the solid was completely dissolved, or the total volume of the solvent reached 1.5 mL, the addition of the solvent was stopped.
  • the solubility (S) of the different crystal forms in the organic solvent was calculated according to the mass (m) of the sample weighed, and the volume of the solvent was added. The results are shown in Table 8.
  • Solubility calculation method S>m/V1 and S ⁇ m/V2; V1 is the maximum volume of solvent added when the crystal form is not completely dissolved, and V2 is the minimum volume of solvent added when the crystal form is completely dissolved.
  • the crystal form K1 was placed in a mortar, manually ground for 5 minutes, and subjected to XRPD test before and after the grinding.
  • the test results are shown in FIG. The results show that the crystalline form K1 has good physical stability under grinding conditions, and the crystal form and crystallinity after grinding have not changed significantly.
  • the crystal form K1 and the WO2017002095A1 crystal form I were respectively weighed about 80 mg, and were pressed by a manual tableting machine, and 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.
  • Form K1 and WO2017002095A1 Form I were respectively added to an 8 mm circular flush, and the sheet was treated with a pressure of 10 kN, and left to stand for about half a minute after tableting, and the amount of powder adsorbed by the punch was weighed. After continuous pressing twice by this method, the cumulative amount of final adhesion and the average amount of adhesion of the punches were recorded. The specific experimental results are shown in Table 10.
  • Dissolution apparatus Agilent 708DS method Paddle method medium 0.1mol/L hydrochloric acid aqueous solution Media volume 900mL Rotating speed 50rpm Medium temperature 37 ° C Sampling point 5,10,15,20,30 and 45min
  • the crystal form K1-containing capsule obtained in Example 11 was subjected to stability test, and placed under conditions of 25 ° C / 60% RH and 40 ° C / 75% RH for a certain period of time to test its XRPD.
  • the test results are shown in Table 15, and the XRPD comparison chart is shown in FIG.
  • Form K1 formulation was stable for at least 6 months at 25 ° C / 60% RH, 40 ° C / 75% RH.
  • the white crystal obtained in this example was a crystalline form CS10.
  • the X-ray powder diffraction data is shown in Fig. 21 and Table 17.

Abstract

本发明涉及Acalabrutinib的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备布鲁顿酪氨酸激酶抑制剂和治疗套细胞淋巴癌药物制剂中的用途。本发明提供的Acalabrutinib晶型比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。（I）

