WO2019137027A1 - Crystal form of galunisertib and preparation method and use thereof - Google Patents

Crystal form of galunisertib and preparation method and use thereof Download PDF

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WO2019137027A1
WO2019137027A1 PCT/CN2018/103417 CN2018103417W WO2019137027A1 WO 2019137027 A1 WO2019137027 A1 WO 2019137027A1 CN 2018103417 W CN2018103417 W CN 2018103417W WO 2019137027 A1 WO2019137027 A1 WO 2019137027A1
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crystal form
present
galunisertib
crystal
preparation
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PCT/CN2018/103417
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
高慧
陈宇浩
张晓宇
刘佳佳
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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
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of Galunisertib, a preparation method thereof and use thereof.
  • TGF- ⁇ Transforming growth factor- ⁇
  • TGF- ⁇ Transforming growth factor- ⁇
  • the increased expression of TGF- ⁇ is closely related to the progression of various tumors, which can promote tumor growth, suppress the immune system and enhance tumors. Diffusion ability.
  • Galunisertib (LY-2157299) is a TGF-beta receptor kinase inhibitor developed by Lilly, which has the potential to treat myelodysplastic syndromes and solid tumors. Its chemical name is 2-(6-methyl-pyridine -2-yl)-3-[6-amido-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (hereinafter referred to as "compound (I) "), its structure is as follows:
  • a crystalline form is a different solid form formed by a different arrangement of a compound molecule or an atom in a lattice space.
  • a crystalline form of a drug refers to a solid drug in which a pharmacodynamic component exists in a specific crystalline form, and a drug polymorph refers to the presence or absence of two or two drugs. Different crystals above.
  • a monohydrate crystal form of Galunisertib (designated "Crystal Form 1" in the present invention) is currently disclosed in the patent document WO2007018818A1.
  • the inventor of the present application discovered the crystal-free R of Galunisertib during the research.
  • the novel crystal form of Galunisertib provided by the present invention has stability, melting point, solubility, dissolution in vitro and in vivo, moisture permeability, bioavailability, adhesion, compressibility, fluidity and processing.
  • the crystal type has a higher content of active ingredients at the same quality, which provides a new and better choice for the development of drugs containing Galunisertib, which is of great significance.
  • the main object of the present invention is to provide a novel crystal form of Galunisertib and a preparation method thereof.
  • the present invention provides a novel crystalline form of Galunisertib, designated as Form R.
  • the crystalline form R provided by the present invention is an anhydride.
  • the X-ray powder diffraction pattern of the crystal form R has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 25.6° ⁇ 0.2°, and 23.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 17.4° ⁇ 0.2°, 11.8° ⁇ 0.2°, and 18.0° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at a diffraction angle 2 ⁇ of 17.4° ⁇ 0.2°, 11.8° ⁇ 0.2°, and 18.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 15.5° ⁇ 0.2°, 28.5° ⁇ 0.2°, and 14.9° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at a diffraction angle 2 ⁇ of 15.5° ⁇ 0.2°, 28.5° ⁇ 0.2°, and 14.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form R is 8.9° ⁇ 0.2°, 25.6° ⁇ 0.2°, 23.8° ⁇ 0.2°, 17.4° ⁇ 0.2° at the diffraction angle 2 ⁇ , Any 3, or 4, or 5, or 6, or 7 of 11.8 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 15.5 ° ⁇ 0.2 °, 28.5 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 ° , or 8 or 9 has characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form R is substantially as shown in FIG.
  • the present invention also provides a method for preparing the crystal form R, which comprises heating the methanol solvate of Galunisertib to 130-150 ° C for 1 to 5 minutes to obtain a crystal form R.
  • the methanol solvate is preferably Form Q of the present invention, the heating temperature is 140 ° C, and the residence time is 2 min.
  • the crystal form Q is a methanol solvate, and the X-ray powder diffraction pattern of the crystal form Q is substantially as shown in FIG.
  • the preparation method of the crystal form Q comprises: mixing the Galunisertib free base with a methanol solvent, stirring at room temperature, separating and drying to obtain a crystal form Q.
  • the crystal form R of the present invention has lower wettability than the prior art.
  • the test results show that the wettability of the crystalline form R of the present invention is less than one-half of that of the prior art solids.
  • the wettability weight gain of the crystal form R under the condition of 80% RH was 0.18%, and the moisture absorption weight gain of the prior art crystal form 1 under the condition of 80% RH was 0.39%.
  • Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity affects the preparation, storage and post-treatment of drugs.
  • the low moisture absorbing crystal form has strict requirements on storage conditions, reduces material storage and quality control costs, and has strong economic value.
  • the crystal form R provided by the present invention has good physical and chemical stability.
  • the crystalline form R bulk drug is placed at 25 ° C / 60% RH, and the crystal form does not change for at least 5 months. It is placed at 40 ° C / 75% RH, and the crystal form does not change for at least 1 month at 60 ° C. /75%RH, placed at 80 °C, the crystal form did not change for at least 1 week, and the chemical purity was above 99.9%, and the purity remained basically unchanged during storage.
  • Form R has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, ensuring the efficacy of the drug.
  • the crystal form R of the present invention has a higher solubility than the prior art. Particularly in FeSSIF, the solubility is three times that of the prior art WO2007018818A1 Form 1.
  • Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
  • crystal form R provided by the present invention has the following beneficial effects:
  • the crystal form R of the present invention has a uniform particle size distribution. Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the “separation” 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.
  • the "drying" can be carried out at room temperature or higher. Dry at room temperature to 60 ° C, or to 40 ° C, or to 50 ° C.
