WO2018157742A1 - Sb-939的盐的晶型及其制备方法和用途 - Google Patents

Sb-939的盐的晶型及其制备方法和用途 Download PDF

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WO2018157742A1
WO2018157742A1 PCT/CN2018/076609 CN2018076609W WO2018157742A1 WO 2018157742 A1 WO2018157742 A1 WO 2018157742A1 CN 2018076609 W CN2018076609 W CN 2018076609W WO 2018157742 A1 WO2018157742 A1 WO 2018157742A1
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crystalline form
present
ray powder
solvent
crystal form
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PCT/CN2018/076609
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French (fr)
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陈敏华
张炎锋
高慧
刘启月
张晓宇
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苏州科睿思制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms

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  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystalline form of a salt of SB-939, a preparation method thereof and use thereof.
  • Histone Deacetylase (HDAC) inhibitors can inhibit DNA replication and RNA transcription of tumor cells, and can achieve the purpose of treating and preventing tumors.
  • HDAC Histone Deacetylase
  • HDAC inhibitors combined with demethylating drugs may have synergistic effects on the original cell epigenetics of acute myeloid leukemia (AML), which can restore the expression of tumor suppressor genes in vivo.
  • AML acute myeloid leukemia
  • SB-939 is an effective oral inhibitor of HDAC being developed by MEI Pharmaceuticals. SB-939 is clinically used for the treatment of prostate cancer, acute myeloid leukemia, and myelodysplastic syndrome, and has achieved good results.
  • the chemical name of SB-939 is: (2E)-3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxypropene Amide (hereinafter referred to as "compound (I)”), its chemical structural formula is as follows:
  • the present invention provides a novel crystalline form CS2 of the dihydrochloride salt of SB-939.
  • the new crystal form provided by the invention has low wettability, good stability, high crystal form purity and high solubility. It provides a new and better choice for the preparation of drugs containing SB-939, which is very important for drug development.
  • the main object of the present invention is to provide a crystal form of a salt of the compound (I), a preparation method thereof and use thereof.
  • the present invention also provides a crystal form CS2 of a dihydrochloride salt of the compound (I) (hereinafter referred to as "crystal form CS2").
  • the X-ray powder diffraction of the crystal form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 4.0° ⁇ 0.2°, 8.4 ⁇ 0.2°, and 10.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 21.6° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 21.6° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 17.3° ⁇ 0.2° and 11.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 17.3° ⁇ 0.2° and 11.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ of 4.0° ⁇ 0.2°, 8.4 ⁇ 0.2°, 10.7° ⁇ 0.2°, 21.6° ⁇ 0.2°, 20.5° ⁇ There are characteristic peaks at 0.2°, 24.5° ⁇ 0.2°, 17.3° ⁇ 0.2°, and 11.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form CS2, which comprises: placing SB-939 free base in acetone and adding an aqueous hydrochloride solution (SB-939 and HCl) The molar ratio is 1:2 to 1:3), and a solid is obtained by stirring; the solid is then dissolved in a single or mixed solvent of an alcohol, an aromatic hydrocarbon, a cyclic ether or water, and volatilized at room temperature.
  • SB-939 and HCl aqueous hydrochloride solution
  • the alcohol solvent is preferably methanol
  • the aromatic hydrocarbon solvent is preferably toluene
  • the cyclic ether solvent is preferably tetrahydrofuran.
  • the SB-939 free form or the dihydrochloride salt of SB-939 refers to the solid, semi-solid, wax or oil form of the compound (I) or its dihydrochloride salt.
  • the "room temperature” is not an accurate temperature value and refers to a temperature range of 10 to 30 °C.
  • the gas-solid permeation method in the present invention means that the starting material is placed in a closed environment having a specific solvent atmosphere, and the starting material is not directly contacted with the solvent, but is prepared by indirect contact of the solvent volatilization diffusion with the starting material. A new solid form method.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction patterns typically vary with instrumental conditions. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having the same or similar characteristic peaks as those in the 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 novel 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 crystal form CS2 provided by the present invention has a weight gain of 4.75% at 80% relative humidity, and has low wettability, which is favorable for long-term storage of medicines, and reduces material storage and quality control costs;
  • the crystal form CS2 provided by the invention has good stability, thereby ensuring that the quality standard of the sample is consistent and controllable, and meets the stringent requirements for the crystal form in the pharmaceutical application and the preparation process.
  • the crystalline form CS2 of the invention is stably placed for at least 6 weeks under the condition of 5 ° C closed condition, has good stability, and is favorable for preservation of the sample and stability of the preparation;
  • the crystal form CS2 provided by the present invention has high purity.