Description

Acalabrutinib的新晶型及其制备方法和用途 技术领域
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。
背景技术
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。
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：
Figure PCTCN2019076944-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。
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。
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。
本申请发明人意外发现了Acalabrutinib的晶型K1，其在理化性质，制剂加工性能及生物利用度等方面具有优势，例如在熔点，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，生物有效性等方面中的至少一 方面存在优势，特别是制备方法简单、重复性好，原料药物理稳定性好，在有机溶剂中的溶解度高，可压性、黏附性好，制剂稳定性好、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。
发明内容
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。
根据本发明的目的，本发明提供化合物(I)的晶型K1(以下称作“晶型K1”)。
一方面，使用Cu-Kα辐射，所述晶型K1的X射线粉末衍射在衍射角2θ为5.8°±0.2°、9.5°±0.2°、14.3°±0.2°处有特征峰。
进一步地，所述晶型K1的X射线粉末衍射在衍射角2θ为13.8°±0.2°、12.8°±0.2°、18.4°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型K1的X射线粉末衍射在衍射角2θ为13.8°±0.2°、12.8°±0.2°、18.4°±0.2°处有特征峰。
进一步地，所述晶型K1的X射线粉末衍射在衍射角2θ为16.3°±0.2°、6.9°±0.2°、11.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型K1的X射线粉末衍射在衍射角2θ为16.3°±0.2°、6.9°±0.2°、11.5°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型K1的X射线粉末衍射在衍射角2θ为5.8°±0.2°、9.5°±0.2°、14.3°±0.2°、13.8°±0.2°、12.8°±0.2°、18.4°±0.2°、16.3°±0.2°、6.9°±0.2°、11.5°±0.2°、8.1°±0.2°、17.7°±0.2°、23.5°±0.2°、24.6°±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、或10处、或11处、或12处、或13处有特征峰。
非限制性地，晶型K1的X射线粉末衍射谱图基本如图1所示。
根据本发明的目的，本发明还提供所述晶型K1的制备方法，其特征在于，所述制备方法包括：
(1)将Acalabrutinib游离碱和酸加入酮类和水的混合溶剂中搅拌，分离干燥得到固体，将该固体加入水中形成悬浮液，向该悬浮液中加入碱性溶液并搅拌，分离得到晶型K1；或
(2)将Acalabrutinib游离碱加入酸性溶液中搅拌，分离并干燥得到的固体，继续将该固体转移至碱性溶液中搅拌，分离得到固体晶型K1。
优选地：
方法(1)中所述酸为马来酸或富马酸；所述碱性溶液为氢氧化钠水溶液；所述酮类溶剂为丙酮、2-丁酮或甲基异丁基酮；
方法(2)中所述酸性溶液为盐酸水溶液；所述碱性溶液为氢氧化钠水溶液。
本发明提供的晶型K1具有以下有益效果：
(1)本发明提供的晶型K1相较于WO2017002095A1晶型I在水中具有良好的物理稳定性。室温和5℃条件下，晶型K1在水中磁力搅拌和震荡分散条件下至少可保持7天晶型不变，而WO2017002095A1中的晶型I在室温下磁力搅 拌4小时，结晶度已经明显下降，几乎变为无定形。
晶型在水中的物理稳定性对药物生产和药物在体内的稳定吸收至关重要。在药物生产过程中，溶液结晶法是最主要的方法，水是溶液结晶中较为常用的溶剂。原料药晶型在水中保持良好的物理稳定性，有利于生产过程中产品的质量控制。此外，原料药晶型在与水充分接触的过程中仍能保持良好的物理稳定性，可降低生产过程中对含水量和湿度的控制要求，降低生产成本。另外，水是人体内生物介质的主要成分，原料药的晶型在水中具有良好的物理稳定性，可避免药物活性成分在人体内发生转晶。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。
(2)本发明提供的晶型K1相较于现有技术在室温和5℃的水中热力学更稳定。晶型K1和WO2017002095A1晶型I的混合固体在室温和5℃条件下在水中搅拌，晶型I转变为本发明的晶型K1。
热力学不稳定晶型有自发转变为热力学稳定晶型的趋势。药物制备和加工过程，如压片、碾磨、湿法制粒和冷冻干燥，会加速热力学不稳定晶型的转晶。此外，热力学稳定晶型晶种的存在可以诱导并加速晶体从热力学亚稳态向热力学稳定态的转变。为避免上市药物晶型发生转变而影响药效，通常选择热力学较稳定的晶型作为原料药，相比现有技术晶型I，本发明的晶型K1热力学更稳定，能够减少上述风险，更加适合用作药物原料药。
(3)本发明提供的晶型K1原料药具有良好的长期和加速稳定性。晶型K1原料药在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K1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K1原料药具有较好的加速稳定性。原料药在储存、运输、制剂生产过程中会遇到季节差异、不同地区气候差异和天气因素等带来的苛刻条件。晶型K1原料药具有较好的加速稳定性，有利于药物在特殊环境条件下储存，例如高温高湿地区。
晶型K1在制剂中具有良好的长期和加速稳定性。本发明晶型K1与辅料混合做成药物制剂后，在25℃/60％RH闭口、40℃/75％RH闭口条件下放置，至少6个月晶型未发生变化。
