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WO2024099396A1 - 芦可替尼晶体及其药物组合物 - Google Patents

芦可替尼晶体及其药物组合物 Download PDF

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Publication number
WO2024099396A1
WO2024099396A1 PCT/CN2023/130777 CN2023130777W WO2024099396A1 WO 2024099396 A1 WO2024099396 A1 WO 2024099396A1 CN 2023130777 W CN2023130777 W CN 2023130777W WO 2024099396 A1 WO2024099396 A1 WO 2024099396A1
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Prior art keywords
ruxolitinib
free base
compound
amorphous
formula
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PCT/CN2023/130777
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English (en)
French (fr)
Inventor
沈连刚
吴先锋
朱荣花
郑志国
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浙江奥翔药业股份有限公司
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Publication of WO2024099396A1 publication Critical patent/WO2024099396A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to crystals and amorphous substances of ruxolitinib free base, preparation methods thereof and applications thereof in pharmaceutical compositions.
  • Ruxolitinib phosphate is an orally administrable selective JAK1/JAK2 kinase inhibitor developed by the U.S. company Incyte. It was the first drug approved by the U.S. FDA for the treatment of myelofibrosis in November 2011 (trade name Jakafi). It was approved for marketing by Novartis in the European Union in August 2012 and in China in March 2017.
  • ruxolitinib phosphate As an oral therapeutic drug with strong selectivity, low toxicity and good tolerance, ruxolitinib phosphate is suitable for the treatment of moderate or high-risk myelofibrosis (MF), including primary MF, MF after polycythemia vera and MF after essential thrombocythemia.
  • MF myelofibrosis
  • Its chemical name is: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, and the chemical structure is as follows:
  • WO2007070514A1 discloses the preparation of R and S configurations of ruxolitinib free base by HPLC, but there is no description of the purity and physical state thereof.
  • WO2008157208A2 discloses methods for preparing ruxolitinib phosphate, sulfate and maleate, but does not describe the physical state of ruxolitinib free base.
  • Angew.Chem.Int.Ed.2015,54,7149-7153 discloses the preparation method of ruxolitinib free base and its physical state is colorless foam, which crystallizes into a solid upon standing, with a melting point of 88°C, but there is no further description of its crystal form.
  • the present invention discovers for the first time a new crystal form of ruxolitinib free base, the preparation method of which is simple, and which is excellent in stability, solubility, hygroscopicity and processability, thus providing a suitable raw material for the development of dry granulation or tableting methods for pharmaceutical preparations.
  • the present invention also relates to the use of the crystal form in a pharmaceutical composition, and a pharmaceutical composition comprising the crystal form and one or more pharmaceutically acceptable excipients or carriers.
  • the present invention provides ruxolitinib dihydrate as shown in Formula I.
  • the compound of formula I is in crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks expressed in 2 ⁇ diffraction angles at 6.92 ⁇ 0.2°, 19.02 ⁇ 0.2°, 22.62 ⁇ 0.2°, 23.12 ⁇ 0.2° and 24.66 ⁇ 0.2°.
  • the compound of formula I is in crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.92 ⁇ 0.2°, 10.54 ⁇ 0.2°, 11.54 ⁇ 0.2°, 15.42 ⁇ 0.2°, 19.02 ⁇ 0.2°, 22.62 ⁇ 0.2°, 23.12 ⁇ 0.2° and 24.66 ⁇ 0.2°, expressed as 2 ⁇ diffraction angles.
  • the compound of formula I is in crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.92 ⁇ 0.2°, 10.54 ⁇ 0.2°, 11.54 ⁇ 0.2°, 15.42 ⁇ 0.2°, 19.02 ⁇ 0.2°, 20.78 ⁇ 0.2°, 22.62 ⁇ 0.2°, 23.12 ⁇ 0.2°, 24.66 ⁇ 0.2° and 25.76 ⁇ 0.2°, expressed as 2 ⁇ diffraction angles.
  • the compound of formula I is in crystalline form, characterized in that its X-ray powder diffraction pattern has a 2 ⁇ diffraction angle expressed at 6.92 ⁇ 0.2°, 10.54 ⁇ 0.2°, 11.54 ⁇ 0.2°, 15.08 ⁇ 0.2°, 15.42 ⁇ 0.2°, 16.20 ⁇ 0.2°, 19.02 ⁇ 0.2°, 20.78 ⁇ 0.2°, 21.78 ⁇ 0.2°, 22.62 ⁇ 0.2°, 22.86 ⁇ 0.2°, 23.12 ⁇ 0.2°, 24.66 ⁇ 0.2°, 25. Characteristic diffraction peaks at 25.76 ⁇ 0.2° and 27.50 ⁇ 0.2°.
