WO2019148789A1 - 布格替尼的晶型及其制备方法 - Google Patents

布格替尼的晶型及其制备方法 Download PDF

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WO2019148789A1
WO2019148789A1 PCT/CN2018/098574 CN2018098574W WO2019148789A1 WO 2019148789 A1 WO2019148789 A1 WO 2019148789A1 CN 2018098574 W CN2018098574 W CN 2018098574W WO 2019148789 A1 WO2019148789 A1 WO 2019148789A1
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crystal form
crystal
crystalline form
preparation
present
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PCT/CN2018/098574
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English (en)
French (fr)
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陈敏华
张炎锋
黄春香
彭欢
杨朝惠
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苏州科睿思制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the invention relates to the field of chemical medicine, in particular to a new crystal form of AP26113 and a preparation method thereof.
  • NSCLC Nonsmall-cell lung cancer
  • ALK Anaplastic lymphoma kinase
  • Crizotinib is an FDA-approved first-line drug for the treatment of ALK-positive NSCLC. The patient initially responded to crizotinib and most patients developed resistance. Therefore, patients need new and effective ALK positive cancer therapies.
  • AP26113 also known as Brigatinib (Buginib)
  • Buginib is a small molecule tyrosine kinase inhibitor developed by Ariad Pharmaceuticals Inc. for the treatment of crizotinib-resistant ALK metastatic non-small Patients with cell lung cancer.
  • the drug was awarded a breakthrough therapeutic drug by the FDA in August 2014 and was approved in the United States on April 28, 2017. Clinical results show that AP26113 has sustained anti-tumor activity in patients with ALK-positive non-small cell lung cancer, including brain metastases.
  • AP26113 chemical name is 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2- ⁇ 2-methoxy-4-[4-(4-methylpiperazin-1-yl) Piperidin-1-yl]pyrimidine-2,4-diamine (hereinafter referred to as "compound (I)”), the structure of which 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. The above different crystal material forms.
  • Patent WO2016065028A1 reports various crystal forms of AP26113, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, crystal form L, wherein crystal form B is anhydrate, crystal form C, crystal form D is a hydrate, but crystal form B, crystal form C and form D are mutually converted under different humidity conditions: crystal form B is easily hygroscopically converted into a hydrate, and Form C and Form D are easily dehydrated and crystallized; Form E, Form F, Form G, Form H are solvates, Form J, Form K, Crystal Type L is a mixed crystal mixed with Form A, which is not suitable for direct medicinal use; only Crystal A is relatively stable, but the inventors have found that Form A has low solubility and slow dissolution rate, which is not conducive to rapid and effective drug. use. Therefore, it is necessary to perform further polymorphic screening of AP26113 to find crystal forms that are more suitable for drug development.
  • the inventor of the present application unexpectedly discovered a new crystal form of AP26113 suitable for drug development after a large number of experiments, and named it as crystal form N6.
  • the crystalline form N6 of AP26113 provided by the present invention is at least one of solubility, melting point, stability, dissolution, moisture absorbing property, adhesion, fluidity, bioavailability, and processing property, purification effect, preparation production, and the like.
  • advantages In particular, it has outstanding advantages in terms of stability, solubility, intrinsic dissolution rate, compressibility and the like.
  • the discovery of the crystalline form N6 of the present invention provides a better choice for the preparation of pharmaceutical preparations containing AP26113, and is of great significance for drug development.
  • the invention provides a new crystal form of AP26113, a preparation method thereof and use thereof.
  • the X-ray powder diffraction of the crystalline form N6 has characteristic peaks at 2 ⁇ values of 17.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 23.7° ⁇ 0.2°, and 5.8° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystal form N6 has a characteristic peak at one or two of 2 ⁇ values of 21.5° ⁇ 0.2° and 8.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form N6 has a characteristic peak at a 2 ⁇ value of 21.5° ⁇ 0.2° and 8.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form N6 has a characteristic peak at one or two or three of the 2 ⁇ values of 13.7° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 29.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form N6 has a characteristic peak at a 2 ⁇ value of 13.7 ° ⁇ 0.2 °, 11.7 ° ⁇ 0.2 °, and 29.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form N6 has a 2 ⁇ value of 17.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 23.7° ⁇ 0.2°, 5.8° ⁇ 0.2°, 21.5°. Any of 4, 5, or 6, or 7 or 8 of ⁇ 0.2 °, 8.3 ° ⁇ 0.2 °, 13.7 ° ⁇ 0.2 °, 11.7 ° ⁇ 0.2 °, 29.7 ° ⁇ 0.2 °, or There are characteristic peaks at 9 places.