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K1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。
(4)本发明提供的晶型K1原料药研磨后具有良好的物理稳定性。制剂加工过程中常需要原料药的研磨粉碎，研磨后良好的物理稳定性能够减小制剂加工过程中原料药晶型结晶度改变和转晶的风险。
(5)与现有技术相比，本发明晶型K1在不同缓冲溶液中具有更高的溶解度。与WO2017002095A1晶型I相比，晶型K1在pH为7.0，7.4，8.7的缓冲液 中具有更高的溶解度。
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，降低药物的剂量，从而降低药品的副作用并提高药品的安全性。
(6)与现有技术相比，本发明晶型K1在有机溶剂中具有更高的溶解度。与WO2017002095A1晶型I相比，晶型K1在甲醇、乙醇、异丙醇、正丙醇、正丁醇、丙酮、甲基异丁基酮、甲乙酮、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、乙腈等结晶常用的有机溶剂中溶解度均高于晶型I。
本发明晶型K1在多种有机溶剂中均有更高的溶解度，使得结晶过程中具有更多的溶剂选择，且可以减少结晶过程中溶剂的使用倍量，降低成本，且更加环保。
(7)晶型K1制剂具有较高的体外溶出度和较快的体外溶出速率，在0.1N盐酸水溶液介质中，20分钟时的溶出度达84％。
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、排泄、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。
进一步地，本发明提供的晶型K1还具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型K1具有更优的可压性。晶型K1良好的可压性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。
(2)与现有技术相比，本发明晶型K1具有更优的黏附性。黏附性评价结果表明，晶型K1的吸附量低于现有技术晶型的吸附量。晶型K1的低黏附性可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型K1的黏附性低还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品的含量均匀度。
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K1及药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提的晶型K1在制备布鲁顿酪氨酸激酶抑制剂药物中的用途。
更进一步地，本发明提供的晶型K1在制备治疗套细胞淋巴瘤和/或慢性淋巴细胞白血病和/或巨球蛋白血症和/或滤泡性淋巴瘤和/或弥漫性大B细胞淋巴瘤和/或多发性骨髓瘤药物中的用途。
根据本发明的另一个目的，本发明提供化合物(I)的乙酸异丙酯溶剂合物晶型CS10(以下称作“晶型CS10”)。
一方面，使用Cu-Kα辐射，所述晶型CS10的X射线粉末衍射在衍射角2θ为8.5°±0.2°、6.0°±0.2°、18.2°±0.2°处有特征峰。
进一步地，所述晶型CS10的X射线粉末衍射在衍射角2θ为20.1°±0.2°、14.9°±0.2°、15.3°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型K1的X射线粉末衍射在衍射角2θ为20.1°±0.2°、14.9°±0.2°、15.3°±0.2°处有特征峰。
进一步地，所述晶型CS10的X射线粉末衍射在衍射角2θ为15.9°±0.2°、26.0°±0.2°、26.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型K1的X射线粉末衍射在衍射角2θ为15.9°±0.2°、26.0°±0.2°、26.6°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CS10的X射线粉末衍射在衍射角2θ为8.5°±0.2°、6.0°±0.2°、18.2°±0.2°、20.1°±0.2°、14.9°±0.2°、15.3°±0.2°、15.9°±0.2°、26.0°±0.2°、26.6°±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。
非限制性地，晶型CS10的X射线粉末衍射谱图基本如图20所示。
根据本发明的目的，本发明还提供所述晶型CS10的制备方法，其特征在于，所述制备方法包括：将Acalabrutinib游离碱加至乙腈和醇类的混合溶剂中，10℃-60℃条件下搅拌，分离得到的固体。将该固体加至乙酸异丙酯，或乙酸异丙酯和卤代烷烃类的混合溶剂，0℃-40℃下悬浮搅拌，分离，得到晶型CS10。
进一步地：
上述方法中所述10℃-60℃优选为50℃；所述0℃-40℃优选为5℃；所述乙酸异丙酯和卤代烷烃的体积比优选为99:1～90:10，更优选为95:5；所述乙腈和醇类的体积比优选为99:1-80:20，更优选为90:10。
更进一步地：
上述方法中所述醇类溶剂优选为甲醇；所述卤代烷烃类溶剂优选为二氯甲烷。
本发明中，所述“室温”不是特定的温度值，是指10-30℃温度范围。
本发明所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图(XRPD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，XRPD图通常会随着仪器的条件而有所改变。特别需要指出的是，XRPD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图中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，峰位置(2θ)的实验误差通常在5％或更少，这些峰位置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XRPD图不必和这里所指的实施例中的XRPD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XRPD图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XRPD图和一个未知晶型的XRPD图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型K1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。
