WO2018077187A1 - Ap26113的新晶型及其制备方法 - Google Patents

Ap26113的新晶型及其制备方法 Download PDF

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WO2018077187A1
WO2018077187A1 PCT/CN2017/107652 CN2017107652W WO2018077187A1 WO 2018077187 A1 WO2018077187 A1 WO 2018077187A1 CN 2017107652 W CN2017107652 W CN 2017107652W WO 2018077187 A1 WO2018077187 A1 WO 2018077187A1
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crystal form
crystalline form
aromatic hydrocarbon
mixed solvent
ray powder
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PCT/CN2017/107652
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English (en)
French (fr)
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陈敏华
张炎锋
王金秋
刘凯
张晓宇
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苏州晶云药物科技有限公司
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Priority to US16/344,443 priority Critical patent/US10544129B2/en
Priority to CN201780061108.3A priority patent/CN110036003B/zh
Publication of WO2018077187A1 publication Critical patent/WO2018077187A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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 non-small cell lung cancer
  • ALK anaplastic lymphoma kinase
  • Crizotinib is an FDA-approved drug for first-line treatment of ALK-positive NSCLC. The patient initially responded to crizotinib, and most patients developed drug resistance and relapsed within 12 months. Therefore, more and more cancer patients need new and effective ALK positive cancer therapies.
  • AP26113 also known as Brigatinib (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 US Food and Drug Administration (FDA) in August 2014 and was listed in the US on April 28, 2017.
  • FDA US Food and Drug Administration
  • AP26113 has sustained anti-tumor activity in patients with ALK-positive non-small cell lung cancer, including brain metastases.
  • the chemical structure of AP26113 is as shown in formula (I):
  • 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 the crystal form J, the crystal form K, the crystal form L are mixed crystals in which the crystal form A is uniformly mixed, and the crystal form E, the crystal form F, the crystal form G, and the form H are solvates, which are uncomfortable.
  • Directly medicinal; Form C, Form D is hydrate, Form B is anhydrate, but Form B, Form C and Form D are phased at different humidity and temperature conditions.
  • crystal form B is easily hygroscopically converted into hydrate
  • crystal form C and crystal form D are easily dehydrated and crystallized
  • only crystalless type A is relatively stable, but the inventors found that the solubility of form A is low, and the dissolution rate is low. Slow, not conducive to the rapid and effective use of drugs. Therefore, it is necessary to perform further polymorph screening on AP26113 to find crystal forms that are more suitable for development.
  • the inventors of the present application unexpectedly discovered two new AP26113 crystal forms suitable for drug development after a large number of experiments, and named the crystal form CS1 and the crystal form CS2.
  • the crystalline form CS1 and the crystalline form CS2 of the AP26113 provided by the present invention have advantages in solubility, stability, wettability and processability, and particularly in terms of solubility, the crystalline form CS1 and the crystalline form CS2 have more than the existing form A. Excellent solubility and dissolution rate.
  • the discovery of the crystalline form CS1 and the crystalline form CS2 of the present invention provides a better choice for the preparation of a pharmaceutical preparation 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 crystal form CS1 is a hydrate.
  • the X-ray powder diffraction of the crystalline form CS1 has a characteristic peak at a 2theta value of 5.5 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, and 10.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three points of the 2theta value of 16.2 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 °, and 27.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS1 has a characteristic peak at a 2theta value of 16.2 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 °, and 27.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS1 has a characteristic peak at one or two or three of the 2theta values of 8.5 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, and 18.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS1 has a characteristic peak at a 2theta value of 8.5 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, and 18.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS1 has a value of 5.5° ⁇ 0.2°, 21.6 ° ⁇ 0.2 °, 10.8 ° ⁇ 0.2 °, 16.2 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2. °, 27.1 ° ⁇ 0.2 °, 8.5 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, 18.6 ° ⁇ 0.2 ° at the characteristic peak.
  • the X-ray powder diffraction pattern of Form CS1 is shown in FIG.
  • Another object of the present invention is to provide a method for preparing the crystal form CS1, the preparation method comprising:
  • the AP26113 free base is dissolved in a mixed solvent of an alcohol and an aromatic hydrocarbon, and volatilized at a temperature of 30 to 60 ° C for 1 to 10 days to obtain a crystal form CS1.
  • AP26113 free base is dissolved in a mixed solvent of methanol and aromatic hydrocarbons, and after filtering, the filtrate is stirred at a temperature of -20-0 ° C until a solid precipitates, and a wet solid is obtained to be dried to obtain a crystal form CS1.
  • the alcohol comprises methanol, ethanol, isopropanol, preferably isopropanol;
  • the aromatic hydrocarbons comprise toluene
  • the volume ratio of the alcohol to the aromatic hydrocarbon comprises 1:4-1:2;
  • the volatilization temperature comprises 35-50 °C.
  • the aromatic hydrocarbons comprise toluene
  • the volume ratio of the mixed solvent of ethanol and aromatic hydrocarbon is 1:4;
  • the water-saturated aromatic hydrocarbon is toluene saturated with water.
  • the aromatic hydrocarbons comprise toluene
  • the mixed solvent ratio of the mixed solvent of methanol and aromatic hydrocarbon is 1:9.
  • Another object of the present invention is to provide a new crystalline form CS2 of AP26113, designated as Form CS2.