  • the drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • the crystalline form R 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.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and prophylactically effective amount of a crystalline form R of the present invention together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of the crystal form R of Galunisertib for the preparation of a TGF-beta receptor kinase inhibitor drug.
  • the present invention provides the use of the crystal form R of Galunisertib for the preparation of a medicament for treating myelodysplastic syndrome.
  • the present invention provides the use of the crystalline form R of Galunisertib for the preparation of a medicament for the treatment of solid tumors.
  • the crystal form R of the Galunisertib provided by the invention is in the aspects of stability, melting point, solubility, dissolution in vitro and in vivo, moisture permeability, bioavailability, adhesion, compressibility, fluidity, processing property, purification effect, preparation production, and the like.
  • There is an advantage in at least one aspect, in particular, low wettability, high solubility, good stability, uniform particle size, and the crystal-free type provided by the present invention has an active ingredient content at the same quality as compared with the prior art crystal form 1. high. It is very important to provide new and better choices for drug development with Galunisertib.
  • Figure 1 is an XRPD pattern of Form Q.
  • Figure 2 is a DSC diagram of Form Q.
  • Figure 3 is a TGA diagram of Form Q.
  • Figure 1 is a 1 H NMR chart of Form Q.
  • Figure 5 is an XRPD pattern of Form R.
  • Figure 6 is a DSC diagram of Form R.
  • Figure 7 is a TGA diagram of Form R.
  • Figure 1 is a 1 H NMR chart of Form R.
  • Figure 9 is a comparison of the XRPD before and after the crystal form R DVS (the figure above is before DVS and the figure below is after DVS).
  • Figure 10 XRPD comparison chart of crystal form R stability (from top to bottom, starting XRPD, XRPD after 5 months at 25 °C / 60% RH, placed at 40 °C / 75% RH) XRPD after one month, XRPD after being left for one week at 60 ° C / 75% RH, and XRPD after being left at 80 ° C for one week).
  • Figure 11 is a PSD diagram of Form R.
  • 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 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 thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • the particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • the Galunisertib starting material used in the following examples can be prepared according to the method described in the prior art WO2007018818A1, and the prepared Galunisertib raw material is a monohydrate crystalline form.
  • the first endothermic peak begins to appear near 117 °C, and a second endothermic peak begins to appear near 163 °C. Then an exothermic peak appears and heats up to around 242 °C. A third endothermic peak begins to appear, and a fourth endothermic peak begins to appear near 248 ° C.
  • the DSC plot is shown in Figure 2. When subjected to thermogravimetric analysis, it had a mass loss of about 7.1% when heated to 150 ° C, and its TGA pattern is shown in FIG.
  • the NMR data of the crystal form Q is shown in Fig. 4.
  • the crystal form Q is a methanol solvate.
  • a methanolic solvate Form Q of 10.5 mg of Galunisertib was weighed and subjected to a heating test on a DSC apparatus. The sample was subjected to cap heating, heated to 140 ° C at 10 ° C/min, and left to stand for 2 minutes to obtain a solid. Upon examination, the obtained solid was in the form of crystal form R, the XRPD data thereof is shown in Table 1, and the XRPD pattern is shown in Fig. 5.
  • the first endothermic peak begins to appear near 169 ° C, followed by an exothermic peak. Heating to 242 ° C begins to appear a second endothermic peak, heating to around 248 ° C. A third endothermic peak begins to appear, and its DSC chart is shown in Figure 6.
  • thermogravimetric analysis when heated to 180 ° C, it had a mass loss of about 0.1%, and its TGA chart is shown in FIG.
  • the wettability weight gain of the crystal form R under the condition of 80% RH is 0.18%, and the wet weight gain of the crystal form 1 of WO2007018818A1 is 0.89% under the condition of 80% RH, and the wettability of the form R is superior to the prior art.
  • the crystal form R can be stabilized for at least 5 months at 25 ° C / 60% RH, and the crystal form R can be stabilized for at least 1 month at 40 ° C / 75% RH, at 60 ° C / 75% RH, 80 At °C for at least one week, the crystal form and chemical purity remain basically unchanged, and the crystal form R has good physical and chemical stability.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
  • the crystal form R of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography.
  • the content of the sample (mg/mL), the results are shown in Table 4.
  • the crystalline form R has higher solubility in the SGF, FaSSIF and FeSSIF than the prior art crystalline form 1, especially in FeSSIF, the solubility of the crystalline form R is about three times that of the crystalline form 1 of WO2007018818A1.
  • D10 indicates a particle diameter corresponding to 10% of the particle size distribution (volume distribution);
  • D50 indicates the particle size corresponding to the particle size distribution (volume distribution), which is 50%, which is also called the median diameter;
  • D90 indicates a particle diameter corresponding to 90% of the particle size distribution (volume distribution).

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Abstract

The present invention relates to crystal form R of galunisertib, a preparation method and use thereof, a pharmaceutical composition comprising the crystal form, and a use of the crystal form in preparing a pharmaceutical preparation for treating myelodysplastic syndrome. The crystal form R provided by the present invention has one or more improved properties than the prior art and is of great value for the optimization and development of the drug in the future. (I)

Description

Galunisertib的晶型及其制备方法和用途Crystal form of Galunisertib and preparation method and use thereof 技术领域Technical field
本发明涉及药物晶体技术领域。具体而言，涉及Galunisertib的晶型及其制备方法和用途。The invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of Galunisertib, a preparation method thereof and use thereof.
