WO2019105217A1 - Galunisertib的晶型及其制备方法和用途 - Google Patents

Galunisertib的晶型及其制备方法和用途 Download PDF

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WO2019105217A1
WO2019105217A1 PCT/CN2018/115150 CN2018115150W WO2019105217A1 WO 2019105217 A1 WO2019105217 A1 WO 2019105217A1 CN 2018115150 W CN2018115150 W CN 2018115150W WO 2019105217 A1 WO2019105217 A1 WO 2019105217A1
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crystal form
present
galunisertib
crystal
preparation
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French (fr)
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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
    • 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. More than one different crystal form.
  • crystal form 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 preparations, the study of crystal form is conducive to the selection of a clinically meaningful and stable and controllable crystal form. From the perspective of drug quality regulation, the drug crystal form must be drug research, detection and The important content of supervision is also an important part of drug quality control.
  • a monohydrate crystal form of Galunisertib (designated "Crystal Form 1" in the present invention) is currently disclosed in the patent document WO2007018818A1.
  • the inventors of the present application discovered the crystal-free P 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 P.
  • the crystalline form P provided by the present invention is an anhydride.
  • the X-ray powder diffraction pattern of the Form P has characteristic peaks at diffraction angles 2 ⁇ of 14.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form P has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 12.3° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 15.4° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form P has a characteristic peak at a diffraction angle 2 ⁇ of 12.3° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 15.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form P has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 10.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, and 13.7° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form P has a characteristic peak at a diffraction angle 2 ⁇ of 10.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, and 13.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form P is 8.6° ⁇ 0.2°, 20.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.9° ⁇ 0.2°, 24.1° ⁇ 0.2°, 25.8 at the diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form P is 14.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 21.1° ⁇ 0.2°, 12.3° ⁇ 0.2° at the diffraction angle 2 ⁇ , 12.0° ⁇ 0.2°, 15.4° ⁇ 0.2°, 10.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, 13.7° ⁇ 0.2°, 8.6° ⁇ 0.2°, 20.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.9° Any 3, or 4, or 5, or 6 of ⁇ 0.2°, 24.1° ⁇ 0.2°, 25.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.6° ⁇ 0.2° , or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18 peak.
  • the X-ray powder diffraction pattern of the Form P is substantially as shown in FIG.
  • the present invention also provides a method for preparing the crystalline form P, which comprises heating the acetylacetone solvate to a temperature of 158-162 ° C at a rate of 5-20 ° C/min for 1-5 min. Obtaining a crystalline form P;
  • the methanol solvate is heated to 175-205 ° C at a rate of 5-20 ° C / min, and left for 1 to 5 minutes to obtain the crystalline form P.
  • the acetylacetone solvate is preferably the crystalline form D of the present invention, the heating rate is 10 ° C / min, the heating temperature is 160 ° C, and the residence time is 2 min.
  • the methanol solvate is preferably the crystalline form Q of the present invention
  • the heating rate is 10 ° C / min
  • the heating temperature is 175 to 185 ° C
  • the residence time is 2 min.
  • Form D provides a new crystalline form of Galunisertib, designated as Form D.
  • Form D provided by the present invention is an acetylacetone solvate.
  • the X-ray powder diffraction pattern of Form D is substantially as shown in FIG.
  • the present invention also provides a preparation method of the crystal form D, which comprises adding a Galunisertib free base to an acetylacetone solvent, stirring at a temperature of 50 ° C to 100 ° C, centrifuging and drying to obtain a crystal form. D.
  • the stirring temperature is 80 °C.
  • the present invention provides a novel crystalline form of Galunisertib, designated as Form Q, and the Form Q provided by the present invention is a methanol solvate.
  • the X-ray powder diffraction pattern of Form Q is substantially as shown in FIG.
  • the present invention further provides a method for preparing the crystal form Q, comprising: mixing a Galunisertib free base with a methanol solvent, stirring at room temperature, separating and drying to obtain a crystal form Q.
  • the crystal form P of the present invention has lower wettability than the prior art.