  • the crystalline form of the compound of formula I when using Cu-K ⁇ Radiation, tube voltage 40KV, tube current 15mA, scanning speed 5°/min, step width 0.02°, DS (slit) 0.625, ⁇ -2 ⁇ continuous scanning in the scanning range 3-40° (2 ⁇ ), has an X-ray powder diffraction pattern as shown in Figure 1. Among them, the main characteristic diffraction lines represented by the 2 ⁇ diffraction angle are shown in Table 1.
  • the single crystal structure data of the compound of formula I of the present invention are shown in Table 2, and the non-hydrogen atom coordinates and various temperature factors of the molecule of the compound of formula I are shown in Table 3.
  • the water molecules in the structure form hydrogen bonds with the amine nitrogen atoms on the pyrazole ring and pyrimidine ring in the ruxolitinib molecule respectively.
  • the configuration of the chiral carbon atoms (C10, C10A) in the two ruxolitinib molecules is consistent, both of which are "R" configurations, and the molecular configuration diagram is shown in Figure 3.
  • the two ruxolitinib molecules are bridged by four water molecules to form a dimer structure as shown in Figure 4. This dimer forms a three-dimensional stacking structure through hydrogen bonding (see Figure 5).
  • the DSC curve of the crystal of the compound of formula I of the present invention is shown in FIG6 , indicating that its melting point is 67.1° C.
  • the infrared spectrum of the crystal of the compound of formula I of the present invention is shown in FIG7 .
  • the present invention provides a method for preparing a crystal of a compound of formula I, the method comprising:
  • reaction temperature is controlled at 10-50°C
  • purified water is added dropwise, and then the internal temperature is controlled at 10-40°C and stirred to precipitate crystals to obtain crystals of the compound of formula I.
  • the organic solvent refers to a solvent capable of dissolving ruxolitinib free base, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, toluene, chlorobenzene, hexane, heptane, DMF, DMAC, DMSO, NMP, methyl acetate, ethyl acetate, isopropyl acetate, or a mixture of two or more thereof.
  • a solvent capable of dissolving ruxolitinib free base such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, e
  • the reaction temperature is controlled at 10-50°C, purified water is added dropwise, at which time the system becomes turbid, the internal temperature is controlled at 10-40°C and stirred for 1-6 hours, a large amount of light yellow to off-white solids are precipitated, and then the temperature is lowered to -5-15°C, stirred for 1-2 hours, filtered and dried to obtain crystals of the compound of formula I.
  • seed crystals prepared according to the above method may be additionally added to induce crystallization.
  • the ruxolitinib raw material used may be a crude product, such as an oily substance, a foamy substance or a non-viscous jelly-like substance, or the amorphous substance described in the present invention.
  • the drying may be vacuum drying.
  • the drying temperature may be 10-50° C., preferably 25-45° C.
  • the drying time is 3-24 hours.
  • the present invention provides amorphous ruxolitinib free base and a method for preparing the same.
  • the present invention provides an amorphous ruxolitinib free base solid, characterized in that when Cu-K ⁇ Radiation, tube voltage 40KV, tube current 15mA, scanning speed 5°/min, step width 0.02°, DS (slit) 0.625, scanning range When ⁇ -2 ⁇ is continuously scanned in the range of 3-40° (2 ⁇ ), an X-ray powder diffraction spectrum is obtained as shown in FIG8 .
  • the X-ray powder diffraction spectrum shows that the solid is in an amorphous form.
  • the infrared spectrum of the amorphous substance is shown in Figure 9.
  • the DSC spectrum of the amorphous substance is shown in Figure 10, and its melting point is 66.14°C.
  • the present invention also provides a method for preparing the amorphous ruxolitinib free base, comprising the following steps: adding a ruxolitinib free base raw material into an organic solvent to dissolve it, and then adding an anti-solvent to crystallize it to obtain an amorphous ruxolitinib free base solid.
  • the method for preparing the amorphous ruxolitinib free base comprises the following steps: adding the ruxolitinib free base raw material to an organic solvent to dissolve it, adding an anti-solvent, controlling the temperature to crystallize it, and filtering to obtain an amorphous ruxolitinib free base solid.
  • the ruxolitinib raw material may be a crude product, such as an oily substance, a foamy substance or a non-viscous jelly-like substance, or a crystal of the compound of formula I.
  • the organic solvent is selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetone, dichloromethane, toluene, xylene, chlorobenzene, or a mixture of two or more thereof.