  • Another object of the present invention is to provide a process for the preparation of the crystalline form N6, which comprises:
  • the AP26113 free base is dissolved in an alcohol solvent at a temperature of 25-60 ° C. After filtration, the filtrate is stirred at a temperature of -20-20 ° C until a solid precipitates, and the obtained wet solid is placed under vacuum to dry. Placed under an ambient humidity of less than 30% RH to give Form N6.
  • the alcohol includes methanol, the dissolution temperature is preferably 45-50 ° C, and the stirring temperature is preferably -10 to -5 °C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100- 300 rpm.
  • the AP26113 and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) and/or its salt as a raw material is in the form of a solid powder.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • 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.
  • 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.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • 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 crystalline form N6 of the present invention is pure, unitary, and 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 effective amount of Form N6 of AP26113 and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the crystalline form N6 of AP26113 provided by the present invention is useful in the production of a therapeutic anticancer drug, particularly for the treatment of an ALK-positive non-small cell lung cancer pharmaceutical preparation.
  • the crystalline form N6 of the present invention has a high solubility. Particularly in simulated artificial gastric juice (SGF), artificial intestinal fluid (FaSSIF) in fasting state and water, the solubility of crystalline form N6 is higher than that of crystalline form A in the prior art WO2016065028A1.
  • SGF simulated artificial gastric juice
  • FaSSIF artificial intestinal fluid
  • AP26113 is a poorly soluble drug belonging to BCS Class I.
  • higher solubility will directly improve the bioavailability of the drug, thereby improving the drug-forming properties and efficacy of the drug; in addition, the increase in solubility can reduce the dose of the drug while reducing the drug's efficacy, thereby reducing the drug's Side effects and improve the safety of the drug.
  • the crystal form N6 of the present invention has superior compressibility compared to the prior art crystal form.
  • the tensile strength of Form N6 is higher than that of Form A in WO2016065028A1.
  • the good compressibility of crystal form N6 can effectively improve the hardness/friability of the raw material processing process, reduce the requirements for the processing of the previous product, make the preparation process more stable, improve the appearance of the product, and improve the product quality. .
  • the crystalline form N6 of the present invention has a superior intrinsic dissolution rate compared to the prior art crystal form, and the dissolution rate of the crystalline form N6 is more than five times that of the crystalline form A of WO2016065028A1.
  • Dissolution rate is an important prerequisite for drug absorption. Good in vitro dissolution results in higher absorption of the drug, better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug; high dissolution rate allows the drug to reach the highest concentration in plasma quickly after administration. To ensure that the drug works quickly.
  • the crystal form of AP26113 currently reported is available for industrial production with fewer crystal forms, and industrial development is difficult.
  • the inventors of the present invention have solved the above problems through research and found a new crystal form suitable for development.
  • the crystalline form N6 of AP26113 provided by the present invention is at least one of solubility, melting point, stability, dissolution, moisture absorbing property, adhesion, fluidity, bioavailability, and processing property, purification effect, preparation production, and the like. There are advantages. The discovery of crystalline form N6 provides a better choice for the development of pharmaceutical preparations for AP26113 and is of great significance for the drug development of AP26113.
  • Figure 1 shows the XRPD pattern of the crystalline form N6 in Example 3.
  • Figure 2 is a TGA diagram of the crystalline form N6 in Example 3.
  • Figure 3 is a DSC diagram of the crystalline form N6 in Example 3.
  • Figure 4 is an XRPD pattern of the crystalline form N6 in Example 4.
  • Figure 5 is an XRPD pattern of the crystal form N3 in Example 2.
