WO2023143090A1 - 一种阿帕他胺溶剂化物新晶型及其制备方法 - Google Patents

一种阿帕他胺溶剂化物新晶型及其制备方法 Download PDF

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WO2023143090A1
WO2023143090A1 PCT/CN2023/071858 CN2023071858W WO2023143090A1 WO 2023143090 A1 WO2023143090 A1 WO 2023143090A1 CN 2023071858 W CN2023071858 W CN 2023071858W WO 2023143090 A1 WO2023143090 A1 WO 2023143090A1
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crystal form
apalutamide
solvate
hexafluoroisopropanol
preparation
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PCT/CN2023/071858
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English (en)
French (fr)
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王磊鑫
谷慧科
陈洪
王颖
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成都苑东生物制药股份有限公司
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Publication of WO2023143090A1 publication Critical patent/WO2023143090A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of pharmaceutical crystal forms, and in particular relates to a new crystal form N1 of apalutamide and a preparation method thereof.
  • Apalutamide (trade name Erleada, Ansenke) is an AR inhibitor, which was first developed by the University of California in the United States. In 2009, it authorized the exclusive development of Aragon Company of the United States. In August 2013, Johnson & Johnson acquired Aragon. Apalutamide is used for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mCSPC). Its original drug, Erleada, was first approved by the FDA on February 14, 2018. At present, Erleada has Approved for marketing in the US, EU, Japan and China. Apalutamide structure is shown in the following formula (I):
  • Solvent compounds are crystals formed by compound molecules and one or more solvent molecules in a certain combination form, and it is a relatively common form of existence of compounds. By forming a solvate, the physical and chemical properties of the drug can be improved, absorption can be promoted, bioavailability can be improved, and more options can be provided for the development of solid drug preparations.
  • Prior art WO2013184681A discloses crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I and crystalline form J of apalutamide , wherein the crystal form C is isopropanol solvate, the crystal form D is methyl tert-butyl ether solvate, the crystal form E is dimethyl sulfoxide solvate, and the crystal form G is 2-methoxyethanol solvent Form J is an acetone solvate.
  • the method of hot-melt extrusion can be used for granulation.
  • the solvent compound After melting at high temperature, the solvent compound will be desolvated and transformed into anhydrous crystal or amorphous form for preparation production.
  • the applicant of the present invention found that the boiling point of the solvent contained in crystal form C, crystal form E and crystal form G in the prior art is relatively high, and the risk of residual solvent in the finished product is relatively high during the preparation process; It is suitable for industrial scale-up; the stability of crystal form G and crystal form J is poor, which is not conducive to the preservation of drugs and the production of preparations.
  • the new crystal form N1 of the apalutamide solvate provided by the present application is hexafluoroisopropanol
  • the solvate has advantages in physical and chemical properties, preparation processing performance, etc., such as solvent boiling point, hygroscopicity, stability, etc., and its preparation method is green and environmentally friendly, with high yield, and is suitable for industrial production scale-up.
  • the present invention aims to provide a new crystal form N1 of apalutamide solvate and a preparation method thereof.
  • the present invention provides a new crystal form N1 of apalutamide solvate, specifically hexafluoroisopropanol solvate, and the molar ratio of apalutamide to hexafluoroisopropanol is 1:1.
  • the X-ray powder diffraction pattern of crystal form N1 is 6.780 ⁇ 0.2°, 9.320 ⁇ 0.2°, 13.776 ⁇ 0.2°, 14.957 ⁇ 0.2°, 18.398 ⁇ 0.2°, 19.078 ⁇ 0.2°, 21.421 ⁇ 0.2° at 2 ⁇ angle °, 23.336 ⁇ 0.2° and 26.441 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of crystal form N1 is 6.780 ⁇ 0.2°, 9.320 ⁇ 0.2°, 13.776 ⁇ 0.2°, 14.957 ⁇ 0.2°, 15.727 ⁇ 0.2°, 17.284 ⁇ 0.2°, 18.398 ⁇ 0.2° at 2 ⁇ angle °, 19.078 ⁇ 0.2°, 21.421 ⁇ 0.2°, 23.336 ⁇ 0.2°, 24.743 ⁇ 0.2° and 26.441 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of crystal form N1 is 6.780 ⁇ 0.2°, 9.320 ⁇ 0.2°, 12.448 ⁇ 0.2°, 13.776 ⁇ 0.2°, 14.957 ⁇ 0.2°, 15.727 ⁇ 0.2°, 17.284 ⁇ 0.2° at 2 ⁇ angle °, 18.398 ⁇ 0.2°, 19.078 ⁇ 0.2°, 20.121 ⁇ 0.2°, 21.421 ⁇ 0.2°, 23.336 ⁇ 0.2°, 24.743 ⁇ 0.2°, 26.441 ⁇ 0.2°, 27.863 ⁇ 0.2°, 28.478 ⁇ 0.2°, 29.102 ⁇ 0.2
  • the crystal form N1 has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the DSC spectrum of crystal form N1 has an endothermic peak at 176 ⁇ 5°C.