背景技术Background technique
转化生长因子-β(TGF-β)是具有多种肿瘤支撑作用的多效性细胞因子，TGF-β的表达增加与多种肿瘤的进展密切相关，能够促进肿瘤生长、抑制免疫系统和增强肿瘤扩散能力。Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with multiple tumor supporting effects. The increased expression of TGF-β is closely related to the progression of various tumors, which can promote tumor growth, suppress the immune system and enhance tumors. Diffusion ability.
Galunisertib(LY-2157299)是由礼来开发的一种TGF-β受体激酶抑制剂，具有治疗骨髓增生异常综合征和实体瘤的潜力，其化学名称为：2-(6-甲基-吡啶-2-基)-3-[6-酰氨基-喹啉-4-基]-5，6-二氢-4H-吡咯并[1，2-b]吡唑(以下称“化合物(I)”)，其结构如下：Galunisertib (LY-2157299) is a TGF-beta receptor kinase inhibitor developed by Lilly, which has the potential to treat myelodysplastic syndromes and solid tumors. Its chemical name is 2-(6-methyl-pyridine -2-yl)-3-[6-amido-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (hereinafter referred to as "compound (I) "), its structure is as follows:
Figure PCTCN2018103417-appb-000001
Figure PCTCN2018103417-appb-000001
晶型是化合物分子或原子在晶格空间排列不同而形成的不同固体形态，晶型药物是指药效成分以特定晶型状态存在的固体药物，药物多晶型是指药物存在两种或两种以上的不同晶体。A crystalline form is a different solid form formed by a different arrangement of a compound molecule or an atom in a lattice space. A crystalline form of a drug refers to a solid drug in which a pharmacodynamic component exists in a specific crystalline form, and a drug polymorph refers to the presence or absence of two or two drugs. Different crystals above.
由于不同晶型的药物可能会影响其在体内的溶出、吸收，进而可能在一定程度上影响药物的临床疗效和安全性；特别是对一些难溶性口服固体或半固体药物，晶型的影响会更大。因此，在研制固体口服制剂时，对晶型的研究有利于选择一种在临床治疗上有意义且稳定可控的晶体。从药物质量监管的角度看，药物晶型必然是药物研究、检测和监管的重要内容，也是药物质量控制的重要内容。Because different crystal forms of the drug may affect its dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to some extent; especially for some poorly soluble oral solid or semi-solid drugs, the effect of crystal form will Bigger. Therefore, in the development of solid oral formulations, the study of crystalline forms facilitates the selection of a crystal that is clinically therapeutically meaningful and stable and controllable. From the perspective of drug quality supervision, drug crystal form must be an important part of drug research, detection and supervision, and an important part of drug quality control.
目前仅有专利文献WO2007018818A1中公开了Galunisertib的一个一水合物晶型(本发明中命名为“晶型1”)。本申请发明人在研究过程中发现Galunisertib的无水晶型R。不同于WO2007018818A1中的晶型1，本发明提供的Galunisertib的新晶型，其在稳定性、熔点、溶解度、体内外溶出、引湿性、生物有效性、黏附性、可压性、流动性以及加工性能、提 纯作用、制剂生产等方面中的至少一方面上存在优势，特别是引湿性低、溶解度高、稳定性好、粒径均一，且相对于现有技术晶型1，本发明提供的无水晶型在同等质量下有效成分含量更高，为含Galunisertib的药物开发提供了新的更好的选择，具有非常重要的意义。A monohydrate crystal form of Galunisertib (designated "Crystal Form 1" in the present invention) is currently disclosed in the patent document WO2007018818A1. The inventor of the present application discovered the crystal-free R of Galunisertib during the research. Different from Form 1 in WO2007018818A1, the novel crystal form of Galunisertib provided by the present invention has stability, melting point, solubility, dissolution in vitro and in vivo, moisture permeability, bioavailability, adhesion, compressibility, fluidity and processing. There are advantages in at least one of performance, purification, formulation production and the like, in particular, low wettability, high solubility, good stability, uniform particle size, and no relative to the prior art crystal form 1. The crystal type has a higher content of active ingredients at the same quality, which provides a new and better choice for the development of drugs containing Galunisertib, which is of great significance.
发明内容Summary of the invention
本发明主要目的是提供Galunisertib的新晶型及其制备方法。The main object of the present invention is to provide a novel crystal form of Galunisertib and a preparation method thereof.
根据本发明的目的，本发明提供Galunisertib的新晶型，命名为晶型R。本发明提供的晶型R是无水物。In accordance with the purpose of the present invention, the present invention provides a novel crystalline form of Galunisertib, designated as Form R. The crystalline form R provided by the present invention is an anhydride.
一方面，使用Cu-Kα辐射，所述晶型R的X射线粉末衍射图在衍射角2θ为8.9°±0.2°、25.6°±0.2°、23.8°±0.2°处有特征峰。On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form R has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 25.6°±0.2°, and 23.8°±0.2°.
进一步的，所述晶型R的X射线粉末衍射图在衍射角2θ为17.4°±0.2°、11.8°±0.2°、18.0°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型R的X射线粉末衍射图在衍射角2θ为17.4°±0.2°、11.8°±0.2°、18.0°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at one or two or three points in the diffraction angle 2θ of 17.4°±0.2°, 11.8°±0.2°, and 18.0°±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at a diffraction angle 2θ of 17.4°±0.2°, 11.8°±0.2°, and 18.0°±0.2°.