本发明中术语“约”，当用来指可测量的数值时，例如化合物和制剂的质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
附图说明
图1实施例1得到的晶型K1的XRPD图
图2实施例1得到的晶型K1的DSC图
图3实施例1得到的晶型K1的TGA图
图4实施例2得到的晶型K1的 1H NMR图
图5晶型K1在室温磁力搅拌条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型K1、搅拌4小时、1天、2天、7天)
图6晶型K1在5℃磁力搅拌条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型K1、搅拌4小时、1天、2天、7天)
图7晶型K1在室温震荡分散条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型K1、震荡4小时、1天、2天、7天)
图8晶型K1在5℃震荡分散条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型K1、震荡4小时、1天、2天、7天)
图9WO2017002095A1晶型I在室温磁力搅拌条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型I、室温搅拌4小时)
图10WO2017002095A1晶型I在5℃磁力搅拌条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型I、5℃搅拌4小时、1天)
图11WO2017002095A1晶型I在室温震荡分散条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型I、室温震荡4小时、1天)
图12WO2017002095A1晶型I在5℃震荡分散条件下的物理稳定性研究的XRPD对比图(由下至上分别为：起始晶型I、5℃震荡4小时、1天、2天、7天)
图13晶型K1和WO2017002095A1晶型I在5℃下的混悬竞争结果(由上至下分别为：起始晶型K1+晶型I的XRPD图，搅拌6天后的XRPD图，晶型K1的XRPD图，晶型I的XRPD图)
图14晶型K1和WO2017002095A1晶型I在室温下的混悬竞争结果(由上至下分别为：起始晶型K1+晶型I的XRPD图，搅拌24天后的XRPD图，晶型K1的XRPD图，晶型I的XRPD图)
图15晶型K1稳定性研究的XRPD对比图(由上至下分别为：起始晶型K1，25℃/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)
图16晶型K1的机械稳定性XRPD对比图(上图为研磨前，下图为研磨后)
图17晶型K1制剂工艺过程中的XRPD对比图(从上至下，依次为晶型K1胶囊制剂、空白辅料对照、晶型K1原料药)
图18晶型K1制剂的溶出曲线
图19晶型K1制剂的稳定性研究的XRPD对比图(由上至下分别为：起始制剂样品、在25℃/60％相对湿度闭口加1g干燥剂放置6个月后、在40℃/75％相对湿度闭口加1g干燥剂放置6个月后)
图20根据本发明实施例14所得晶型CS10的XRPD图
图21根据本发明实施例15所得晶型CS10的XRPD图
具体实施方式
结合以下实施例对本发明做详细说明，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。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热
TGA：热重分析
1H NMR：液态核磁氢谱
HPLC：高效液相色谱
采集数据所用的仪器及方法：
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：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2019076944-appb-000002
1.54060；Kα2
Figure PCTCN2019076944-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
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：
扫描速率：10℃/min
保护气体：氮气
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：
扫描速率：10℃/min
保护气体：氮气
核磁共振氢谱数据( 1HNMR)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。
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：
1、色谱柱：Ultimate LP-C18,250×4.6mm,5μm
2、流动相：A:0.1％H 3PO 4水溶液(pH＝3.5,TEA)
B:乙腈
洗脱梯度如下：
时间(min) ％B
0.0 20
9.0 34
11.0 40
18.0 50
22.0 70
30.0 70
31.0 20
40.0 20
3、1.0mL/min
4、进样量：10μL
5、检测波长：230nm
6、柱温：40℃
7、稀释剂：乙腈
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。
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。
具体实施方式
实施例1 晶型K1的制备方法
称取200.1mg Acalabrutinib游离碱和51.8mg马来酸至5mL玻璃小瓶中，加入4mL丙酮/H 2O(95:5,v/v)，室温搅拌过夜后，真空抽滤并室温真空干燥，得到干燥固体218.0mg。
称取上述固体118.1mg至3mL玻璃小瓶中，加入2mL水，室温搅拌形成悬浮液。将22.3mg的NaOH溶于1mL水中得到NaOH水溶液，室温下将该NaOH水溶液加至上述悬浮液中，搅拌，分离后得到固体。经检测，本实施例得到的固体为晶型K1，其XRPD图如附图1所示，其XRPD数据如表1所示。
其DSC如附图2所示，加热至69℃附近时，开始出现脱水吸热峰；其TGA图如图3所示，加热至100℃附近时，约有14.2％的质量损失。非限定性地，晶型K1为水合物。