  • Figure 7 crystal form N6 placed at 40 ° C / 75% relative humidity for 1 month before and after comparison chart
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • Time(min) %B 0.0 15.0 25.0 30.0 35.0 80.0 40.0 80.0 41.0 15.0 48.0 15.0
  • the AP26113 starting material used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2016065028A1, but the starting crystalline form is not a limiting condition for preparing the crystalline form of the present invention.
  • Example 2 The solid obtained in Example 2 was crystal form N6 as determined by XRPD, and the X-ray powder diffraction data thereof are shown in Fig. 1 and Table 2.
  • the TGA of Form N6 is shown in Figure 2. When heated to 120 ° C, it has a mass loss of about 1.0%.
  • the DSC of Form N6 is shown in Figure 3.
  • the first endothermic peak begins to appear near 122 °C, followed by the first exothermic peak, and a second endothermic peak begins to appear near 215 °C.
  • the crystal form N6 of the present invention and the crystal form A of WO2016065028A1 are separately prepared into a saturated solution by SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal juice under fasting state) and pure water, and are filtered after being equilibrated at 1 hour, 4 hours and 24 hours, A saturated solution was obtained.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC), and the results are shown in Table 4.
  • the tablet is pressed by a manual tableting machine, and when the tablet is pressed, a circular flat punch which can be pressed into a cylindrical tablet is selected, and 80 mg of the crystalline form N6 and WO2016065028A1 crystal form A are respectively added, and a circular tablet is placed by pressure pressing at 10 kN, and placed.
  • the radial crushing force (hardness, H) was tested using a tablet hardness tester after complete elastic recovery.
  • the crystal form N6 and WO2016065028A1 crystal form A were each weighed about 100 mg, poured into an intrinsic dissolution mold, and kept at a pressure of 5 kN for 1 min to prepare a sheet having a surface area of 0.5 cm 2 , and the whole tablet was transferred to a dissolution apparatus to test the intrinsic dissolution rate, and the dissolution was performed.
  • the conditions are shown in Table 6, the dissolution profile is shown in Figure 8, and the elution data is shown in Table 7.
  • the slope is calculated from the measurement points between 10 and 30 minutes, expressed in mg/mL, and the intrinsic dissolution rate is further calculated from the slope (Intrinsic Dissolution rate, IDR), expressed in mg/min/cm 2 , and IDR results are shown in Table 8.