  • the test results show that the wettability of the crystalline form P of the present invention is less than one quarter of that of the prior art solids.
  • the moisture absorption of crystal form P under the condition of 80% relative humidity was 0.09%, and the moisture absorption of the prior art crystal form 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 P provided by the present invention has good physical and chemical stability.
  • the Form P drug substance is placed at 25 ° C / 60% RH, 40 ° C / 75% RH, and the crystal form does not change for at least 6 months. It is placed at 60 ° C / 75% RH, 80 ° C for at least 1 week. The crystal form did not change, and the chemical purity was above 99.9%, and the purity remained basically unchanged during storage.
  • Form P 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 crystalline form P of the present invention has a higher solubility than the prior art. Particularly in FeSSIF, the solubility is more than six 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.
  • the crystalline form P provided by the present invention also has the following beneficial effects:
  • the crystalline form P 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 crystals, saving costs, reducing the risk of crystallinity change and crystal transformation during grinding, and improving 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 "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. 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 P 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 Form P of the present invention together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of crystal form P of Galunisertib for the preparation of a TGF-beta receptor kinase inhibitor drug.
  • the present invention provides the use of crystal form P of Galunisertib for the preparation of a medicament for treating myelodysplastic syndrome.
  • the present invention provides the use of Form P of Galunisertib for the preparation of a medicament for the treatment of solid tumors.
  • the crystal form P of Galunisertib provided by the invention has the advantages 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 P.
  • Figure 2 is a DSC diagram of Form P.
  • Figure 3 is a TGA diagram of Form P.
  • Figure 1 is a 1 H NMR chart of Form P.
  • Figure 5 is an XRPD pattern of Form D.
  • Figure 6 is a TGA diagram of Form D.
  • Figure 1 is a 1 H NMR chart of Form D.
  • Figure 8 is a comparison of the XRPD before and after the crystal form P DVS (the figure above is before DVS and the figure below is after DVS).
  • Figure 9 XRPD comparison chart of crystal form P stability (from top to bottom, starting XRPD, XRPD after 6 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 10 is a PSD diagram of Form P.
  • Figure 11 is an XRPD pattern of Form Q.
  • Figure 12 is a DSC diagram of Form Q.
  • Figure 13 is a TGA diagram of Form Q.
  • Figure 1 is a 1 H NMR chart of Form Q.
  • 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 appeared when heated to 241 ° C, followed by an exothermic peak, and a second endothermic peak appeared when heated to 248 ° C.
  • the DSC chart is shown in FIG. 2 .
  • thermogravimetric analysis when heated to 180 ° C, it has a mass loss of about 0.1%, and its TGA chart is shown in FIG.
  • the wettability weight gain of the crystalline form P under the condition of 80% RH was 0.09%, and the wet weight gain of the crystalline form 1 of WO2007018818A1 was 0.39% under the condition of 80% RH, and the wettability of the crystalline form P was lower, which was superior to the prior art.
  • the crystalline form P can be stable for at least 6 months at 25 ° C / 60% RH, 40 ° C / 75% RH, and stable for at least 1 week at 60 ° C / 75% RH, 80 ° C, crystal form and The chemical purity remains basically unchanged, and the crystalline form P 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.
  • Form P has higher solubility in SGF, FaSSIF, FeSSIF and water than in the prior art Form 1, especially in FeSSIF, the solubility of Form P is more than 6 times that of WO2007018818A1 Form 1.
  • 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).
  • Crystalline D liquid nucleus is shown in Fig. 7.
  • the crystal form D is an acetylacetone solvate in which the molar ratio of the Galunisertib compound to acetylacetone is 1:0.5, wherein the acetylacetone has two isomers of a keto form and an enol 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 chart is shown in Figure 12. When subjected to thermogravimetric analysis, when heated to 150 ° C, it had a mass loss of about 7.1%, and its TGA chart is shown in FIG.
  • the crystal form Q is a methanol solvate.

