WO2024125543A1 - Crystal form of darovasertib, method for preparing same, and use thereof - Google Patents

Crystal form of darovasertib, method for preparing same, and use thereof Download PDF

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WO2024125543A1
WO2024125543A1 PCT/CN2023/138380 CN2023138380W WO2024125543A1 WO 2024125543 A1 WO2024125543 A1 WO 2024125543A1 CN 2023138380 W CN2023138380 W CN 2023138380W WO 2024125543 A1 WO2024125543 A1 WO 2024125543A1
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csi
crystalline
compound
crystal form
crystalline form
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PCT/CN2023/138380
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French (fr)
Chinese (zh)
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李英杰
黄春香
孟丽苹
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苏州科睿思制药有限公司
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Publication of WO2024125543A1 publication Critical patent/WO2024125543A1/en

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  • the present invention relates to the field of crystal chemistry, and in particular to a crystal form of dalosertib, a preparation method thereof and a use thereof.
  • Uveal melanoma is the most common eye cancer in adults, and most UM patients will have the cancer spread. UM patients often carry mutations in the GNAQ (guanine nucleotide-binding protein G(q) subunit alpha) and GNA11 (guanine nucleotide-binding protein G(q) subunit 11) genes. These mutations activate the PKC (protein kinase C) pathway, which further leads to the constitutive activation of the MAPK (mitogen-activated protease) signaling pathway, which is involved in the uncontrolled cell growth in many proliferative diseases. To date, there is no treatment that can cure UM.
  • GNAQ guanine nucleotide-binding protein G(q) subunit alpha
  • GNA11 guanine nucleotide-binding protein G(q) subunit 11
  • Darovasertib is a potent small molecule PKC inhibitor with positive results in Phase II clinical trials for the treatment of metastatic uveal melanoma (MUM).
  • Darovasertib has inhibitory activity against multiple PKC isoforms and is highly selective relative to other kinases.
  • the chemical name of darosertib is 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (hereinafter referred to as "Compound I").
  • Example 9 of WO2016020864A1 only discloses the synthesis method of Compound I, but does not disclose any crystal form of Compound I and the XRPD characteristics of the crystal form.
  • the structural formula of Compound I is as follows:
  • a crystal is a solid in which compound molecules are arranged in a three-dimensional orderly manner in a microstructure to form a lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms.
  • a compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically expected.
  • APIs of different crystal forms have different physicochemical properties, including chemical stability, thermal stability, solubility, hygroscopicity and/or particle size, which may cause different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent.
  • APIs of different crystal forms have different manufacturability, including yield, purification properties, filtration properties, drying properties and milling properties, and the stability relative to pressure during tableting may affect the processing and treatment during the production process of the API. Therefore, polymorphism is an important part of drug research and drug quality control.
  • the compound I crystal form provided by the invention has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and biological effectiveness, especially good physical stability and humidity stability, good stability under mechanical force and low hygroscopicity, which solves the problems existing in the prior art and is of great significance to the development of drugs containing compound I.
  • the present invention provides a new crystal form of Compound I and a preparation method thereof, as well as a pharmaceutical composition comprising the crystal form.
  • the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 8.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 23.7° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 8.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 23.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 11.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, and 21.9° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 11.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, and 21.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one or two of the diffraction angles 2 ⁇ of 18.4° ⁇ 0.2° and 22.4° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 18.4° ⁇ 0.2° and 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2 ⁇ values of 8.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 23.7° ⁇ 0.2°, 11.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, 24.8° ⁇ 0.2°, 26.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, 19.4° ⁇ 0.2°, and 28.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG. 1 .
  • thermogravimetric analysis graph of the crystalline form CSI is substantially as shown in FIG. 2 , and there is almost no weight loss when heated to about 200° C.
  • differential scanning calorimetry diagram of the crystalline form CSI is substantially as shown in FIG. 3 , which has an endothermic peak at about 242° C.
  • the crystalline form CSI is an anhydrate.
  • the present invention also provides a method for preparing the crystalline form CSI, the preparation method comprising:
  • the solid compound I is dissolved in an alcohol solvent and evaporated to obtain the crystalline form CSI.
  • the alcohol solvent is preferably methanol.
  • the present invention provides the use of the crystal form CSI for preparing other crystal forms or salts of compound I.
  • the present invention provides a pharmaceutical composition
  • the pharmaceutical composition comprises An effective therapeutic amount of crystalline CSI and pharmaceutically acceptable excipients.
  • the present invention provides use of crystalline CSI in preparing PKC inhibitor drugs.
  • the present invention provides use of crystalline CSI in preparing a drug for treating uveal melanoma.
  • Crystalline CSI has lower hygroscopicity.
  • the hygroscopic weight gain of the crystal CSI under 80% RH is 1.04%, while the hygroscopic weight gain of the prior art under 80% RH is 11.46%.
  • the hygroscopic weight gain of the prior art is 11 times that of the crystalline CSI of the present invention.
  • the hygroscopicity of the crystal CSI is low, and the requirements for drug production and storage are not strict, which reduces the cost of drug production, storage and quality control, and has strong economic value.
  • Crystalline CSI has better humidity stability. After the crystalline CSI experiences humidity changes from 0% RH-95% RH-0% RH, the crystalline remains unchanged. After the prior art experiences humidity changes from 0% RH-95% RH-0% RH, the crystalline changes. This indicates that crystalline CSI has better humidity stability than the prior art.