  • Dissolution apparatus CSE-051Agilent 708DS method Slurry method medium pH 6.8 phosphate buffer Media volume 900mL Rotating speed 100rpm Medium temperature 37 ° C Sampling point 1,2,3,4,5,10,15,20,25,30min Supplementary medium No

Abstract

提供了一种布格替尼的晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备酪氨酸激酶抑制剂和治疗ALK阳性的非小细胞肺癌药物制剂中的用途。所述晶型比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。

Description

[根据细则37.2由ISA制定的发明名称]　布格替尼的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及AP26113的新晶型及其制备方法。
背景技术
根据美国癌症学会发布的《2017癌症统计》报告，在肺癌中，约有85％的病例是非小细胞肺癌(Nonsmall-cell lung cancer,NSCLC)。其中，3％-5％的非小细胞肺癌呈现间变性淋巴瘤激酶(Anaplastic lymphoma kinase,ALK)阳性。
克唑替尼是FDA批准的用于治疗ALK阳性NSCLC的第一线药物。病人起初对克唑替尼有响应，大部分的患者会出现抗药性。因此，患者需要新型且有效的ALK阳性癌症疗法。
AP26113，又名Brigatinib(布格替尼)，是由Ariad制药公司开发的一种靶向小分子酪氨酸激酶抑制剂的药物，用于治疗对克唑替尼耐药的ALK转移性非小细胞肺癌患者。该药于2014年8月被FDA授予了突破性治疗药物资格，于2017年4月28日在美国获批。临床结果显示，AP26113对ALK阳性的非小细胞肺癌患者，包括脑转移患者，均有持续性抗肿瘤活性。AP26113化学名称为5-氯-N4-[2-(二甲基磷酰基)苯基]-N2-{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]嘧啶-2,4-二胺(以下称“化合物(I)”)，其结构如下图：
Figure PCTCN2018098574-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物质形态。
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；特别是一些难溶性口服固体或半固体，晶型的影响会更大。因此，对于多晶型药物，在研制固体口服制剂时，对晶型进行研究有利于选择一种在临床治疗上有意义且稳定可控的活性成分。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。
专利WO2016065028A1报导了AP26113的多种晶型，包括晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型J、晶型K、晶型L，其中晶型B为无水物，晶型C、晶型D为水合物，但晶型B、晶型C和晶型D在不同湿度温度条件下会相互转化：晶型B极易吸湿转变成水合物，晶型C和晶型D易脱水转晶；晶型E、晶型F、晶型G、晶型H为溶剂合物，晶型J、晶型K、晶型L均为混有晶型A的混晶，不适于直接药用；仅无水晶型A较稳定，但是本发明人发现晶型A的溶解度较低，溶出速率慢，不利于药物快速有效的利用。因此，有必要对AP26113进行进一步的多晶型筛选，以发现更适合药物开发的晶型。
本申请发明人经过大量实验后意外发现了一种适合于药物开发的AP26113新晶型，命名为晶型N6。本发明提供的AP26113的晶型N6其在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势。特别是在稳定性、溶解度、固有溶出速率、可压性等方面具有突出的优势。本发明晶型N6的发现为含AP26113的药物制剂的制备提供了更好的选择，对于药物开发具有重要意义。
发明内容
本发明提供了AP26113的新晶型及其制备方法和用途。
本发明的一个目的是提供一种AP26113的新晶型，命名为晶型N6。
一方面，使用Cu-Kα辐射，所述晶型N6的X射线粉末衍射在2θ值为17.7°±0.2°,16.6°±0.2°,23.7°±0.2°,5.8°±0.2°处有特征峰。
进一步的，所述晶型N6的X射线粉末衍射在2θ值为21.5°±0.2°,8.3°±0.2°中的一处或两处有特征峰。优选的，所述晶型N6的X射线粉末衍射在2θ值为21.5°±0.2°,8.3°±0.2°处有特征峰。
进一步的，所述晶型N6的X射线粉末衍射在2θ值为13.7°±0.2°,11.7°±0.2°,29.7°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型N6的X射线粉末衍射在2θ值为13.7°±0.2°,11.7°±0.2°,29.7°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型N6的X射线粉末衍射在2θ值为17.7°±0.2°,16.6°±0.2°,23.7°±0.2°,5.8°±0.2°,21.5°±0.2°,8.3°±0.2°,13.7°±0.2°,11.7°±0.2°,29.7°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