  • the anti-solvent is selected from pentane, n-pentane, neopentane, hexane, n-hexane, cyclohexane, methylcyclohexane, n-heptane, or a mixture of two or more thereof.
  • the crystallization temperature is -10-20°C, preferably -5-15°C, and most preferably 0-10°C.
  • the present invention provides a method for preparing the amorphous ruxolitinib free base, comprising: vacuum drying the compound of formula I of the present invention to lose its crystal water, thereby obtaining the amorphous ruxolitinib free base.
  • the drying temperature is 30-65° C., preferably 35-60° C., and most preferably 45-55° C.
  • the vacuum degree of the vacuum drying is ⁇ -0.1Mpa.
  • the drying time is 3-24h, preferably 8-15h.
  • the present invention also relates to an amorphous ruxolitinib free base solid, which is obtained by the above-mentioned preparation method.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising ruxolitinib and one or more pharmaceutically acceptable excipients or carriers.
  • the ruxolitinib can be selected from the above-mentioned crystal of the compound of formula I or amorphous ruxolitinib free base.
  • compositions of the present invention can be prepared according to conventional methods in the art, and they can be suitable for enteral administration (e.g., oral or rectal administration) or parenteral administration to mammals, including humans.
  • the composition comprises a therapeutically effective amount of ruxolitinib, which is used in combination with at least one pharmaceutically acceptable excipient or carrier.
  • Typical oral formulations include tablets, capsules, sugars, and Slurries, elixirs and suspensions.
  • compositions or carriers suitable for use in the present invention include, but are not limited to, diluents, fillers, disintegrants, glidants, lubricants, binders, colorants, and combinations thereof, provided that they are chemically inert and thus do not have a negative impact on the active ingredients.
  • the amount of each excipient or carrier in the solid preparation may vary within the conventional range in the art.
  • Examples of typical pharmaceutically acceptable excipients or carriers are: sugars, such as lactose, sucrose, mannitol and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; povidone K30; sodium carboxymethyl starch; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; colloidal silicon dioxide; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glyco
  • compositions for enteral or parenteral administration may be in unit dosage form, such as coated tablets, tablets, capsules or suppositories and ampoules. They may be prepared according to conventional methods in the art, such as by conventional mixing, granulation, coating, dissolution or freeze drying. Therefore, a pharmaceutical composition for oral administration may be obtained by mixing ruxolitinib with a solid excipient, and optionally granulating the mixture obtained above, then optionally adding other excipients, and preparing the mixture or granules into tablets or cores of coated tablets.
  • the pharmaceutical composition comprises ruxolitinib, an organic acid and other excipients or carriers.
  • the ruxolitinib can be selected from the above-mentioned crystals of the compound of formula I or amorphous ruxolitinib free base.
  • the organic acid can be selected from one or more of malonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and malic acid.
  • the other excipients or carriers may include microcrystalline cellulose, lactose monohydrate and povidone K30.
  • the present invention also provides a method for preparing the composition, which comprises: uniformly mixing a certain proportion of ruxolitinib and an organic acid, adding other excipients or carriers, stirring and mixing, and then dry tableting or granulating.
  • the ruxolitinib can be selected from the above-mentioned formula I compound crystal or amorphous ruxolitinib free base.
  • the beneficial effect of the present invention is that dihydrate crystals and amorphous products of ruxolitinib free base are provided, and the crystals are excellent in stability, solubility, hygroscopicity and processability, and thus are suitable for dry granulation or tableting of pharmaceutical preparations.
  • the development provides suitable raw materials.
  • the preparation method of the amorphous material is simple, the obtained product has high yield, good purity, stable properties, and is also suitable for industrial production, and also provides suitable raw materials and methods for dry granulation or tableting of drugs.
  • FIG1 is a PXRD spectrum of the compound of formula I crystal.
  • FIG. 2 is a molecular thermal ellipsoid diagram (ORTEP diagram, ellipsoid probability 50%) of the crystal of the compound of formula I.
  • FIG3 is a molecular configuration diagram of the crystal of the compound of formula I (solvent molecules and hydrogen atoms on non-chiral atoms are ignored).
  • FIG. 4 is a dimer structure of the crystal of the compound of formula I.
  • FIG5 is a three-dimensional stacking structure of the crystal of the compound of formula I.
  • FIG6 is a DSC spectrum of the crystal of the compound of formula I.
  • FIG. 7 is an infrared spectrum of the crystal of the compound of formula I.
  • FIG8 is a PXRD spectrum of amorphous ruxolitinib.