进一步的，所述晶型R的X射线粉末衍射图在衍射角2θ为15.5°±0.2°、28.5°±0.2°、14.9°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型R的X射线粉末衍射图在衍射角2θ为15.5°±0.2°、28.5°±0.2°、14.9°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at one or two or three points in the diffraction angle 2θ of 15.5°±0.2°, 28.5°±0.2°, and 14.9°±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form R has a characteristic peak at a diffraction angle 2θ of 15.5°±0.2°, 28.5°±0.2°, and 14.9°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型R的X射线粉末衍射图在衍射角2θ为8.9°±0.2°、25.6°±0.2°、23.8°±0.2°、17.4°±0.2°、11.8°±0.2°、18.0°±0.2°、15.5°±0.2°、28.5°±0.2°、14.9°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form R is 8.9°±0.2°, 25.6°±0.2°, 23.8°±0.2°, 17.4°±0.2° at the diffraction angle 2θ, Any 3, or 4, or 5, or 6, or 7 of 11.8 ° ± 0.2 °, 18.0 ° ± 0.2 °, 15.5 ° ± 0.2 °, 28.5 ° ± 0.2 °, 14.9 ° ± 0.2 ° , or 8 or 9 has characteristic peaks.
非限制性地，所述晶型R的X射线粉末衍射图基本如图5所示。Without limitation, the X-ray powder diffraction pattern of the crystalline form R is substantially as shown in FIG.
根据本发明的目的，本发明还提供所述晶型R的制备方法，所述制备方法包括：将Galunisertib的甲醇溶剂合物加热至130～150℃，停留1～5min得到晶型R。According to the object of the present invention, the present invention also provides a method for preparing the crystal form R, which comprises heating the methanol solvate of Galunisertib to 130-150 ° C for 1 to 5 minutes to obtain a crystal form R.
优选的，所述甲醇溶剂合物优选本发明晶型Q，所述加热温度为140℃，所述停留时间为2min。Preferably, the methanol solvate is preferably Form Q of the present invention, the heating temperature is 140 ° C, and the residence time is 2 min.
进一步地，所述晶型Q是甲醇溶剂合物，晶型Q的X射线粉末衍射图基本如图1所示。Further, the crystal form Q is a methanol solvate, and the X-ray powder diffraction pattern of the crystal form Q is substantially as shown in FIG.
更进一步地，所述晶型Q的制备方法包括：将Galunisertib游离碱与甲醇溶剂混合，在室温下搅拌，分离、干燥得到晶型Q。Further, the preparation method of the crystal form Q comprises: mixing the Galunisertib free base with a methanol solvent, stirring at room temperature, separating and drying to obtain a crystal form Q.
本发明提供的晶型R具有以下有益效果：The crystal form R provided by the present invention has the following beneficial effects:
(1)与现有技术相比，本发明晶型R具有更低的引湿性。测试结果表明，本发明晶型R的引湿性不到现有技术固体的二分之一。晶型R在80％RH条件下引湿性增重为0.18％，，现有技术晶型1在80％RH条件下引湿性增重为0.39％。(1) The crystal form R of the present invention has lower wettability than the prior art. The test results show that the wettability of the crystalline form R of the present invention is less than one-half of that of the prior art solids. The wettability weight gain of the crystal form R under the condition of 80% RH was 0.18%, and the moisture absorption weight gain of the prior art crystal form 1 under the condition of 80% RH was 0.39%.
引湿性会影响药物的稳定性、加工时的流动性和均匀性等，最终影响药物制剂的质量。引湿性会影响药物的制备、储存与后处理工艺。低引湿性晶型对储存条件要求不苛刻，降低了物料储存以及质量控制成本，具有很强的经济价值。Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity affects the preparation, storage and post-treatment of drugs. The low moisture absorbing crystal form has strict requirements on storage conditions, reduces material storage and quality control costs, and has strong economic value.
(2)本发明提供的晶型R物理、化学稳定性好。晶型R原料药在25℃/60％RH条件下放置，至少5个月晶型未发生变化，在40℃/75％RH条件下放置，至少1个月晶型未发生变化，在60℃/75％RH、80℃条件下放置，至少1周晶型未发生变化，且化学纯度均在99.9％以上，储存过程中纯度基本保持不变。(2) The crystal form R provided by the present invention has good physical and chemical stability. The crystalline form R bulk drug is placed at 25 ° C / 60% RH, and the crystal form does not change for at least 5 months. It is placed at 40 ° C / 75% RH, and the crystal form does not change for at least 1 month at 60 ° C. /75%RH, placed at 80 °C, the crystal form did not change for at least 1 week, and the chemical purity was above 99.9%, and the purity remained basically unchanged during storage.
晶型的转变会导致药物的吸收发生变化，影响药物的毒副作用，尤其是在毒性靶器官中的浓度变化，直接影响药物的毒副作用。晶型R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，最大可能地减少药物由于晶型改变引起的毒性增加，保证药物疗效发挥。The transformation of the crystal form will lead to changes in the absorption of the drug, affecting the toxic side effects of the drug, especially the concentration change in the toxic target organ, directly affecting the toxic side effects of the drug. Form R has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, ensuring the efficacy of the drug.
(3)与现有技术相比，本发明晶型R具有较高的溶解度。特别是在FeSSIF中，溶解度是现有技术WO2007018818A1晶型1的3倍。(3) The crystal form R of the present invention has a higher solubility than the prior art. Particularly in FeSSIF, the solubility is three times that of the prior art WO2007018818A1 Form 1.
更高的溶解度有利于提高药物在人体内被吸收的速度和程度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
进一步地，本发明提供的晶型R还具有以下有益效果：Further, the crystal form R provided by the present invention has the following beneficial effects:
本发明的晶型R具有均一的粒径分布。其均匀的粒径有助于简化制剂过程的后处理工艺，如可减少对晶体的研磨，节约成本，也减小研磨中晶型结晶度变化和转晶的风险，提高质量控制。The crystal form R of the present invention has a uniform particle size distribution. Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control.