  • the crystal form CS2 is a hydrate.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a 2theta value of 17.1 ° ⁇ 0.2 °, 22.9 ° ⁇ 0.2 °, and 28.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or two or three points of 2theta value of 27.3 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, and 5.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a 2theta value of 27.3 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, and 5.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or two or three of the 2theta values of 11.4° ⁇ 0.2°, 8.7° ⁇ 0.2°, and 16.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a 2theta value of 11.4 ° ⁇ 0.2 °, 8.7 ° ⁇ 0.2 °, and 16.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS2 has a value of 17.1 ° ⁇ 0.2 °, 22.9 ° ⁇ 0.2 °, 28.7 ° ⁇ 0.2 °, 27.3 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2. °, 5.7 ° ⁇ 0.2 °, 11.4 ° ⁇ 0.2 °, 8.7 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 ° at the characteristic peak.
  • the X-ray powder diffraction pattern of Form CS2 is shown in FIG.
  • the invention also provides a preparation method of the crystalline form CS2, the preparation method comprising:
  • AP26113 free base is dissolved in a mixed solvent of alcohol and water. After filtration, the filtrate is stirred at -20-0 ° C until solids are precipitated, and the wet solid is placed at 25-40 ° C, 30%. Drying under RH-75% RH humidity gave crystal form CS2.
  • the humidity condition is 50% RH to 80% RH;
  • the placement time is 5-16 days.
  • the alcohol comprises methanol
  • the volume ratio of the mixed solvent of the alcohol and water is 93:7-98:2;
  • the standing condition temperature was 35 ° C and the standing humidity was 40% RH.
  • room temperature as used herein is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • the "water-saturated toluene” means that a certain amount of toluene and water are sufficiently shaken and mixed to obtain a layered toluene layer and an aqueous layer, and the toluene layer is obtained to be toluene saturated with water.
  • crystal form or “polymorph” means that it is confirmed by the X-ray diffraction pattern characterization shown.
  • 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.
  • 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 CS1, crystalline form CS2 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 CS1 or Form CS2 of AP26113 or a mixture thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • crystalline form CS1 or the crystalline form CS2 of AP26113 or a mixture thereof for the production of a therapeutic anticancer drug, in particular for the treatment of an ALK-positive non-small cell lung cancer pharmaceutical preparation.
  • the crystal form of AP26113 is available for industrial production, and the inventors of the present invention have found a new crystal form suitable for development.
  • Solubility is one of the key properties of drugs, directly affecting the absorption of drugs in the human body.
  • the solubility of different crystal forms may be significantly different, and the absorption dynamics in the body may also change, resulting in differences in bioavailability, which ultimately affects the clinical safety and efficacy of the drug.
  • the crystal form CS2 provided by the invention has better solubility and dissolution rate, especially in FaSSIF (artificial intestinal juice under fasting state), the solubility of the crystal form CS2 is higher than that of the crystal form A.
  • the dissolution rate of the crystalline form CS2 was increased by 5 times compared with the crystalline form A, which produced an unexpected effect.
  • the existing crystal form A has poor solubility in water, only 0.061 mg/mL, while the crystalline form CS1 of the invention has superior water solubility, and the solubility of the crystalline form CS1 in water is 16 times higher than that of the existing crystal form A, resulting in Unexpected results.
  • Increased solubility will help improve the bioavailability of the drug, thereby increasing the drug's drug properties.
  • the increase in solubility also reduces the difficulty of formulation process development.
  • a sufficiently high solubility crystal form can be developed using a conventional formulation process, while for a less soluble crystal form, in order to achieve an ideal bioavailability, it is necessary to adopt a more Complex formulation process.
  • the increase in solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the crystal form CS2 provided by the invention has good stability, low wettability, high purity, uniform particle size, and the crystal form CS2 is not changed under the condition of 25° C./60% RH for three months, and is suitable for the preparation process. Process and long-term storage.
  • the discovery of the crystalline form CS1 and the crystalline form CS2 provides a better choice for the development of the pharmaceutical preparation of AP26113, and is of great significance for the drug development of AP26113.
  • Figure 2 is a DSC diagram of the crystalline form CS1 in Example 1.
  • Figure 3 is a TGA diagram of the crystalline form CS1 in Example 1.
  • Figure 4 is an XRPD pattern of the crystal form N1 in Example 6.
  • Figure 5 shows the XRPD pattern of the crystalline form CS2 in Example 7.
  • Figure 6 is a DSC diagram of the crystalline form CS2 in Example 7.
  • Figure 7 is a TGA diagram of the crystalline form CS2 in Example 7.
  • Figure 8 is an XRPD pattern of the crystalline form CS2 in Example 8.
  • Figure 9 is an XRPD pattern of the crystalline form CS2 in the embodiment 9.
  • Figure 10 is an XRPD pattern of the crystal form N3 in the embodiment 10.
  • Figure 11 is a DSC diagram of the crystalline form CS2 in Example 10.
  • Figure 12 is a TGA diagram of the crystalline form CS2 in Example 10.
  • Figure 13 is an XRPD overlay of the crystalline form CS2 in Example 11 at 25 ° C, 60% RH for one month and three months (from top to bottom, before placement, after one month, after three months) )
  • Figure 14 is a dissolution profile of the crystalline form CS2 and the crystalline form A in Example 13.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean 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 Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dissolution data of the present invention was tested on an Agilent 708-DS.
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • the AP26113 starting material is Form A reported in WO2016065028A1, but the starting crystalline form is not a limiting condition for preparing the crystalline form of the present invention.
  • the DSC of the crystal form CS1 is as shown in Fig. 2.
  • the first endothermic peak begins to appear when heated to 42 ° C
  • the second endothermic peak begins to appear when heated to 93 ° C, and is heated to 210.
  • a third endothermic peak begins to appear at °C.
  • the TGA of the crystal form CS1 is as shown in Fig. 3.
  • thermogravimetric analysis when heated to 63 ° C, it has a mass loss gradient of 3.4%. Heating to 134 ° C further has a mass loss gradient of 3.1%.