  • the purity of the crystalline form CS2 provided by the present invention is greater than 98%, and in another specific embodiment, the purity of the crystalline form CS2 provided by the present invention is greater than 99%;
  • the crystal form CS2 provided by the present invention has good solubility and solubility in water is higher than 10 mg/mL. High solubility can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug, and high doses can be used after oral administration to achieve the desired therapeutic blood concentration, which is beneficial to the absorption of the drug in the human body, thereby achieving The ideal bioavailability and efficacy of the drug meet the medicinal requirements.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form CS2 of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of the crystalline form CS2 of SB-939 for the preparation of a medicament for the treatment of prostate cancer and/or acute myeloid leukemia and/or myelodysplastic syndrome diseases.
  • Figure 1 is an XRPD pattern of a crystal form CS2 obtained according to Example 1 of the present invention.
  • FIG. 2 is an XRPD overlay of the crystal form CS2 of the present invention before and after being placed under a closed condition of 5 ° C (the upper image shows the XRPD pattern before placement, and the lower view shows the XRPD pattern after placement).
  • 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 dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorption instrument are as follows: temperature: 25 ° C
  • Relative humidity range 0%RH-95%RH
  • the lower moisture permeability of the crystalline form CS2 can overcome the drawbacks caused by the high wettability of the crystalline form of the drug, and simplify the preparation and post-treatment processes of the CS2 containing the crystalline form of the present invention, such as the process of preparing the process without having to control the environmental humidity, on the packaging and Storage conditions are not particularly demanding, cost-saving, easy to industrialize production and long-term storage of pharmaceuticals. Because the storage conditions are not demanding, the material storage and quality control costs will be greatly reduced, and it has strong economic value and is suitable for medicinal use.
  • Example 7 Stability study of crystalline form CS2
  • the crystal form CS2 of the present invention was placed under a closed condition of 5 ° C, and the samples before and after the placement were subjected to XRPD test. The results are shown in Table 4.
  • the stability of the drug is very important, especially during the commercial period. Maintaining good stability can reduce the risk of drug dissolution rate and bio-profit change due to crystal form changes, and ensure the efficacy and safety of the drug.
  • the occurrence of adverse drug reactions is of great significance.
  • the more stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystal, and it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent quality control of the sample and ensuring the preparation.
  • the dissolution profile of the product does not change as the storage time changes.
