WO2019149262A1 - Sb-939的晶型及其制备方法和用途 - Google Patents

Sb-939的晶型及其制备方法和用途 Download PDF

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WO2019149262A1
WO2019149262A1 PCT/CN2019/074336 CN2019074336W WO2019149262A1 WO 2019149262 A1 WO2019149262 A1 WO 2019149262A1 CN 2019074336 W CN2019074336 W CN 2019074336W WO 2019149262 A1 WO2019149262 A1 WO 2019149262A1
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crystalline form
solvent
crystal form
crystalline
present
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PCT/CN2019/074336
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English (en)
French (fr)
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翟晓婷
杨朝惠
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms

Definitions

  • the invention relates to the field of medicinal chemistry. Specifically, it relates to a crystal form of SB-939, a preparation method thereof and use thereof.
  • Histone Deacetylase (HDAC) inhibitors can inhibit DNA replication and RNA transcription of tumor cells, and can prevent and treat tumors.
  • HDAC Histone Deacetylase
  • AML acute myeloid leukemia
  • SB-939 is an effective oral inhibitor of HDAC being developed by MEI Pharmaceuticals. SB-939 is clinically used to treat acute myeloid leukemia, myelodysplastic syndrome, and myelofibrosis, and has achieved good results.
  • the chemical name of SB-939 is: (2E)-3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxypropene
  • An amide (hereinafter referred to as "Compound I”) having the following structural formula:
  • a crystal is a solid material whose constituents are highly ordered in the microstructure to form a lattice of crystals that extend in all directions.
  • the phenomenon of drug polymorphism refers to the presence of two or more different crystal forms of the drug. Because of the 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 influence of crystal form will be greater. Therefore, the drug crystal form is inevitably an important part of drug research and an important part of drug quality control.
  • Form X has poor stability and high hygroscopicity and is not suitable for use in pharmaceutical preparations.
  • the inventors of the present application have unexpectedly discovered the compound I crystal forms CS2 and CS5 provided by the present invention, which have advantages in physical and chemical properties, formulation processability and bioavailability, such as melting point, solubility, moisture permeability, purification, and stability.
  • At least one of the aspects of sex, adhesion, compressibility, fluidity, dissolution in vitro and in vivo, and bioavailability have advantages, especially good stability and low moisture permeability, which provides new development for drugs containing SB-939. A better choice has a very important meaning.
  • the main object of the present invention is to provide a novel crystalline form of Compound I and a process for its preparation and use.
  • the present invention provides a crystal form CS2 of Compound I (hereinafter referred to as "Form CS2").
  • the X-ray powder diffraction of the crystal form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 5.6° ⁇ 0.2°, 23.1° ⁇ 0.2°, and 15.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 20.0° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 16.4° ⁇ 0.2°. Peak; Preferably, the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 20.0° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 16.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 20.8° ⁇ 0.2° and 24.6° ⁇ 0.2°; preferably, the crystal form CS2
  • the X-ray powder diffraction has characteristic peaks at two points in the diffraction angle 2 ⁇ value of 20.8° ⁇ 0.2° and 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ values of 5.6° ⁇ 0.2°, 23.1° ⁇ 0.2°, 15.1° ⁇ 0.2°, 20.0° ⁇ 0.2°, Any of the three, or four, or five, or six, or seven, or eight of 25.2 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, 24.6 ° ⁇ 0.2 ° peak.
  • the X-ray powder diffraction pattern of Form CS2 is substantially as shown in FIG.
  • the differential scanning calorimetry chart of Form CS2 is substantially as shown in FIG. 3, and an endothermic peak begins to appear at 79 ° C ⁇ 5 ° C.
  • the present invention also provides a method for preparing the crystalline form CS2, the preparation method comprising:
  • the alcohol solvent in the method (1) is preferably ethanol or isopropanol, and the halogenated hydrocarbon solvent is preferably chloroform;
  • ester solvent in the method (2) is preferably ethyl acetate
  • the cycloether solvent is preferably tetrahydrofuran or 2-methyltetrahydrofuran
  • the halogenated hydrocarbon solvent is preferably dichloromethane
  • the present invention provides a crystal form CS5 of Compound I (hereinafter referred to as "Form CS5").
  • the X-ray powder diffraction of the crystal form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 17.9° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 18.3° ⁇ 0.2°. Peak; preferably, the X-ray powder diffraction of the crystal form CS5 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 17.9° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 18.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 11.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 24.6° ⁇ 0.2°. Peak; Preferably, the X-ray powder diffraction of the crystal form CS5 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 11.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has a diffraction angle 2 ⁇ of 7.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, 18.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, Any 3, or 4, or 5, or 6, or 7 of 22.8 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, 13.0 ° ⁇ 0.2 °, 24.6 ° ⁇ 0.2 ° , or 8 or 9 has characteristic peaks.
  • the X-ray powder diffraction pattern of Form CS5 is substantially as shown in FIG.
  • differential scanning calorimetry chart of Form CS5 is substantially as shown in Figure 7, and an endothermic peak begins to appear at 102 °C ⁇ 5 °C.
  • the present invention also provides a method for preparing the crystalline form CS5, the preparation method comprising:
  • ester solvent in the method (1) is preferably isopropyl acetate
  • the cyclic ether solvent is preferably 1,4-dioxane or tetrahydrofuran.
  • the crystal forms CS2 and CS5 provided by the present invention have the following beneficial effects:
  • the crystal form of the present invention has lower wettability than the prior art.
  • the test results show that the wettability of the crystalline form CS2 and the crystalline form CS5 of the present invention is less than one-half of that of the prior art solid.
  • the wettability weight gain of the crystalline forms CS2 and CS5 of the present invention under the condition of 80% relative humidity were 0.36% and 0.51%, respectively, while the wet weight gain of the prior art under the condition of 80% relative humidity was 1.04%.
  • the hygroscopicity directly affects the physicochemical stability of the drug, and the high wettability tends to cause chemical degradation and crystal transformation.
  • high moisture permeability will reduce the fluidity of the drug, thereby affecting the processing of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which imposes higher requirements on production and requires high costs.
  • high moisture permeability is likely to cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the low moisture absorbing crystal form is not demanding on the environment, which reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form of the present invention has better stability than the prior art.
  • the crystalline CS2 and CS5 APIs were placed at 25 ° C / 60% relative humidity, and the crystal form did not change for at least 9 months, and the purity changes during storage were only 0.11% and 0.02%, respectively, and the purity remained basically unchanged.