  • Crystalline CSI has better stability under mechanical force. Before and after ball milling, tableting and preparation, the crystal form of crystalline CSI remains unchanged and the crystallinity does not change significantly. After ball milling, the crystallinity of the prior art decreases significantly and the crystal form changes, and the crystal form changes after tableting. This shows that crystalline CSI has better stability under mechanical force than the prior art.
  • Crystalline CSI has good physical stability. Crystalline CSI has no change in crystal form for at least 9 months when placed under 25°C/60%RH and 40°C/75%RH conditions; and has no change in crystal form for at least 2 months when placed under 60°C/75%RH conditions.
  • Crystalline CSI preparations have good stability. Crystalline CSI is mixed with excipients to make pharmaceutical preparations, and placed under 25°C/60%RH and 40°C/75%RH conditions. The crystal form does not change for at least 1 month, and the purity remains basically unchanged during storage.
  • Crystalline CSI has good stability. On the one hand, it is helpful to avoid the impact of drug quality on drug quality due to crystal transformation during drug storage, transportation, and production. On the other hand, it can reduce the risk of API crystallinity reduction and crystal transformation during preparation processing. This ensures that the quality of APIs is consistent and controllable, and reduces changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form.
  • Figure 1 is the XRPD diagram of crystal form CSI
  • Figure 2 is the TGA graph of crystal form CSI
  • Figure 3 is the DSC graph of crystal form CSI
  • Figure 4 is a comparison of XRPD images of the crystal CSI sealed package before and after being placed under different conditions (from bottom to top: before placement, after 9 months at 25°C/60%RH, after 9 months at 40°C/75%RH, after 2 months at 60°C/75%RH)
  • Figure 5 is a comparison of XRPD images of the crystalline CSI before and after being exposed under different conditions (from bottom to top). The times are: before placement, after 9 months at 25°C/60%RH, after 9 months at 40°C/75%RH, after 2 months at 60°C/75%RH)
  • Figure 6 is a comparison of XRPD images of the crystal form CSI before and after ball milling (from bottom to top: after ball milling, before ball milling)
  • Figure 7 is a comparison of XRPD images of Compound I in WO2016020864A1 before and after solid ball milling (from bottom to top: after ball milling, before ball milling)
  • Figure 8 is a comparison of XRPD images of the crystalline CSI before and after tableting (from bottom to top: after tableting, before tableting)
  • Figure 9 is a comparison of XRPD images of Compound I in WO2016020864A1 before and after solid tableting (from bottom to top: after tableting, before tableting)
  • Figure 10 is a DVS adsorption curve of crystalline CSI
  • FIG. 11 is a DVS adsorption curve of the solid compound I in WO2016020864A1
  • Figure 12 is a comparison of XRPD images of crystalline CSI before and after DVS testing (from top to bottom: before DVS, after DVS)
  • Figure 13 is a comparison of XRPD of crystalline CSI before and after formulation and blank mixed powder (from bottom to top: crystalline CSI API, crystalline CSI after formulation process, blank mixed powder after formulation process)
  • FIG14 is a comparison of XRPD images of the crystalline CSI preparation before and after storage under different conditions (from bottom to top: before storage, after storage at 25°C/60% RH for 1 month, after storage at 40°C/75% RH for 1 month)
  • the X-ray powder diffraction pattern described in the embodiment of the present invention was collected on a Bruker D8 X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction are as follows:
  • thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:
  • the differential scanning calorimetry (DSC) graphs described in the present invention were collected on a METTLER TOLEDO DSC 3.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • the liquid nuclear magnetic hydrogen spectrum data ( 1 H NMR) of the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample is weighed and dissolved in 0.5 mL of deuterated methanol to prepare a 2-10 mg/mL solution.
  • the dynamic moisture adsorption (DVS) graph of the present invention is collected on an Intrinsic dynamic moisture adsorption instrument produced by SMS (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the dynamic moisture adsorption instrument are as follows:
  • volatilization is accomplished by conventional methods in the art, such as slow volatilization or fast volatilization.
  • Slow volatilization is to seal the container with a sealing film, pierce holes, and leave it to volatilize;
  • fast volatilization is to leave the container open to volatilize.
  • room temperature is not a specific temperature value, but refers to the temperature range of 10-30°C.
  • anhydrous substance refers to a solid substance that does not contain crystal water or crystallization solvent.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-K ⁇ radiation, the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of the experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns belongs to the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the crystalline form CSI of the present invention is pure 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, particularly less than 10% (by weight) of other crystalline forms, more preferably less than 5% (by weight) of other crystalline forms, and even more preferably less than 1% (by weight) of other crystalline forms.
  • the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as a raw material is in solid form.
  • the compound I and the compound I solid used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2016020864A1.
  • the obtained crystalline solid is the crystal form CSI of the present invention, and its X-ray powder diffraction pattern is shown in FIG1 , and the X-ray powder diffraction data are shown in Table 2.
  • TGA shows that when heated to about 200°C, there is almost no weight loss, and the crystalline form CSI is anhydrous.
  • Example 2 DSC and 1 H NRM of Crystalline CSI
  • the DSC graph of crystalline CSI is shown in FIG3 , which has an endothermic peak at about 242° C.
  • the NMR data of the crystal form CSI are: ⁇ 8.97–8.87 (m, 1H), 8.68 (s, 1H), 8.47–8.27 (m, 1H), 8.17–8.06 (m, 1H), 7.83–7.55 (m, 2H), 7.21–7.13 (m, 1H), 3.02–2.65 (m, 4H), 1.54–1.24 (m, 4H), 0.74 (s, 3H), among which the five active hydrogens of compound I did not show peaks.
  • the NMR results show that the crystal form CSI is the free state crystal form of compound I.