  • the purity of the crystalline form CS2 of the present invention was determined by HPLC to be 99.49%.
  • the purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • High impurity content will result in a significantly lower drug content or reduced activity, and a significant increase in toxic side effects, and therefore cannot be used as a bulk drug for the preparation of the formulation.
  • the crystal form CS2 of the invention has high purity and is advantageous for industrial production.
  • the crystal form of the invention has strong impurity elimination ability, and can also obtain a higher purity bulk drug by a crystallization process, so that the residual solvent of the sample is easy to reach the standard and meets the quality requirements, and is suitable for medicinal use.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

本发明涉及化合物（I）的盐的晶型及其制备方法和用途。本发明提供的新晶型CS2的引湿性较低、稳定性良好、晶型纯度高且溶解度高。为含化合物（I）药物的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

SB-939的盐的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及SB-939的盐的晶型及其制备方法和用途。
背景技术
组蛋白去乙酰化酶(Histone Deacetylase，简称HDAC)抑制剂可抑制肿瘤细胞的DNA复制和RNA转录，可达到治疗和预防肿瘤的目的。作为一类表观遗传修饰酶，HDAC对染色体的结构修饰和基因表达调控发挥着重要的作用。研究表明，HDAC抑制剂联合去甲基化药物可能会对急性髓性白血病(Acute Myeloid Leukemia，AML)原始细胞表观遗传学产生协同作用，使机体内抑癌基因的表达得以恢复。
Pracinostat，又称SB-939，是MEI制药公司正在开发的一种HDAC的有效口服抑制剂。SB-939临床用于治疗前列腺癌、急性髓性白血病、骨髓发育异常综合征，并取得了良好的效果。SB-939的化学名称为：(2E)-3-[2-丁基-1-[2-(二乙基氨基)乙基]-1H-苯并咪唑-5-基]-N-羟基丙烯酰胺(以下称为“化合物(I)”)，其化学结构式如下所示：
Figure PCTCN2018076609-appb-000001
在药物研究领域，不同的药物晶型具有不同的颜色、熔点、溶解度、溶出性能、化学稳定性、机械稳定性等，这些特性可以影响药物制剂的质量、安全性和有效性，从而导致临床药效差异。因此，晶型研究和控制成为药物研发过程中的重要研究内容。
目前没有SB-939相关的晶型信息报道，因此，需要开发SB-939的新晶型，寻找适合药用的优势晶型，以适于药物的工业化生产要求。本发明提供SB-939的二盐酸盐的新晶型CS2。本发明提供的新晶型引湿性较低、稳定性良好、晶型纯度高且溶解度高。为含SB-939的药物的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物(I)的盐的晶型及其制备方法和用途。
根据本发明的目的，本发明还提供化合物(I)的二盐酸盐的晶型CS2(以下称作“晶型CS2”)。
使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为4.0°±0.2°、8.4±0.2°、10.7°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为21.6°±0.2°、20.5°±0.2°、24.5°±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射线粉末衍射在衍射角2θ值为21.6°±0.2°、20.5°±0.2°、24.5°±0.2°处均有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为17.3°±0.2°、11.5°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为17.3°±0.2°、11.5°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS2的X射线粉末衍射在衍射角2θ值为4.0°±0.2°、8.4±0.2°、10.7°±0.2°、21.6°±0.2°、20.5°±0.2°、24.5°±0.2°、17.3°±0.2°、11.5°±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附图1所示。
根据本发明的目的，本发明还提供晶型CS2的制备方法，其特征在于，所述方法包括：将SB-939游离碱置于丙酮中，并加入盐酸盐水溶液(SB-939与HCl的摩尔比为1:2～1:3)，搅拌得到固体；后将该固体溶解在醇类、芳香烃类，环醚类、水的单一或混合溶剂中，于室温下挥发得到。
进一步的，所述醇类溶剂优选为甲醇，所述芳香烃类溶剂优选为甲苯，所述环醚类溶剂优选为四氢呋喃。
在本发明的晶型CS2的制备方法中：
所述SB-939游离形式或SB-939的二盐酸盐是指化合物(I)或其二盐酸盐的固体、半固体、蜡或油形式。所述“室温”不是精确的温度值，是指10～30℃温度范围。
本发明中所述气固渗透法是指：将起始原料置于具有特定溶剂氛围的密闭环境中，起始原料不直接与溶剂接触，而是通过溶剂挥发扩散与起始原料间接接触制备得到新固体形态的方法。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器 的条件变化而有所改变。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，本发明的新晶型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实验条件的不同，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。
本发明提供的新晶型具有以下有益效果：
(1)本发明提供的晶型CS2在80％相对湿度的增重量为4.75％，引湿性较低，有利于药品的长期贮存，降低物料储存以及质量控制成本；
(2)本发明提供的晶型CS2稳定性良好，从而保证样品的质量标准一致可控，符合药物应用及制剂工艺中对晶型的苛刻要求。本发明晶型CS2在5℃闭口条件下至少稳定放置6周，具有良好的稳定性，有利于样品的保存和制剂的稳定；