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Abstract

Galunisertib的晶型P及其制备方法和用途，含有该晶型的药物组合物，以及该晶型在制备治疗骨髓增生异常综合症药物制剂中的用途。晶型P比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。

Description

Galunisertib的晶型及其制备方法和用途 技术领域
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。
背景技术
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。
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：
Figure PCTCN2018115150-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型。
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型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。
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P。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。
发明内容
本发明主要目的是提供Galunisertib的新晶型及其制备方法。
根据本发明的目的，本发明提供Galunisertib的新晶型，命名为晶型P。本发明提供的晶型P是无水物。
一方面，使用Cu-Kα辐射，所述晶型P的X射线粉末衍射图在衍射角2θ为14.5°±0.2°、18.0°±0.2°、21.1°±0.2°处有特征峰。
进一步的，所述晶型P的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、12.0°±0.2°、15.4°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型P的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、12.0°±0.2°、15.4°±0.2°处有特征峰。
进一步的，所述晶型P的X射线粉末衍射图在衍射角2θ为10.0°±0.2°、19.4°±0.2°、13.7°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型P的X射线粉末衍射图在衍射角2θ为10.0°±0.2°、19.4°±0.2°、13.7°±0.2°处有特征峰。
进一步的，所述晶型P的X射线粉末衍射图在衍射角2θ为8.6°±0.2°、20.4°±0.2°、23.5°±0.2°、24.9°±0.2°、24.1°±0.2°、25.8°±0.2°、17.3°±0.2°、21.9°±0.2°、22.6°±0.2°中的一处或多处有特征峰；优选地，所述晶型P的X射线粉末衍射图在衍射角2θ为8.6°±0.2°、20.4°±0.2°、23.5°±0.2°、24.9°±0.2°、24.1°±0.2°、25.8°±0.2°、17.3°±0.2°、21.9°±0.2°、22.6°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型P的X射线粉末衍射图在衍射角2θ为14.5°±0.2°、18.0°±0.2°、21.1°±0.2°、12.3°±0.2°、12.0°±0.2°、15.4°±0.2°、10.0°±0.2°、19.4°±0.2°、13.7°±0.2°、8.6°±0.2°、20.4°±0.2°、23.5°±0.2°、24.9°±0.2°、24.1°±0.2°、25.8°±0.2°、17.3°±0.2°、21.9°±0.2°、22.6°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处、或13处、或14处、或15处、或16处、或17处、或18处有特征峰。
非限制性地，所述晶型P的X射线粉末衍射图基本如图1所示。
根据本发明的目的，本发明还提供所述晶型P的制备方法，所述制备方法包括：将乙酰丙酮溶剂合物以5-20℃/min速率加热至158-162℃，停留1-5min得到晶型P；
或将甲醇溶剂合物以5-20℃/min的速率加热至175～205℃，停留1～5min得到晶型P。
优选的，方法一中，所述乙酰丙酮溶剂合物优选本发明晶型D，所述加热速率为10℃/min，所述加热温度是160℃，所述停留时间为2min。
优选的，方法二中，所述甲醇溶剂合物优选本发明晶型Q，所述加热速率为10℃/min，所述加热温度为175～185℃，所述停留时间为2min。
进一步地，本发明提供Galunisertib的新晶型，命名为晶型D。本发明提供的晶型D是乙酰丙酮溶剂合物。
非限制性地，所述晶型D的X射线粉末衍射图基本如图5所示。
更进一步地，本发明还提供所述晶型D的制备方法，所述制备方法包括：将Galunisertib游离碱加入到乙酰丙酮溶剂中，在50℃-100℃温度下搅拌，离心、干燥得到晶型D。
优选的，所述搅拌温度为80℃。
进一步地，本发明提供Galunisertib的新晶型，命名为晶型Q，本发明提供的晶型Q是甲醇溶剂合物。
非限制性地，所述晶型Q的X射线粉末衍射图基本如图11所示。
更进一步地，本发明还提供所述晶型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。
本发明提供的晶型P具有以下有益效果：
(1)与现有技术相比，本发明晶型P具有更低的引湿性。测试结果表明，本发明晶型P的引湿性不到现有技术固体的四分之一。晶型P在80％相对湿度条件下引湿性增重为0.09％，现有技术晶型在80％RH条件下引湿性增重为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。