  • the prior art Form X was partially rotated at a temperature of 25 ° C / 60% relative humidity for one month.
  • the crystal forms CS2 and CS5 were mixed with the excipients to form a pharmaceutical preparation, they were placed at 25 ° C / 60% relative humidity, and the crystal form did not change for at least 3 months. It is indicated that the crystalline CS2 and CS5 APIs and preparations have good stability under long-term conditions and are beneficial for drug storage.
  • the crystal form of CS2 and CS5 drug substance did not change under the condition of 40 °C/75% relative humidity for at least 9 months, and the purity change during storage was only 0.06% and 0.03%, respectively, and the purity remained basically unchanged. change.
  • the crystal forms CS2 and CS5 were mixed with the excipients to form a pharmaceutical preparation, they were placed at 40 ° C / 75% relative humidity, and the crystal form did not change for at least 3 months.
  • the crystal forms CS2 and CS5 are circulated in the range of 0-95% relative humidity, the crystal form does not change, and the prior art crystal form X undergoes partial crystal transformation.
  • the crystalline CS2 and CS5 bulk drugs and preparations have good stability under accelerated conditions and more severe conditions.
  • the stability of drug substances and preparations under accelerated conditions and under more severe conditions is critical to the drug.
  • the raw materials and preparations will encounter high temperature and/or high humidity or low humidity conditions caused by weather and seasonal differences, climate differences in different regions.
  • the crystalline CS2 and CS5 APIs have good stability under severe conditions, which is beneficial to avoid the influence of the storage conditions on the label on the quality of the drug.
  • the crystal forms CS2 and CS5 have good grinding stability.
  • the crystalline CS2 and CS5 APIs have good physical stability after grinding, whereas the prior art Form X is converted to amorphous after grinding. Grinding and pulverizing of the raw material medicine is often required in the processing of the preparation, and good physical stability can reduce the risk of crystallinity change and crystal transformation of the raw material medicine during the processing of the preparation.
  • 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.
  • Good chemical stability ensures that no impurities are produced during storage.
  • the crystalline forms CS2 and CS5 have good physicochemical stability, ensuring consistent controllable quality of the drug substance and preparation, and minimizing changes in drug quality and bioavailability caused by changes in crystal form or impurities.
  • the crystal forms CS2 and CS5 of the present invention have high solubility.
  • the 24-hour solubility of Form CS2 in SGF and FeSSIF was 5.5 mg/mL and 9.0 mg/mL, respectively, and the 24-hour solubility of Form CS5 in SGF and FeSSIF was 5.5 mg/mL and 7.1 mg/mL, respectively.
  • the high solubility is beneficial to improve the absorption of the drug in the human body, improve the bioavailability, and enable the drug to exert a better therapeutic effect; in addition, the high solubility can reduce the dose of the drug while reducing the side effect of the drug while ensuring the efficacy of the drug. And improve the safety of drugs.
  • the crystalline form CS2 and CS5 formulations of the present invention have good in vitro dissolution.
  • the dissolution of the Form CS2 formulation at 60 minutes reached 86.1%
  • the dissolution of the Form CS5 formulation at 86 minutes reached 86.6%.
  • Dissolution is an important prerequisite for the absorption of a drug.
  • Good in vitro dissolution indicates that the drug has a higher level of absorption in the body and better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug.
  • crystalline form CS2 and the crystalline form CS5 provided by the present invention have the following beneficial effects:
  • the crystal forms CS2 and CS5 of the present invention have good adhesion.
  • the results of adhesion evaluation showed that the adsorption amounts of the crystalline forms CS2 and CS5 were low.
  • the excellent adhesion of the crystalline form CS2 and CS5 can effectively improve or avoid the phenomenon of sticky wheel and sticking caused by dry granulation and tableting, and is beneficial to improve the appearance and weight difference of the product.
  • the excellent adhesion of the crystalline forms CS2 and CS5 can also effectively reduce the agglomeration of the raw materials, facilitate the dispersion of the raw materials and the mixing with other auxiliary materials, and ensure the mixing uniformity and content uniformity of the preparation.
  • the crystal form CS2 provided by the present invention has good compressibility.
  • the good compressibility of the crystalline form CS2 can effectively improve the hardness/friability degree, cracking and the like in the tableting process, 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 crystal form CS5 provided by the present invention has good fluidity. Good fluidity can avoid clogging production equipment and improve production efficiency; the good flowability of crystal form CS5 ensures the uniformity of mixing and content uniformity of the preparation, reduces the weight difference of the preparation, and improves the product quality.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS2, the crystalline form CS5 or any combination of the two crystalline forms and a pharmaceutically acceptable carrier, diluted Agent or auxiliary.
  • the use of the crystalline form CS2, the crystalline form CS5 or any mixture thereof provided by the present invention for the preparation of a medicament for treating acute myeloid leukemia and/or myelodysplastic syndrome and/or myelofibrosis disease.
  • the "stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, mechanical stirring. It is preferably from 100 to 300 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation was carried out 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.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • the "cooling down” is accomplished using conventional methods in the art, such as slow cooling and rapid cooling.
  • Slow cooling is usually carried out at 0.1 ° C / min.
  • Rapid cooling is usually to transfer the sample directly from the environment below room temperature, such as cooling in the refrigerator.
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction patterns typically vary with instrumental conditions. It should be particularly noted that the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of the intensity of the diffraction peaks cannot be the sole or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the intensity of the diffraction peaks shown herein is illustrative and not for absolute comparison.
  • the experimental error of the diffraction 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 diffraction peak angle is caused, and a certain offset is usually allowed.
  • the X-ray powder diffraction pattern of one crystal form in the present invention does not have to be exactly identical to the X-ray powder diffraction pattern in the examples referred to herein, and any having characteristic peaks in these patterns Crystal forms of the same or similar X-ray powder diffraction patterns are within the scope of the present invention.
  • Those skilled in the art will be able to compare the X-ray powder diffraction pattern listed herein with an X-ray powder diffraction pattern of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CS2 and crystalline form CS5 of the present invention are 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.
  • Example 1 is an XRPD pattern of the crystal form CS2 obtained in Example 1.
  • Example 2 is a TGA curve of the crystalline form CS2 obtained in Example 1.
  • Example 3 is a DSC curve of the crystalline form CS2 obtained in Example 1.
  • Example 4 is an XRPD pattern of the crystalline form CS2 obtained in Example 5.
  • Figure 5 is an XRPD pattern of the crystalline form CS5 obtained in Example 6.
  • Example 6 is a TGA curve of the crystalline form CS5 obtained in Example 6.