  • the obtained solid was crystalline form N1, and its X-ray powder diffraction data is shown in FIG. 4 and Table 6.
  • the crystal form N1 was dried to form the crystal form CS1, and the X-ray powder diffraction data thereof is shown in Table 7.
  • the crystal form N1 is 4.9 ° ⁇ 0.2 °, 9.8 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, 19.9 ° ⁇ 0.2 °, 24.9 ° ⁇ 0.2 °, 25.8 ° ⁇ 0.2
  • the DSC of the crystal form CS2 is as shown in Fig. 6.
  • the first endothermic peak begins to appear when heated to 45 ° C
  • the second endothermic peak begins to appear when heated to 72 ° C, and is heated to 210.
  • a third endothermic peak begins to appear at °C.
  • the TGA of Form CS2 is shown in Figure 7, heated to 49 ° C, with a mass loss gradient of 2.3%, heated to 151 ° C, and further with a 1.5% mass loss gradient.
  • the TGA of the crystal form CS2 is as shown in Fig. 12, and when subjected to thermogravimetric analysis, it has a mass loss gradient of 4.3% when heated to 100 °C.
  • the crystal form N3 is 4.9 ° ⁇ 0.2 °, 8.3 ° ⁇ 0.2 °, 9.9 ° ⁇ 0.2 °, 14.8 ° ⁇ 0.2 °, 15.4 ° ⁇ 0.2 °, 19.8 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 °, characteristic peak at 24.8 ° ⁇ 0.2 °.
  • the other conditions are the same, and only the ratio of methanol to water of the mixed solvent is adjusted to 93:7, and the crystal form CS2 can also be obtained.
  • Example 11 Stability study of crystalline form CS2
  • Stability is one of the important properties for evaluating whether a crystal form is pharmaceutically acceptable.
  • the stability of the crystal form is crucial for the stability of the drug, especially maintaining good stability during the commercial period, reducing the drug due to the crystal form. Changes in drug dissolution rate and bioavailability change are important for ensuring drug efficacy and safety and preventing adverse drug reactions.
  • Solubility is one of the most important properties affecting bioavailability. Whether it is the discovery stage or development stage of a new drug or the development stage of a generic drug, solubility is a key factor to study, especially to simulate the improvement of solubility in human environment solutions. It is important to improve the absorption and bioavailability of drugs.
  • the crystal form CS2 prepared by the present invention and the crystal form A sample were prepared into a saturated solution by using FaSSIF (simulated liquid in the simulated fasting state), sampled at a fixed time point, and the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). content.
  • FaSSIF simulated liquid in the simulated fasting state
  • HPLC high performance liquid chromatography
  • the crystal form CS1 prepared in the present invention and the crystal form A sample were formulated into a saturated solution in H2O, and samples were taken after 1 hour and 4 hours, and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 14.
  • the crystal form A has poor solubility in water, which is disadvantageous to the absorption and utilization of the drug, and the crystal form CS1 of the present invention can increase the solubility by up to 16 times compared with the existing crystal form A, resulting in a Unexpected effects are important for improving drug absorption and bioavailability.
  • Dissolution medium phosphate buffer pH 6.8
  • Dissolution method disc transfer method
  • the use of the crystalline form CS2 with a higher dissolution rate can accelerate the rapid dissolution and absorption in the body after the administration of the drug, and can control the rapid action of the drug in a specific part by adjusting the packaging material and the auxiliary material, thereby improving the onset rate of the drug and bioavailability.
  • the crystal form CS1, the form CS2 of the present invention, and the existing form A were tested for particle size distribution.
  • the results showed that the average particle diameter of the crystal form A was 12.58 ⁇ m, and the particle diameter was too small to be suitable for the separation by the crystallization process, while the average particle diameters of the crystalline form CS1 and the crystalline form CS2 of the present invention were 175.0 ⁇ m and 151.9 ⁇ m, respectively, compared with the crystal.
  • Type A larger particle size.
  • the large-sized crystal form CS1 and the form CS2 are less affected by electrostatic adsorption, and are more easily separated during the crystallization process, and the mixing unevenness in the preparation process can be avoided, and the quality of the drug is further improved. Controllable, while the crystals with large particle size, the growth is more perfect, can avoid the adsorption of solvents or impurities on the crystal, and is more conducive to purification.