(2)本发明提供的晶型P物理、化学稳定性好。晶型P原料药在25℃/60％RH、40℃/75％RH条件下放置，至少6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。
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P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。
(3)与现有技术相比，本发明晶型P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6倍多。
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。
进一步地，本发明提供的晶型P还具有以下有益效果：
本发明的晶型P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，也可减小研磨中晶型结晶度变化和转晶的风险，提高质量控制。
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。
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。
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。
在一些实施方案中，本发明的晶型P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P以及药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提供Galunisertib的晶型P在制备TGF-β受体激酶抑制剂药物中的用途。
进一步地，本发明提供Galunisertib的晶型P在制备治疗骨髓增生异常综合症的药物中的用途。
进一步地，本发明提供Galunisertib的晶型P在制备治疗实体瘤的药物中的用途。
本发明提供的Galunisertib的晶型P，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。
附图说明
图1晶型P的XRPD图。
图2晶型P的DSC图。
图3晶型P的TGA图。
图4晶型P的 1H NMR图。
图5晶型D的XRPD图。
图6晶型D的TGA图。
图7晶型D的 1H NMR图。
图8晶型P DVS前后XRPD对比图(上图为DVS前，下图为DVS后)。
图9晶型P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6个月后的XRPD、在40℃/75％RH条件下放置6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)。
图10晶型P的PSD图。
图11晶型Q的XRPD图。
图12晶型Q的DSC图。
图13晶型Q的TGA图。
图14晶型Q的 1H NMR图。
具体实施方式
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。
采集数据所用的仪器及方法：
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
1H NMR：核磁共振氢谱
HPLC：高效液相色谱
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 PCTCN2018115150-appb-000002
1.54060；
Figure PCTCN2018115150-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。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
核磁共振氢谱数据( 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。
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：
Figure PCTCN2018115150-appb-000004
Figure PCTCN2018115150-appb-000005
*：流速60％为65毫升/秒的60％。
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：
1、色谱柱：Waters XBridge 150*4.6mm，5μm
2、流动相：A：2mmol/L庚烷磺酸钠水溶液，pH3.0
B：乙腈溶液
洗脱梯度如下：
Time(min) ％B
0.0 10
20.0 40
40.0 80
45.0 80
46.0 10
55.0 10
3、流速：1mL/min
4、进样量：5μl
5、检测波长：220nm
6、柱温：40℃
7、稀释剂：50％乙腈
除非特殊说明，以下实施例均在室温条件下操作。
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。
实施例1：晶型P的制备
称取212.7mg Galunisertib原料放入3mL玻璃小瓶中，加入1.2mL的乙酰丙酮溶剂形成悬浊液，置于80℃下搅拌2天，离心分离将所得固体置于50℃鼓风干燥5小时，然后将所得物在DSC仪器上进行加热实验，样品开盖以10℃/min加热至160℃，停留2min，得到固体。经检测，所得固体为晶型P，其XRPD数据如表1所示，其XRPD图如图1所示。
当进行差示扫描量热分析时，加热至241℃出现第一个吸热峰，随后出现一个放热峰， 加热至248℃出现第二个吸热峰，其DSC图如图2。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3。
晶型P的核磁数据如图4所示，结果如下： 1H NMR(400MHz,DMSO)δ8.87(d,J＝4.5Hz,1H),8.25(s,1H),8.12(d,J＝8.8Hz,1H),8.04(d,J＝8.8Hz,2H),7.61-7.54(m,2H),7.41(d,J＝4.4Hz,1H),7.36(s,1H),6.96-6.89(m,1H),4.31(t,J＝7.2Hz,2H),2.83(s,2H),2.69-2.59(m,2H),1.74(s,3H)。