  • Example 7 is a DSC curve of the crystalline form CS5 obtained in Example 6.
  • Example 8 is an XRPD pattern of the crystalline form CS5 obtained in Example 8.
  • Figure 9 is an XRPD diagram of the crystalline form CS2 of the present invention placed at 25 ° C / 60% relative humidity for 9 months (the top view is before placement, the lower figure is after placement)
  • Figure 10 is an XRPD diagram of the crystalline form CS5 of the present invention placed at 25 ° C / 60% relative humidity for 9 months (the figure above is before placing, the lower figure is after placing)
  • Figure 11 is an XRPD diagram of the prior art Form X placed at 25 ° C / 60% relative humidity for 1 month (the top image is before placement, the lower image is after placement)
  • Figure 12 is an XRPD diagram of the crystalline form CS2 of the present invention placed at 40 ° C / 75% relative humidity for 9 months (the top view is before placement, the lower figure is after placement)
  • Figure 13 is an XRPD diagram of the crystalline form CS5 of the present invention placed at 40 ° C / 75% relative humidity for 9 months (the top view is before placement, the lower figure is after placement)
  • Figure 14 is an XRPD diagram of the crystal form CS2 of the present invention before and after cycling in the range of 0-95% relative humidity (the figure above is before the cycle, and the figure below is after the cycle)
  • Figure 15 is an XRPD diagram of the crystal form CS5 of the present invention before and after cycling in the range of 0-95% relative humidity (the figure above is before the cycle, and the figure below is after the cycle)
  • Figure 16 is an XRPD diagram of the prior art Form X before and after cycling in the range of 0-95% relative humidity (the figure above is before the cycle, and the figure below is after the cycle)
  • Figure 17 is an XRPD diagram of the crystal form CS2 before and after polishing according to the present invention (the figure above is before grinding, and the figure below is after grinding)
  • Figure 18 is an XRPD diagram of the crystal form CS5 before and after polishing according to the present invention (the figure above is before grinding, and the figure below is after grinding)
  • Figure 19 is an XRPD diagram of the prior art Form X before and after grinding (the figure above is before grinding, and the figure below is after grinding)
  • Figure 20 is an XRPD pattern of the preparation of the crystalline form CS2 before and after the preparation of the present invention (XRPD pattern of the auxiliary material from top to bottom, XRPD pattern of the crystalline form CS2 preparation, and XRPD pattern of the crystalline form CS2 raw material)
  • Figure 21 is an XRPD pattern of the preparation of the crystalline form CS5 of the present invention before and after preparation (the XRPD pattern of the excipient from the top to the bottom, the XRPD pattern of the crystalline CS5 preparation, and the XRPD pattern of the crystalline CS5 raw material)
  • Figure 22 is an XRPD pattern of the crystalline form CS2 formulation of the present invention before and after standing at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity (from top to bottom, the initial XRPD pattern, at 25 ° C / 60% XRPD pattern after placement at relative humidity and XRPD pattern after placement at 40 ° C / 75% relative humidity)
  • Figure 23 is an XRPD pattern of the crystalline form CS5 formulation of the present invention before and after standing at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity (from top to bottom, the initial XRPD pattern, at 25 ° C / 60% XRPD pattern after placement at relative humidity and XRPD pattern after placement at 40 ° C / 75% relative humidity)
  • Figure 24 is a dissolution curve of the crystalline form CS2 preparation of the present invention
  • Figure 25 is a dissolution curve of the crystalline form CS5 preparation 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 DSC according to 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 TGA of the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software
  • the analysis software is DVS-Intrinsic Analysis software.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • HPLC High performance liquid chromatography
  • HPLC method parameters of the test purity described in the present invention are as follows:
  • the elution gradient is as follows:
  • HPLC method parameters used in the concentration test of the present invention are as follows:
  • the elution gradient is as follows:
  • Diluent equal volume mixing of 0.1% aqueous trifluoroacetic acid solution and 0.1% trifluoroacetic acid acetonitrile solution
  • room temperature is not a specific temperature value and refers to a temperature range of 10-30 °C.
  • the compound I as a starting material is in the form of a solid (crystalline or amorphous), semi-solid, wax or oil.
  • the compound I as a raw material is in the form of a solid powder.
  • the compound I starting materials used in the following examples can be prepared according to the prior art, for example, according to the method described in the literature J. Med. Chem. 2011, 54, 4694-4720.
  • Example 1-2 Volatilization method for preparing crystal form CS2
  • Samples 1 and 2 were both crystalline form CS2 as determined by XRPD. Sample 1 was selected for XRPD/TGA/DSC test characterization. The XRPD diagram is shown in Figure 1, and the XRPD data is shown in Table 2.
  • the TGA had a mass loss of about 0.3% when heated to around 150 °C.
  • the DSC begins to show an endothermic peak around 79 °C.
  • Sample 2 has the same or similar XRPD pattern as Sample 1, which is the same crystalline form and has the same properties.
  • Example 3-5 Preparation of crystal form CS2 by stirring method
  • Samples 3-5 were all crystalline CS2 by XRPD.
  • the XRPD pattern of Sample 5 is shown in Figure 4, and the XRPD data is shown in Table 4.
  • Samples 3-5 have the same or similar XRPD patterns, are the same crystalline form, and have the same properties.
  • Example 6-8 Preparation of Crystal Form CS5 by Stirring Method
  • Samples 6-8 were all crystalline CS5 by XRPD. Sample 6 was selected for XRPD/TGA/DSC test characterization. The XRPD diagram is shown in Figure 5, and the XRPD data is shown in Table 6.
  • the TGA had a mass loss of about 0.2% when heated to around 150 °C.
  • Sample 8 was selected for XRPD test characterization.
  • the XRPD diagram is shown in Figure 8, and the XRPD data is shown in Table 7.
  • Samples 6-8 have the same or similar XRPD patterns, are the same crystalline form, and have the same properties.
  • Example 9 Dynamic solubility of crystalline form CS2 and crystalline form CS5
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid) and FeSSIF (simulated feeding intestinal fluid) are biologically relevant media that better reflect the effects of the gastrointestinal physiology on drug release and are tested in such media.
  • the solubility is closer to the solubility in the human environment.
  • Example 10 Stability of Form CS2, Form CS5 and Prior Art Form X
  • the crystalline form CS2 and the crystalline form CS5 are stable for at least 9 months at 25 ° C / 60% RH and 40 ° C / 75% RH, and the purity remains substantially unchanged. It can be seen that the crystalline form CS2 and the crystalline form CS5 maintain good physicochemical stability under long-term and accelerated conditions. However, the prior art crystal form X is partially crystallized under the condition of 25 ° C / 60% RH for one month, and the stability is poor, which is not conducive to the practical application of the drug.