  • TGA spectrum of crystal form N1 is basically shown in FIG. 3 .
  • the adsorption weight change of crystal form N1 from 0% RH to 98% RH is 4.54%, and the adsorption water is less.
  • the present invention also provides a method for preparing the new crystal form N1 of the above-mentioned apalutamide solvate, the steps are as follows:
  • apalutamide the compound shown in formula (I)
  • hexafluoroisopropanol or a mixed solvent of hexafluoroisopropanol and other solvents suspending and beating at a certain temperature, and filtering after suspending for a certain period of time to obtain a white
  • the solid was dried to obtain a new crystal form N1 of apalutamide solvate.
  • the solvent can be a single solvent of hexafluoroisopropanol, or a mixture of hexafluoroisopropanol and water, n-hexane, cyclohexane, n-heptane and other solvents.
  • the mass of the solvent hexafluoroisopropanol used is 12 to 20 times, preferably 15 times, that of the starting material.
  • the mass of other solvents in the mixed solvent used is 15 to 25 times, preferably 20 times, that of the starting material.
  • suspension beating temperature is 5-50°C, preferably 25°C.
  • suspension and beating time is 10-48 hours, preferably 24 hours.
  • the obtained apalutamide crystal form N1 has good physical and chemical stability, crystal form stability and hygroscopicity.
  • the preparation process is simple, repeatable, high in yield, environmentally friendly, easy to operate, easy to recycle, and easy to realize large-scale enlarged production.
  • Figure 1 is the XRD pattern of apalutamide crystal form N1.
  • Figure 2 is the DSC chart of apalutamide crystal form N1.
  • Fig. 3 is a TGA diagram of apalutamide crystal form N1.
  • Fig. 4 is a DVS diagram of apalutamide crystal form N1.
  • Fig. 5 is a comparison chart of crystal forms of apalutamide crystal form J in stability investigation of factors affecting the stability.
  • Fig. 6 is a comparison chart of crystal forms of apalutamide crystal form G in the stability investigation of factors affecting the stability.
  • Fig. 7 is a comparison chart of crystal forms of apalutamide crystal form N1 affecting factors stability investigation.
  • Fig. 8 is a comparison chart of crystal forms of apalutamide crystal form J accelerated stability investigation.
  • Fig. 9 is a comparison chart of crystal forms of apalutamide crystal form G in accelerated stability investigation.
  • Fig. 10 is a comparison chart of crystal forms of apalutamide crystal form N1 after two months of accelerated stability investigation.
  • Fig. 11 is a comparison chart of crystal forms of apalutamide crystal form N1 accelerated stability investigation for 3 months.
  • Fig. 12 is a single crystal analysis molecular structure diagram of apalutamide crystal form N1.
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) described in this application is collected by METTLER TOLEDO model TGA-2, the heating rate is 10°C/min, the temperature range is 30-300°C, and the nitrogen purging rate during the test is 20mL /min.
  • a dynamic vapor adsorption instrument Q5000 (TA Instruments, USA) is used to detect the change of sample weight with humidity at 25°C. Specific parameters: Balance at 25°C and 0% relative humidity for 200 minutes, and then perform a 10% relative humidity jump every 150 minutes. If the weight change within 15 minutes is less than 0.01%, jump directly to 10% relative humidity, and the relative humidity reaches 98%. After 150 minutes, a relative humidity jump is performed in reverse. Relative humidity changes as follows: 0%—10%—20%—30%—40%—50%—60%—70%—80%—90%—98%—90%—80%—70%—60%— 50%-40%-30%-20%-10%-0%. Data analysis software TA Universal Analysis (TA Instruments, USA).