表1
2theta(±0.2°) d间隔 强度％
8.65 10.22 22.78
9.86 8.97 41.51
10.02 8.83 44.30
11.95 7.41 46.00
12.34 7.17 62.02
13.48 6.57 16.26
13.72 6.46 43.43
14.56 6.08 100.00
15.42 5.74 47.54
15.63 5.67 41.69
17.31 5.12 34.63
17.97 4.94 52.48
19.40 4.57 46.55
19.67 4.51 34.17
19.98 4.44 12.26
20.42 4.35 42.17
20.66 4.30 23.39
21.08 4.22 59.42
21.94 4.05 35.28
22.55 3.94 20.63
23.14 3.84 14.69
23.53 3.78 21.41
24.12 3.69 21.32
24.80 3.59 33.27
24.96 3.57 31.20
25.77 3.46 33.46
26.87 3.32 8.33
28.55 3.13 3.85
30.70 2.91 2.43
31.31 2.86 8.64
实施例2：晶型P的引湿性
称取本发明晶型P与现有技术晶型各约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P DVS前后的XRPD对比图如图8所示。
表2
Figure PCTCN2018115150-appb-000006
晶型P在80％RH条件下引湿性增重为0.09％，WO2007018818A1晶型1在80％RH条件下引湿性增重为0.39％，晶型P的引湿性更低，优于现有技术。
实施例3：晶型P的稳定性
称取本发明制备得到的晶型P各5mg，分别在25℃/60％RH、40℃/75％RH、60℃/75％RH、80℃条件下放置，采用XRPD和HPLC测定晶型与纯度的变化。结果如表3所示，XRPD对比图如图9所示。
表3
Figure PCTCN2018115150-appb-000007
结果表明，晶型P在25℃/60％RH、40℃/75％RH条件下至少可稳定6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P具有 较好的物理化学稳定性。
实施例4：晶型P的溶解度
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。
取本发明的晶型P及WO2007018818A1晶型1各30mg分别置于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。
表4
Figure PCTCN2018115150-appb-000008
结果表明晶型P在SGF、FaSSIF、FeSSIF及水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P的溶解度是WO2007018818A1晶型1的6倍多。
实施例5：晶型P的粒径分布
取10-30mg制备得到的晶型P，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P的粒度分布图如图10所示。
表5
晶型 MV(μm) D10(μm) D50(μm) D90(μm)
晶型P 130 35 98 266
MV：按照体积计算的平均粒径；
D10：表示粒径分布中(体积分布)占10％所对应的粒径；
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；
D90：表示粒径分布中(体积分布)占90％所对应的粒径。
结果表明，晶型P具有均一的粒径分布。
实施例6：晶型D的制备
称取201.2mg Galunisertib游离碱放入3mL玻璃小瓶中，加入1.2mL的乙酰丙酮溶剂形成悬浊液，置于80℃下搅拌4天，离心得到固体，置于50℃鼓风干燥2小时。经检测，本实施例得到固体为晶型D，其X射线粉末衍射数据如表6所示，XRPD图如图5所示。
当进行热重分析时，加热至180℃时，具有11.8％的质量损失，其TGA如图6所示。
晶型D液态核磁如图7，核磁数据如下： 1H NMR(400MHz,DMSO)δ8.88(d,J＝4.5Hz,1H),8.26(d,J＝1.6Hz,1H),8.13(dd,J＝8.8,1.9Hz,1H),8.05(d,J＝8.7Hz,2H),7.58(dd,J＝7.0,6.0Hz,2H),7.42(d,J＝4.4Hz,1H),7.36(s,1H),6.97–6.88(m,1H),4.31(t,J＝7.2Hz,2H),2.83(s,2H),2.70–2.59(m,2H),2.14-2.03(d,3H),1.75(s,3H)。根据核磁数据可知，晶型D为乙酰丙酮溶剂合物，其中Galunisertib化合物与乙酰丙酮的摩尔比为1:0.5，其中乙酰丙酮具有酮式和烯醇式两种异构体。
表6
2theta(±0.2°) d间隔 强度％
8.61 10.07 6.89
9.93 8.90 15.76
10.55 8.39 34.11
11.14 7.94 100.00
12.91 6.86 27.49
14.39 6.15 5.20
15.40 5.75 8.02
15.56 5.69 17.57
16.47 5.38 74.95
17.01 5.21 2.93
17.62 5.03 7.72
18.82 4.72 31.69
19.16 4.63 9.28
19.71 4.50 18.28
20.07 4.42 64.34
20.50 4.33 3.20
21.54 4.13 6.16
21.85 4.07 3.91
22.23 4.00 7.68
22.61 3.93 10.85
23.38 3.80 2.71
23.80 3.74 19.66
24.50 3.63 5.40
24.76 3.60 49.57
25.67 3.47 55.15