  • the crystalline form CS2, the crystalline form CS5 and the prior art form X of the present invention were weighed about 10 mg each, and the 0-95% relative humidity range was cycled once, and the crystal form before and after the humidity cycle was measured.
  • the crystal form CS2 and the crystal form CS5 of the present invention did not undergo crystal transformation, and the prior art crystal form X was crystallized.
  • the crystal form CS2, the crystal form CS5 and the prior art form X were 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 Table 11. The results show that the crystalline form CS2 and the crystalline form CS5 of the present invention have better stability under the grinding conditions than the prior art Form X.
  • Example 11 Wettability of Form CS2, Form CS5 and Form X
  • the wettability weight gain of the crystalline form CS2 and the crystalline form CS5 of the present invention under the condition of 80% RH was 0.36% and 0.51%, respectively, whereas the prior art form X had a wettability gain of 1.01% under the condition of 80% RH.
  • the wettability of the crystalline form CS2 and the crystalline form CS5 is superior to the prior art.
  • Example 13 Stability of Form CS2 and Form CS5 in Formulations
  • the capsule containing the crystalline form CS2 and the crystalline form CS5 was sampled at 25 ° C / 60% RH and 40 ° C / 75% RH for 3 months, and the crystal form was sampled to investigate the formulation stability of the crystalline form CS2 and the crystalline form CS5.
  • the results are shown in Table 15 below. The results showed that the crystalline form CS2 and the crystalline form CS5 formulation were stable for at least 3 months at 25 ° C / 60% RH and 40 ° C / 75% RH (the stability of the crystalline form CS2 formulation is shown in Figure 22, crystal form The stability of CS5 formulation placement is shown in Figure 23).
  • Example 14 In vitro dissolution of crystalline CS2 and crystalline CS5 formulations
  • the CS2 and CS2-containing capsules obtained in Example 12 were tested for in vitro dissolution, and the dissolution was measured according to the Chinese Pharmacopoeia 2015 edition 0931 dissolution and release assay conditions as follows:
  • Dissolution method paddle method + sedimentation basket
  • the in vitro dissolution of the Form CS2 formulation is shown in Table 16, Figure 24 below.
  • the in vitro dissolution of the crystalline CS5 formulation is shown in Table 17, Figure 25.
  • the results showed that the capsules having the crystalline form CS2 and the crystalline form CS5 of the present invention as active ingredients had good dissolution.
  • Example 15 Adhesion of Form CS2 and Form CS5
  • Example 16 Compressibility of Form CS2
  • the tablet was pressed with ENERPAC manual tableting machine.
  • ENERPAC electronic book reader
  • select a round punch with a diameter of 6mm add 80mg of crystal form CS2, use a pressure of 10kN to make a round tablet, and place it in the dryer for 24h, to be fully elastic.
  • the radial crushing force (hardness, H) was measured using a tablet hardness tester.
  • Table 19 The specific experimental results are shown in Table 19.
  • Example 17 Fluidity of Form CS5
  • the compressibility index or the Carr Index is usually used to evaluate the fluidity of the powder or the intermediate particles by measuring a certain amount of the powder into the measuring cylinder.
  • the fluidity evaluation results of the crystalline form CS5 are shown in Table 21, and the results show that the crystalline form CS5 has acceptable fluidity.

Abstract

本发明涉及SB-939的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备组蛋白去乙酰化酶抑制剂和治疗急性髓性白血病和/或骨髓发育异常综合征和/或骨髓纤维化疾病药物制剂中的用途。本发明提供的SB-939的晶型比现有技术具有一种或多种改进的性质，对未来该药物的优化和开发具有重要价值。(I)

Description

SB-939的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SB-939的晶型及其制备方法和用途。