表1
2θ(±0.2°) d间隔 相对强度％
4.78 18.48 8.80
5.75 15.38 100.00
6.90 12.82 16.56
8.12 10.88 16.64
9.50 9.31 94.77
11.48 7.71 15.98
12.75 6.95 34.72
13.80 6.42 42.93
14.28 6.20 70.60
16.28 5.44 25.72
17.66 5.02 18.50
18.38 4.83 32.12
19.95 4.45 13.11
20.99 4.23 17.58
23.00 3.87 24.98
23.50 3.79 32.18
24.58 3.62 51.94
25.84 3.45 49.46
28.24 3.16 18.63
29.22 3.06 11.93
30.01 2.98 15.30
32.81 2.73 3.85
35.57 2.52 2.70
36.71 2.45 3.04
实施例2 晶型K1的制备方法
称取1.0g的Acalabrutinib游离碱至玻璃小瓶中，加入10mL浓度为1mol/L的盐酸水溶液，固体溶解后过滤得到澄清溶液。将所得清液在5℃下搅拌，同时加入7.9mL浓度为1mol/L的氢氧化钠水溶液，加入少量晶种，继续添加2.1mL的氢氧化钠水溶液。搅拌2天后，分离得到固体，并在35℃鼓风干燥约40小时。经检测，本实施例得到的固体为晶型K1，其XRPD数据如表2所示。
该晶型样品的 1H NMR图谱如图4所示，核磁数据与该化合物结构(C 26H 23N 7O 2)一致。核磁数据为： 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.41(d,J＝4.8Hz,1H),8.22(d,J＝8.3Hz,1H),8.16(dd,J＝8.4,2.6Hz,2H),7.80(ddd,J＝28.2,16.5,8.2Hz,4H),7.23–7.06(m,2H),6.15(d,J＝24.9Hz,2H),5.60(ddd,J＝94.6,7.6,4.2Hz,1H),3.82(t,J＝6.6Hz,1H),3.71–3.48(m,1H),2.32(d,J＝9.9Hz,2H),2.18–1.87(m,4H),1.62(s,1H)。
表2
2θ(±0.2°) d间隔 强度％
5.84 15.13 96.93
6.94 12.74 17.67
8.19 10.80 18.97
9.59 9.22 100.00
11.56 7.66 11.69
12.19 7.26 7.50
12.85 6.89 32.87
13.85 6.40 39.31
14.37 6.16 70.53
15.51 5.71 4.84
16.37 5.41 24.75
17.74 5.00 17.31
18.45 4.81 24.80
18.95 4.68 13.77
21.05 4.22 14.50
21.63 4.11 9.92
23.46 3.79 31.53
24.53 3.63 56.95
25.88 3.44 50.10
27.80 3.21 18.40
28.27 3.16 17.16
29.32 3.05 9.84
30.09 2.97 12.54
实施例3 晶型K1在水中的物理稳定性
进行如下实验，对比本发明晶型K1和WO2017002095A1晶型I在水中的物理稳定性。分别称量约10mg不同晶型的固体样品，加入1.0mL的纯水形成悬浊液，放置在室温和5℃条件下分散。选用了磁力搅拌和震荡分散的方式，评估晶型K1和WO2017002095A1晶型I在水中的物理稳定性。结果表明：室温和5℃条件下，本发明晶型K1在磁力搅拌和震荡下晶型均未发生改变，而晶型I的结晶度降低，几乎转变为无定形。结果表明，本发明的晶型K1在水中具有更优的物理稳定性。
表3
Figure PCTCN2019076944-appb-000004
表4
Figure PCTCN2019076944-appb-000005
实施例4 晶型K1和WO2017002095A1晶型I的混悬竞争实验
称取晶型K1和WO2017002095A1晶型I各约30mg置于水中，在5℃和室温条件下悬浮搅拌，评估晶型K1和WO2017002095A1晶型I的稳定性，结果如表5所示。结果表明，在5℃和室温条件下，晶型I会转变为本发明的晶型K1，说明本发明的晶型K1具有更优的热力学稳定性。
表5
起始样品 搅拌温度 搅拌时间 晶型 附图
晶型K1+晶型I 5℃ 6天 晶型K1 图13
晶型K1+晶型I 室温 24天 晶型K1 图14
实施例5 晶型K1的长期和加速稳定性
称取4份本发明晶型K1，各约10mg，置于HPLC玻璃小瓶中，使用配套的瓶盖密封(闭口包装)，或用封口膜密封后在瓶口扎3～5个针孔(开口包装)。将准备好的各个小瓶包装的样品按如下表所列的条件放置，并在1个月时采用XRPD测定晶型变化，测试结果如表6所示，XRPD对比图如图15所示。
表6
Figure PCTCN2019076944-appb-000006
结果表明，晶型K1在25℃/60％RH闭口、25℃/60％RH敞口、40℃/75％RH闭口、40℃/75％RH敞口条件下至少可稳定1个月，可见，晶型K1在长期和加速条件下均可保持良好的稳定性。
实施例6 晶型K1在不同缓冲溶液中的溶解度
分别称取足量的晶型K1与WO2017002095A1晶型I样品悬浮分散在pH为7.0，7.4，8.7的缓冲溶液中，室温下搅拌平衡2小时，再离心分离取上层清液，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7所示。
表7
Figure PCTCN2019076944-appb-000007
结果表明，与WO2017002095A1晶型I相比，晶型K1在pH为7.0，7.4，8.7的缓冲液中具有更高的溶解度。
小肠是口服药物吸收的主要部位。已知小肠内为偏中性环境，本发明晶型K1在中性或弱碱性介质中溶解度高于晶型I，一方面有利于药物成功递送到肠道，另一方面有利于药物在肠道内的溶解和吸收。
实施例7 晶型K1在有机溶剂中的溶解度
分别称取一定质量晶型K1与WO2017002095A1晶型I至玻璃小瓶。向小瓶中逐步添加有机溶剂，每次添加100μL。通过震荡或超声促使固体在溶剂中快速分散，并观察固体是否完全溶解。当观察到固体完全溶解，或溶剂总体积达到1.5mL时，则停止添加溶剂。根据称取样品的质量(m)，添加溶剂的体积，计算不同晶型在有机溶剂中的溶解度(S)，结果如表8所示。
表8