  • FIG9 is an infrared spectrum of amorphous ruxolitinib.
  • FIG10 is a DSC spectrum of amorphous ruxolitinib.
  • FIG. 11a is a PXRD spectrum of the crystals of the compound of formula I at 0 month
  • FIG. 11b is a PXRD spectrum of the crystals of the compound of formula I after being placed at 30-35° C. for 3 months.
  • the raw materials of the free base compound of ruxolitinib used are prepared by referring to the method of patent WO2007070514A1.
  • the organic solvent reagents used such as methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, hexane, n-heptane, citric acid, etc., can be purchased from commercial sources.
  • ruxolitinib oil (R-ruxolitinib purity is 85.3%) and 80.0 g of tetrahydrofuran were added to a 500 mL reaction bottle, the temperature was raised to 20-30 ° C and stirred to dissolve, the temperature in the bottle was controlled at 20-30 ° C, 120 g of purified water was added dropwise, and the bottle was turbid after the addition was completed.
  • 0.1 g of the compound of formula I in the above embodiment was added as a seed, the internal temperature was controlled at 20-30 ° C and stirred for 1-2 hours.

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Abstract

一种芦可替尼晶体及其药物组合物。具体而言，提供了芦可替尼二水合物晶体及其制备方法，还提供了无定形形式的芦可替尼游离碱及其制备方法，以及包含芦可替尼二水合物晶体或无定形形式的芦可替尼游离碱的药物组合物。所述的晶体、无定形物及其药物组合物的制备方法简单、产品收率高，且晶体在稳定性、吸湿性和可加工性方面均表现优异，因此适合于工业化生产。

Description

芦可替尼晶体及其药物组合物 技术领域
本发明属于药物化学领域。具体而言，本发明涉及芦可替尼游离碱的晶体和无定形物、其制备方法以及其在药物组合物的应用。
背景技术
磷酸芦可替尼，是由美国Incyte公司开发的一种可口服给药的选择性JAK1/JAK2激酶抑制剂，是2011年11月由美国FDA批准的首个用于骨髓纤维化治疗的药物(商品名Jakafi)，它于2012年8月由诺华公司获欧盟批准上市，2017年3月获中国批准上市。
作为选择性强、毒副作用小和耐受性良好的口服治疗药物，磷酸芦可替尼适用于治疗中度或高危骨髓纤维化(MF)，包括原发性MF、真性红细胞增多症后MF和原发性血小板增多症后MF。近年来其适应症不断得到拓展，显示出良好的应用前景。其化学名为：(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈磷酸盐，化学结构式如下:
WO2007070514A1公布了通过HPLC法制备R和S构型的芦可替尼游离碱，但没有其纯度和物理状态相关的描述。
WO2008157208A2公布了芦可替尼磷酸盐、硫酸盐和马来酸盐制备方法，但是也没有对芦可替尼游离碱的物理状态的描述。
文献Organic Letters,2009,11(9),1999-2002和专利申请WO2010083283A2，分别公布了芦可替尼游离碱的制备方法及其物理状态，其物理状态均为白色或淡黄色泡沫状固体。经重复实验并测定，该泡沫状固体化合物为无定形物。此外，Organic Letters,2009,11(9),1999-2002还公布了柱层析后获得的芦可替尼游离碱为油状物，其在室温真空下发生固化，但没有对其 熔点及晶型的任何描述。
