技术领域technical field
本发明涉及作为JAK抑制剂的巴瑞克替尼三氟乙酸盐的多晶型，具体地，涉及巴瑞克替尼三氟乙酸盐A晶型和B晶型及其制备方法。The present invention relates to polymorphic forms of baricitinib trifluoroacetate salt as a JAK inhibitor, in particular, to baricitinib trifluoroacetic acid salt A crystal form and B crystal form and a preparation method thereof.
背景技术Background technique
JAK即两面神激酶(Janus Kinase)，是一种非受体型酪氨酸蛋白激酶，也是一类非跨膜型的酪氨酸激酶。这是因为JAK既能磷酸化与其相结合的细胞因子受体，又能磷酸化多个含特定SH2结构域的信号分子。JAK蛋白家族共包括4个成员：JAK1、JAK2、JAK3以及TYK2，它们在结构上有7个JAK同源结构域(JAK homology domain,JH)，其中JH1结构域为激酶区、JH2结构域是“假”激酶区、JH6和JH7是受体结合区域。JAK, Janus Kinase, is a non-receptor tyrosine protein kinase and a non-transmembrane tyrosine kinase. This is because JAK can not only phosphorylate the cytokine receptors associated with it, but also phosphorylate multiple signaling molecules containing specific SH2 domains. The JAK protein family consists of four members: JAK1, JAK2, JAK3 and TYK2, which have seven JAK homology domains (JAK homology domain, JH) in structure, of which the JH1 domain is the kinase domain and the JH2 domain is the " The "pseudo" kinase domain, JH6 and JH7, are receptor binding regions.
TYK2是免疫炎性疾病的潜在靶点，已经通过人遗传学和小鼠剔除研究确证(LevyD.和Loomis C.，New England Journal of Medicine 357(2007年)1655-1658页)。TYK2 is a potential target for immunoinflammatory diseases, which has been confirmed by human genetics and mouse knockout studies (Levy D. and Loomis C., New England Journal of Medicine 357 (2007) pp. 1655-1658).
JAK1是免疫炎性疾病领域的新靶点。将JAK1与其它JAK杂二聚化，能转导细胞因子驱动的促炎信号传导。因此，预期抑制JAK1和或其它JAK对于一系列炎性病症和其它由JAK介导的信号转导驱动的疾病是有治疗益处的。JAK1 is a novel target in the field of immunoinflammatory diseases. Heterodimerization of JAK1 with other JAKs transduces cytokine-driven pro-inflammatory signaling. Therefore, inhibition of JAK1 and or other JAKs is expected to be of therapeutic benefit for a range of inflammatory disorders and other diseases driven by JAK-mediated signaling.
本发明中的巴瑞克替尼(Baricitinib)三氟乙酸盐是化学名为{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈三氟乙酸盐，如式(I)所示的化合物，Baricitinib (Baricitinib) trifluoroacetate in the present invention has the chemical name of {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl] azetidin-3-yl} acetonitrile trifluoroacetate, as the compound shown in formula (I),
其是一种JAK类抑制剂化合物，可用于治疗JAK参与的自身免疫疾病、炎性疾病或癌症疾病。在中国发明专利CN 102026999(WO 2009/114512)中，公开了该化合物及其衍生物，本发明中称为“巴瑞克替尼三氟乙酸盐半晶体”。It is a JAK inhibitor compound and can be used for treating autoimmune diseases, inflammatory diseases or cancer diseases in which JAK is involved. In the Chinese invention patent CN 102026999 (WO 2009/114512), the compound and its derivatives are disclosed, which are called "baricitinib trifluoroacetate semi-crystal" in the present invention.
众所周知，同一种药物，晶型不同，其生物利用度也可能会存在差别，另外其稳定性、流动性、可压缩性也可能会不同，这些理化性质对药物的应用产生一定的影响，从而影响药物的疗效。因此，需要具有优越的生理化学特性的巴瑞克替尼三氟乙酸盐的晶型，其可有利地在药物加工和药物组合物中使用。本发明研制的巴瑞克替尼三氟乙酸盐的新晶型未见报道。As we all know, the same drug has different crystal forms, and its bioavailability may also be different. In addition, its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug, thereby affecting The efficacy of the drug. Therefore, there is a need for a crystalline form of baricitinib trifluoroacetate with superior physiochemical properties, which can be advantageously used in pharmaceutical processing and pharmaceutical compositions. The new crystal form of baricitinib trifluoroacetate developed by the present invention has not been reported.