(3)本发明提供的晶型CS2纯度高。在具体的实施例中，本发明提供的晶型CS2纯度大于98％，在另一个具体的实施例中，本发明提供的晶型CS2的纯度大于99％；
(4)本发明提供的晶型CS2溶解性良好，在水中的溶解度高于10mg/mL。高溶解性可降低给药剂量从而降低药品的副作用并提高药品的安全性，且在口服后不需要高剂量即可达到所需的治疗血药浓度，有利于药物在人体内的吸收，从而达到理想的药物生物利用度和药效，符合药用要求。
此外，本发明提供一种药用组合物，所述药用组合物包含有效治疗量的本发明晶型CS2 以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步的，本发明提供SB-939的晶型CS2在制备治疗前列腺癌和/或急性髓性白血病和/或骨髓发育异常综合征疾病的药物中的用途。
附图说明
图1为根据本发明实施例1所得晶型CS2的XRPD图。
图2为本发明晶型CS2在5℃闭口条件下放置前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
具体实施方式
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DVS：动态水分吸附
采集数据所用的仪器及方法：
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
Kα1
Figure PCTCN2018076609-appb-000002
：1.540598；Kα2
Figure PCTCN2018076609-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。所述的动态水分吸附仪的方法参数如下：温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用到的SB-939游离形式是根据现有技术制备得到。
实施例1～5：晶型CS2的制备
称取约1克的SB-939游离碱，加入15毫升的丙酮，搅拌并滴加1毫升的6摩尔/升的 盐酸水溶液，室温下继续搅拌，离心收集固体。称取约20毫克上述得到的固体，溶于如表1所示的溶剂中，过滤后于室温下敞口置于通风橱中挥发5天，收集所得固体。实施例1～5所得样品分别标记为样品1～5，经检测，样品1～5均为晶型CS2。选取样品1进行测试表征，其X射线粉末衍射图如图1，数据如表2所示。选取样品2进行测试表征，其X射线粉末衍射数据如表3所示。
表1
实施例 溶剂 正溶剂体积(mL) 样品
1 甲醇/甲苯1:2 1.5 样品1
2 甲醇/四氢呋喃1:1 2.0 样品2
3 水/乙腈1:4 1.5 样品3
4 水/甲醇1:2 1.5 样品4
5 水/乙醇1:2 1.5 样品5
表2
衍射角2θ d值 相对强度(％)
4.00 22.10 100.00
7.02 12.58 15.52
8.40 10.53 54.79
10.74 8.24 84.62
11.45 7.73 20.60
12.87 6.88 16.71
15.33 5.78 8.46
16.22 5.46 12.87
17.38 5.10 25.78
18.73 4.74 12.62
20.54 4.32 87.28
21.65 4.11 56.56
22.71 3.92 37.35
24.43 3.64 64.36
25.55 3.49 33.90
表3
衍射角2θ d值 相对强度(％)
4.00 22.07 100.00
7.10 12.45 12.49
8.42 10.51 54.17
10.75 8.23 87.66
11.47 7.71 18.44
12.87 6.88 19.56
17.26 5.14 25.34
20.55 4.32 53.24
21.65 4.11 52.49
24.51 3.63 42.78
29.06 3.07 16.57
实施例6：晶型CS2的引湿性研究
在25℃条件下，取本发明的晶型CS2约10mg进行动态水分吸附(DVS)测试其引湿性，结果表明本发明的晶型CS2在80％相对湿度的增重量为4.75％，具有较低的引湿性。
晶型CS2较低的引湿性，能够克服药物晶型高引湿性带来的弊端，简化含本发明晶型CS2药物的制备与后处理工艺，如制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，适合药用。
实施例7：晶型CS2的稳定性研究
取本发明的晶型CS2置于5℃闭口条件下放置，对放置前后的样品进行XRPD测试。结果如表4所示。
表4
Figure PCTCN2018076609-appb-000004
结果表明，晶型CS2在5℃闭口条件下至少放置6周晶型保持不变，稳定性良好。
药物的稳定性至关重要，尤其在市售有效期内，保持较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的风险，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。更稳定的晶型在结晶工艺过程中更加可控，不容易出现混晶，且在制剂工艺及储存过程中，不容易转变成其它晶型，从而保证样品的质量标准一 致可控，并确保制剂产品的溶出曲线不会随着储存的时间变化而发生改变。
结果表明，本发明晶型CS2具有良好的稳定性，符合药物应用及制剂工艺中对晶型的苛刻要求。
实施例8：晶型CS2的纯度研究
采用HPLC测得本发明的晶型CS2的纯度为99.49％。药物的纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义。杂质含量高会使药物含量明显偏低或活性降低，毒副作用显著增加，因此不能作为原料药用于制剂的制备。
本发明晶型CS2的纯度较高，有利于工业化生产。本发明的晶型具有较强的杂质排除能力，且还可通过结晶工艺得到纯度更高的原料药，使得样品残留溶剂容易达标并符合质量要求，适合药用。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (7)

  1. 一种化合物(I)的二盐酸盐的晶型CS2，其特征在于，其X射线粉末衍射图在2θ值为4.0°±0.2°、8.4±0.2°、10.7°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS2，其特征还在于，其X射线粉末衍射图在2θ值为21.6°±0.2°、20.5°±0.2°、24.5°±0.2°的一处或两处或三处具有特征峰。
  3. 根据权利要求1或2所述的晶型CS2，其特征还在于，其X射线粉末衍射图在2θ值为17.3°±0.2°、11.5°±0.2°的一处或两处具有特征峰。
  4. 一种权利要求1所述的晶型CS2的制备方法，其特征在于，所述方法为：将SB-939游离碱置于丙酮中，并加入盐酸盐水溶液(SB-939与HCl的摩尔比为1:2～1:3)，搅拌得到固体；将该固体溶解在醇类、芳香烃类，环醚类、水的单一或混合溶剂中，于室温下挥发得到。
  5. 根据权利要求4所述的制备方法，其特征在于所述醇类溶剂为甲醇，所述芳香烃类溶剂为甲苯，所述环醚类溶剂为四氢呋喃。
  6. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的晶型CS2及药学上可接受的载体、稀释剂或赋形剂。
  7. 权利要求1所述的晶型CS2在制备治疗前列腺癌和/或急性髓性白血病和/或骨髓发育异常综合征疾病的药物中的用途。
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