文献Angew.Chem.Int.Ed.2015,54,7149-7153公布了芦可替尼游离碱的制备方法及其物理状态为无色泡沫，静置结晶得出固体，熔点为88℃，但并没有对其晶型的进一步描述。
本发明首次发现了芦可替尼游离碱的新晶型，该晶型的制备方法简单，并且在稳定性、溶解度、吸湿性和可加工性方面表现优异，因此为药物制剂的干法制粒或压片法开发提供了合适原料。本发明还涉及该晶型在药物组合物中的应用，以及包含该晶型和一种或多种药学上可接受的赋形剂或载体的药物组合物。
发明内容
第一方面，本发明提供了式I所示的芦可替尼二水合物。
在一个实施方案中，式I化合物为结晶形式，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、19.02±0.2°、22.62±0.2°、23.12±0.2°和24.66±0.2°处的特征衍射峰。
在一个优选的实施方案中，式I化合物为结晶形式，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、10.54±0.2°、11.54±0.2°、15.42±0.2°、19.02±0.2°、22.62±0.2°、23.12±0.2°和24.66±0.2°处的特征衍射峰。
在一个更优选的实施方案中，式I化合物为结晶形式，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、10.54±0.2°、11.54±0.2°、15.42±0.2°、19.02±0.2°、20.78±0.2°、22.62±0.2°、23.12±0.2°、24.66±0.2°和25.76±0.2°处的特征衍射峰。
在一个更优选的实施方案中，式I化合物为结晶形式，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、10.54±0.2°、11.54±0.2°、15.08±0.2°、15.42±0.2°、16.20±0.2°、19.02±0.2°、20.78±0.2°、21.78±0.2°、22.62±0.2°、22.86±0.2°、23.12±0.2°、24.66±0.2°、 25.76±0.2°和27.50±0.2°处的特征衍射峰。
所述式I化合物的结晶形式，当采用Cu-Kα辐射，管电压40KV，管电流15mA，扫描速度5°/min，步宽0.02°，DS(狭缝)0.625，扫描范围3-40°(2θ)的θ-2θ连续扫描时，具有如图1所示的X射线粉末衍射图谱。其中，以2θ衍射角表示的主要特征衍射谱线如表1所示。
表1：式I化合物的主要特征衍射谱线表
本发明的式I化合物的单晶结构数据如表2所示，式I化合物分子的非氢原子坐标及各温度因子如表3所示。
晶体结构解析结果表明，式I化合物的晶体属正交晶系，P212121(19#)空间群，晶胞参 数为：Z＝8,分子式为：C17H18N6·2(H2O)，分子的结构式如式I所示(系统命名为：((3R)-3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)吡唑-1-基]丙腈)·2H2O)。其最小不对称单元中含有两个芦可替尼分子和四个水分子，即为芦可替尼二水合物晶型，原子编号见图2，结构中的水分子分别与芦可替尼分子中的吡唑环和嘧啶环上的胺基氮原子形成氢键。两个芦可替尼分子中手性碳原子(C10、C10A)的构型一致，都为“R”构型，分子构型图显示于图3。两个芦可替尼分子通过四个水分子的桥连形成二聚体结构见图4，此二聚体通过氢键作用形成三维堆积结构(见图5)。
本发明的式I化合物晶体的DSC曲线如图6所示，表明其熔点为67.1℃。
本发明的式I化合物晶体的红外图谱如图7所示。
表2：式I化合物分子的单晶结构数据和结构修正数据
表3：非氢原子的原子坐标及温度因子

第二方面，本发明提供了式I的化合物晶体的制备方法，该方法包括：
将芦可替尼游离碱加入有机溶剂溶解后，滴加纯化水，使其结晶，得到式I化合物晶体。
在一个优选的实施方案中，将芦可替尼游离碱加入有机溶剂溶解后，控制反应温度为10-50℃，滴加纯化水，随后控制内温为10-40℃并搅拌，使晶体析出，得到式I化合物晶体。
在一个优选的实施方案中，所述的有机溶剂指的是能够溶解芦可替尼游离碱的溶剂，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、丙酮、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷、乙腈、二氯甲烷、氯仿、甲苯、氯苯、己烷、庚烷、DMF、DMAC、DMSO、NMP、乙酸甲酯、乙酸乙酯、乙酸异丙酯、或其两种或两种以上的混合物。