发明内容Contents of the invention
本发明所要解决的问题是现有巴瑞克替尼三氟乙酸盐稳定性有待提高而影响生物利用度的问题，同时希望能够寻求巴瑞克替尼三氟乙酸盐的新晶型，为固体药物的疗效研究提供更多的定性定量信息。The problem to be solved by the present invention is the problem that the stability of the existing baricitinib trifluoroacetate needs to be improved to affect the bioavailability. At the same time, it is hoped that a new crystal form of baricitinib trifluoroacetate can be sought, Provide more qualitative and quantitative information for the curative effect research of solid medicine.
为了解决上述技术问题，本发明的第一个方面提供了一种巴瑞克替尼三氟乙酸盐的新的晶型，更具体地，为{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈三氟乙酸盐的新的晶型(以下称“巴瑞克替尼三氟乙酸盐A晶型”)，其XRPD图谱在2θ＝8.60，10.12，10.72，14.02，16.66，17.24，17.84，18.90，19.54，20.26，21.54，21.94，23.40，23.78，24.66，25.64，25.98，26.32，27.12，28.16，30.34，31.12处有衍射峰，其中2θ值误差范围为±0.2。In order to solve the above technical problems, the first aspect of the present invention provides a new crystal form of baricitinib trifluoroacetate, more specifically, {1-(ethylsulfonyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trifluoroacetate Crystal form (hereinafter referred to as "baricitinib trifluoroacetate salt A crystal form"), its XRPD spectrum is at 2θ=8.60, 10.12, 10.72, 14.02, 16.66, 17.24, 17.84, 18.90, 19.54, 20.26, 21.54, There are diffraction peaks at 21.94, 23.40, 23.78, 24.66, 25.64, 25.98, 26.32, 27.12, 28.16, 30.34, and 31.12, and the error range of the 2θ value is ±0.2.
本发明所述的巴瑞克替尼三氟乙酸盐A晶型，具有与说明书附图图1基本上相同的XRPD图谱。The crystal form A of baricitinib trifluoroacetate according to the present invention has substantially the same XRPD pattern as that in Fig. 1 of the attached drawing of the specification.
本发明还提供了制备巴瑞克替尼三氟乙酸盐A晶型的方法，包括以下步骤：The present invention also provides a method for preparing the crystal form A of baricitinib trifluoroacetate, comprising the following steps:
(1)将用于溶解的有机溶剂加入巴瑞克替尼三氟乙酸盐半晶体中得到巴瑞克替尼三氟乙酸盐半晶体的溶液，并且升高所述溶液的温度；(1) adding an organic solvent for dissolving to baricitinib trifluoroacetate semi-crystals to obtain a solution of baricitinib trifluoroacetate semi-crystals, and increasing the temperature of the solution;
(2)对所述巴瑞克替尼三氟乙酸盐半晶体的溶液进行超声，并快速冷却至室温或低于室温的温度，得到悬浮液；(2) ultrasonicating the solution of baricitinib trifluoroacetate semi-crystals, and rapidly cooling to room temperature or a temperature lower than room temperature to obtain a suspension;
(3)将所得悬浮液过滤得到巴瑞克替尼三氟乙酸盐A晶型。(3) The resulting suspension was filtered to obtain the A crystal form of baricitinib trifluoroacetate.
在一些实施例中，所述用于溶解的有机溶剂为酮类中的任意一种溶剂或者两种以上溶剂以任意比例的混合溶剂。In some embodiments, the organic solvent used for dissolving is any one solvent among ketones or a mixed solvent of two or more solvents in any proportion.
在一些优选的实施方式中，所述用于溶解的有机溶剂为丙酮。In some preferred embodiments, the organic solvent used for dissolving is acetone.
在一些实施例中，上述步骤(2)的所述溶液中所述巴瑞克替尼三氟乙酸盐半晶体与所述有机溶剂的初始比例为不小于80:1mg/mL。In some embodiments, the initial ratio of the baricitinib trifluoroacetate salt semi-crystal to the organic solvent in the solution of the above step (2) is not less than 80:1 mg/mL.