背景技术
组蛋白去乙酰化酶(Histone Deacetylase，简称HDAC)抑制剂可抑制肿瘤细胞的DNA复制和RNA转录，可达到预防和治疗肿瘤的目的。作为一类表观遗传修饰酶，HDAC对染色体的结构修饰和基因表达调控发挥着重要的作用。研究表明，HDAC抑制剂联合去甲基化药物可能会对急性髓性白血病(Acute Myeloid Leukemia，AML)原始细胞表观遗传学产生协同作用，使机体内抑癌基因的表达得以恢复。
Pracinostat，又称SB-939，是MEI制药公司正在开发的一种HDAC的有效口服抑制剂。SB-939临床用于治疗急性髓性白血病、骨髓发育异常综合征、骨髓纤维化，并取得了良好的效果。SB-939的化学名称为：(2E)-3-[2-丁基-1-[2-(二乙基氨基)乙基]-1H-苯并咪唑-5-基]-N-羟基丙烯酰胺(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2019074336-appb-000001
晶体是一种固体材料，其组成成分在微观结构中高度有序排列，形成在所有方向上延伸的晶体点阵。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。因为理化性质不同，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。
目前没有化合物I相关的晶型信息报道。文献J.Med.Chem.2011,54,4694–4720.公开了SB-939固体的制备方法，申请人根据该方法得到SB-939的一种晶型(以下称为“晶型X”)。晶型X的稳定性差，引湿性较高，不适合应用于药物制剂。本申请的发明人意外发现了本发明提供的化合物I晶型CS2和CS5，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，特别是稳定性好、引湿性低，为含SB-939的药物开发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化合物I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CS2(以下称作“晶型CS2”)。
一方面，使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为5.6°±0.2°、23.1°±0.2°、15.1°±0.2°处有特征峰。
进一步地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为20.0°±0.2°、25.2°±0.2°、16.4°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为20.0°±0.2°、25.2°±0.2°、16.4°±0.2°中的3处有特征峰。
进一步地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为20.8°±0.2°、24.6°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为20.8°±0.2°、24.6°±0.2°中的2处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为5.6°±0.2°、23.1°±0.2°、15.1°±0.2°、20.0°±0.2°、25.2°±0.2°、16.4°±0.2°、20.8°±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处有特征峰。
非限制性地，晶型CS2的X射线粉末衍射谱图基本如图1所示。
非限制性地，晶型CS2的差示扫描量热分析图基本如图3所示，在79℃±5℃开始出现一个吸热峰。
根据本发明的目的，本发明还提供所述晶型CS2的制备方法，所述制备方法包括:
(1)将化合物I原料溶解于醇类，或醇类与卤代烃类的混合溶剂中，在4℃-50℃条件下挥发得到；或
(2)将化合物I原料加至酯类溶剂，或环醚类溶剂，或卤代烷烃类溶剂中，或酯类和环醚类的混合溶剂中，在4℃-50℃条件下搅拌，离心得到固体。
进一步的，方法(1)中所述醇类溶剂优选为乙醇或异丙醇，所述卤代烃类溶剂优选为氯仿；
进一步的，方法(2)中所述酯类溶剂优选为乙酸乙酯，所述环醚类溶剂优选为四氢呋喃或2-甲基四氢呋喃，所述卤代烃类溶剂优选为二氯甲烷。
根据本发明的另一个目的，本发明提供化合物I的晶型CS5(以下称作“晶型CS5”)。
一方面，使用Cu-Kα辐射，所述晶型CS5的X射线粉末衍射在衍射角2θ值为7.8°±0.2°、24.1°±0.2°、18.9°±0.2°处有特征峰。
进一步地，所述晶型CS5的X射线粉末衍射在衍射角2θ值为17.9°±0.2°、22.8°±0.2°、18.3°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CS5的X射线粉末衍射在衍射角2θ值为17.9°±0.2°、22.8°±0.2°、18.3°±0.2°中的3处有特征峰。
进一步地，所述晶型CS5的X射线粉末衍射在衍射角2θ值为11.0°±0.2°、13.0°±0.2°、24.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CS5的X射线粉末衍射在衍射角2θ值为11.0°±0.2°、13.0°±0.2°、24.6°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CS5的X射线粉末衍射在衍射角2θ值为7.8°±0.2°、24.1°±0.2°、18.9°±0.2°、17.9°±0.2°、22.8°±0.2°、18.3°±0.2°、11.0°±0.2°、13.0°±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处有特征峰。
非限制性地，晶型CS5的X射线粉末衍射谱图基本如图5所示。
非限制性地，晶型CS5的差示扫描量热分析图基本如图7所示，在102℃±5℃开始出现一个吸热峰。
根据本发明的另一个目的，本发明还提供所述晶型CS5的制备方法，所述制备方法包括:
(1)将化合物I原料加入酯类溶剂，或环醚类溶剂和水的混合溶剂体系中，在4℃-50℃条件下搅拌，离心收集固体；或
(2)将化合物I原料溶于乙酸乙酯和乙醇的混合溶剂体系中，在4℃-50℃条件下挥发得到。
进一步的，方法(1)中所述酯类溶剂优选为乙酸异丙酯，环醚类溶剂优选为1,4-二氧六环或四氢呋喃。
本发明提供的晶型CS2和CS5具有以下有益效果：
(1)与现有技术相比，本发明晶型具有更低的引湿性。测试结果表明，本发明晶型CS2和晶型CS5的引湿性不到现有技术固体的二分之一。本发明晶型CS2和CS5在80％相对湿度条件下引湿性增重分别为0.36％和0.51％，而现有技术在80％相对湿度条件下引湿性增重为1.04％。
引湿性直接影响药物的物理化学稳定性，引湿性高易引起化学降解和晶型转变。此外，引湿性高会降低药物的流动性，从而影响药物的加工工艺。不仅如此，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。低引湿性晶型对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(2)与现有技术相比，本发明的晶型具有更好的稳定性。晶型CS2和CS5原料药在25℃/60％相对湿度条件下放置，至少9个月晶型未发生变化，且储存过程中纯度变化量分别仅为0.11％和0.02％，纯度基本保持不变。而现有技术晶型X在25℃/60％相对湿度条件下放置一个月发生部分转晶。晶型CS2和CS5与辅料混合做成药物制剂后，在25℃/60％相对湿度条件下放置，至少3个月晶型未发生变化。说明晶型CS2和CS5原料药和制剂在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CS2和CS5原料药在40℃/75％相对湿度条件下放置至少9个月晶型未发生变化，且储存过程中纯度变化量分别仅为0.06％和0.03％，纯度基本保持不变。晶型CS2和CS5与辅料混合做成药物制剂后，在40℃/75％相对湿度条件下放置，至少3个月晶型未发生变化。此外，晶型CS2和CS5在0-95％相对湿度范围内循环后，晶型未发生转变，而现有技术晶型X发生部分转晶。说明相比现有技术，晶型CS2和CS5原料药和制剂在加速条件及更严苛的条件下，具有良好的稳定性。
原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。原料药和制剂在储存、运输、生产过程中会遇到天气和季节差异、不同地区气候差异等带来的高温和/或高湿或低湿条件。晶型CS2和CS5原料药在苛刻的条件下具有较好的稳定性，有利于避免偏离标签上的贮藏条件对药物质量的影响。