  • Sealed packaging Place the sample in a glass vial, cover it with a lid and seal it in an aluminum foil bag.
  • Open packaging Place the sample in a glass vial without a lid and place it in an open environment.
  • Example 4 Stability of Crystalline CSI under Mechanical Force
  • Example 5 Hygroscopicity and humidity stability of crystalline CSI
  • the crystalline form CSI has a hygroscopic weight gain of 1.04% from 0% to 80% RH, and there is no change in the crystal form before and after the DVS test.
  • the hygroscopic weight gain of the compound I solid from 0% to 80% RH is 11.46%, and the solid crystal form of the compound I changes after the DVS test. It can be seen that the hygroscopicity of the crystalline form CSI is lower and the humidity stability is better.
  • the crystalline CSI preparation and blank mixed powder preparation were prepared using the preparation prescriptions shown in Tables 5 and 6 and the preparation process shown in Table 7.
  • the XRPD of the blank mixed powder and the samples before and after the preparation prescription were tested, and the results are shown in Figure 13.
  • the results show that the crystalline form of crystalline CSI remains stable before and after the preparation prescription process.

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Abstract

The present invention relates to a crystal form of darovasertib (hereinafter referred to as "compound I"), a method for preparing same, a pharmaceutical composition comprising the crystal form, and the use of the crystal form in treating uveal melanoma.

Description

达洛色替的晶型及其制备方法和用途Crystal form of darosertib, preparation method and use thereof 技术领域Technical Field
本发明涉及晶体化学领域。具体而言，涉及达洛色替的晶型及其制备方法和用途。The present invention relates to the field of crystal chemistry, and in particular to a crystal form of dalosertib, a preparation method thereof and a use thereof.
背景技术Background technique
葡萄膜黑色素瘤(UM)是成年人最常见的眼部癌症，且大多数UM患者会出现癌细胞扩散。UM患者通常携带GNAQ(鸟嘌呤核苷酸结合蛋白G(q)亚基α)和GNA11(鸟嘌呤核苷酸结合蛋白G(q)亚基11)突变基因。这些突变激活PKC(蛋白激酶C)通路，进一步导MAPK(有丝分裂原活化蛋白酶)信号通路的组成性激活，该信号通路与许多增生性疾病中不受控制的细胞生长有关。迄今为止，尚没有可治愈UM的治疗方法。Uveal melanoma (UM) is the most common eye cancer in adults, and most UM patients will have the cancer spread. UM patients often carry mutations in the GNAQ (guanine nucleotide-binding protein G(q) subunit alpha) and GNA11 (guanine nucleotide-binding protein G(q) subunit 11) genes. These mutations activate the PKC (protein kinase C) pathway, which further leads to the constitutive activation of the MAPK (mitogen-activated protease) signaling pathway, which is involved in the uncontrolled cell growth in many proliferative diseases. To date, there is no treatment that can cure UM.
达洛色替(Darovasertib)是一种有效的小分子PKC抑制剂，在用于治疗转移性葡萄膜黑色素瘤(MUM)的二期临床结果积极。达洛色替对多种PKC亚型具有抑制活性，并且相对于其他激酶具有高度选择性。Darovasertib is a potent small molecule PKC inhibitor with positive results in Phase II clinical trials for the treatment of metastatic uveal melanoma (MUM). Darovasertib has inhibitory activity against multiple PKC isoforms and is highly selective relative to other kinases.
达洛色替的化学名称为3-氨基-N-(3-(4-氨基-4-甲基哌啶-1-基)吡啶-2-基)-6-(3-(三氟甲基)吡啶-2-基)吡嗪-2-甲酰胺(以下称为“化合物I”)，WO2016020864A1实施例9仅公开了化合物I的合成方法，但没有公开任何化合物I的晶型及晶型的XRPD特征。化合物I的结构式如下：
The chemical name of darosertib is 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (hereinafter referred to as "Compound I"). Example 9 of WO2016020864A1 only discloses the synthesis method of Compound I, but does not disclose any crystal form of Compound I and the XRPD characteristics of the crystal form. The structural formula of Compound I is as follows:
本领域公知，在小分子药物开发中，药物多晶型是药物研发中的常见现象，是影响药物质量的重要因素。晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，包括化学稳定性、热稳定性、溶解性、吸湿性和/或粒子大小，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。此外，不同晶型的原料药有不同的可制造性，包括产率、提纯性质、过滤性质、干燥性质和碾磨性质，压片期间的相对于压力的稳定性，可能会对原料药的生产过程中的加工处理产生影响。因此，多晶型是药物研究和药物质量控制的重要内容。It is well known in the art that in the development of small molecule drugs, drug polymorphism is a common phenomenon in drug research and development and an important factor affecting drug quality. A crystal is a solid in which compound molecules are arranged in a three-dimensional orderly manner in a microstructure to form a lattice. Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms. A compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically expected. APIs of different crystal forms have different physicochemical properties, including chemical stability, thermal stability, solubility, hygroscopicity and/or particle size, which may cause different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. In addition, APIs of different crystal forms have different manufacturability, including yield, purification properties, filtration properties, drying properties and milling properties, and the stability relative to pressure during tableting may affect the processing and treatment during the production process of the API. Therefore, polymorphism is an important part of drug research and drug quality control.