非限制性地，晶型N6的X射线粉末衍射图如图1所示。
本发明的另一个目的是提供所述晶型N6的制备方法，所述制备方法包括：
将AP26113游离碱在25-60℃温度下溶解于醇类溶剂中，过滤后将滤液于-20-20℃温度下搅拌直至有固体析出，将得到的湿样固体放置在真空条件下干燥后，放置在低于30％RH环境湿度下，得到晶型N6。
所述醇类包括甲醇，所述溶解温度优选45-50℃，搅拌温度优选-10到-5℃。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
根据本发明，作为原料的所述AP26113和/或其盐指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物(I)和/或其盐为固体粉末形式。
本发明中，“晶体”或“多晶型”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，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允 许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的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，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些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。
在一些实施方案中，本发明的晶型N6是纯的、单一的，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。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
此外，本发明提供一种药物组合物，包含有效治疗量的AP26113的晶型N6以及至少一种药学上可接受的载体、稀释剂或赋形剂。
本发明提供的AP26113的晶型N6在生产小分子酪氨酸激酶抑制剂药物中的用途。
本发明提供的AP26113的晶型N6在生产治疗抗癌药物，特别是用于治疗对ALK阳性的非小细胞肺癌药物制剂中的用途。
本发明晶型N6的有益效果为：
(1)本发明晶型N6具有较高的溶解度。特别是在模拟人工胃液(SGF)、空腹状态下人工肠液(FaSSIF)和水中，晶型N6溶解度均高于现有技术WO2016065028A1中的晶型A。
AP26113是难溶性药物，属于BCS Class I。对于难溶性药物，较高的溶解度将直接提高药品的生物利用度，从而提高药品的成药性及药效；另外，溶解度的提高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。
(2)本发明晶型N6相比于现有技术晶型具有更优的可压性。晶型N6的抗张强度高于WO2016065028A1中的晶型A。晶型N6可压性好可以有效改善原料药加工过程中的硬度/脆碎度不合格等问题，降低对前续产品工艺处理的要求，使制剂工艺更为稳健，改善产品外观，提升产品质量。
(3)本发明晶型N6相比于现有技术晶型具有更优的固有溶出速率,晶型N6的溶出速率是WO2016065028A1晶型A的5倍多。
不同的晶型可能导致制剂在体内有不同的溶出速率，直接影响制剂在体内的吸收、分布、排泄、代谢，最终因其生物利用度不同而导致临床药效的差异。溶出速率是药物被吸收的重要前提。良好的体外溶出度使得药物的吸收程度较高，在体内暴露特性更好，从而提高生物利用度，提高药物的疗效；高的溶出速率使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。
目前报导的AP26113的晶型可供工业化生产的晶型较少，且工业开发难度大，本发明的发明人经过研究解决了上述问题，找到了适合开发的新晶型。
本发明提供的AP26113的晶型N6其在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势。晶型N6的发现为AP26113的药物制剂的开发提供了更好的选择，对于AP26113的药物开发具有重要意义。
附图说明
图1实施例3中晶型N6的XRPD图
图2实施例3中晶型N6的TGA图
图3实施例3中晶型N6的DSC图
图4实施例4中晶型N6的XRPD图
图5实施例2中晶型N3的XRPD图
图6晶型N6在25℃/60％相对湿度条件下放置3个月前后对比图
图7晶型N6在40℃/75％相对湿度条件下放置1个月前后对比图
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
HPLC：高效液相色谱
RH：相对湿度
本发明所述的X射线粉末衍射图在Bruker D2PHASER 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 PCTCN2018098574-appb-000002
1.54060；
Figure PCTCN2018098574-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
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：N 2
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)。本发明所述的测试溶解度的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18,150×4.6mm,5μm
2、流动相：A：25mmol/L KH 2PO 4水溶液
B：乙腈溶液
洗脱梯度如下：
Time(min) ％B
0.0 15.0