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystal" or "crystal form" refers to the characterization by the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal. The peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
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，优选300～900转/分钟。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 to 1800 rpm, preferably 300 to 900 rpm.
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。The "separation" 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.
所述“干燥”可以在室温或更高的温度下进行。干燥温度室温至60℃，或者到40℃，或者到50℃。干燥时间可以为2～48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。The "drying" can be carried out at room temperature or higher. Dry at room temperature to 60 ° C, or to 40 ° C, or to 50 ° C. The drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
在一些实施方案中，本发明的晶型R是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, the crystalline form R of the present invention is pure, substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
本发明提供一种药用组合物，所述药用组合物包含治疗和预防有效量的本发明晶型R以及药学上可接受的载体、稀释剂或赋形剂。The present invention provides a pharmaceutical composition comprising a therapeutically and prophylactically effective amount of a crystalline form R of the present invention together with a pharmaceutically acceptable carrier, diluent or excipient.
进一步地，本发明提供Galunisertib的晶型R在制备TGF-β受体激酶抑制剂药物中的用途。Further, the present invention provides the use of the crystal form R of Galunisertib for the preparation of a TGF-beta receptor kinase inhibitor drug.
进一步地，本发明提供Galunisertib的晶型R在制备治疗骨髓增生异常综合症的药物中的用途。Further, the present invention provides the use of the crystal form R of Galunisertib for the preparation of a medicament for treating myelodysplastic syndrome.
进一步地，本发明提供Galunisertib的晶型R在制备治疗实体瘤的药物中的用途。Further, the present invention provides the use of the crystalline form R of Galunisertib for the preparation of a medicament for the treatment of solid tumors.
本发明提供的Galunisertib的晶型R，在稳定性、熔点、溶解度、体内外溶出、引湿性、生物有效性、黏附性、可压性、流动性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势，特别是引湿性低、溶解度高、稳定性好、粒径均一，且相对于现有技术晶型1，本发明提供的无水晶型在同等质量下有效成分含量更高。为含Galunisertib的药物开发提供了新的更好的选择，具有非常重要的意义。The crystal form R of the Galunisertib provided by the invention is in the aspects of stability, melting point, solubility, dissolution in vitro and in vivo, moisture permeability, bioavailability, adhesion, compressibility, fluidity, processing property, purification effect, preparation production, and the like. There is an advantage in at least one aspect, in particular, low wettability, high solubility, good stability, uniform particle size, and the crystal-free type provided by the present invention has an active ingredient content at the same quality as compared with the prior art crystal form 1. high. It is very important to provide new and better choices for drug development with Galunisertib.
附图说明DRAWINGS
图1晶型Q的XRPD图。Figure 1 is an XRPD pattern of Form Q.
图2晶型Q的DSC图。Figure 2 is a DSC diagram of Form Q.
图3晶型Q的TGA图。Figure 3 is a TGA diagram of Form Q.
图4晶型Q的 1H NMR图。 Figure 1 is a 1 H NMR chart of Form Q.
图5晶型R的XRPD图。Figure 5 is an XRPD pattern of Form R.
图6晶型R的DSC图。Figure 6 is a DSC diagram of Form R.
图7晶型R的TGA图。Figure 7 is a TGA diagram of Form R.
图8晶型R的 1H NMR图。 Figure 1 is a 1 H NMR chart of Form R.
图9晶型R DVS前后XRPD对比图(上图为DVS前，下图为DVS后)。Figure 9 is a comparison of the XRPD before and after the crystal form R DVS (the figure above is before DVS and the figure below is after DVS).
图10晶型R稳定性的XRPD对比图(从上至下分别为起始XRPD、在25℃/60％RH条件下放置5个月后的XRPD、在40℃/75％RH条件下放置1个月后的XRPD、在60℃/75％RH条件下放置1周后的XRPD、在80℃条件下放置1周后的XRPD)。Figure 10 XRPD comparison chart of crystal form R stability (from top to bottom, starting XRPD, XRPD after 5 months at 25 °C / 60% RH, placed at 40 °C / 75% RH) XRPD after one month, XRPD after being left for one week at 60 ° C / 75% RH, and XRPD after being left at 80 ° C for one week).
图11晶型R的PSD图。Figure 11 is a PSD diagram of Form R.
具体实施方式Detailed ways
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。The invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.
采集数据所用的仪器及方法：Instruments and methods used to collect data:
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
DVS：动态水分吸附DVS: Dynamic moisture adsorption
1H NMR：核磁共振氢谱 1 H NMR: Nuclear Magnetic Resonance Spectroscopy
HPLC：高效液相色谱HPLC: high performance liquid chromatography
本发明所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:
X射线光源：Cu,KαX-ray source: Cu, Kα
Kα1
Figure PCTCN2018103417-appb-000002
：1.54060；Kα2
Figure PCTCN2018103417-appb-000003
：1.54439 Kα1
Figure PCTCN2018103417-appb-000002
:1.54060;Kα2
Figure PCTCN2018103417-appb-000003
:1.54439
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：30仟伏特(kV)Voltage: 30 volts (kV)
电流：10毫安培(mA)Current: 10 milliamperes (mA)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
本发明所述的DSC图在TA Q2000上采集。本发明所述的DSC的方法参数如下：The 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:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。 Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：The particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer. The Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system. This test uses a wet method and the test dispersion medium is Isopar G. The method parameters of the laser particle size analyzer are as follows:
Figure PCTCN2018103417-appb-000004
Figure PCTCN2018103417-appb-000004
*：流速60％为65毫升/秒的60％。*: The flow rate is 60% of 60% of 65 ml/sec.