Abstract

本发明涉及AP26113的两种晶型及其制备方法。本发明提供的AP26113晶型CS1和晶型CS2在溶解度、稳定性等方面存在优势，适合于工艺开发，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。

Description

AP26113的新晶型及其制备方法 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(American Cancer Society)发布的《2017癌症统计》(Cancer Facts&Figures 2017)报告，在肺癌中，约有85％的病例是非小细胞肺癌(NSCLC)。其中，3％-5％的非小细胞肺癌呈现间变性淋巴瘤激酶(ALK)阳性。
克唑替尼是一种FDA批准的用于第一线治疗ALK阳性NSCLC的药物。病人起初对克唑替尼有响应，大部分的患者会出现抗药性，在12个月内复发。因此，越来越多的癌症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月被美国食品药品监督管理局(FDA)授予了突破性治疗药物资格，并于2017年4月28日在美国上市。临床显示，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化学结构如式(I)：
Figure PCTCN2017107652-appb-000001
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，导致临床药效的差异。
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J、晶型K、晶型L为均混有晶型A的混晶，晶型E、晶型F、晶型G、晶型H为溶剂合物，不适于直接药用；晶型C、晶型D为水合物，晶型B为无水物，但晶型B、晶型C和晶型D间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；只有无水晶型A是较稳定，但是本发明人发现晶型A的溶解度较低，溶出速率慢，不利于药物的快速有效的利用。因此，有必要对AP26113进行进一步的多晶型筛选，以发现更适合开发的晶型。
本申请发明人经过大量实验后意外发现了两种适合于药物开发的AP26113新晶型，命名为晶型CS1和晶型CS2。本发明提供的AP26113的晶型CS1和晶型CS2在溶解度、稳定性、引湿性以及加工性能等方面存在优势，特别是溶解性方面，晶型CS1和晶型CS2较已有晶型A具有更优异的溶解性能和溶出速率。本发明晶型CS1和晶型CS2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CS1，命名为晶型CS1。所述晶型CS1为水合物。
使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在2theta值为5.5°±0.2°,21.6°±0.2°,10.8°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在2theta值为16.2°±0.2°,21.0°±0.2°,27.1°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在2theta值为16.2°±0.2°,21.0°±0.2°,27.1°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在2theta值为8.5°±0.2°,11.8°±0.2°,18.6°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在2theta值为8.5°±0.2°,11.8°±0.2°,18.6°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在2theta值为5.5°±0.2°,21.6°±0.2°,10.8°±0.2°,16.2°±0.2°,21.0°±0.2°,27.1°±0.2°,8.5°±0.2°,11.8°±0.2°,18.6°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射谱图如图1所示。
本发明的另一个目的是提供所述晶型CS1的制备方法，所述制备方法包括：
1)将AP26113游离碱溶于醇类和芳香烃类的混合溶剂中，并于30-60℃温度下挥发1-10天而获得晶型CS1。
或2)将AP26113游离碱溶于乙醇和芳香烃类混合溶剂或者溶于用水饱和的芳香烃中，过滤后将滤液于-20-0℃温度下搅拌直至有固体析出，该固体即为晶型CS1。
或3)将AP26113游离碱溶于甲醇和芳香烃类的混合溶剂中，过滤后将滤液于-20-0℃温度下搅拌直至有固体析出，将得到湿样固体干燥得到晶型CS1。
方法1)中：
所述醇类包含甲醇、乙醇、异丙醇，优选为异丙醇；
所述芳香烃类包含甲苯；
所述醇类和芳香烃的体积比包含1:4-1:2；
所述挥发温度包含35-50℃。
方法2)中：
所述芳香烃类包含甲苯；
所述乙醇和芳香烃混合溶剂的体积比为1:4；
所述用水饱和的芳香烃为用水饱和的甲苯。
方法3)中：
所述芳香烃类包含甲苯；
所述甲醇和芳香烃的混合溶剂的混合体积比为1:9。
本发明的另一个目的是提供另一种AP26113的新晶型CS2，命名为晶型CS2。所述晶型CS2为水合物。
使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在2theta值为17.1°±0.2°,22.9°±0.2°,28.7°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在2theta值为27.3°±0.2°,21.4°±0.2°,5.7°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在2theta值为27.3°±0.2°,21.4°±0.2°,5.7°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在2theta值为11.4°±0.2°,8.7°±0.2°,16.0°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在2theta值为11.4°±0.2°,8.7°±0.2°,16.0°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型CS2的X射线粉末衍射在2theta值为17.1°±0.2°,22.9°±0.2°,28.7°±0.2°,27.3°±0.2°,21.4°±0.2°,5.7°±0.2°,11.4°±0.2°,8.7°±0.2°,16.0°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS2的X射线粉末衍射谱图如图5所示。
本发明还提供所述晶型CS2的制备方法，所述制备方法包括：