为了寻找可以改善药物性能的新固态形式，本申请的发明人意外发现了本 发明提供的化合物I晶型，其在溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是具有良好的物理稳定性、湿度稳定性，在机械力作用下稳定性好且引湿性低，解决了现有技术存在的问题，对含化合物I的药物开发具有非常重要的意义。In order to find a new solid form that can improve the performance of drugs, the inventors of the present application accidentally discovered the present The compound I crystal form provided by the invention has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and biological effectiveness, especially good physical stability and humidity stability, good stability under mechanical force and low hygroscopicity, which solves the problems existing in the prior art and is of great significance to the development of drugs containing compound I.
发明内容Summary of the invention
本发明提供化合物I的新晶型及其制备方法以及包含该晶型的药物组合物。The present invention provides a new crystal form of Compound I and a preparation method thereof, as well as a pharmaceutical composition comprising the crystal form.
根据本发明的目的，本发明提供化合物I的晶型CSI(以下称作“晶型CSI”)。According to the purpose of the present invention, the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为8.3°±0.2°、15.0°±0.2°、23.7°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为8.3°±0.2°、15.0°±0.2°、23.7°±0.2°处有特征峰。On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.3°±0.2°, 15.0°±0.2°, and 23.7°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 8.3°±0.2°, 15.0°±0.2°, and 23.7°±0.2°.
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为11.8°±0.2°、17.3°±0.2°、21.9°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为11.8°±0.2°、17.3°±0.2°、21.9°±0.2°处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 11.8°±0.2°, 17.3°±0.2°, and 21.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 11.8°±0.2°, 17.3°±0.2°, and 21.9°±0.2°.
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为18.4°±0.2°、22.4°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为18.4°±0.2°、22.4°±0.2°处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one or two of the diffraction angles 2θ of 18.4°±0.2° and 22.4°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 18.4°±0.2° and 22.4°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为8.3°±0.2°、15.0°±0.2°、23.7°±0.2°、11.8°±0.2°、17.3°±0.2°、21.9°±0.2°、18.4°±0.2°、22.4°±0.2°、23.1°±0.2°、20.2°±0.2°、19.9°±0.2°、24.8°±0.2°、26.5°±0.2°、16.6°±0.2°、19.4°±0.2°、28.7°±0.2°中的任意1处、或2处、或3处、或4处、或5处，或6处，或7处，或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values of 8.3°±0.2°, 15.0°±0.2°, 23.7°±0.2°, 11.8°±0.2°, 17.3°±0.2°, 21.9°±0.2°, 18.4°±0.2°, 22.4°±0.2°, 23.1°±0.2°, 20.2°±0.2°, 19.9°±0.2°, 24.8°±0.2°, 26.5°±0.2°, 16.6°±0.2°, 19.4°±0.2°, and 28.7°±0.2°.
非限制性地，使用Cu-Kα辐射，晶型CSI的X射线粉末衍射图基本如图1所示。Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG. 1 .
非限制性地，晶型CSI的热重分析图基本如图2所示，在加热至约200℃时，几乎无失重。Without limitation, the thermogravimetric analysis graph of the crystalline form CSI is substantially as shown in FIG. 2 , and there is almost no weight loss when heated to about 200° C.
非限制性地，晶型CSI的差式扫描量热图基本如图3所示，其在约242℃存在一个吸热峰。Without limitation, the differential scanning calorimetry diagram of the crystalline form CSI is substantially as shown in FIG. 3 , which has an endothermic peak at about 242° C.
非限制性地，晶型CSI为无水物。Without limitation, the crystalline form CSI is an anhydrate.
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括：According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, the preparation method comprising:
将化合物I固体溶解于醇类溶剂中，挥发得到晶型CSI。The solid compound I is dissolved in an alcohol solvent and evaporated to obtain the crystalline form CSI.
进一步地，所述醇类溶剂优选甲醇。Furthermore, the alcohol solvent is preferably methanol.
根据本发明的目的，本发明提供晶型CSI用于制备化合物I其他晶型或盐的用途。According to the purpose of the present invention, the present invention provides the use of the crystal form CSI for preparing other crystal forms or salts of compound I.
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有 效治疗量的晶型CSI及药学上可接受的辅料。According to the purpose of the present invention, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprises An effective therapeutic amount of crystalline CSI and pharmaceutically acceptable excipients.
根据本发明的目的，本发明提供晶型CSI在制备PKC抑制剂药物中的用途。According to the purpose of the present invention, the present invention provides use of crystalline CSI in preparing PKC inhibitor drugs.
进一步地，本发明提供晶型CSI在制备治疗葡萄膜黑色素瘤药物中的用途。Furthermore, the present invention provides use of crystalline CSI in preparing a drug for treating uveal melanoma.
本发明提供的晶型CSI具有以下预料不到的技术效果：The crystalline CSI provided by the present invention has the following unexpected technical effects:
(1)晶型CSI具有更低的引湿性。(1) Crystalline CSI has lower hygroscopicity.
晶型CSI在80％RH条件下引湿性增重为1.04％，现有技术在80％RH条件下引湿增重为11.46％。现有技术的引湿增重是本发明晶型CSI引湿增重的11倍。晶型CSI引湿性低，对药物生产和储存要求不苛刻，降低了药品生产、保存和质量控制成本，具有很强的经济价值。The hygroscopic weight gain of the crystal CSI under 80% RH is 1.04%, while the hygroscopic weight gain of the prior art under 80% RH is 11.46%. The hygroscopic weight gain of the prior art is 11 times that of the crystalline CSI of the present invention. The hygroscopicity of the crystal CSI is low, and the requirements for drug production and storage are not strict, which reduces the cost of drug production, storage and quality control, and has strong economic value.
(2)晶型CSI具有良好的稳定性。(2) Crystalline CSI has good stability.