Figure PCTCN2019076944-appb-000008
Figure PCTCN2019076944-appb-000009
备注：溶解度计算方法，S>m/V1和S<m/V2；V1为观察到晶型未完全溶解时添加溶剂的最大体积，V2为观察到晶型完全溶解时添加溶剂的最小体积。
结果表明，在结晶工艺常用的有机溶剂如甲醇、乙醇、异丙醇、正丙醇、正丁醇、丙酮、甲基异丁基酮、甲乙酮、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、乙腈中，本发明晶型K1的溶解度均高于晶型I。
实施例8 晶型K1的研磨后的物理稳定性
将晶型K1置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，测试结果如图16所示。结果表明，晶型K1在研磨条件下具有较好的物理稳定性，在研磨之后的晶型和结晶度都没有明显变化。
实施例9 晶型K1的可压性
分别称取晶型K1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9所示。
表9
晶型 抗张强度(MPa)
WO2017002095A1晶型I 无法压制成片
晶型K1 1.31
结果表明，晶型K1较WO2017002095A1晶型I抗张强度更大，具有更优的可压性。
实施例10 晶型K1的黏附性
将约30mg晶型K1和WO2017002095A1晶型I分别加入到8mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉 末量。采用该方法连续压制两次后，记录冲头累计的最终黏附量和平均黏附量。具体的实验结果见表10。
表10
晶型 累计的最终黏附量(μg) 平均黏附量(μg)
WO2017002095A1晶型I 90 45
晶型K1 60 30
实验结果表明，WO2017002095A1晶型I的吸附量高于晶型K1，晶型K1的黏附性优于WO2017002095A1晶型I。
实施例11 晶型K1的制剂处方工艺
使用本发明中的晶型K1，根据表11中所列的制剂配方，按照表12所述的制剂步骤，制备成相应的胶囊，并分别检测制成胶囊前后药物晶型的变化，测试结果如图17所示。
表11
Figure PCTCN2019076944-appb-000010
表12
Figure PCTCN2019076944-appb-000011
结果表明，晶型K1在胶囊制剂的工艺中，晶型保持不变。
实施例12 晶型K1制剂的溶出度
使用实施例11中制备的含晶型K1的胶囊，测试在0.1mol/L盐酸的水溶液中的溶出度。测试方法如表13所示，测试结果如表14和图18所示。
表13
溶出仪 Agilent 708DS
方法 桨法
介质 0.1mol/L盐酸水溶液
介质体积 900mL
转速 50rpm
介质温度 37℃
取样点 5,10,15,20,30和45min
表14
时间(min) 累积溶出度(％)
0 0.0
5 80.3
10 83.2
15 83.5
20 84.1
30 84.0
45 84.1
结果表明，晶型K1的胶囊制剂在0.1mol/L盐酸的水溶液中，具有较高的体外溶出度和较快的体外溶出速率，20分钟即可达到84％的溶出度。
实施例13 晶型K1制剂的稳定性
对实施例11获得的含晶型K1的胶囊进行稳定性测试，将其分别放置在25℃/60％RH、40℃/75％RH条件下一定时间，测试其XRPD。测试结果如表15所示，其XRPD对比图如图19所示。
表15
Figure PCTCN2019076944-appb-000012
结果表明，晶型K1制剂在25℃/60％RH、40℃/75％RH条件下可以至少保持6个月稳定。
实施例14 晶型CS10的制备方法
称取20g的Acalabrutinib游离碱溶解于200mL的体积比为9:1的乙腈和甲醇的混合溶剂中，搅拌并升温至50℃，分离析出的固体。称取50mg的该固体置于1.5mL的玻璃瓶中，加入1mL乙酸异丙酯溶剂，在5℃下搅拌20h，得到白色结晶。
经检测，本实施例所得白色结晶为晶型CS10。其X射线粉末衍射数据如图 20，表16所示。
表16
2θ(±0.2°) d值 强度％
6.03 14.67 48.76
8.52 10.38 100.00
12.28 7.21 5.06
13.19 6.71 14.04
14.91 5.94 14.72
15.31 5.79 29.95
15.82 5.60 16.47
18.21 4.87 67.09
18.71 4.74 21.77
20.03 4.43 13.55
21.50 4.13 3.67
24.40 3.65 23.73
25.35 3.51 7.00
25.97 3.43 11.64
26.55 3.36 13.32
29.05 3.07 3.09
30.61 2.92 3.86
32.07 2.79 6.80
实施例15 晶型CS10的制备方法
称取20g的Acalabrutinib游离碱溶解于200mL的体积比为9:1的乙腈和甲醇的混合溶剂中，搅拌并升温至50℃，分离析出的固体。称取310mg的该固体置于50mL结晶釜中，加入15mL体积比为95:5的乙酸异丙酯与二氯甲烷的混合溶剂，加入约2mg晶型CS10作为晶种，5℃下悬浮搅拌21小时，得到白色结晶。
经检测，本实施例所得白色结晶为晶型CS10。其X射线粉末衍射数据如图21，表17所示。
表17
2θ(±0.2°) d值 强度％
6.08 14.54 57.84
8.52 10.38 100.00
12.34 7.17 4.78
13.25 6.68 14.17
14.50 6.11 8.22
14.89 5.95 12.87
15.36 5.77 23.48
15.88 5.58 19.54
18.26 4.86 97.57
18.71 4.74 22.32
19.09 4.65 12.23
20.05 4.43 17.53
21.53 4.13 4.79
22.72 3.91 3.37
23.36 3.81 5.96
24.08 3.70 25.00
24.41 3.65 39.61
25.42 3.50 12.55
26.02 3.42 23.08
26.59 3.35 22.77
28.79 3.10 5.34
29.20 3.06 6.70
30.64 2.92 7.83
32.08 2.79 12.46
34.92 2.57 2.23
36.98 2.43 3.97
38.58 2.33 3.11
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。