25.0 30.0
35.0 80.0
40.0 80.0
41.0 15.0
48.0 15.0
3、流速：1.0mL/min
4、进样量：5μl
5、检测波长：220nm
6、柱温：40℃
7、稀释剂：MeOH/H 2O 1:1
下述实施例中所使用的AP26113起始物可根据现有技术制备得到，例如根据WO2016065028A1中所记载的方法制备获得，但起始晶型并非制备本发明晶型的限定条件。
实施例1：晶型N3的制备
将400mg AP26113游离碱在45℃下溶解于4.0mL甲醇中，过滤，在20℃下搅拌2h后，即得到晶型N3的悬浊液。
实施例2：晶型N3的制备
将48.7mg Brigatinib游离碱加入0.5mL甲醇溶液中配成悬浊液，在4℃下，搅拌1天后，所得固体湿样为本发明所述晶型N3，其X射线粉末衍射数据如表1所示，其XRPD图如图5所示。
衍射角2θ d值 强度％
4.85 18.22 79.41
8.27 10.70 100.00
9.82 9.01 17.46
10.74 8.24 12.88
11.17 7.92 5.60
12.26 7.22 7.15
12.76 6.94 18.43
14.86 5.96 13.33
15.38 5.76 16.21
15.97 5.55 13.59
16.88 5.25 39.77
17.25 5.14 21.19
18.38 4.83 31.89
18.86 4.71 31.06
19.26 4.61 23.14
19.87 4.47 44.49
20.31 4.37 30.50
21.10 4.21 48.35
22.57 3.94 22.84
25.00 3.56 21.19
25.77 3.46 11.88
26.92 3.31 14.47
28.48 3.13 10.26
实施例3：晶型N6的制备
将1.0g AP26113游离碱在45℃下溶解于18.0mL甲醇中，过滤后，在滤液中加入一定量N3的悬浮液(溶剂为甲醇)作晶种，15℃下搅拌1小时后，以0.1℃/min的速度降温至-10℃，继续搅拌11小时，将分离得到的固体在50℃，25％RH-45％RH条件下干燥24h后，继续放置在25℃下真空干燥1.5小时，于20％RH的环境湿度下放置后，收集固体可得晶型N6。
经XRPD检测，实施例2所得固体为晶型N6，其X射线粉末衍射数据如图1，表2所示。
表2
衍射角2θ(±0.2°) d值 强度％
5.83 15.15 36.34
8.26 10.71 17.97
8.66 10.21 5.61
8.88 9.96 5.13
9.96 8.88 1.07
10.85 8.16 1.40
11.77 7.52 12.93
12.34 7.17 2.43
13.68 6.47 16.81
16.59 5.34 47.60
16.88 5.25 12.28
17.67 5.02 100.00
19.16 4.63 3.74
20.03 4.43 7.96
20.34 4.37 6.46
20.73 4.29 8.23
21.47 4.14 22.96
22.74 3.91 3.54
23.66 3.76 22.29
25.05 3.55 4.19
25.84 3.45 4.91
26.83 3.32 1.54
28.69 3.11 2.99
29.69 3.01 9.91
31.32 2.86 5.65
32.90 2.72 1.09
37.41 2.40 1.04
38.83 2.32 1.11
晶型N6的TGA如图2所示，将其加热至120℃时，具有约1.0％的质量损失。
晶型N6的DSC如图3所示，加热至122℃附近开始出现第一个吸热峰，随后出现第一个放热峰，加热至215℃附近开始出现第二个吸热峰。
实施例4：晶型N6的制备
将20.0g AP26113游离碱在50℃下溶于350.0mL甲醇中，过滤后，在滤液中加入一定量N3悬浊液(溶剂为甲醇)作晶种，17℃搅拌1h后，以0.1℃/min的速度降温至-5℃，继续搅拌11h，过滤，将滤饼在45℃下真空干燥20h得到固体，于20％RH的环境湿度下放置后，经检测，所得固体为本发明所述晶型N6，其X射线粉末衍射数据如表3所示，其XRPD图如图4所示。实施例3所得固体与实施例2具有相同或相似的XRPD图，说明实施例3所得晶型N6与实施例2所得晶型N6是相同的物质，具有相同的性质。
表3
衍射角2θ(±0.2°) d值 强度％
5.84 15.12 38.85
8.28 10.68 12.55
8.78 10.07 1.68
11.74 7.54 12.53
12.31 7.19 0.94
13.70 6.47 18.07
16.62 5.33 35.27
16.87 5.26 10.56
17.67 5.02 100.00
19.08 4.65 2.20
20.10 4.42 4.74
20.40 4.35 4.15
20.75 4.28 5.03
21.53 4.13 14.85
22.74 3.91 2.82
23.65 3.76 22.17
25.08 3.55 2.96
25.87 3.44 4.96
26.76 3.33 1.88
28.68 3.11 3.60
29.69 3.01 10.38
31.35 2.85 4.57
32.91 2.72 1.32
33.51 2.67 1.08
37.42 2.40 1.09
实施例5晶型N6的溶解度
将本发明晶型N6与WO2016065028A1中晶型A用SGF(模拟人工胃液)、FaSSIF(空腹状态下人工肠液)和纯水分别配制成饱和溶液，在1小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量，结果如表4所示。
表4
Figure PCTCN2018098574-appb-000004
由表4动态溶解度结果可知，在SGF、FaSSIF和水中，本发明的晶型N6在每个取样点的溶解度均高于现有技术晶型A。