  • Example 12 Single crystal cultivation and single crystal diffraction of new crystal form N1 of apalutamide solvate
  • Test Example 1 Stability investigation experiment of new crystal form N1 of apalutamide solvate
  • Example 1 of the present invention In order to investigate the storage stability of the new crystal form N1 of apalutamide solvate prepared in Example 1 of the present invention, the obtained sample was placed under high temperature (60° C.), high humidity (RH92.5%) and light for 15 days to investigate its stability. Crystal form stability, the sample was placed under the accelerated stability conditions of 20°C/RH60% and 40°C/RH75% for 3 months to investigate its crystal form stability, the results are shown in Table 5 below:
  • Example 1 of the present invention In order to investigate the storage stability of the crystal form N1 prepared in Example 1 of the present invention, the comparative crystal form J and crystal form G, the obtained samples were placed under high temperature (60°C), high humidity (RH92.5%) and light The stability of its crystal form was investigated for 15 days, and the sample was placed under the accelerated stability conditions of 20°C/RH60% and 40°C/RH75% for 2 months to investigate its crystal form stability. The results are shown in Table 6 below:

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Abstract

提供一种阿帕他胺六氟异丙醇溶剂化物晶型N1及其制备方法，所得晶型N1具有较好的理化稳定性，晶型稳定性和吸湿性。其制备工艺简单重复性好，收率高，绿色环保，易于操作，便于回收，容易实现规模化放大生产。

Description

一种阿帕他胺溶剂化物新晶型及其制备方法 技术领域
本发明属于药物晶型领域，具体涉及一种阿帕他胺新晶型晶型N1及其制备方法。
背景技术
阿帕他胺(商品名Erleada，安森珂)是一种AR抑制剂，由美国加利福尼亚大学首先研制，2009年授权美国Aragon公司独家开发，2013年8月强生收购了Aragon。阿帕他胺用于治疗非转移性去势抵抗性前列腺癌(nmCRPC)和转移性激素敏感性前列腺癌(mCSPC)，其原研制剂Erleada于2018年2月14日首次获FDA批准上市，目前Erleada已在美国、欧盟、日本和中国获批上市。阿帕他胺结构如下式(I)所示：
溶剂化合物是化合物分子与一种或多种溶剂分子以一定结合形式共同形成的晶体，它是化合物种一种比较普遍的存在形式。通过形成溶剂化合物可以改善药物的物理化学性能，促进吸收，提高生物利用，为药物固体制剂的开发提供更多的选择。
现有技术WO2013184681A公开了阿帕他胺的晶型A，晶型B，晶型C，晶型D，晶型E，晶型F，晶型G，晶型H，晶型I和晶型J，其中晶型C为异丙醇溶剂合物，晶型D为甲基叔丁基醚溶剂合物，晶型E为二甲亚砜溶剂合物，晶型G是2-甲氧基乙醇溶剂合物，晶型J为丙酮溶剂合物。制剂生产中可以采用热熔挤出的方法进行制粒，通过高温加热熔融，溶剂化合物会脱溶剂转为无水晶型或无定型进行制剂生产。本发明申请人发现，现有技术中晶型C、晶型E和晶型G中所含溶剂沸点较高，制剂过程中成品溶剂残留风险较大；晶型D制备方法为静置缓慢挥发不适合工业放大；晶型G和晶型J的稳定性较差，不利于药物进行保存和制剂生产。
发明内容
本申请的发明人意外的发现了本申请提供的阿帕他胺溶剂化物新晶型N1，为六氟异丙醇 溶剂合物，其在理化性质、制剂加工性能等方面具有优势，例如在溶剂沸点，吸湿性，稳定性等方面具有优势，同时其制备方法绿色环保，收率高，适用于工业生产放大。