Claims (8)

  1. 一种Acalabrutinib的晶型K1，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为5.8°±0.2°、9.5°±0.2°、14.3°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型K1，其特征还在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为13.8°±0.2°、12.8°±0.2°、18.4°±0.2°中的1处、或2处、或3处具有特征峰。
  3. 根据权利要求1所述的晶型K1，其特征还在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为16.3°±0.2°、6.9°±0.2°、11.5°±0.2°中的1处、或2处、或3处具有特征峰。
  4. 一种根据权利要求1所述的晶型K1的制备方法，其特征在于，所述方法为：
    (1)将Acalabrutinib游离碱和酸加入酮类和水的混合溶剂中搅拌，分离并干燥得到固体，将该固体加入水中形成悬浮液，向该悬浮液中加入碱性溶液并搅拌，分离得到晶型K1；或
    (2)将Acalabrutinib游离碱加入酸性溶液中搅拌，分离并干燥得到的固体，继续将该固体转移至碱性溶液中搅拌，分离得到固体晶型K1。
  5. 根据权利要求4所述的制备方法，方法(1)中所述酸为马来酸或富马酸，所述碱性溶液为氢氧化钠水溶液，所述酮类溶剂为丙酮、2-丁酮或甲基异丁基酮；方法(2)中所述酸性溶液为盐酸水溶液，所述碱性溶液为氢氧化钠水溶液。
  6. 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K1及药学上可接受的载体、稀释剂或赋形剂。
  7. 权利要求1中所述的晶型K1在制备布鲁顿酪氨酸激酶抑制剂药物中的用途。
  8. 权利要求1中所述的晶型K1在制备治疗套细胞淋巴瘤和/或慢性淋巴细胞白血病和/或巨球蛋白血症和/或滤泡性淋巴瘤和/或弥漫性大B细胞淋巴瘤和/或多发性骨髓瘤药物中的用途
PCT/CN2019/076944 2018-04-26 2019-03-05 Acalabrutinib的新晶型及其制备方法和用途 WO2019205812A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US17/050,329 US20210087195A1 (en) 2018-04-26 2019-03-05 New crystal form of acalbrutinib, preparation method therefor and use thereof
CN201980002375.2A CN110650960B (zh) 2018-04-26 2019-03-05 Acalabrutinib的新晶型及其制备方法和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810387686 2018-04-26
CN201810387686.2 2018-04-26