26.10 3.41 32.51
26.63 3.35 2.52
27.08 3.29 5.78
27.73 3.22 17.39
28.85 3.10 9.10
29.44 3.03 2.25
30.35 2.95 4.12
31.01 2.88 13.24
33.12 2.70 2.17
33.59 2.67 2.64
34.85 2.57 1.23
36.37 2.47 5.02
38.28 2.35 1.66
39.03 2.31 1.24
39.46 2.28 1.17
实施例7：晶型Q的制备
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11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。
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12。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13。
晶型Q的核磁数据如图14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。
实施例8：晶型P的制备
称取10.2mg Galunisertib甲醇溶剂合物样品(晶型Q)使用DSC以10℃/min加热至180℃，停留2min，得到固体。经检测，所得固体为晶型P，其X射线粉末衍射数据如表7所示。
表7
2theta(±0.2°) d间隔 强度％
8.70 10.17 22.47
10.05 8.80 39.14
11.91 7.43 35.55
12.34 7.18 66.75
13.46 6.58 14.34
13.68 6.47 28.62
14.04 6.31 6.33
14.56 6.08 100.00
15.43 5.74 29.44
15.61 5.68 43.06
17.26 5.14 26.85
17.97 4.94 52.64
18.48 4.80 11.76
19.35 4.59 42.46
19.64 4.52 35.07
20.39 4.35 32.92
21.14 4.20 35.57
21.90 4.06 27.71
22.55 3.94 16.01
23.49 3.79 19.75
24.09 3.69 20.53
24.94 3.57 40.02
25.79 3.45 28.52
26.83 3.32 7.32
28.42 3.14 3.83
31.30 2.86 13.30
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 (7)

  1. 一种Galunisertib的晶型P，其特征在于，其X射线粉末衍射图在2θ值为14.5°±0.2°、18.0°±0.2°、21.1°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型P，其特征在于，其X射线粉末衍射图在2θ值为12.3°±0.2°、12.0°±0.2°、15.4°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的晶型P，其特征在于，其X射线粉末衍射图在2θ值为10.0°±0.2°、19.4°±0.2°、13.7°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种权利要求1中所述晶型P的制备方法，其特征在于，所述制备方法包含：将乙酰丙酮溶剂合物以5-20℃/min的速率加热至158-162℃，停留1-5min得到晶型P；或将甲醇溶剂合物以5-20℃/min的速率加热至175～205℃，停留1～5min得到晶型P。
  5. 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中所述晶型P及药学上可接受的载体、稀释剂或赋形剂。
  6. 权利要求1中所述的晶型P在制备TGF-β受体激酶抑制剂药物中的用途。
  7. 权利要求1中所述的晶型P在制备治疗骨髓增生异常综合症药物中的用途。
PCT/CN2018/115150 2017-11-30 2018-11-13 Galunisertib的晶型及其制备方法和用途 WO2019105217A1 (zh)

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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
WO2014191559A1 (en) * 2013-05-30 2014-12-04 Institució Catalana De Recerca I Estudis Avançats Methods and kits for the prognosis of colorectal cancer
WO2017076924A1 (en) * 2015-11-02 2017-05-11 Tigenix, S.A.U. Mesenchymal stem cell-derived exosomes and their uses

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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
WO2014191559A1 (en) * 2013-05-30 2014-12-04 Institució Catalana De Recerca I Estudis Avançats Methods and kits for the prognosis of colorectal cancer
WO2017076924A1 (en) * 2015-11-02 2017-05-11 Tigenix, S.A.U. Mesenchymal stem cell-derived exosomes and their uses

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