在一些实施例中，上述步骤(2)的所述溶液中所述巴瑞克替尼三氟乙酸盐半晶体与所述有机溶剂的初始比例在80:1mg/mL至120:1mg/mL的范围内。在一些优选实施例中，上述步骤(2)的所述溶液中所述巴瑞克替尼三氟乙酸盐半晶体与所述有机溶剂的初始比例为100:1mg/mL。In some embodiments, the initial ratio of the semi-crystal of baricitinib trifluoroacetate to the organic solvent in the solution of the above step (2) is 80:1 mg/mL to 120:1 mg/mL In the range. In some preferred embodiments, the initial ratio of the baricitinib trifluoroacetate salt semi-crystal to the organic solvent in the solution of the above step (2) is 100:1 mg/mL.
在一些实施例中，所述溶液的温度为40至80℃。具体温度一般由所用溶剂的沸点决定。比如，在具体实施例中丙酮沸点为55℃；同时高温下溶质易发生变质。所以，在优选的实施例中，所述溶液的温度为50℃至54℃。In some embodiments, the temperature of the solution is 40 to 80°C. The specific temperature is generally determined by the boiling point of the solvent used. For example, in a specific embodiment, the boiling point of acetone is 55° C.; meanwhile, the solute is prone to deterioration at high temperature. Therefore, in a preferred embodiment, the temperature of the solution is 50°C to 54°C.
在一些实施例中，所述低于室温的温度为0～20℃。In some embodiments, the temperature below room temperature is 0-20°C.
此外，本发明的第二个方面提供了另一种巴瑞克替尼三氟乙酸盐的新的晶型，更具体地，为{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈三氟乙酸盐的新的晶型(以下称“巴瑞克替尼三氟乙酸盐B晶型”)，其XRPD图谱在2θ＝5.34，9.00，10.08，10.70，16.12，17.44，17.80，18.92，19.48，20.22，21.56，22.68，23.42，23.98，25.84，27.22，28.76，29.46，32.66处有衍射峰，其中2θ值误差范围为±0.2。In addition, the second aspect of the present invention provides another new crystal form of baricitinib trifluoroacetate, more specifically, {1-(ethylsulfonyl)-3-[4- A new crystal form of (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trifluoroacetate ( Hereinafter referred to as "Baricitinib Trifluoroacetate Salt Form B"), its XRPD spectrum is at 2θ=5.34, 9.00, 10.08, 10.70, 16.12, 17.44, 17.80, 18.92, 19.48, 20.22, 21.56, 22.68, 23.42 , There are diffraction peaks at 23.98, 25.84, 27.22, 28.76, 29.46, and 32.66, and the error range of the 2θ value is ±0.2.
本发明所述的巴瑞克替尼三氟乙酸盐B晶型，具有与说明书附图图8基本上相同的XRPD图谱。The crystal form B of baricitinib trifluoroacetate according to the present invention has substantially the same XRPD pattern as that shown in Figure 8 of the accompanying drawing.
本发明还提供了制备巴瑞克替尼三氟乙酸盐B晶型的方法，包括以下步骤：The present invention also provides a method for preparing the crystal form B of baricitinib trifluoroacetate, comprising the following steps:
(1)将有机溶剂加入巴瑞克替尼三氟乙酸盐半晶体中得到巴瑞克替尼三氟乙酸盐的悬浮物，并且升高所述悬浮物的温度；(1) adding an organic solvent to baricitinib trifluoroacetate semi-crystals to obtain a suspension of baricitinib trifluoroacetate, and increasing the temperature of the suspension;
(2)将所述巴瑞克替尼三氟乙酸盐的悬浮物悬浮一定时间后向其中加入有机溶剂继续悬浮，然后冷却；(2) After suspending the suspension of baricitinib trifluoroacetate for a certain period of time, an organic solvent is added therein to continue the suspension, and then cooled;
(3)将冷却后的所述巴瑞克替尼三氟乙酸盐的悬浮物过滤并干燥，得到巴瑞克替尼三氟乙酸盐B晶型。(3) The cooled suspension of baricitinib trifluoroacetate was filtered and dried to obtain the B crystal form of baricitinib trifluoroacetate.
在一些实施例中，所述有机溶剂为酮类中的任意一种溶剂或者两种以上溶剂以任意比例的混合溶剂。In some embodiments, the organic solvent is any one of ketones or a mixed solvent of two or more solvents in any proportion.
在一些优选实施例中，所述有机溶剂为丙酮。In some preferred embodiments, the organic solvent is acetone.