Publications (1)

Publication Number Publication Date
WO2019205812A1 true WO2019205812A1 (zh) 2019-10-31

Family

ID=68294746

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/076944 WO2019205812A1 (zh) 2018-04-26 2019-03-05 Acalabrutinib的新晶型及其制备方法和用途

Country Status (3)

Country Link
US (1) US20210087195A1 (zh)
CN (1) CN110650960B (zh)
WO (1) WO2019205812A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021135346A1 (zh) * 2019-12-31 2021-07-08 苏州科睿思制药有限公司 Acalabrutinib的新晶型及其制备方法和用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112028896A (zh) * 2020-10-14 2020-12-04 奥锐特药业(天津)有限公司 阿卡替尼的新晶型及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN107056786A (zh) * 2016-10-14 2017-08-18 苏州明锐医药科技有限公司 阿卡替尼的制备方法
CN107522701A (zh) * 2017-09-01 2017-12-29 苏州富士莱医药股份有限公司 一种治疗慢性淋巴细胞白血病的BTK抑制剂Acalabrutinib的合成方法
WO2018064797A1 (zh) * 2016-10-05 2018-04-12 杭州领业医药科技有限公司 Acp-196的晶型及其制备方法和药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2018064797A1 (zh) * 2016-10-05 2018-04-12 杭州领业医药科技有限公司 Acp-196的晶型及其制备方法和药物组合物
CN107056786A (zh) * 2016-10-14 2017-08-18 苏州明锐医药科技有限公司 阿卡替尼的制备方法
CN107522701A (zh) * 2017-09-01 2017-12-29 苏州富士莱医药股份有限公司 一种治疗慢性淋巴细胞白血病的BTK抑制剂Acalabrutinib的合成方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021135346A1 (zh) * 2019-12-31 2021-07-08 苏州科睿思制药有限公司 Acalabrutinib的新晶型及其制备方法和用途

Also Published As

Publication number Publication date
CN110650960A (zh) 2020-01-03
US20210087195A1 (en) 2021-03-25
CN110650960B (zh) 2021-08-24

Similar Documents

Publication Publication Date Title
WO2018108101A1 (zh) {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的新晶型及其制备方法
US11066384B2 (en) Crystalline forms of ARN-509, preparation method and use thereof
WO2019019959A1 (zh) 瑞博西尼的单琥珀酸盐晶型及其制备方法和用途
WO2022017478A1 (zh) 一种环己烷甲酰胺的新晶型及其制备方法
WO2021136477A1 (zh) 化合物i二盐酸盐的共晶及其制备方法和用途
WO2016155670A1 (zh) 一种cdk抑制剂和mek抑制剂的共晶及其制备方法
WO2019205812A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2018103726A1 (zh) 一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途
WO2022170864A1 (zh) Belumosudil甲磺酸盐的晶型及其制备方法和用途
WO2020063939A1 (zh) 一种Upadacitinib的晶型及其制备方法和用途
CA3216258A1 (en) Solid state forms of (s)-n-(3-(2-(((r)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof
WO2018133705A1 (zh) Gft-505的晶型及其制备方法和用途
WO2020057622A1 (zh) 卡博替尼苹果酸盐晶型及其制备方法和用途
WO2019134455A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
WO2022258060A1 (zh) 一种lanifibranor的晶型及其制备方法
WO2019105359A1 (zh) Acalabrutinib的晶型及其制备方法和用途
WO2021000687A1 (zh) Pac-1晶型的制备方法
WO2019149262A1 (zh) Sb-939的晶型及其制备方法和用途
CN116802183A (zh) 二氮杂双环类化合物的对甲苯磺酸盐新晶型及其制备方法
WO2018157741A1 (zh) Sb-939的盐的晶型及其制备方法和用途
WO2024022275A1 (zh) Xevinapant的晶型及其制备方法和用途
WO2023109939A1 (zh) 吡啶类衍生物的晶型及其制备方法
WO2020151672A1 (zh) 一种达格列净晶型及其制备方法和用途
WO2022144042A1 (zh) Tas-116的晶型及其制备方法、药物组合物和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19792541

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19792541

Country of ref document: EP

Kind code of ref document: A1