晶型CSI具有更好的湿度稳定性。晶型CSI在经历从0％RH-95％RH-0％RH湿度变化后，晶型保持不变。现有技术在经历从0％RH-95％RH-0％RH湿度变化后，晶型发生变化。说明晶型CSI比现有技术具有更好的湿度稳定性。Crystalline CSI has better humidity stability. After the crystalline CSI experiences humidity changes from 0% RH-95% RH-0% RH, the crystalline remains unchanged. After the prior art experiences humidity changes from 0% RH-95% RH-0% RH, the crystalline changes. This indicates that crystalline CSI has better humidity stability than the prior art.
晶型CSI在机械力作用下具有更好的稳定性。晶型CSI在球磨、压片和制剂前后，晶型不变且结晶度无明显变化。现有技术球磨后结晶度明显下降且晶型发生变化，在压片后晶型发生变化。说明晶型CSI比现有技术在机械力作用下具有更好的稳定性。Crystalline CSI has better stability under mechanical force. Before and after ball milling, tableting and preparation, the crystal form of crystalline CSI remains unchanged and the crystallinity does not change significantly. After ball milling, the crystallinity of the prior art decreases significantly and the crystal form changes, and the crystal form changes after tableting. This shows that crystalline CSI has better stability under mechanical force than the prior art.
晶型CSI具有良好的物理稳定性。晶型CSI在25℃/60％RH和40℃/75％RH条件下放置，至少9个月晶型未发生变化；在60℃/75％RH条件下放置，至少2个月晶型未发生变化。Crystalline CSI has good physical stability. Crystalline CSI has no change in crystal form for at least 9 months when placed under 25°C/60%RH and 40°C/75%RH conditions; and has no change in crystal form for at least 2 months when placed under 60°C/75%RH conditions.
晶型CSI制剂具有良好的稳定性。晶型CSI与辅料混合做成药物制剂，在25℃/60％RH和40℃/75％RH条件下放置，至少1个月晶型未发生变化，且储存过程中纯度基本保持不变。Crystalline CSI preparations have good stability. Crystalline CSI is mixed with excipients to make pharmaceutical preparations, and placed under 25°C/60%RH and 40°C/75%RH conditions. The crystal form does not change for at least 1 month, and the purity remains basically unchanged during storage.
季节差异、不同地区气候差异和环境因素等带来的高湿条件会影响原料药的储存、运输、生产。此外，制剂加工过程中常需要将原料药研磨或粉碎。晶型CSI具有良好的稳定性，一方面有利于避免药物储存、运输、生产过程中因转晶对药物质量产生影响，另一方面能够降低制剂加工过程中原料药结晶度降低和转晶的风险。进而保证原料药质量一致可控，减少由于晶型改变引起的药物质量变化，生物利用度变化，和毒副作用。High humidity conditions caused by seasonal differences, climate differences in different regions, and environmental factors will affect the storage, transportation, and production of APIs. In addition, APIs often need to be ground or crushed during the preparation process. Crystalline CSI has good stability. On the one hand, it is helpful to avoid the impact of drug quality on drug quality due to crystal transformation during drug storage, transportation, and production. On the other hand, it can reduce the risk of API crystallinity reduction and crystal transformation during preparation processing. This ensures that the quality of APIs is consistent and controllable, and reduces changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为晶型CSI的XRPD图Figure 1 is the XRPD diagram of crystal form CSI
图2为晶型CSI的TGA图Figure 2 is the TGA graph of crystal form CSI
图3为晶型CSI的DSC图Figure 3 is the DSC graph of crystal form CSI
图4为晶型CSI密封包装后在不同条件下放置前后的XRPD对比图(从下至上依次为：放置前，25℃/60％RH放置9个月后，40℃/75％RH放置9个月后，60℃/75％RH放置2个月后)Figure 4 is a comparison of XRPD images of the crystal CSI sealed package before and after being placed under different conditions (from bottom to top: before placement, after 9 months at 25°C/60%RH, after 9 months at 40°C/75%RH, after 2 months at 60°C/75%RH)
图5为晶型CSI在不同条件下敞口放置前后的XRPD对比图(从下至上依 次为：放置前，25℃/60％RH放置9个月后，40℃/75％RH放置9个月后，60℃/75％RH放置2个月后)Figure 5 is a comparison of XRPD images of the crystalline CSI before and after being exposed under different conditions (from bottom to top). The times are: before placement, after 9 months at 25℃/60％RH, after 9 months at 40℃/75％RH, after 2 months at 60℃/75％RH)
图6为晶型CSI球磨前后的XRPD对比图(从下至上依次为：球磨后，球磨前)Figure 6 is a comparison of XRPD images of the crystal form CSI before and after ball milling (from bottom to top: after ball milling, before ball milling)
图7为WO2016020864A1中的化合物I固体球磨前后的XRPD对比图(从下至上依次为：球磨后，球磨前)Figure 7 is a comparison of XRPD images of Compound I in WO2016020864A1 before and after solid ball milling (from bottom to top: after ball milling, before ball milling)
图8为晶型CSI压片前后的XRPD对比图(从下至上依次为：压片后，压片前)Figure 8 is a comparison of XRPD images of the crystalline CSI before and after tableting (from bottom to top: after tableting, before tableting)
图9为WO2016020864A1中的化合物I固体压片前后的XRPD对比图(从下至上依次为：压片后，压片前)Figure 9 is a comparison of XRPD images of Compound I in WO2016020864A1 before and after solid tableting (from bottom to top: after tableting, before tableting)
图10为晶型CSI的DVS吸附曲线图Figure 10 is a DVS adsorption curve of crystalline CSI
图11为WO2016020864A1中的化合物I固体的DVS吸附曲线图FIG. 11 is a DVS adsorption curve of the solid compound I in WO2016020864A1
图12为晶型CSI在DVS测试前后的XRPD对比图(从上至下依次为：DVS前，DVS后)Figure 12 is a comparison of XRPD images of crystalline CSI before and after DVS testing (from top to bottom: before DVS, after DVS)
图13为晶型CSI在制剂处方前后和空白混粉的XRPD对比图(从下到上依次为：晶型CSI原料药，晶型CSI制剂工艺后，空白混粉制剂工艺后)Figure 13 is a comparison of XRPD of crystalline CSI before and after formulation and blank mixed powder (from bottom to top: crystalline CSI API, crystalline CSI after formulation process, blank mixed powder after formulation process)
图14为晶型CSI制剂不同条件下放置前后的XRPD对比图(从下至上依次为：放置前，25℃/60％RH放置1个月后，40℃/75％RH放置1个月后)FIG14 is a comparison of XRPD images of the crystalline CSI preparation before and after storage under different conditions (from bottom to top: before storage, after storage at 25°C/60% RH for 1 month, after storage at 40°C/75% RH for 1 month)
具体实施方式Detailed ways
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the present invention.