1)将晶型CS1在室温、30％RH-80％RH湿度下放置1-30天，得到晶型CS2。
或2)将AP26113游离碱溶于醇类和水的混合溶剂中，过滤后将滤液于-20-0℃温度下搅拌直至有固体析出，将得到湿样固体放置在25-40℃，30％RH-75％RH湿度下干燥，得到晶型CS2。
方法1)中：
所述湿度条件为50％RH～80％RH；
所述放置时间为5-16天。
方法2)中：
所述醇类包含甲醇；
所述醇类和水的混合溶剂体积比为93:7-98:2；
所述放置条件温度为35℃，放置湿度为40％RH。
本发明所述“室温”不是精确的温度值，是指10-30℃温度范围。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“用水饱和的甲苯”指将一定量的甲苯和水充分震荡混合后，得到分层的甲苯层和水层，分液获得甲苯层即为用水饱和的甲苯。
本发明中，“晶型”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，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CS1、晶型CS2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CS1或晶型CS2或其混合物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CS1或晶型CS2或其混合物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CS1或晶型CS2或其混合物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。
本发明的有益效果为：
目前报导的AP26113的晶型可供工业化生产的晶型较少，本发明的发明人经过研究，找到了适合开发的新晶型。
溶解度是药物的关键性质之一，直接影响药物在人体内的吸收。不同晶型药物的溶解度可能会存在明显差异，体内吸收动态也会发生变化，造成生物利用度的差异，最终影响到药物的临床安全性和疗效。
与现有晶型A相比，本发明提供的晶型CS2具有较好的溶解性和溶出速率，尤其是在FaSSIF(空腹状态下人工肠液)中，晶型CS2的溶解度较晶型A提高了43％，晶型CS2的溶出速率较晶型A提高了5倍，产生了预料不到的效果。现有晶型A在水中的溶解度较差，仅有0.061mg/mL，而本发明的晶型CS1具有优越的水溶性，晶型CS1在水中溶解度较现有晶型A提高了16倍，产生了预料不到的效果。溶解度的提高将有助于提高药物的生物利用度，从而提高药物的成药性。另外，溶解度的提高也降低了制剂工艺开发的难度，足够高溶解度的晶型可以采用传统的制剂工艺进行开发，而对于溶解度较低的晶型，为了达到理想的生物利用度，则需要采取更加复杂的制剂工艺。此外，溶解度升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。
此外，本发明提供的晶型CS2稳定性好、引湿性低、纯度高，粒径大小均一，晶型CS2放置在25℃/60％RH条件下三个月晶型未发生变化，适合制剂工艺过程和长期存储。
因此，晶型CS1和晶型CS2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1中晶型CS1的XRPD图
图2实施例1中晶型CS1的DSC图
图3实施例1中晶型CS1的TGA图
图4实施例6中晶型N1的XRPD图
图5实施例7中晶型CS2的XRPD图
图6实施例7中晶型CS2的DSC图
图7实施例7中晶型CS2的TGA图
图8实施例8中晶型CS2的XRPD图
图9实施例9中晶型CS2的XRPD图
图10实施例10中晶型N3的XRPD图
图11实施例10中晶型CS2的DSC图
图12实施例10中晶型CS2的TGA图
图13实施例11中晶型CS2在25℃,60％RH条件下放置一个月和三个月前后的XRPD叠图(从上至下依次为放置前，放置一个月后，放置三个月后)
图14实施例13中晶型CS2和晶型A的溶出曲线图
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
PLM：偏光显微镜
RH：相对湿度
本发明所述的X射线粉末衍射图在Panalytical Empyrean 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射线反射参数：Cu,Kα
Figure PCTCN2017107652-appb-000002
1.540598；
Figure PCTCN2017107652-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40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：氮气
本发明所述的热重分析(TGA)图在TA Q5000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
本发明的溶出数据是安捷伦708-DS上测试。
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VWD检测器。本发明所述的测试纯度的HPLC方法参数如下：
1、色谱柱：L021Infinity lab Proshell 120EC-C18 50×3.0mm,2.7μm
2、流动相：A：25mM KH2PO4
B：乙腈
洗脱梯度如下：
Time(min) ％B
0.0 20
5.0 40
7.0 80
8.0 80
8.1 20
12.0 20
3、流速：0.6mL/min
4、进样量：2μL
5、检测波长：210nm
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。
下述实施例中，AP26113起始物为WO2016065028A1中报导的晶型A，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CS1的制备
将12.5mg AP26113游离碱溶解在0.5mL异丙醇和甲苯的混合溶液中(异丙醇与甲苯的体积比为1:4)，过滤后将滤液封上扎孔的封口膜，于50℃下挥发2天有固体析出。
经检测，所得固体为本发明所述晶型CS1，其X射线粉末衍射数据如图1、表1所示。
晶型CS1的DSC如图2所示，当进行差示扫描量热分析时，加热至42℃开始出现第一个吸热峰，加热至93℃开始出现第二个吸热峰，加热至210℃开始出现第三个吸热峰。
晶型CS1的TGA如图3所示，当进行热重分析时，加热至63℃时，具有3.4％的质量损失梯度。加热到134℃，进一步具有3.1％的质量损失梯度。
表1
2theta值 d值 强度％
5.45 16.22 95.62
5.60 15.77 28.96
7.11 12.44 1.65
8.47 10.44 9.54
9.88 8.95 5.91
10.31 8.58 3.15
10.81 8.19 50.33
11.81 7.49 14.41