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。本发明有关物质的HPLC方法参数如下：The high performance liquid chromatography (HPLC) data of the present invention was taken from the Agilent 1260, and the detector used was a diode array detector (DAD). The HPLC method parameters of the substances related to the present invention are as follows:
1、色谱柱：Waters XBridge 150*4.6mm，5μm1. Column: Waters XBridge 150*4.6mm, 5μm
2、流动相：A：2mmol/L庚烷磺酸钠水溶液，pH3.02. Mobile phase: A: 2mmol/L sodium heptanesulfonate solution, pH3.0
           B：乙腈溶液B: acetonitrile solution
洗脱梯度如下：The elution gradient is as follows:
Time(min)Time(min) ％B%B
0.00.0 1010
20.020.0 4040
40.040.0 8080
45.045.0 8080
46.046.0 1010
55.055.0 1010
3、流速：1mL/min3. Flow rate: 1mL/min
4、进样量：5μl4, injection volume: 5μl
5、检测波长：220nm5, detection wavelength: 220nm
6、柱温：40℃6, column temperature: 40 ° C
7、稀释剂：50％乙腈7. Thinner: 50% acetonitrile
除非特殊说明，以下实施例均在室温条件下操作。The following examples were operated at room temperature unless otherwise stated.
以下实施例中所使用的Galunisertib原料可根据现有技术WO2007018818A1文献所记载的方法制备获得，制备得到的Galunisertib原料为一水合物晶型。The Galunisertib starting material used in the following examples can be prepared according to the method described in the prior art WO2007018818A1, and the prepared Galunisertib raw material is a monohydrate crystalline form.
实施例1：晶型Q的制备Example 1: Preparation of Form Q
称取20.0mg Galunisertib原料放入1.5mL玻璃小瓶中，加入0.4mL的甲醇形成悬浊液，置于25℃下搅拌48小时，离心所得固体为晶型Q，XRPD图如图1所示，XRPD图显示晶型Q在7.7°±0.2°、8.9°±0.2°、11.2°±0.2°、11.9°±0.2°、16.7°±0.2°、17.5°±0.2°、18.8°±0.2°、23.9°±0.2°、24.8°±0.2°中的一处或多处具有特征峰。20.0 mg of Galunisertib raw material was weighed into a 1.5 mL glass vial, 0.4 mL of methanol was added to form a suspension, and the mixture was stirred at 25 ° C for 48 hours. The solid obtained by centrifugation was a crystalline form Q, and the XRPD pattern is shown in Fig. 1, XRPD. The figure shows that the crystal form Q is 7.7°±0.2°, 8.9°±0.2°, 11.2°±0.2°, 11.9°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.8°±0.2°, 23.9°. One or more of ±0.2°, 24.8°±0.2° has characteristic peaks.
当进行差示扫描量热分析时，加热至117℃附近开始出现第一个吸热峰，加热至163℃附近开始出现第二个吸热峰，随后出现一个放热峰，加热至242℃附近开始出现第三个吸热峰，加热至248℃附近开始出现第四个吸热峰，其DSC图如图2。当进行热重分析时，加热至150℃时，具有约7.1％的质量损失，其TGA图如图3。When performing differential scanning calorimetry, the first endothermic peak begins to appear near 117 °C, and a second endothermic peak begins to appear near 163 °C. Then an exothermic peak appears and heats up to around 242 °C. A third endothermic peak begins to appear, and a fourth endothermic peak begins to appear near 248 ° C. The DSC plot is shown in Figure 2. When subjected to thermogravimetric analysis, it had a mass loss of about 7.1% when heated to 150 ° C, and its TGA pattern is shown in FIG.
晶型Q的核磁数据如图4所示，结果如下： 1H NMR(400MHz,DMSO)δ8.87(d,1H),8.25(d,J＝1.7,1H),8.12(dd,1H),8.07-7.96(m,2H),7.62-7.53(m,2H),7.44-7.30(m,2H),6.93(p,1H),4.31(t,2H),4.11(q,1H),3.17(d,2H),2.83(s,2H),2.63(dt,2H),1.74(s,3H).根据核磁数据可知，晶型Q为甲醇溶剂合物。 The NMR data of the crystal form Q is shown in Fig. 4. The results are as follows: 1 H NMR (400 MHz, DMSO) δ 8.87 (d, 1H), 8.25 (d, J = 1.7, 1H), 8.12 (dd, 1H), 8.07-7.96 (m, 2H), 7.62-7.53 (m, 2H), 7.44-7.30 (m, 2H), 6.93 (p, 1H), 4.31 (t, 2H), 4.11 (q, 1H), 3.17 ( d, 2H), 2.83 (s, 2H), 2.63 (dt, 2H), 1.74 (s, 3H). According to the nuclear magnetic data, the crystal form Q is a methanol solvate.
实施例2：晶型R的制备Example 2: Preparation of Form R
称取10.5mg Galunisertib的甲醇溶剂合物晶型Q在DSC仪器上进行加热实验，样品进行闭盖加热，以10℃/min加热至140℃，停留2min，得到固体。经检测，所得固体为晶型R，其XRPD数据如表1所示，XRPD图如图5所示。A methanolic solvate Form Q of 10.5 mg of Galunisertib was weighed and subjected to a heating test on a DSC apparatus. The sample was subjected to cap heating, heated to 140 ° C at 10 ° C/min, and left to stand for 2 minutes to obtain a solid. Upon examination, the obtained solid was in the form of crystal form R, the XRPD data thereof is shown in Table 1, and the XRPD pattern is shown in Fig. 5.