本发明中所用到的缩写的解释如下：The explanations of the abbreviations used in the present invention are as follows:
RH：相对湿度RH: Relative humidity
TGA：热重分析TGA: Thermogravimetric analysis
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
DVS：动态水分吸附DVS: Dynamic Water Sorption
1H NMR：液态核磁氢谱 1 H NMR: liquid hydrogen nuclear magnetic spectrum
HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
采集数据所用的仪器及方法：Instruments and methods used to collect data:
本发明实施例所述的X射线粉末衍射图在Bruker D8射线粉末衍射仪上采集。所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction pattern described in the embodiment of the present invention was collected on a Bruker D8 X-ray powder diffractometer. The method parameters of the X-ray powder diffraction are as follows:
X射线光源：Cu,KαX-ray source: Cu, Kα
Kα11.54060；Kα21.54439Kα1 1.54060; Kα2 1.54439
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：40仟伏特(kV) Voltage: 40 kilovolts (kV)
电流：40毫安培(mA)Current: 40 milliamperes (mA)
扫描范围(2θ)：自4.0至40.0度Scanning range (2θ): from 4.0 to 40.0 degrees
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:
扫描速率：10℃/minScan rate: 10℃/min
保护气体：N2 Protective gas: N2
本发明所述的差式扫描量热分析(DSC)图在METTLER TOLEDO DSC 3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：The differential scanning calorimetry (DSC) graphs described in the present invention were collected on a METTLER TOLEDO DSC 3. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10℃/min
保护气体：N2 Protective gas: N2
本发明所述的液态核磁氢谱数据(1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代甲醇溶解，配成2-10mg/mL的溶液。The liquid nuclear magnetic hydrogen spectrum data ( 1 H NMR) of the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample is weighed and dissolved in 0.5 mL of deuterated methanol to prepare a 2-10 mg/mL solution.
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：The dynamic moisture adsorption (DVS) graph of the present invention is collected on an Intrinsic dynamic moisture adsorption instrument produced by SMS (Surface Measurement Systems Ltd.). The instrument control software is DVS-Intrinsic control software. The method parameters of the dynamic moisture adsorption instrument are as follows:
温度：25℃Temperature: 25℃
载气，流速：N2,200mL/minCarrier gas, flow rate: N 2 , 200mL/min
本发明所述有关物质的测试方法如表1所示。The testing methods of the related substances described in the present invention are shown in Table 1.
表1
Table 1
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发或快速挥发。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。The "volatilization" is accomplished by conventional methods in the art, such as slow volatilization or fast volatilization. Slow volatilization is to seal the container with a sealing film, pierce holes, and leave it to volatilize; fast volatilization is to leave the container open to volatilize.
所述“室温”不是特定的温度值，是指10-30℃温度范围。The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.
所述“无水物”是指不含结晶水或结晶溶剂的固态物质。The "anhydrous substance" refers to a solid substance that does not contain crystal water or crystallization solvent.
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射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X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。In the present invention, "crystal" or "crystal form" can be characterized by X-ray powder diffraction. Those skilled in the art will understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample. The relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of the experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor for determining the crystal form. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns belongs to the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.
在一些实施方案中，本发明的晶型CSI是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, the crystalline form CSI of the present invention is pure and substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more preferably less than 5% (by weight) of other crystalline forms, and even more preferably less than 1% (by weight) of other crystalline forms.
除非特殊说明，以下实施例均在室温条件下操作。Unless otherwise specified, the following examples were all operated at room temperature.
根据本发明，作为原料的所述化合物I包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I为固体形式。According to the present invention, the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I as a raw material is in solid form.
以下实施例中所使用的化合物I以及化合物I固体可根据现有技术制备得到，例如根据WO2016020864A1所记载的方法制备获得。The compound I and the compound I solid used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2016020864A1.
实施例1：晶型CSI的制备方法Example 1: Preparation method of crystalline CSI
称取10.3mg化合物I于玻璃小瓶中，加入0.3mL甲醇，溶清后过滤，所得滤液置于玻璃瓶中，用封口膜密封并扎10个小孔，室温下缓慢挥发析出固体，将该固体于35℃下真空干燥约3h后得到结晶固体。Weigh 10.3 mg of compound I into a glass vial, add 0.3 mL of methanol, dissolve and filter, place the filtrate in a glass bottle, seal with a sealing film and pierce 10 small holes, slowly evaporate at room temperature to precipitate a solid, and vacuum dry the solid at 35°C for about 3 hours to obtain a crystalline solid.