同时，晶型CS2和CS5具有良好的研磨稳定性。晶型CS2和CS5原料药研磨后具有良好的物理稳定性，而现有技术晶型X研磨后转变为无定形。制剂加工过程中常需要原料药的研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药晶型结晶度改变和转晶的风险。
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。 良好的化学稳定性可以确保在储存过程中基本没有杂质产生。晶型CS2和CS5具有良好的物理化学稳定性，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或杂质产生引起的药物质量变化、生物利用度改变。
(3)本发明晶型CS2和CS5具有高的溶解度。晶型CS2在SGF和FeSSIF中24小时溶解度分别达5.5mg/mL和9.0mg/mL，晶型CS5在SGF和FeSSIF中24小时溶解度分别达5.5mg/mL和7.1mg/mL。高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，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。
(4)本发明晶型CS2和CS5制剂具有良好的体外溶出度。在pH＝4.5的醋酸盐缓冲溶液中，晶型CS2制剂在60分钟时的溶出度达86.1％，晶型CS5制剂在60分钟时的溶出度达86.6％。
不同的晶型可能导致药物在体内有不同的溶出度，直接影响药物在体内的吸收、分布、代谢、排泄，最终因其生物利用度不同而导致临床药效的差异。溶出度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。
进一步地，本发明提供的晶型CS2和晶型CS5还具有以下有益效果：
(1)本发明晶型CS2和CS5具有良好的黏附性。黏附性评价结果表明，晶型CS2和CS5的吸附量较低。晶型CS2和CS5优良的黏附性可有效改善或者避免干法制粒和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CS2和CS5优良的黏附性还能有效减少原料的团聚现象，利于原料的分散及与其他辅料的混合，保证制剂的混合均匀度及含量均匀度。
(2)本发明提供的晶型CS2具有良好的可压性。晶型CS2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。
(3)本发明提供的晶型CS5具有良好的流动性。良好的流动性可以避免堵塞生产设备，提升生产效率；晶型CS5良好的流动性能保证制剂的混合均匀度及含量均匀度、降低制剂的重量差异，提升产品质量。
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CS2、晶型CS5或两种晶型的任意混合及药学上可接受的载体、稀释剂或辅料。
进一步地，本发明提的晶型CS2、晶型CS5或它们的任意混合在制备组蛋白去乙酰化酶抑制剂药物中的用途。
更进一步地，本发明提供的晶型CS2、晶型CS5或它们的任意混合在制备治疗急性髓性白血病和/或骨髓发育异常综合征和/或骨髓纤维化疾病药物中的用途。
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
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。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“降温”，采用本领域的常规方法完成，例如缓慢降温和快速降温。缓慢降温通常以0.1℃/分钟进行。快速降温通常是将样品从不低于室温的环境直接转移如冰箱中进行降温操作。
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射线粉末衍射图通常会随着仪器条件的不同而有所改变。特别需要指出的是，X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度的顺序不能作为唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的衍射峰强度为说明性而非用于绝对比较。另外，衍射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，会造成衍射峰角度的整体偏移，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，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射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X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，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CS2和晶型CS5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为实施例1所得晶型CS2的XRPD图
图2为实施例1所得晶型CS2的TGA曲线
图3为实施例1所得晶型CS2的DSC曲线
图4为实施例5所得晶型CS2的XRPD图
图5为实施例6所得晶型CS5的XRPD图
图6为实施例6所得晶型CS5的TGA曲线
图7为实施例6所得晶型CS5的DSC曲线
图8为实施例8所得晶型CS5的XRPD图
图9为本发明晶型CS2在25℃/60％相对湿度条件下放置9个月前后的XRPD图(上图为放置前，下图为放置后)
图10为本发明晶型CS5在25℃/60％相对湿度条件下放置9个月前后的XRPD图(上 图为放置前，下图为放置后)
图11为现有技术晶型X在25℃/60％相对湿度条件下放置1个月前后的XRPD图(上图为放置前，下图为放置后)
图12为本发明晶型CS2在40℃/75％相对湿度条件下放置9个月前后的XRPD图(上图为放置前，下图为放置后)
图13为本发明晶型CS5在40℃/75％相对湿度条件下放置9个月前后的XRPD图(上图为放置前，下图为放置后)
图14为本发明晶型CS2在0-95％相对湿度范围内循环前后的XRPD图(上图为循环前，下图为循环后)
图15为本发明晶型CS5在0-95％相对湿度范围内循环前后的XRPD图(上图为循环前，下图为循环后)
图16为现有技术晶型X在0-95％相对湿度范围内循环前后的XRPD图(上图为循环前，下图为循环后)
图17为本发明晶型CS2研磨前后的XRPD图(上图为研磨前，下图为研磨后)
图18为本发明晶型CS5研磨前后的XRPD图(上图为研磨前，下图为研磨后)
图19为现有技术晶型X研磨前后的XRPD图(上图为研磨前，下图为研磨后)
图20为本发明晶型CS2制备成为制剂前后的XRPD图(从上到下依次为辅料的XRPD图、晶型CS2制剂的XRPD图和晶型CS2原料的XRPD图)
图21为本发明晶型CS5制备成为制剂前后的XRPD图(从上到下依次为辅料的XRPD图、晶型CS5制剂的XRPD图和晶型CS5原料的XRPD图)
图22为本发明晶型CS2制剂在25℃/60％相对湿度和40℃/75％相对湿度下放置前后的XRPD图(从上到下依次为起始的XRPD图、在25℃/60％相对湿度下放置后的XRPD图和在40℃/75％相对湿度下放置后的XRPD图)
图23为本发明晶型CS5制剂在25℃/60％相对湿度和40℃/75％相对湿度下放置前后的XRPD图(从上到下依次为起始的XRPD图、在25℃/60％相对湿度下放置后的XRPD图和在40℃/75％相对湿度下放置后的XRPD图)
图24为本发明晶型CS2制剂的溶出曲线
图25为本发明晶型CS5制剂的溶出曲线
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：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
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
Figure PCTCN2019074336-appb-000002
1.54060；
Figure PCTCN2019074336-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TGA的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software，分析软件是DVS-Intrinsic Analysis software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260。
本发明所述的测试纯度的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18,150×4.6mm,5μm