当进行差示扫描量热分析时，加热至169℃附近开始出现第一个吸热峰，随后出现一个放热峰，加热至242℃附近开始出现第二个吸热峰，加热至248℃附近开始出现第三个吸热峰，其DSC图如图6。当进行热重分析时，加热至180℃时，具有约0.1％的质量损失，其TGA图如图7。When performing differential scanning calorimetry, the first endothermic peak begins to appear near 169 ° C, followed by an exothermic peak. Heating to 242 ° C begins to appear a second endothermic peak, heating to around 248 ° C. A third endothermic peak begins to appear, and its DSC chart is shown in Figure 6. When subjected to thermogravimetric analysis, when heated to 180 ° C, it had a mass loss of about 0.1%, and its TGA chart is shown in FIG.
晶型R的核磁数据如图8所示，结果如下： 1H NMR(400MHz,DMSO)δ8.88(d,1H),8.25(d,1H),8.12(dd,1H),8.08-7.99(m,2H),7.58(d,2H),7.44-7.34(m,2H),6.96-6.89(m,1H),4.31(t,2H),2.83(s,2H),2.69-2.58(m,2H),1.74(s,3H)。 The NMR data of the crystal form R is shown in Fig. 8. The results are as follows: 1 H NMR (400 MHz, DMSO) δ 8.88 (d, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 8.08-7.99 ( m, 2H), 7.58 (d, 2H), 7.44 - 7.34 (m, 2H), 6.96-6.89 (m, 1H), 4.31 (t, 2H), 2.83 (s, 2H), 2.69-2.58 (m, 2H), 1.74 (s, 3H).
表1Table 1
2θ2θ d间隔d interval 强度％strength%
8.908.90 9.949.94 100.00100.00
11.8311.83 7.487.48 29.9129.91
14.8914.89 5.955.95 14.0514.05
15.5015.50 5.725.72 24.0224.02
17.2817.28 5.135.13 32.3332.33
17.4717.47 5.085.08 37.7237.72
17.9717.97 4.944.94 27.0027.00
19.1619.16 4.634.63 6.786.78
19.6219.62 4.534.53 10.0310.03
20.0320.03 4.434.43 6.576.57
21.1021.10 4.214.21 7.047.04
21.6421.64 4.114.11 4.424.42
22.0722.07 4.034.03 2.272.27
23.7623.76 3.743.74 38.5438.54
25.5725.57 3.483.48 56.6556.65
27.1127.11 3.293.29 3.123.12
28.3228.32 3.153.15 10.9810.98
28.5328.53 3.133.13 14.5914.59
30.1630.16 2.962.96 3.763.76
实施例3：晶型R的引湿性Example 3: Humidity of crystal form R
称取本发明晶型R与WO2007018818A1晶型1各约10mg采用动态水分吸附(DVS)仪测试其引湿性，在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化。实验结果如表2所示，晶型R DVS前后的XRPD对比图如图9所示。About 10 mg of the crystalline form R of the present invention and the crystalline form 1 of WO2007018818A1 were weighed by a dynamic moisture adsorption (DVS) instrument and cycled once at 0-95%-0 relative humidity, and the mass change at each humidity was recorded. The experimental results are shown in Table 2. The XRPD comparison chart before and after the crystal form R DVS is shown in Fig. 9.
表2Table 2
Figure PCTCN2018103417-appb-000005
Figure PCTCN2018103417-appb-000005
晶型R在80％RH条件下引湿性增重为0.18％，WO2007018818A1晶型1在80％RH条件下引湿性增重为0.39％，晶型R的引湿性优于现有技术。The wettability weight gain of the crystal form R under the condition of 80% RH is 0.18%, and the wet weight gain of the crystal form 1 of WO2007018818A1 is 0.89% under the condition of 80% RH, and the wettability of the form R is superior to the prior art.
实施例12：晶型R的稳定性Example 12: Stability of Form R
称取本发明制备得到的晶型R各5mg，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH、80℃条件下放置，采用HPLC和XRPD法测定晶型与纯度的变化。结果如表3所示，XRPD对比图如图10所示。Weigh 5 mg of each of the crystal forms R prepared in the present invention and place them at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, 80 ° C, and determine the crystal by HPLC and XRPD. Type and purity changes. The results are shown in Table 3, and the XRPD comparison chart is shown in FIG.
表3table 3
Figure PCTCN2018103417-appb-000006
Figure PCTCN2018103417-appb-000006
结果表明，晶型R在25℃/60％RH条件下至少可稳定5个月，晶型R在40℃/75％RH条件下至少可稳定1个月，在60℃/75％RH、80℃条件下至少可稳定1周，晶型与化学纯度基本保持不变，晶型R具有较好的物理化学稳定性。The results show that the crystal form R can be stabilized for at least 5 months at 25 ° C / 60% RH, and the crystal form R can be stabilized for at least 1 month at 40 ° C / 75% RH, at 60 ° C / 75% RH, 80 At °C for at least one week, the crystal form and chemical purity remain basically unchanged, and the crystal form R has good physical and chemical stability.
实施例13：晶型R的溶解度Example 13: Solubility of Form R
模拟胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)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。Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The effect of the solubility tested in such media is closer to that in the human environment.