本发明旨在提供一种阿帕他胺溶剂化物新晶型N1及其制备方法。
本发明提供了一种阿帕他胺溶剂化物新晶型N1，具体为六氟异丙醇溶剂化合物，所述阿帕他胺与六氟异丙醇的摩尔比为1:1。
进一步地，晶型N1的X-射线粉末衍射图谱在2θ角为6.780±0.2°、9.320±0.2°、13.776±0.2°、14.957±0.2°、18.398±0.2°、19.078±0.2°、21.421±0.2°、23.336±0.2°和26.441±0.2°处有特征峰。
进一步地，晶型N1的X-射线粉末衍射图谱在2θ角为6.780±0.2°、9.320±0.2°、13.776±0.2°、14.957±0.2°、15.727±0.2°、17.284±0.2°、18.398±0.2°、19.078±0.2°、21.421±0.2°、23.336±0.2°、24.743±0.2°和26.441±0.2°处有特征峰。
进一步地，晶型N1的X-射线粉末衍射图谱在2θ角为6.780±0.2°、9.320±0.2°、12.448±0.2°、13.776±0.2°、14.957±0.2°、15.727±0.2°、17.284±0.2°、18.398±0.2°、19.078±0.2°、20.121±0.2°、21.421±0.2°、23.336±0.2°、24.743±0.2°、26.441±0.2°、27.863±0.2°、28.478±0.2°、29.102±0.2°、29.884±0.2°、30.992±0.2°、32.022±0.2°、33.738±0.2°、34.725±0.2°和36.893±0.2°处有特征峰。
更进一步地，晶型N1具有基本如图1所示的X射线粉末衍射图。
进一步地，晶型N1的DSC图谱在176±5℃处有吸热峰。
进一步地，晶型N1的DSC图谱基本如图2所示。
进一步地，晶型N1的TGA图谱基本如图3所示。
进一步地，晶型N1从0％RH到98％RH的吸附重量变化为4.54％，吸附水份较少。
进一步地，晶型N1的DVS图谱基本如图4所示。
本发明还提供了上述阿帕他胺溶剂化物新晶型N1的制备方法，步骤如下：
将式(I)所示化合物阿帕他胺加入到六氟异丙醇或六氟异丙醇与其他溶剂的混合溶剂中，在一定温度下进行混悬打浆，混悬一定时间后过滤得到白色固体，干燥得到阿帕他胺溶剂化物新晶型N1。
进一步地，溶剂可以选用六氟异丙醇单一溶剂，也可以选用六氟异丙醇与水、正己烷、环己烷、正庚烷等溶剂的混合。
进一步地，所用溶剂六氟异丙醇质量为起始原料质量的12～20倍，优选15倍。
进一步地，所用混合溶剂其他溶剂质量为起始原料质量的15～25倍，优选20倍。
进一步地，混悬打浆温度为5～50℃，优选25℃。
进一步地，混悬打浆时间为10～48h，优选24h。
本发明带来的有益效果有：
1.所得阿帕他胺晶型N1具有较好的理化稳定性，晶型稳定性和吸湿性。
2.其制备工艺简单重复性好，收率高，绿色环保，易于操作，便于回收，容易实现规模化放大生产。
附图说明
图1为阿帕他胺晶型N1的XRD图。
图2为阿帕他胺晶型N1的DSC图。
图3为阿帕他胺晶型N1的TGA图。
图4为阿帕他胺晶型N1的DVS图。
图5为阿帕他胺晶型J影响因素稳定性考察晶型对比图。
图6为阿帕他胺晶型G影响因素稳定性考察晶型对比图。
图7为阿帕他胺晶型N1影响因素稳定性考察晶型对比图。
图8为阿帕他胺晶型J加速稳定性考察晶型对比图。
图9为阿帕他胺晶型G加速稳定性考察晶型对比图。
图10为阿帕他胺晶型N1加速稳定性考察2个月晶型对比图。
图11为阿帕他胺晶型N1加速稳定性考察3个月晶型对比图。
图12为阿帕他胺晶型N1的单晶解析分子结构图。
具体实施方式
以下结合实施例对本发明作进一步的详细描述，但并非对本发明的限制，凡依照本发明公开内容所作的任何本领域的等同替换，均属于本发明的保护范围。
本申请中所用到的缩写的解释如下：
XRD：X射线粉末衍射
本申请所述的X射线粉末衍射(XRD)的测定是采用辽宁丹东浩元DX-2700B粉末衍射仪进行采集，具体参数如表1：
表1
DSC：差式扫描量热仪
本申请所述的差式扫描量热(DSC)的测定是采用METTLER TOLEDO型号DSC-1进行采集，升温速率为10℃/min，温度范围为25-250℃，测试过程中的氮气吹扫速率是60mL/min。
TGA：热重分析仪
本申请所述的热重分析(TGA)的测定是采用METTLER TOLEDO型号TGA-2进行采集，升温速率为10℃/min，温度范围为30-300℃，测试过程中的氮气吹扫速率是20mL/min。
DVS：动态蒸汽吸附仪
本申请所述的采用动态蒸汽吸附仪Q5000(美国TA仪器)检测25℃时样品重量随湿度的变化。具体参数：在25℃、0％相对湿度条件下平衡200min，之后每150min进行10％的相对湿度跳跃，如果每15min内重量变化小于0.01％直接跳跃10％的相对湿度，相对湿度达到98％，150min后逆向进行一次相对湿度跳跃。相对湿度变化如下：0％—10％—20％—30％—40％—50％—60％—70％—80％—90％—98％—90％—80％—70％—60％—50％—40％—30％—20％—10％—0％。数据分析软件TA Universal Analysis(美国TA仪器)。
X射线单晶衍射仪
本申请所述的单晶衍射数据测定是采用理学XtaL AB-PRO单晶X射线衍射仪进行采集，具体参数如下表：
表2