2、流动相：A：0.1％的三氟乙酸水溶液
B：0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
时间(min) ％B
0.0 5
10.0 5
30.0 50
35.0 80
40.0 80
41.0 5
48.0 5
3、流速：1.0mL/min
4、进样量：5μL
5、检测波长：235nm
6、柱温：40℃
7、稀释剂：0.1％的三氟乙酸水溶液
本发明所述浓度测试所用的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18，150×4.6mm,5μm
2、流动相：A：0.1％的三氟乙酸水溶液
B：0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
时间(min) ％B
0.0 12
7.0 12
3、流速：1.0mL/min
4、进样量：3μL
5、检测波长：235nm
6、柱温：40℃
7、稀释剂：0.1％的三氟乙酸水溶液和0.1％的三氟乙酸乙腈溶液的等体积混合
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是特定的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述化合物I为固体(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为固体粉末形式。
以下实施例中所使用的化合物I原料可根据现有技术制备得到，例如根据文献J.Med.Chem.2011,54,4694–4720.所记载的方法制备获得。
具体实施方式
实施例1-2：挥发方法制备晶型CS2
称取一定质量的化合物I原料，溶解于如下表1中所示的溶剂体系中，过滤后将溶液挥发至有固体析出。取样，检测XRPD结果。实施例1和2所得的固体分别标记为样品1和2。
表1
Figure PCTCN2019074336-appb-000004
经XRPD检测，样品1和2均为晶型CS2。选取样品1进行XRPD/TGA/DSC测试表征。其XRPD图如图1所示，XRPD数据如表2所示。
TGA如图2所示，将其加热至150℃附近时，具有约0.3％的质量损失。
DSC如图3所示，在79℃附近开始出现一个吸热峰。
样品2与样品1具有相同或相似的XRPD图，为相同的晶型，具有相同的性质。
表2
衍射角2θ d值 强度％
5.63 15.70 100.00
8.30 10.66 3.81
10.09 8.77 4.11
14.15 6.26 2.16
15.14 5.85 19.43
15.99 5.54 3.18
16.35 5.42 8.60
16.73 5.30 2.33
20.01 4.44 12.83
20.81 4.27 8.03
21.66 4.10 5.49
23.07 3.86 30.38
24.67 3.61 5.33
25.24 3.53 8.97
26.52 3.36 3.68
29.03 3.08 4.46
31.83 2.81 2.46
32.33 2.77 1.72
33.55 2.67 1.98
34.96 2.57 1.69
35.62 2.52 3.26
35.77 2.51 2.74
37.55 2.40 2.36
38.52 2.34 1.59
39.31 2.29 1.27
实施例3-5：搅拌方法制备晶型CS2
称取一定质量的化合物I原料，加至如下表3所示的溶剂体系中，搅拌后离心分离收集固体。取样，检测XRPD结果。实施例3-5所得的固体分别标记为样品3-5。
表3
Figure PCTCN2019074336-appb-000005
Figure PCTCN2019074336-appb-000006
经XRPD检测，样品3-5均为晶型CS2。样品5的XRPD图如图4所示，XRPD数据如表4所示。
样品3-5具有相同或相似的XRPD图，为相同的晶型，具有相同的性质。
表4
衍射角2θ d值 强度％
5.63 15.71 100.00
8.28 10.68 7.37
9.14 9.67 3.18
9.98 8.86 4.26
14.15 6.26 4.49
15.16 5.84 25.94
16.37 5.42 14.02
16.81 5.27 2.53
20.04 4.43 12.20
20.75 4.28 10.81
23.09 3.85 38.80
24.65 3.61 8.17
25.25 3.53 12.98
26.09 3.42 2.38
26.76 3.33 3.58
27.21 3.28 1.29
28.97 3.08 7.26
29.66 3.01 2.26
30.81 2.90 4.87
32.46 2.76 1.91
34.00 2.64 2.78
37.08 2.42 4.04
38.40 2.34 2.05
39.11 2.30 2.64
实施例6-8：搅拌方法制备晶型CS5
称取一定质量的化合物I原料，加至如下表5所示的溶剂体系中，搅拌后离心分离收集固体。取样，检测XRPD结果。实施例6-8所得的固体分别标记为样品6-8。
表5
Figure PCTCN2019074336-appb-000007
经XRPD检测，样品6-8均为晶型CS5。选取样品6进行XRPD/TGA/DSC测试表征。其XRPD图如图5所示，XRPD数据如表6所示。
TGA如图6所示，将其加热至150℃附近时，具有约0.2％的质量损失。
DSC如图7所示，在102℃附近开始出现一个吸热峰。
选取样品8进行XRPD测试表征。其XRPD图如图8所示，XRPD数据如表7所示。
样品6-8具有相同或相似的XRPD图，为相同的晶型，具有相同的性质。
表6
衍射角2θ d值 强度％
4.26 20.72 1.87
7.84 11.28 100.00
11.04 8.02 7.68
11.87 7.46 1.93
13.02 6.80 5.08
14.89 5.95 3.62
16.60 5.34 3.81
17.67 5.02 9.86
17.89 4.96 28.23
18.24 4.86 14.18
18.89 4.70 18.44
21.12 4.21 2.25
22.75 3.91 16.38
23.37 3.81 3.83
24.06 3.70 43.94
24.57 3.62 14.13
25.23 3.53 2.99
25.88 3.44 4.12
26.63 3.35 3.51
26.83 3.32 2.55
27.35 3.26 3.04
28.76 3.10 2.93
29.31 3.05 2.76
31.91 2.80 2.99
表7
衍射角2θ d值 强度％
7.84 11.28 100.00
11.05 8.01 4.17
13.03 6.79 3.64
14.89 5.95 4.28
16.58 5.35 2.57
17.90 4.96 21.62
18.30 4.85 9.13
18.88 4.70 12.68
22.73 3.91 7.21
23.27 3.82 6.21
24.07 3.70 23.95
24.59 3.62 6.29
26.37 3.38 1.91
29.36 3.04 1.80
30.43 2.94 2.05
34.41 2.61 2.43
34.59 2.59 1.78
36.71 2.45 1.96
37.31 2.41 1.61
38.43 2.34 1.80
实施例9：晶型CS2和晶型CS5的动态溶解度
模拟胃肠道液体例如SGF(模拟胃液)和FeSSIF(模拟进食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
取本发明的晶型CS2和晶型CS5各20 mg分别加至1.5 mL的SGF和1.5 mL的FeSSIF中配制成饱和溶液，平衡1小时、4小时和24小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表8所示。
表8
Figure PCTCN2019074336-appb-000008
FeSSIF 8.7 8.9 9.0 6.9 6.9 7.1
结果表明本发明的晶型CS2和晶型CS5在SGF和FeSSIF中具有良好的溶解度。
实施例10：晶型CS2、晶型CS5和现有技术晶型X的稳定性
1. 25℃/60％RH和40℃/75％RH条件下放置的物理化学稳定性
称取本发明制备得到的晶型CS2、晶型CS5和现有技术晶型X各5mg，分别放置在25℃/60％RH和40℃/75％RH条件下，采用HPLC和XRPD法测定纯度与晶型。结果如表9所示。
表9
Figure PCTCN2019074336-appb-000009