经检测，所得结晶固体为本发明晶型CSI，其X射线粉末衍射图如图1所示，X射线粉末衍射数据如表2所示。After testing, the obtained crystalline solid is the crystal form CSI of the present invention, and its X-ray powder diffraction pattern is shown in FIG1 , and the X-ray powder diffraction data are shown in Table 2.
TGA如图2所示，其加热至约200℃时，几乎无失重，晶型CSI为无水物。 As shown in Figure 2, TGA shows that when heated to about 200°C, there is almost no weight loss, and the crystalline form CSI is anhydrous.
表2

Table 2

实施例2：晶型CSI的DSC和1H NRMExample 2: DSC and 1 H NRM of Crystalline CSI
晶型CSI的DSC图如图3所示，其在约242℃存在一个吸热峰。The DSC graph of crystalline CSI is shown in FIG3 , which has an endothermic peak at about 242° C.
晶型CSI的核磁数据为：δ8.97–8.87(m,1H),8.68(s,1H),8.47–8.27(m,1H),8.17–8.06(m,1H),7.83–7.55(m,2H),7.21–7.13(m,1H),3.02–2.65(m,4H),1.54–1.24(m,4H),0.74(s,3H)，其中化合物I的5个活泼氢未出峰。核磁结果表明晶型CSI是化合物I的游离态晶型。The NMR data of the crystal form CSI are: δ8.97–8.87 (m, 1H), 8.68 (s, 1H), 8.47–8.27 (m, 1H), 8.17–8.06 (m, 1H), 7.83–7.55 (m, 2H), 7.21–7.13 (m, 1H), 3.02–2.65 (m, 4H), 1.54–1.24 (m, 4H), 0.74 (s, 3H), among which the five active hydrogens of compound I did not show peaks. The NMR results show that the crystal form CSI is the free state crystal form of compound I.
实施例3：晶型CSI的稳定性Example 3: Stability of Crystalline CSI
取适量晶型CSI，采用表3所示的包装条件，分别将其放置在25℃/60％RH，40℃/75％RH和60℃/75％RH条件下，采用XRPD测定晶型。结果如表3所示，XRPD对比图如图4和图5所示。结果表明本发明晶型CSI在25℃/60％RH和40℃/75％RH条件下至少可稳定9个月，晶型保持不变。可见，晶型CSI在长期和加速条件下均可保持良好的稳定性。晶型CSI在60℃/75％RH条件下至少可稳定2个月，晶型保持不变。可见，晶型CSI在更严苛的条件下稳定性也很好。Take an appropriate amount of crystalline CSI, use the packaging conditions shown in Table 3, place it under 25℃/60%RH, 40℃/75%RH and 60℃/75%RH respectively, and use XRPD to determine the crystal form. The results are shown in Table 3, and the XRPD comparison charts are shown in Figures 4 and 5. The results show that the crystalline CSI of the present invention can be stable for at least 9 months under 25℃/60%RH and 40℃/75%RH conditions, and the crystal form remains unchanged. It can be seen that the crystalline CSI can maintain good stability under both long-term and accelerated conditions. The crystalline CSI can be stable for at least 2 months under 60℃/75%RH conditions, and the crystal form remains unchanged. It can be seen that the crystalline CSI is also very stable under more stringent conditions.
表3
table 3
密封包装：将样品置于玻璃小瓶中，盖盖子密封于一层铝箔袋中。Sealed packaging: Place the sample in a glass vial, cover it with a lid and seal it in an aluminum foil bag.
敞口包装：将样品置于玻璃小瓶中，不盖盖子，敞口于对应环境下放置Open packaging: Place the sample in a glass vial without a lid and place it in an open environment.
实施例4：晶型CSI在机械力作用下的稳定性Example 4: Stability of Crystalline CSI under Mechanical Force
取适量晶型CSI和WO2016020864A1中的化合物I固体进行球磨，参数：500rpm，2min。球磨前后进行XRPD测试，结果分别如图6和图7所示。结果表明球磨前后晶型CSI的晶型不变且结晶度无明显变化，而WO2016020864A1中的化合物I固体球磨后结晶度明显下降且晶型发生变化。Take appropriate amounts of the solids of the crystalline form CSI and compound I in WO2016020864A1 for ball milling, parameters: 500rpm, 2min. XRPD tests were performed before and after ball milling, and the results are shown in Figures 6 and 7, respectively. The results show that the crystal form of the crystalline form CSI remains unchanged before and after ball milling, and the crystallinity does not change significantly, while the crystallinity of the solid compound I in WO2016020864A1 decreases significantly after ball milling and the crystal form changes.
取适量晶型CSI和WO2016020864A1中的化合物I固体，选择Φ6mm圆形平冲，在手动压片机下用5kN的压力压制成片，压片前后进行XRPD测试，结 果分别如图8和图9所示。结果表明压片前后晶型CSI的晶型无变化，WO2016020864A1中的化合物I固体晶型发生变化。可见，晶型CSI在机械力作用下具有更好的稳定性。Take appropriate amount of solid of compound I in crystalline form CSI and WO2016020864A1, select Φ6mm round flat punch, press into tablets with a pressure of 5kN on a manual tablet press, and perform XRPD test before and after tableting. The results are shown in Figures 8 and 9, respectively. The results show that the crystal form of crystal form CSI does not change before and after tableting, and the solid crystal form of compound I in WO2016020864A1 changes. It can be seen that crystal form CSI has better stability under mechanical force.