实施例1：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(75.0g)和水(100.0g)的混合溶剂，升温至25℃，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.85g，收率97.0％，XRD图谱如图1所示，DSC图谱如图2所示，TGA如图3所示，DVS图谱如图4所示。特征峰寻峰报表如表3所示：
表3
实施例2：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(60.0g)和水(75.0g)的混合溶剂，升温至25℃，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.55g，收率91.0％，XRD图谱与图1一致。
实施例3：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(100.0g)和水(125.0g)的混合溶剂，升温至25℃，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.64g，收率92.8％，XRD图谱与图1一致。
实施例4：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(75.0g)和水(100.0g)的混合溶剂，降温至5℃，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.91g，收率98.2％，XRD图谱与图1一致。
实施例5：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(75.0g)和水(100.0g)的混合溶剂，升温至50℃，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.21g，收率84.2％，XRD图谱与图1一致。
实施例6：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(75.0g)和水(100.0g)的混合溶剂，升温至25℃，在此温度下搅拌混悬析晶10h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.73g，收率94.6％，XRD图谱与图1一致。
实施例7：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇(75.0g)和水(100.0g)的混合溶剂，升温至25℃，在此温度下搅拌混悬析晶48h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.83g，收率96.6％，XRD图谱与图1一致。
实施例8：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇75.0g，降温至5℃，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N1 4.05g，收率81.0％，XRD图谱与图1一致。
实施例9：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇75.0g，室温下溶清后将125.0g正己烷加入溶液中，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N13.95g，收率79.0％，XRD图谱与图1一致。
实施例10：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇75.0g，室温下溶清后将125.0g环己烷加入溶液中，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N14.13g，收率82.6％，XRD图谱与图1一致。
实施例11：阿帕他胺溶剂化物新晶型N1的制备
称取阿帕他胺5.0g，加入六氟异丙醇75.0g，室温下溶清后将125.0g正庚烷加入溶液中，在此温度下搅拌混悬析晶24h，收集所得白色固体，干燥，得阿帕他胺溶剂化物新晶型N13.97g，收率79.4％，XRD图谱与图1一致。
实施例12：阿帕他胺溶剂化物新晶型N1的单晶培养及单晶衍射
称取阿帕他胺50.0mg，在室温下溶解于2.0g六氟异丙醇和0.5g水的混合溶剂中溶解，溶清后在室温下进行缓慢挥发得到单晶，所得单晶数据如表4所示，单晶解析分子结构图如图12所示。
表4阿帕他胺溶剂化物新晶型N1单晶数据
试验例1：阿帕他胺溶剂化物新晶型N1稳定性考察实验
为了考察本发明实施例1制备所得阿帕他胺溶剂化物新晶型N1的储存稳定性，将所得样品于高温(60℃)、高湿(RH92.5％)和光照下放置15天考察其晶型稳定性，将样品于20℃/RH60％和40℃/RH75％加速稳定性条件下放置3个月考察其晶型稳定性，结果如下表5所示：
表5阿帕他胺溶剂化物新晶型N1稳定性实验
稳定性试验结果如图7、图10和图11表明，阿帕他胺晶型N1在所考察的条件下均具有良好的晶型稳定性。
试验例2：对比晶型的稳定性考察实验
为了考察本发明实施例1制备所得晶型N1的对比晶型晶型J和晶型G的储存稳定性，将所得样品于高温(60℃)、高湿(RH92.5％)和光照下放置15天考察其晶型稳定性，将样品于20℃/RH60％和40℃/RH75％加速稳定性条件下放置2个月考察其晶型稳定性，结果如下表6所示：