实施例6晶型N6的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，分别加入80mg晶型N6和WO2016065028A1晶型A，采用10kN压力压制成圆形片剂，放置于干燥器中24小时，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好，实验结果如表5所示。
表5
晶型 抗张强度(MPa)
WO2016065028A1晶型A 1.78
晶型N6 2.81
结果表明，晶型N6较现有技术晶型A抗张强度更大，具有更优的可压性。
实施例7晶型N6的固有溶出速率
称取晶型N6和WO2016065028A1晶型A各约100mg，倒入固有溶出模具，在5kN压力下持续1min，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，溶出条件如表6所示，溶出曲线如图8所示，溶出数据如表7所示，根据10～30min之间的测定点计算斜率，以mg/mL表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以mg/min/cm 2表示，IDR结果如表8所示。
表6
溶出仪 CSE-051Agilent 708DS
方法 浆法
介质 pH6.8磷酸盐缓冲液
介质体积 900mL
转速 100rpm
介质温度 37℃
取样点 1,2,3,4,5,10,15,20,25,30min
补充介质 No
表7
Figure PCTCN2018098574-appb-000005
Figure PCTCN2018098574-appb-000006
注：从10～30min计算斜率。
表8
晶型 IDR(mg/min/cm 2)
WO2016065028A1晶型A 0.2328
晶型N6 1.2062
结果表明，晶型N6的溶出速率是WO2016065028A1晶型A的5倍多。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (8)

  1. 一种AP26113的晶型N6，其特征在于，其X射线粉末衍射图在2θ值为17.7°±0.2°,16.6°±0.2°,23.7°±0.2°,5.8°±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型N6，其特征在于，其X射线粉末衍射图在2θ值为21.5°±0.2°,8.3°±0.2°中的一处或两处具有特征峰。
  3. 根据权利要求1或2所述的晶型N6，其特征在于，其X射线粉末衍射图在2θ值为13.7°±0.2°,11.7°±0.2°,29.7°±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所述的晶型N6的制备方法，其特征在于，所述方法包含：将AP26113游离碱在25-60℃温度下溶解于醇类溶剂中，过滤后将滤液于-20℃-20℃温度下搅拌直至有固体析出，将得到的湿样固体放置在真空条件下干燥后，放置在低于30％RH环境湿度下，得到晶型N6。
  5. 根据权利要求4所述的制备方法，其特征在于，所述醇类溶剂为甲醇，所述溶解温度为45-50℃，所述搅拌温度为-10℃到-5℃。
  6. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的晶型N6及药学上可接受的载体、稀释剂或赋形剂。
  7. 权利要求1所述的晶型N6在生产小分子酪氨酸激酶抑制剂药物制剂中的用途。
  8. 权利要求1所述的晶型N6在生产用于治疗ALK阳性的非小细胞肺癌药物制剂中的用途。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN107108559A (zh) * 2014-10-21 2017-08-29 阿瑞雅德制药公司 5‑氯‑n4‑[2‑(二甲基磷酰基)苯基]‑n2‑{2‑甲氧基‑4‑[4‑(4‑甲基哌嗪‑1‑基)哌啶‑1‑基]嘧啶‑2,4‑二胺的晶形
CN108129513A (zh) * 2018-02-01 2018-06-08 安庆奇创药业有限公司 一种合成布格替尼中间体的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN107108559A (zh) * 2014-10-21 2017-08-29 阿瑞雅德制药公司 5‑氯‑n4‑[2‑(二甲基磷酰基)苯基]‑n2‑{2‑甲氧基‑4‑[4‑(4‑甲基哌嗪‑1‑基)哌啶‑1‑基]嘧啶‑2,4‑二胺的晶形
CN108129513A (zh) * 2018-02-01 2018-06-08 安庆奇创药业有限公司 一种合成布格替尼中间体的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUANG, WEISHENG: "Discovery of Brigatinib ( AP 26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase", JOURNAL OF MEDICINAL CHEMISTRY, 4 May 2016 (2016-05-04), pages 4948 - 4964, XP055480025, ISSN: 0022-2623 *
YANG XIUXIU ET AL.: "Improved synthesis of ALK inhibitor brigatinib", vol. 27, no. 4, 31 August 2017 (2017-08-31), pages 292 - 296 *

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