12.65 7.00 3.19
13.32 6.65 5.36
16.20 5.47 80.34
16.53 5.36 25.36
17.85 4.97 5.35
18.59 4.77 8.55
20.07 4.42 2.92
21.03 4.22 23.74
21.62 4.11 100.00
23.11 3.85 1.65
24.46 3.64 1.63
26.06 3.42 2.24
27.08 3.29 53.57
27.69 3.22 5.12
28.39 3.14 1.55
31.24 2.86 1.74
32.64 2.74 1.22
33.23 2.70 1.26
38.28 2.35 2.66
实施例2：晶型CS1的制备
将43.5mg AP26113游离碱加入2.0mL异丙醇和甲苯的混合溶剂中(异丙醇与甲苯的体积比为1:4)，溶解后过滤，35℃下挥发10天，得CS1固体，其X射线粉末衍射数据如表2所示。
表2
2theta值 d值 强度％
4.56 19.39 8.93
5.44 16.25 85.31
8.42 10.50 26.03
9.74 9.08 15.05
10.80 8.19 39.68
11.79 7.51 24.38
12.56 7.05 9.26
13.32 6.65 32.31
14.52 6.10 9.41
16.17 5.48 68.38
16.56 5.35 33.12
17.36 5.11 17.98
17.84 4.97 26.59
18.47 4.80 34.08
19.47 4.56 17.30
20.09 4.42 19.58
21.02 4.23 100.00
21.62 4.11 85.24
22.96 3.87 8.52
23.98 3.71 9.52
25.93 3.44 9.64
27.07 3.29 54.21
27.64 3.23 10.20
29.39 3.04 3.36
31.26 2.86 4.98
33.16 2.70 1.55
38.22 2.36 3.06
实施例3：晶型CS1的制备
将9.5mg AP26113游离碱加入0.6mL异丙醇和甲苯的混合溶剂中(异丙醇与甲苯的体积比为1:2)，溶解后过滤，50℃下挥发6天，得CS1固体，其X射线粉末衍射数据如表3所示。
表3
2theta值 d值 强度％
4.44 19.91 5.73
5.47 16.17 75.65
8.44 10.48 16.26
9.80 9.02 5.01
10.80 8.19 33.01
11.83 7.48 19.22
13.32 6.65 16.96
16.19 5.48 79.29
16.51 5.37 54.50
17.80 4.98 13.38
18.60 4.77 34.13
18.82 4.72 28.94
20.07 4.42 7.59
20.91 4.25 100.00
21.61 4.11 60.99
25.95 3.43 3.41
27.13 3.29 42.70
28.51 3.13 5.27
31.21 2.87 5.82
实施例4：晶型CS1的制备
将1.3g AP26113游离碱在60℃下溶于5.0mL乙醇和甲苯的混合溶液中(乙醇与甲苯的体积比为1:4)，过滤后将滤液密封，在-20℃下搅拌一定时间，直至有固体析出。该固体为CS1，其X射线粉末衍射数据如表4所示。
表4
2theta值 d值 强度％
5.44 16.25 100.00
8.45 10.47 11.68
9.76 9.07 2.98
10.28 8.60 3.34
10.82 8.18 16.22
11.79 7.51 13.87
12.23 7.24 4.85
13.27 6.67 10.26
14.13 6.27 1.60
16.16 5.48 35.67
16.55 5.36 23.48
17.86 4.97 8.93
18.64 4.76 31.22
20.02 4.44 7.10
20.86 4.26 51.39
21.63 4.11 30.45
23.12 3.85 3.26
24.48 3.64 5.64
26.07 3.42 5.86
27.24 3.27 31.51
实施例5：晶型CS1的制备
将99.5mg AP26113游离碱在50℃下溶于6.0mL用水饱和的甲苯中，过滤后将滤液密封，在-20℃下搅拌一定时间，直至有固体析出，该固体即为CS1，其X射线粉末衍射数据如表5所示。
表5
2theta值 d值 强度％
5.44 16.24 100.00
8.41 10.51 6.81
10.73 8.24 15.17
11.80 7.50 13.68
13.36 6.63 7.03
16.23 5.46 31.64
16.55 5.36 22.16
17.87 4.96 5.72
18.72 4.74 16.06
20.17 4.40 7.12
20.88 4.26 38.70
21.65 4.10 27.43
24.59 3.62 2.37
27.22 3.28 39.58
实施例6：晶型CS1的制备
将207.5mg AP26113游离碱在50℃下溶解于1.0mL甲醇和甲苯的混合溶液中(甲醇与甲苯的体积比为1:9)，过滤后将滤液密封，在-5℃下搅拌一定时间，直至有固体析出。
经检测，所得固体为晶型N1，其X射线粉末衍射数据如图4、表6所示。晶型N1干燥后为晶型CS1，其X射线粉末衍射数据如表7所示。
如图4所示，晶型N1在4.9°±0.2°,9.8°±0.2°,14.9°±0.2°,16.0°±0.2°,19.9°±0.2°,24.9°±0.2°,25.8°±0.2°处具有特征峰。
表6
2theta值 d值 强度％
4.96 17.83 100.00
8.40 10.53 4.14
9.86 8.97 16.79
10.20 8.67 5.34
12.14 7.29 1.19
12.74 6.95 1.35
13.88 6.38 6.52
14.87 5.96 16.39
16.02 5.53 28.31
18.14 4.89 10.42
18.77 4.73 7.66
19.52 4.55 11.19
19.89 4.47 61.95
20.39 4.36 21.32
20.85 4.26 21.33
21.21 4.19 17.06
22.40 3.97 3.76
23.37 3.81 4.35
24.87 3.58 19.34
25.82 3.45 15.23
表7
2theta值 d值 强度％
5.44 16.25 100.00
6.92 12.77 0.90
8.45 10.47 21.99
9.79 9.03 5.70
10.32 8.57 4.40
10.82 8.18 16.24
11.84 7.47 16.54
12.19 7.26 7.14
12.61 7.02 6.70
13.29 6.66 18.08
14.23 6.23 2.14
16.21 5.47 47.45
16.54 5.36 31.64
16.79 5.28 15.68
17.43 5.09 5.67
17.83 4.97 14.54
18.72 4.74 45.91
19.34 4.59 6.66