结果表明，晶型CS2和晶型CS5在25℃/60％RH和40℃/75％RH条件下至少可稳定9个月，且纯度基本保持不变。可见，晶型CS2和晶型CS5在长期和加速条件下均可保持良好的物理化学稳定性。而现有技术晶型X在25℃/60％RH条件下放置1个月发生部分转晶，稳定性差，不利于药物的实际应用。
2.  0-95％相对湿度范围内循环前后的物理稳定性
称取本发明晶型CS2、晶型CS5和现有技术晶型X各约10mg，0-95％相对湿度范围内循环一次，测量湿度循环前后的晶型。结果如下表10所示，本发明晶型CS2和晶型CS5未发生晶型转变，而现有技术晶型X发生转晶。
表10
Figure PCTCN2019074336-appb-000010
3. 研磨稳定性
将晶型CS2、晶型CS5和现有技术晶型X于研钵中，手动研磨5分钟，研磨前后进行 XRPD测试，测试结果如表11所示。结果表明，在研磨条件下，与现有技术晶型X相比，本发明的晶型CS2和晶型CS5具有更好的稳定性。
表11
Figure PCTCN2019074336-appb-000011
实施例11：晶型CS2、晶型CS5和晶型X的引湿性
称取本发明晶型CS2、晶型CS5和晶型X各约10mg采用动态水分吸附(DVS)仪测试其引湿性，在0-95％相对湿度范围内循环一次，记录每个湿度下的质量变化。实验结果如表12所示。
表12
Figure PCTCN2019074336-appb-000012
本发明晶型CS2和晶型CS5在80％RH条件下引湿性增重分别为0.36％和0.51％，而现有技术晶型X在80％RH条件下引湿性增重为1.01％。晶型CS2和晶型CS5引湿性优于现有技术。
实施例12：晶型CS2和晶型CS5的制剂制备
1. 制剂处方
表13
Figure PCTCN2019074336-appb-000013
Figure PCTCN2019074336-appb-000014
2. 制剂工艺
表14
Figure PCTCN2019074336-appb-000015
将晶型CS2和CS5原料药制备成为制剂后，测试晶型的变化，结果分别如图20和21。结果表明，将晶型CS2和CS5原料药制备成为制剂后，晶型均未发生改变。
实施例13：晶型CS2和晶型CS5在制剂中的稳定性
将含晶型CS2和晶型CS5的胶囊，在25℃/60％RH和40℃/75％RH条件下放置3个月后取样检测晶型，考察晶型CS2和晶型CS5的制剂稳定性，结果如下表15所示。结果表明，晶型CS2和晶型CS5制剂在25℃/60％RH和40℃/75％RH条件下可以至少保持3个月稳定(晶型CS2制剂放置稳定性如图22所示，晶型CS5制剂放置稳定性如图23所示)。
表15
Figure PCTCN2019074336-appb-000016
实施例14：晶型CS2和晶型CS5制剂的体外溶出度
对实施例12获得的含CS2和晶型CS5的胶囊测试体外溶出情况，溶出度的测定按照中国药典2015年版0931溶出度与释放度测定法，条件如下：
溶出介质：pH＝4.5的醋酸盐缓冲溶液
溶出方法：桨法+沉降篮
介质体积：900mL
转速：50rpm
介质温度：37℃
晶型CS2制剂的体外溶出情况如下表16，图24所示。晶型CS5制剂的体外溶出情况如下表17，图25所示。结果表明，以本发明晶型CS2和晶型CS5为活性成分的胶囊具有良好的溶出度。
表16
时间(min) 累积溶出度(％)
0 0.0
5 30.9
10 62.7
15 68.3
20 71.8
30 76.9
45 82.6
60 86.1
表17
时间(min) 累积溶出度(％)
0 0.0
5 31.7
10 51.7
15 71.2
20 78.5
30 83.1
45 85.5
60 86.6
实施例15：晶型CS2和晶型CS5的黏附性
分别将约30mg晶型CS2和晶型CS5原料药加至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、压制过程中的最高黏附量和平均黏附量。具体的实验结果见表18。
表18
晶型 最高黏附量(mg) 平均黏附量(mg)
晶型CS2 0.10 0.06
晶型CS5 0.15 0.12
实验结果表明，本发明晶型CS2和晶型CS5具有良好的黏附性。
实施例16：晶型CS2的可压性
采用ENERPAC手动压片机进行压片，压片时，选择直径为6mm圆形平冲，加入80mg的晶型CS2，采用10kN压力压制成圆形片剂，放置于干燥器中24h，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)。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。具体的实验结果见表19。
表19
Figure PCTCN2019074336-appb-000017
结果表明，本发明的晶型CS2具有良好的可压性。
实施例17：晶型CS5的流动性
制剂工艺过程中，通常可采用可压性系数(Compressibility index)或卡尔系数(Carr Index)来评价粉体或中间体颗粒的流动性，测定方法为将一定量的粉体轻轻装入量筒后测量最初松体积；采用轻敲法使粉体处于最紧状态，测量最终的体积；计算松密度ρ 0与振实密度ρ f；根据公式c＝(ρ f－ρ 0)/ρ f计算可压性系数。
可压性系数对粉体流动性的界定标准参考ICH Q4B附录13，详见表20。
表20
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型CS5的流动性评价结果见表21，结果表明晶型CS5具有可接受的流动性。
表21
晶型 松密度(ρ 0,g/mL) 振实密度(ρ f,g/mL) 可压性指数(％) 流动性
晶型CS5 0.252 0.335 25 可接受
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 (12)

  1. 一种化合物I的晶型CS2，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为5.6°±0.2°、23.1°±0.2°、15.1°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS2，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为20.0°±0.2°、25.2°±0.2°、16.4°±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CS2，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为20.8°±0.2°、24.6°±0.2°中的1处或2处具有特征峰。
  4. 一种权利要求1所述晶型CS2的制备方法，其特征在于，所述方法为：
    (1)将化合物I原料溶解于醇类，或醇类与卤代烃类的混合溶剂中，在4℃-50℃条件下挥发得到；或
    (2)将化合物I原料加至环醚类溶剂，或卤代烷烃类溶剂中，或酯类和环醚类的混合溶剂中，在4℃-50℃条件下搅拌，离心分离得到固体。
  5. 根据权利要求4所述的制备方法，其特征在于，方法(1)中所述醇类溶剂为乙醇或异丙醇，所述卤代烃类溶剂为氯仿；方法(2)中所述酯类溶剂为乙酸乙酯，所述环醚类溶剂为四氢呋喃或2-甲基四氢呋喃，所述卤代烃类溶剂为二氯甲烷。
  6. 一种化合物I的晶型CS5，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.8°±0.2°、24.1°±0.2°、18.9±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型CS5，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为17.9°±0.2°、22.8±0.2°、18.3°±0.2°中的1处或2处或3处具有特征峰。
  8. 一种权利要求6所述晶型CS5的制备方法，其特征在于，所述方法为：将化合物I原料加入酯类溶剂，或环醚类溶剂和水的混合溶剂体系中，在4℃-50℃条件下搅拌，离心收集固体；或
  9. 根据权利要求8所述的制备方法，其特征在于，所述酯类溶剂为乙酸异丙酯，所述环醚类溶剂为1,4-二氧六环或四氢呋喃。
  10. 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CS2、权利要求6中所述的晶型CS5或两种晶型的任意混合及药学上可接受的载体、稀释剂或辅料。
  11. 权利要求1中所述的晶型CS2、权利要求6中所述的晶型CS5或两种晶型的任意混合在制备组蛋白去乙酰化酶抑制剂药物中的用途。
  12. 权利要求1中所述的晶型CS2、权利要求6中所述的晶型CS5或两种晶型的任意混合在制备治疗急性髓性白血病和/或骨髓发育异常综合征和/或骨髓纤维化疾病药物中的用途。
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