实施例5：晶型CSI的引湿性和湿度稳定性Example 5: Hygroscopicity and humidity stability of crystalline CSI
取各约10mg晶型CSI和WO2016020864A1中的化合物I固体采用动态水分吸附(DVS)仪试其引湿性，在0％RH-95％RH-0％RH下循环一次，记录每个湿度下的质量变化，并用XRPD测试DVS测试前后的样品晶型。实验结果如表4所示，晶型CSI和WO2016020864A1中的化合物I固体的DVS吸附曲线如图10和图11所示。晶型CSI在DVS测试前后的XRPD对比图如图12所示。结果表明晶型CSI从0％至80％RH的引湿增重为1.04％，且DVS测试前后晶型无变化。化合物I固体从0％至80％RH的引湿增重为11.46％，且DVS测试后化合物I固体晶型发生变化。可见，晶型CSI的引湿性更低，湿度稳定性更好。Take about 10 mg of each of the crystalline form CSI and the compound I solid in WO2016020864A1 and use a dynamic moisture sorption (DVS) instrument to test its hygroscopicity, cycle once at 0% RH-95% RH-0% RH, record the mass change at each humidity, and use XRPD to test the sample crystal form before and after the DVS test. The experimental results are shown in Table 4, and the DVS adsorption curves of the crystalline form CSI and the compound I solid in WO2016020864A1 are shown in Figures 10 and 11. The XRPD comparison diagram of the crystalline form CSI before and after the DVS test is shown in Figure 12. The results show that the crystalline form CSI has a hygroscopic weight gain of 1.04% from 0% to 80% RH, and there is no change in the crystal form before and after the DVS test. The hygroscopic weight gain of the compound I solid from 0% to 80% RH is 11.46%, and the solid crystal form of the compound I changes after the DVS test. It can be seen that the hygroscopicity of the crystalline form CSI is lower and the humidity stability is better.
表4
Table 4
实施例6：晶型CSI制剂制备Example 6: Preparation of Crystalline CSI Preparation
采用表5和表6所示的制剂处方以及表7所示的制剂工艺，制备晶型CSI制剂和空白混粉制剂。测试空白混粉和制剂处方前后样品的XRPD，结果如图13所示。结果表明，晶型CSI在制剂处方工艺前后晶型保持稳定。The crystalline CSI preparation and blank mixed powder preparation were prepared using the preparation prescriptions shown in Tables 5 and 6 and the preparation process shown in Table 7. The XRPD of the blank mixed powder and the samples before and after the preparation prescription were tested, and the results are shown in Figure 13. The results show that the crystalline form of crystalline CSI remains stable before and after the preparation prescription process.
表5
table 5
表6
Table 6
表7
Table 7
实施例7：晶型CSI制剂的稳定性Example 7: Stability of Crystalline CSI Formulations
将适量晶型CSI制剂样品采用密封包装，放置在25℃/60％RH和40℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表8，图14所示。结果表明晶型CSI制剂密封包装后可在25℃/60％RH以及40℃/75％RH下至少稳定1个月，且纯度无明显变化。可见晶型CSI制剂具有良好的稳定性。An appropriate amount of crystalline CSI preparation samples were sealed and placed under 25°C/60%RH and 40°C/75%RH conditions, and the purity and crystal form were determined by HPLC and XRPD. The results are shown in Table 8 and Figure 14. The results show that the crystalline CSI preparation can be stable for at least 1 month at 25°C/60%RH and 40°C/75%RH after sealing and packaging, and the purity does not change significantly. It can be seen that the crystalline CSI preparation has good stability.
表8
Table 8
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。 The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (9)

  1. 一种化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.3°±0.2°、15.0°±0.2°、23.7°±0.2°处具有特征峰，
    A crystalline form of compound I, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 8.3°±0.2°, 15.0°±0.2°, and 23.7°±0.2°,
  2. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为11.8°±0.2°、17.3°±0.2°、21.9°±0.2°的至少一处具有特征峰。The crystalline form of Compound I according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 11.8°±0.2°, 17.3°±0.2°, and 21.9°±0.2°.
  3. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.4°±0.2°、22.4°±0.2°的至少一处具有特征峰。The crystalline form of Compound I according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 18.4°±0.2° and 22.4°±0.2°.
  4. 根据权利要求2所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.4°±0.2°、22.4°±0.2°的至少一处具有特征峰。The crystalline form of Compound I according to claim 2, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 18.4°±0.2° and 22.4°±0.2°.
  5. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。The crystalline form of Compound I according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 1.
  6. 根据权利要求1所述的化合物I的晶型，其特征在于，为无水物。The crystalline form of Compound I according to claim 1, characterized in that it is an anhydrate.
  7. 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所述的化合物I的晶型及药学上可接受的辅料。A pharmaceutical composition comprising an effective therapeutic amount of the crystalline form of Compound I according to claim 1 and a pharmaceutically acceptable excipient.
  8. 一种抑制蛋白激酶C的方法，包括给有此需要的受试者施用权利要求1所述的化合物I的晶型。A method for inhibiting protein kinase C, comprising administering the crystalline form of Compound I according to claim 1 to a subject in need thereof.
  9. 一种治疗葡萄膜黑色素瘤的方法，包括给有此需要的受试者施用权利要求1所述的化合物I的晶型。 A method for treating uveal melanoma, comprising administering the crystalline form of Compound I according to claim 1 to a subject in need thereof.
PCT/CN2023/138380 2022-12-16 2023-12-13 Crystal form of darovasertib, method for preparing same, and use thereof WO2024125543A1 (en)

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