表6对比晶型稳定性实验
稳定性试验结果，如图5和图8表明，晶型J在所有条件下放置转为晶型B；如图6和图9表明，晶型G只有在光照条件下晶型稳定，其他条件下均有晶型转为晶型B。与本申请 的晶型N1对比，晶型J和晶型G的晶型稳定性较差。

Claims (10)

  1. 一种阿帕他胺溶剂化物新晶型N1，其特征在于：所述溶剂化物为六氟异丙醇溶剂化合物，所述阿帕他胺与六氟异丙醇的摩尔比为1:1。
  2. 根据权利要求1所述的晶型N1，其特征在于，所述晶型N1的X-射线粉末衍射图谱在2θ角为6.780±0.2°、9.320±0.2°、13.776±0.2°、14.957±0.2°、18.398±0.2°、19.078±0.2°、21.421±0.2°、23.336±0.2°和26.441±0.2°处有特征峰。
  3. 根据权利要求2所述的晶型N1，其特征在于，所述晶型N1的X-射线粉末衍射图谱在2θ角为6.780±0.2°、9.320±0.2°、13.776±0.2°、14.957±0.2°、15.727±0.2°、17.284±0.2°、18.398±0.2°、19.078±0.2°、21.421±0.2°、23.336±0.2°、24.743±0.2°和26.441±0.2°处有特征峰。
  4. 根据权利要求3所述的晶型N1，其特征在于，所述晶型N1的X-射线粉末衍射图谱在2θ角为6.780±0.2°、9.320±0.2°、12.448±0.2°、13.776±0.2°、14.957±0.2°、15.727±0.2°、17.284±0.2°、18.398±0.2°、19.078±0.2°、20.121±0.2°、21.421±0.2°、23.336±0.2°、24.743±0.2°、26.441±0.2°、27.863±0.2°、28.478±0.2°、29.102±0.2°、29.884±0.2°、30.992±0.2°、32.022±0.2°、33.738±0.2°、34.725±0.2°和36.893±0.2°处有特征峰。
  5. 根据权利要求4所述的晶型N1，其特征在于，所述晶型N1具有基本如图1所示的X射线粉末衍射图。
  6. 根据权利要求1-5任一权利要求所述的晶型N1，其特征在于：所述晶型N1的DSC图谱在110.47±5℃处有吸热峰。
  7. 根据权利要求6所述的晶型N1，其特征在于：所述晶型N1的DSC图谱基本如图2所示。
  8. 根据权利要求1-5任一权利要求所述的晶型N1，其特征在于：所述晶型N1的TGA图谱基本如图3所示。
  9. 一种如权利要求1～8任一权利要求所述晶型N1的制备方法，其特征在于，包括以下步骤：将阿帕他胺加入到六氟异丙醇单一溶剂或六氟异丙醇与其他溶剂的混合溶剂中，在一定温度下进行混悬打浆，混悬一定时间后过滤得到白色固体，干燥得到阿帕他胺晶型N1。
  10. 根据权利要求9所述的制备方法，其特征在于，所述其他溶剂选自水、正己烷、环己烷或正庚烷；所述六氟异丙醇单一溶剂质量为起始原料质量的12～20倍，优选15倍；所述混合溶剂质量为起始原料质量的15～25倍，优选20倍；混悬打浆温度为5～50℃，优选25℃；混悬打浆时间为10～48h，优选24h。
PCT/CN2023/071858 2022-01-25 2023-01-12 一种阿帕他胺溶剂化物新晶型及其制备方法 WO2023143090A1 (zh)

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CN104619692A (zh) * 2012-06-07 2015-05-13 阿拉贡药品公司 雄激素受体调节剂的晶形
WO2018112001A1 (en) * 2016-12-13 2018-06-21 Watson Laboratories Inc. Solid state forms of apalutamide
IN201741043701A (zh) * 2017-12-06 2019-06-07
WO2019242439A1 (zh) * 2018-06-20 2019-12-26 苏州科睿思制药有限公司 Arn-509的晶型及其制备方法和用途
CN112679468A (zh) * 2021-01-05 2021-04-20 四川科伦药物研究院有限公司 阿帕他胺的晶体形式、制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104619692A (zh) * 2012-06-07 2015-05-13 阿拉贡药品公司 雄激素受体调节剂的晶形
WO2018112001A1 (en) * 2016-12-13 2018-06-21 Watson Laboratories Inc. Solid state forms of apalutamide
IN201741043701A (zh) * 2017-12-06 2019-06-07
WO2019242439A1 (zh) * 2018-06-20 2019-12-26 苏州科睿思制药有限公司 Arn-509的晶型及其制备方法和用途
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