取本发明的晶型R及WO2007018818A1晶型1各30mg分别溶于2mL的SGF、2mL的FaSSIF、2mL的FeSSIF及2mL的水配制成饱和溶液，平衡0.25小时后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4所示。The crystal form R of the present invention and 30 mg of WO2007018818A1 crystal form 1 were respectively dissolved in 2 mL of SGF, 2 mL of FaSSIF, 2 mL of FeSSIF and 2 mL of water to prepare a saturated solution, and after 0.25 hours of equilibration, the saturated solution was tested by high performance liquid chromatography. The content of the sample (mg/mL), the results are shown in Table 4.
表4Table 4
Figure PCTCN2018103417-appb-000007
Figure PCTCN2018103417-appb-000007
结果表明晶型R在SGF、FaSSIF和FeSSIF中均比现有技术晶型1具有更高的溶解度，特别是在FeSSIF中，晶型R的溶解度约是WO2007018818A1晶型1的3倍。The results show that the crystalline form R has higher solubility in the SGF, FaSSIF and FeSSIF than the prior art crystalline form 1, especially in FeSSIF, the solubility of the crystalline form R is about three times that of the crystalline form 1 of WO2007018818A1.
实施例14：晶型R的粒径分布Example 14: Particle size distribution of Form R
分别取10-30mg制备得到的晶型R，然后加入10mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，超声30s，使样品量指示图达到合适位置， 开始实验，进行粒径分布的测试，从而得到按照体积计算的平均粒径、粒径分布中(体积分布)占10％所对应的粒径、粒径分布中(体积分布)占50％所对应的粒径，测试结果如表5示，晶型R的粒度分布图如图11所示。Take 10-30mg of the prepared crystal form R, then add 10mL Isopar G (containing 0.2% lecithin), mix the sample to be tested and then add it to the SDC injection system for 30s, so that the sample quantity indicator is suitable. Position, start the experiment, and carry out the test of the particle size distribution, thereby obtaining the average particle diameter by volume, the particle size distribution (volume distribution), the particle diameter corresponding to 10%, and the particle size distribution (volume distribution) accounting for 50%. The corresponding particle diameter, the test results are shown in Table 5, and the particle size distribution of the crystal form R is shown in FIG.
表5table 5
晶型Crystal form MV(μm)MV (μm) D10(μm)D10 (μm) D50(μm)D50 (μm) D90(μm)D90 (μm)
晶型RCrystal form R 1717 88 1515 2727
MV：按照体积计算的平均粒径；MV: average particle size by volume;
D10：表示粒径分布中(体积分布)占10％所对应的粒径；D10: indicates a particle diameter corresponding to 10% of the particle size distribution (volume distribution);
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径；D50: indicates the particle size corresponding to the particle size distribution (volume distribution), which is 50%, which is also called the median diameter;
D90：表示粒径分布中(体积分布)占90％所对应的粒径。D90: indicates a particle diameter corresponding to 90% of the particle size distribution (volume distribution).
结果表明，晶型R具有均一的粒径分布。The results show that the crystal form R has a uniform particle size distribution.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (8)

  1. 一种Galunisertib的晶型R，其特征在于，其X射线粉末衍射图在2θ值为8.9°±0.2°、25.6°±0.2°、23.8°±0.2°处具有特征峰。A crystal form R of Galunisertib characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 8.9 ° ± 0.2 °, 25.6 ° ± 0.2 °, and 23.8 ° ± 0.2 °.
  2. 根据权利要求1所述的晶型R，其特征在于，其X射线粉末衍射图在2θ值为17.4°±0.2°、11.8°±0.2°、18.0°±0.2°中的一处或两处或三处具有特征峰。The crystal form R according to claim 1, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 17.4°±0.2°, 11.8°±0.2°, 18.0°±0.2° or There are characteristic peaks in three places.
  3. 根据权利要求1所述的晶型R，其特征在于，其X射线粉末衍射图在2θ值为15.5°±0.2°、28.5°±0.2°、14.9°±0.2°中的一处或两处或三处具有特征峰。The crystal form R according to claim 1, wherein the X-ray powder diffraction pattern is at one or two of 2θ values of 15.5°±0.2°, 28.5°±0.2°, 14.9°±0.2° or There are characteristic peaks in three places.
  4. 一种权利要求1中所述晶型R的制备方法，其特征在于，所述制备方法包含：将Galunisertib的甲醇溶剂合物加热至130～150℃，停留1～5min得到晶型R。A method for preparing a crystalline form R according to claim 1, wherein the preparation method comprises: heating a methanol solvate of Galunisertib to 130 to 150 ° C for 1 to 5 minutes to obtain a crystalline form R.
  5. 根据权利要求4所述的制备方法，其特征在于：所述加热温度为140℃，所述停留时间为2min。The preparation method according to claim 4, wherein the heating temperature is 140 ° C and the residence time is 2 min.
  6. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1中所述的晶型R及药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of Form R as described in Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
  7. 权利要求1中所述的晶型R在制备TGF-β受体激酶抑制剂药物中的用途。Use of the crystalline form R as claimed in claim 1 for the manufacture of a TGF-beta receptor kinase inhibitor drug.
  8. 权利要求1中所述的晶型R在制备治疗骨髓增生异常综合症药物中的用途。Use of the crystalline form R as claimed in claim 1 for the manufacture of a medicament for the treatment of myelodysplastic syndrome.
PCT/CN2018/103417 2018-01-12 2018-08-31 Crystal form of galunisertib and preparation method and use thereof WO2019137027A1 (en)

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WO2007018818A1 (en) * 2005-07-22 2007-02-15 Eli Lilly And Company A pyridin quinolin substituted pyrrolo [1,2-b] pyrazole monohydrate as tgf-beta inhibitor
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