在一个更优选的实施方案中，将芦可替尼游离碱加入有机溶剂溶解后，控制反应温度10-50℃，滴加纯化水，此时体系变浑浊，控制内温10-40℃搅拌1-6h，析出大量浅黄色至类白色固体，然后降温至-5-15℃，搅拌1-2h，过滤并干燥，得到式I的化合物晶体。
在制备式I化合物晶体时，为方便快速析晶，可额外加入按照上述方法制备的晶种诱导析晶。
所用的芦可替尼原料可以为粗品，例如油状物、泡沫状物或非粘性胶状物，或为本发明所述的无定形物。
所述干燥可以为真空干燥。干燥温度可以是10-50℃，优选25-45℃。干燥时间为3-24h。
第三方面，本发明提供了无定形的芦可替尼游离碱及其制备方法。
本发明提供了无定形的芦可替尼游离碱固体，其特征在于，当采用Cu-Kα辐射，管电压40KV，管电流15mA，扫描速度5°/min，步宽0.02°，DS(狭缝)0.625，扫描范 围3-40°(2θ)的θ-2θ连续扫描时，具有如图8所示的X射线粉末衍射谱图。
X射线粉末衍射谱图表明该固体为无定形形式。该无定形物的红外光谱图如9所示。该无定形物的DSC谱图如图10所示，其熔点为66.14℃。
本发明还提供了所述无定形的芦可替尼游离碱的制备方法，包括以下步骤：将芦可替尼游离碱原料加入有机溶剂溶解后，加入反溶剂使其结晶，得到无定形的芦可替尼游离碱固体。
在一个优选的实施方案中，所述无定形的芦可替尼游离碱的制备方法包括以下步骤：将芦可替尼游离碱原料加入有机溶剂溶解后，加入反溶剂，控制温度使其结晶，过滤，得到无定形的芦可替尼游离碱固体。
所述的芦可替尼原料可以为粗品，例如油状物、泡沫状物或非粘性胶状物，或者为式I的化合物晶体。
所述的有机溶剂选自甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六烷、丙酮、二氯甲烷、甲苯、二甲苯、氯苯、或其两种或两种以上的混合物。
所述的反溶剂选自戊烷、正戊烷、新戊烷、己烷、正己烷、环己烷、甲基环己烷、正庚烷，或其两种或两种以上的混合物。
所述的结晶温度为-10-20℃，优选-5-15℃，最优选0-10℃。
在另一个实施方案中，本发明提供了所述无定形的芦可替尼游离碱的制备方法，包括：真空干燥本发明所述的式I化合物，使其失去结晶水，得到无定形的芦可替尼游离碱。
所述的干燥温度为30-65℃，优选35-60℃，最优选45-55℃。所述的真空干燥，其真空度≤-0.1Mpa。所述的干燥时间为3-24h，优选8-15h。
本发明还涉及无定形的芦可替尼游离碱固体，其通过上述的制备方法获得。
第四方面，本发明提供了包含芦可替尼和一种或多种药学上可接受的赋形剂或载体的药物组合物。所述的芦可替尼可以选自上述的式I化合物晶体或者无定形的芦可替尼游离碱。
本发明的药物组合物可以根据本领域常规的方法制备，它们可适用于胃肠内施用(例如口服或直肠给药)或胃肠外施用于哺乳动物，包括人。所述组合物包含治疗有效量的芦可替尼，其与至少一种药学上可接受的赋形剂或载体组合使用。典型的口服制剂包括片剂、胶囊、糖 浆、酏剂和悬浮液。
适用于本发明的药学上可接受的赋形剂或载体包括但不限于稀释剂、填充剂、崩解剂、助流剂、润滑剂、粘合剂、着色剂及其组合，前提是它们是化学惰性的，因而不会对活性成分产生负面影响，固体制剂中每一种赋形剂或载体的量可以在本领域常规范围内改变。典型的药学上可接受的赋形剂或载体的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如微晶纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚维酮K30；羧甲基淀粉钠；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；胶态二氧化硅；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和阴离子表面活性剂；乙二醇聚合物；β-环糊精；脂肪醇类；和谷物水解固形物，以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
用于胃肠内或胃肠外给药的药物制剂可以为单位剂型，例如包衣片剂、片剂、胶囊或栓剂以及安瓿。它们可以根据本领域常规的方法制备，例如采用传统的混合、制粒、包衣、溶解或冷冻干燥。所以，用于口服的药物组合物可以通过以下方法获得：将芦可替尼与固体赋形剂混合，并且任选地将上述获得的混合物制粒，随后可任选地加入其他赋形剂，并将所述混合物或颗粒制成片剂或包衣片剂的片芯。
在一个优选的实施方案中，所述药物组合物的组成包括芦可替尼、有机酸和其它赋形剂或载体。
所述的芦可替尼可以选自上述的式I化合物晶体或者无定形的芦可替尼游离碱。所述的有机酸可以选自丙二酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸中的一种或多种。