20.03 4.43 13.12
20.90 4.25 76.00
21.34 4.16 45.23
21.66 4.10 42.50
23.14 3.84 6.28
24.53 3.63 9.90
26.06 3.42 9.77
27.17 3.28 53.81
实施例7：晶型CS2的制备
将10.0mg AP26113游离碱加入到0.5mL异丙醇和甲苯的混合溶剂中(异丙醇与甲苯的体积比为1:4)，溶解后过滤，于50℃下挥发2天，得粉末状固体，将该固体在室温(环境湿度50-80％RH)下放置8天，得到晶型CS2。晶型CS2的X射线粉末衍射数据如图5，表8所示。
晶型CS2的DSC如图6所示，当进行差示扫描量热分析时，加热至45℃开始出现第一个吸热峰，加热至72℃开始出现第二个吸热峰，加热至210℃开始出现第三个吸热峰。
晶型CS2的TGA如图7所示，将其加热至49℃，具有2.3％的质量损失梯度，加热至151℃，进一步有1.5％的质量损失梯度。
表8
2theta值 d值 强度％
4.74 18.63 3.79
5.69 15.53 61.71
8.46 10.45 4.10
8.67 10.20 3.12
9.56 9.25 0.76
11.39 7.77 28.05
13.72 6.45 4.68
16.01 5.54 12.37
16.34 5.43 8.02
16.65 5.32 9.66
17.12 5.18 100.00
17.55 5.05 7.94
18.70 4.74 5.80
19.36 4.58 6.42
20.07 4.42 8.60
20.31 4.37 6.84
21.37 4.16 30.59
21.63 4.11 14.29
22.89 3.89 47.93
23.92 3.72 2.89
25.56 3.49 2.19
27.33 3.26 22.28
28.72 3.11 29.29
30.76 2.91 3.03
32.37 2.77 1.54
38.06 2.36 1.15
实施例8：晶型CS2的制备
将38.0mg AP26113游离碱加入到2.0mL异丙醇和甲苯的混合溶剂中(异丙醇与甲苯的体积比为1:4)，溶解后过滤，敞口于50℃下挥发3天得到固体，将该固体放置于室温、57.6％RH条件下12天，得到CS2固体。其X射线粉末衍射数据如图8，表9所示。
表9
2theta值 d值 强度％
4.51 19.61 4.96
5.69 15.54 70.28
8.72 10.14 21.62
11.38 7.77 30.53
13.73 6.45 8.64
16.08 5.51 27.38
17.13 5.18 100.00
18.82 4.72 12.30
20.40 4.35 12.90
21.38 4.16 52.38
21.68 4.10 46.61
22.94 3.88 49.09
25.69 3.47 6.99
27.36 3.26 49.47
28.73 3.11 25.41
38.12 2.36 3.58
实施例9：晶型CS2的制备
将约10mg纯的晶型CS1固体放置于室温、57.6％RH条件下16天，得到晶型CS2固体。其X射线粉末衍射数据如图9，表10所示。
表10
2theta值 d值 强度％
4.50 19.66 16.38
5.74 15.40 73.60
8.46 10.46 30.33
8.74 10.12 40.47
11.41 7.76 25.37
16.05 5.52 22.74
17.14 5.17 100.00
17.52 5.06 34.37
18.80 4.72 42.02
21.39 4.15 72.32
22.88 3.89 53.06
27.37 3.26 27.67
28.73 3.11 31.37
实施例10：晶型CS2的制备
将1.8g AP26113游离碱在60℃下溶解于5.0mL甲醇和水的混合溶剂中(甲醇与水的体积比为98:2)，过滤后将滤液密封，在-20℃下搅拌一定时间，直至有固体析出。经检测该湿样固体为晶型N3，其X射线粉末衍射数据如图10、表11所示。晶型N3在35℃、40％RH条件下干燥后得到晶型CS2固体，其X射线粉末衍射数据如表12所示。晶型CS2的DSC如图11所示，当进行差示扫描量热分析时，加热至121℃开始出现第一个吸热峰，加热至214℃开始出现第二个吸热峰。
晶型CS2的TGA如图12所示，当进行热重分析时，加热至100℃时，具有4.3％的质量损失梯度。
如图10所示，晶型N3在4.9°±0.2°,8.3°±0.2°,9.9°±0.2°,14.8°±0.2°,15.4°±0.2°,19.8°±0.2°,21.0°±0.2°,24.8°±0.2°处具有特征峰。
按照上述步骤，其他条件相同，只调整混合溶剂甲醇和水的比例为93:7，亦可以得到晶型CS2。
表11
2theta值 d值 强度％
4.92 17.97 100.00
8.35 10.59 35.51
9.89 8.94 35.54
10.81 8.18 21.78
12.85 6.89 13.59
14.85 5.97 34.52
15.37 5.76 37.07
17.21 5.15 28.22
18.25 4.86 20.40
18.89 4.70 26.28
19.84 4.47 81.32
20.22 4.39 55.98
21.04 4.22 49.84
21.68 4.10 26.36
22.99 3.87 24.35
24.83 3.59 70.55
27.40 3.26 34.83
表12
2theta值 d值 强度％
5.91 14.96 47.44
8.57 10.32 19.19
8.83 10.01 19.50
11.46 7.72 26.64
12.39 7.14 7.23
13.07 6.77 7.66
13.76 6.44 17.20
16.09 5.51 35.73
17.12 5.18 100.00
17.65 5.02 38.85
18.87 4.70 22.25
19.53 4.55 13.19
20.28 4.38 21.00
21.39 4.15 70.00
21.70 4.09 59.71
22.94 3.88 53.81
25.71 3.46 8.80
27.33 3.26 34.46
28.79 3.10 31.99
30.83 2.90 7.90
32.30 2.77 3.61
38.27 2.35 2.91
实施例11：晶型CS2的稳定性研究
稳定性是评估晶型是否可药用的重要性质之一，晶型的稳定性对药物的稳定性是至关重要的，尤其在市售有效期内保持较好的稳定性，减少药物由于晶型变化而导致药物溶出速率及生物利用度改变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
取晶型CS2固体约10mg放置于25℃/60％RH恒温恒湿箱中，并在起始放置时和放置1个月和3个月后分别取样进行XRPD测试。由图13可以看出，晶型CS2的晶型未发生变化，表明晶型CS2稳定性好，且纯度均在99％以上，适合于药物开发。
实施例12：溶解度研究