所述的其它赋形剂或载体可以包括微晶纤维素、一水乳糖和聚维酮K30。
本发明还提供了该组合物的制备方法，该方法包括：将一定比例的芦可替尼和有机酸混合均匀后，加入其它赋形剂或载体，搅拌混合均匀，然后干法压片或制粒。所述的芦可替尼可以选自上述的式I化合物晶体或者无定形的芦可替尼游离碱。
本发明的有益效果是，提供了芦可替尼游离碱的二水合物晶体以及无定形物，所述晶体在稳定性、溶解度、吸湿性和可加工性方面表现优异，因此为药物制剂的干法制粒或压片法 开发提供了合适原料。而且，所述无定形物的制备方法简单，得到的产物收率高、纯度好、性质稳定，也适合于工业化生产，同时也为药物的干法制粒或压片提供了合适的原料和方法。
附图说明
图1为式I化合物晶体的PXRD谱图。
图2为式I化合物晶体的分子热椭球图(ORTEP图，椭球几率50％)。
图3为式I化合物晶体的分子构型图(溶剂分子、非手性原子上的氢原子忽略)。
图4为式I化合物晶体的二聚体结构。
图5为式I化合物晶体的三维堆积结构。
图6为式I化合物晶体的DSC谱图。
图7为式I化合物晶体的红外光谱图。
图8为无定形芦可替尼的PXRD谱图。
图9为无定形芦可替尼的红外光谱图。
图10为无定形芦可替尼的DSC谱图。
图11a为式I化合物晶体0个月的PXRD谱图，图11b为式I化合物晶体在30-35℃放置3个月后的PXRD谱图。
具体实施方式
通过以下实施例对本发明的方法进行进一步的说明。应当理解，提供以下实施例的目的仅仅是为了能够更好的理解本发明，而不是以任何方式限定本发明的范围。
所使用的芦可替尼游离碱化合物原料参考专利WO2007070514A1的方法制备。所用的有机溶剂试剂，如甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、己烷、正庚烷、柠檬酸等，可从商业途径购得。
式I化合物的制备
实施例1
2L反应瓶中加入芦可替尼泡沫物85.1g(R-芦可替尼纯度为86.5％)，异丙醇297.5g， 升温25-30℃搅拌溶清，控制瓶内温度25-30℃，滴加425.0g纯化水，加毕，瓶内浑浊，控制内温25-30℃搅拌1-3小时，析出大量固体后，降温至0-10℃，保温搅拌1-2h，过滤，少量0-10℃的41％异丙醇水溶液淋洗，滤干，40-45℃真空干燥4-7h，收料得式I化合物74.9g，R-芦可替尼纯度99.8％。
实施例2
2L反应瓶中投入芦可替尼油状物90.0g(R-芦可替尼纯度为85.3％)，乙醇270.0g，升温30-40℃搅拌溶清，控制瓶内温度30-40℃，滴加630.0g纯化水，加毕，瓶内浑浊，搅拌1-3h，析出大量固体后，降温至-5-5℃，保温搅拌1-2h，过滤，少量-5-5℃的30％乙醇水溶液淋洗，滤干，35-40℃真空干燥5-8h，收料得式I化合物77.0g，R-芦可替尼纯度99.0％。
实施例3
500mL反应瓶中加入芦可替尼油状物45.0g(R-芦可替尼纯度为85.3％)，四氢呋喃80.0g，升温20-30℃搅拌溶清，控制瓶内温度20-30℃，滴加120g纯化水，加毕，瓶内浑浊，加入0.1g上述实施例式I化合物为晶种，控制内温20-30℃搅拌1-2小时，析出大量固体后，降温至-2-8℃保温搅拌1-2小时，过滤，少量-2-8℃的40％四氢呋喃水溶液淋洗，滤干，40-45℃真空干燥6-9h，收料得式I化合物36.7g，R-芦可替尼纯度98.6％。
实施例4
1L反应瓶中加入游离碱无定形物45.0g(R-芦可替尼纯度为86.5％)，甲醇70.0g，升温25-35℃搅拌溶清，控制瓶内温度25-35℃，滴加180g纯化水，加毕，瓶内浑浊，加入0.1g上述实施例式I化合物为晶种，控制内温25-35℃搅拌1-2小时，析出大量类白色固体后，降温至0-5℃保温搅拌1-2小时，过滤，少量0-5℃的28％甲醇水溶液淋洗，滤干，35-45℃真空干燥4-7h，收料得式I化合物38.7g，R-芦可替尼纯度99.4％。
无定形的芦可替尼的制备
实施例5
在250mL反应瓶中加入芦可替尼油状物50.0g(R-芦可替尼纯度为85.3％)，乙酸异丙 酯75.0g，搅拌溶清，待用。
在2L反应瓶中加入800g正庚烷，冷却至-5-5℃后，然后滴加上述配置的芦可替尼乙酸异丙酯溶液。加毕，控制内温0-5℃搅拌析晶2-4h，析出淡黄色大量固体，过滤，少量0-5℃的8.6％乙酸异丙酯正庚烷溶液洗涤滤饼，滤干，30-40℃真空干燥5-6h，收料得无定型芦可替尼45.8g，R-芦可替尼纯度91.3％。
实施例6
将70.0g式I化合物(R-芦可替尼纯度为99.8％)，控温50-55℃，真空度≤-0.09Mpa，干燥10-12h，得到82.3g无定形乐可替尼，R-芦可替尼纯度99.8％。
实施例7：磷酸芦可替尼的制备