溶解度是影响生物利用度的最重要的性质之一，不管是新药的发现阶段或开发阶段，仿制药的研发阶段，溶解度都是重点考察因素，尤其是模拟人体环境溶液中的溶解度的提高，对于提高药物的吸收和生物利用度具有重要意义。
将本发明制备得到的晶型CS2与晶型A样品用FaSSIF(模拟空腹状态下肠液)配制成饱和溶液，在固定的时间点取样并通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表13所示。
表13
Figure PCTCN2017107652-appb-000004
结果表明，晶型CS2和晶型A在SGF中均具有较好的溶解度，而在FaSSIF中，晶型CS2较晶型A具有明显优越的溶解度，1h时的溶解度比现有晶型A提高了43％，产生了出乎预料的效果。肠道是药物吸收的主要部位，晶型A在FaSSIF中溶解度的显著提高，有利于提高药物在胃肠的吸收和增加AP26113的生物利用度。
将本发明制备得到的晶型CS1与晶型A样品在H2O配制成饱和溶液，1小时和4小时后取样并通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表14所示。
表14
Figure PCTCN2017107652-appb-000005
通过上述对比结果可以看出，晶型A在水中溶解度较差，不利于药物的吸收和利用，而本发明的晶型CS1与现有晶型A相比，溶解度最大可提高16倍，产生了出乎预料的效果，对提高药物的吸收和生物利用度具有重要意义。
实施例13：溶出度研究
称取晶型CS2和晶型A各100mg，分别放入固有溶出模具进行压片，在12KN压力条件下持续一分钟，然后测试所压片子的溶出情况，测试条件如下，结果见表15。
溶出介质：pH6.8的磷酸盐缓冲液
溶出方法：转碟法
介质体积：900mL
转速：100rpm
介质温度：37℃
表15
Figure PCTCN2017107652-appb-000006
结果表明晶型CS2在10-30min测定的溶出量均明显高于晶型A，通过将累计溶出量和时间作图线性拟合后(如图14所示)，得到晶型CS2的固有溶出速率为0.268mg/min，晶型A的固有溶出速率为0.052mg/min。晶型CS2溶出 速率的提高对于AP26113的研究开发具有重要的意义。在制剂开发中，使用溶出速率较高的晶型CS2可加快药物服用后在体内快速溶解和吸收，可通过调整包材和辅料，控制药物在特定部位快速发挥作用，提高药物的起效速率和生物利用度。
实施例14：粒径研究实验
粒径研究实验：
取本发明的晶型CS1、晶型CS2以及现有晶型A测试粒径分布。结果显示晶型A的平均粒径为12.58μm，其粒径太小不适合结晶工艺分离，而本发明的晶型CS1和晶型CS2平均粒径分别为175.0μm和151.9μm，相比于晶型A，粒径更大。与晶型A相比，粒度大的晶型CS1和晶型CS2受静电吸附的影响小，更易在结晶工艺过程中分离，并且可以避免制剂工艺过程中混合不均匀的情况，使药物的质量更加可控，同时粒径大的晶体，生长更加完善，可以避免溶剂或杂质在晶体上的吸附，更有助于提纯。
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 (13)

  1. 一种AP26113的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为17.1°±0.2°,22.9°±0.2°,28.7°±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为27.3°±0.2°,21.4°±0.2°,5.7°±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CS2，其特征在于，其X射线粉末衍射图在2theta值为11.4°±0.2°,8.7°±0.2°,16.0°±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CS2的制备方法，其特征在于，所述方法包含：
    1)将晶型CS1在室温、30％RH-80％RH湿度下放置1-30天，获得晶型CS2；
    或2)将AP26113游离碱溶于醇类和水的混合溶剂中，过滤后将滤液于-20-0℃温度下搅拌直至有固体析出，将得到湿样固体放置在25-40℃，30％RH-75％RH湿度下干燥，得到晶型CS2。
  5. 根据权利要求4所述的制备方法，其特征在于，方法1)中所述放置湿度为50％RH-80％RH；所述放置时间为5-16天；方法2)中所述醇类包含甲醇；所述醇类和水的混合溶剂体积比为93:7-98:2；所述放置温度为35℃；所述放置湿度为40％RH。
  6. 一种AP26113的晶型CS1，其特征在于，其X射线粉末衍射图在衍射角2θ为2theta值为5.5°±0.2°,21.6°±0.2°,10.8°±0.2°处有特征峰。
  7. 根据权利要求6所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2theta值为16.2°±0.2°,21.0°±0.2°,27.1°±0.2°中的一处或两处或三处具有特征峰。
  8. 根据权利要求6所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2theta值为8.5°±0.2°,11.8°±0.2°,18.6°±0.2°中的一处或两处或三处具有特征峰。
  9. 一种权利要求6所述的晶型CS1的制备方法，其特征在于，所述方法包含：1)将AP26113游离碱溶于醇类和芳香烃类的混合溶剂中，于30-60℃温度下挥发1-10天，得到晶型CS1；
    或2)将AP26113游离碱溶于乙醇和芳香烃类混合溶剂或者溶于用水饱和的芳香烃溶剂中，过滤后将滤液于-20-0℃温度下搅拌直至有固体析出，该固体即为晶型CS1；
    或3)将AP26113游离碱溶于甲醇和芳香烃类的混合溶液中，过滤后将滤液于-20-0℃温度下搅拌直至有固体析出，将得到湿样固体干燥得到晶型CS1。
  10. 根据权利要求9所述的制备方法，其特征在于，方法1)中所述醇类包含异丙醇；所述芳香烃类包含甲苯；所述醇类和芳香烃的体积比为1:4-1:2；所述挥发温度为35-50℃；方法2)中所述芳香烃类包含甲苯；所述乙醇和芳香烃的混合溶剂的混合体积比为1:4；所述用水饱和的芳香烃为用水饱和的甲苯；方法3)中所述芳香烃类包含甲苯；所述甲醇和芳香烃的混合溶剂的混合体积比为1:9。
  11. 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CS2或权利要求6所述的晶型CS1或其混合物及药学上可接受的载体、稀释剂或赋形剂。
  12. 权利要求1所述的晶型CS2或权利要求6所述的晶型CS1或其混合物在生产小分子酪氨酸激酶抑制剂药物制剂中的用途。
  13. 权利要求1所述的晶型CS2或权利要求6所述的晶型CS1或其混合物在生产用于治疗ALK阳性的非小细胞肺癌药物制剂中的用途。
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