氮气保护下，在150ml反应瓶中，加入芦可替尼油状物30.7g(R-芦可替尼纯度为99.0％)和磷酸11.3g，然后加入异丙醇30g，加热溶清后，自然降温析晶，5-10℃搅拌0.5-1.0小时，过滤，50-55℃真空干燥至5-8h，得到35.7g磷酸芦可替尼(R-芦可替尼纯度为99.0％)。
实施例8：固体形式的稳定性
将3.0g不同固体形式的芦可替尼游离碱储存在稳定室中，将温度和湿度分别控制在温度25℃、相对湿度60％和温度40℃、相对湿度75％的条件放置2小时和8小时，通过外观或XPRD分析样品以检查其固体形式与其初始固体形式进行比较。根据表4显示的结果，实施例1和实施例4制备的式I化合物(二水合物晶体)显示出比芦可替尼泡沫状物(按照Organic Letters,2009,11(9),1999-2002的方法制备)和实施例5制备的无定形物更好的稳定性。
表4.芦可替尼游离碱不同固体形式的稳定性

另外，取实施例1的式I化合物晶体10.0g，置于透明聚乙烯自封袋中，在30-35℃放置3个月后，PXRD谱图显示，晶型保持稳定，如图11a和图11b所示。

Claims (15)

  1. 式I所示的芦可替尼二水合物，
    其为结晶形式，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、19.02±0.2°、22.62±0.2°、23.12±0.2°和24.66±0.2°处的特征衍射峰。
  2. 根据权利要求1所述的化合物，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、10.54±0.2°、11.54±0.2°、15.42±0.2°、19.02±0.2°、22.62±0.2°、23.12±0.2°和24.66±0.2°处的特征衍射峰。
  3. 根据权利要求1所述的化合物，其特征在于，其X射线粉末衍射图谱具有以2θ衍射角表示的在6.92±0.2°、10.54±0.2°、11.54±0.2°、15.42±0.2°、19.02±0.2°、20.78±0.2°、22.62±0.2°、23.12±0.2°、24.66±0.2°和25.76±0.2°处的特征衍射峰。
  4. 根据权利要求1所述的化合物，其具有如图1所示的X射线粉末衍射谱图。
  5. 制备根据权利要求1-4任一项所述的化合物的方法，该方法包括：将芦可替尼游离碱加入有机溶剂溶解后，滴加纯化水，使其结晶，得到式I化合物晶体。
  6. 根据权利要求5所述的制备方法，其中所述有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、丙酮、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷、乙腈、二氯甲烷、氯仿、甲苯、氯苯、己烷、庚烷、DMF、DMAC、DMSO、NMP、乙酸甲酯、乙酸乙酯、乙酸异丙酯、或其两种或两种以上的混合物。
  7. 一种无定形的芦可替尼游离碱的制备方法，包括以下步骤：将芦可替尼游离碱原料加入有机溶剂溶解后，加入反溶剂使其结晶，得到无定形的芦可替尼游离碱固体。
  8. 根据权利要求7的制备方法，其中所述的有机溶剂选自甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六烷、丙酮、二氯甲烷、甲苯、二甲苯、氯苯、或其两种或两种以上的混合物。
  9. 根据权利要求7或8的制备方法，其中所述的反溶剂选自戊烷、正戊烷、新戊烷、己烷、正己烷、环己烷、甲基环己烷、正庚烷，或其两种或两种以上的混合物。
  10. 一种无定形芦可替尼游离碱的制备方法，该方法包括：真空干燥权利要求1-4任一项所述的式I化合物，使其失去结晶水，得到无定形的芦可替尼游离碱。
  11. 根据权利要求10所述的制备方法，其中真空干燥条件为：
    真空度为≤-0.1Mpa，且
    干燥温度为30-65℃，优选35-60℃，最优选45-55℃。
  12. 无定形形式的芦可替尼游离碱，其通过权利要求7-11任一项的方法制备。
  13. 根据权利要求12所述的无定形形式的芦可替尼游离碱，其具有如图8所示的X射线粉末衍射谱图。
  14. 药物组合物，其包含权利要求1-4任一项所述的式I化合物晶体或权利要求12或13所述的无定形形式的芦可替尼游离碱以及一种或多种药学上可接受的赋形剂或载体。
  15. 根据权利要求14所述的药物组合物，其包括芦可替尼、有机酸和其它赋形剂或载体，其中有机酸选自丙二酸、马来酸、富马酸、柠檬酸、酒石酸和苹果酸中的一种或多种。
PCT/CN2023/130777 2022-11-11 2023-11-09 芦可替尼晶体及其药物组合物 WO2024099396A1 (zh)

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