在一些实施例中，所述巴瑞克替尼三氟乙酸盐半晶体与所述有机溶剂的初始比例为不小于200:1mg/mL。其原因在于，巴瑞克替尼三氟乙酸盐的丙酮饱和溶液浓度大约为100:1mg/mL，为了采用悬浮转晶法获得结晶，使用本发明的溶剂溶质比例来得到悬浮物，即大于丙酮饱和溶液的浓度。In some embodiments, the initial ratio of the semi-crystals of baricitinib trifluoroacetate to the organic solvent is not less than 200:1 mg/mL. The reason is that the acetone saturated solution concentration of baricitinib trifluoroacetate is about 100:1mg/mL, in order to adopt the suspension crystallization method to obtain crystallization, the solvent-solute ratio of the present invention is used to obtain the suspension, which is greater than The concentration of a saturated solution of acetone.
在一些实施例中，所述巴瑞克替尼三氟乙酸盐半晶体与所述有机溶剂的初始比例在200:1mg/mL至300:1mg/mL的范围内。在一些优选实施例中，所述巴瑞克替尼三氟乙酸盐半晶体与所述有机溶剂的初始比例为250:1mg/mL。In some embodiments, the initial ratio of baricitinib trifluoroacetate salt semi-crystals to the organic solvent is in the range of 200:1 mg/mL to 300:1 mg/mL. In some preferred embodiments, the initial ratio of the baricitinib trifluoroacetate salt semi-crystal to the organic solvent is 250:1 mg/mL.
在一些实施例中，所述步骤(2)中悬浮巴瑞克替尼三氟乙酸盐的悬浮物的温度为40℃至80℃。具体温度一般由所用溶剂的沸点决定。比如，在具体实施例中丙酮沸点为55℃；同时高温下溶质易发生变质。所以，在优选的实施例中，所述悬浮物的温度为50℃至54℃。In some embodiments, the temperature of the suspension of baricitinib trifluoroacetate in the step (2) is 40°C to 80°C. The specific temperature is generally determined by the boiling point of the solvent used. For example, in a specific embodiment, the boiling point of acetone is 55° C.; meanwhile, the solute is prone to deterioration at high temperature. Therefore, in a preferred embodiment, the temperature of the suspension is 50°C to 54°C.
在一优选些实施例中，所述步骤(2)中加入有机溶剂的量为所述步骤(1)中加入有机溶剂的量的50％。In some preferred embodiments, the amount of the organic solvent added in the step (2) is 50% of the amount of the organic solvent added in the step (1).
在一优选些实施例中，在所述步骤(2)中将悬浮物冷却至室温。In some preferred embodiments, in the step (2), the suspension is cooled to room temperature.
本领域普通技术人员可以根据其知识和经验，对本发明方法所用试剂的用量进行调整，包括按比例放大或缩小原料用量和调整溶剂用量，并且可以改变本发明方法的温度。这些调整的方案也包含在本发明的方法中。Those skilled in the art can adjust the amount of reagents used in the method of the present invention based on their knowledge and experience, including scaling up or down the amount of raw materials and adjusting the amount of solvent, and can change the temperature of the method of the present invention. These adjustments are also included in the method of the present invention.
本发明所述的巴瑞克替尼三氟乙酸盐A晶型和B晶型，其稳定性都高于巴瑞克替尼三氟乙酸盐半晶型，有利于其药物加工和在药物组合物中的使用。巴瑞克替尼三氟乙酸盐A晶型和B晶型可以在治疗自身免疫疾病、炎性疾病或癌症的药物中应用，并且具有较高的稳定性，同时提供的定性定量信息，对进一步研究此类固体药物的疗效具有重要的意义。The A crystal form and the B crystal form of baricitinib trifluoroacetate described in the present invention have higher stability than the semi-crystalline form of baricitinib trifluoroacetate, which is beneficial to its pharmaceutical processing and Use in pharmaceutical compositions. Baricitinib trifluoroacetate crystal form A and B crystal form can be used in drugs for the treatment of autoimmune diseases, inflammatory diseases or cancer, and have high stability, and provide qualitative and quantitative information, which is helpful for It is of great significance to further study the curative effect of this kind of solid medicine.
附图说明Description of drawings
图1为本发明提供的巴瑞克替尼三氟乙酸盐A晶型的XRPD图谱。Fig. 1 is the XRPD spectrum of the crystal form A of baricitinib trifluoroacetate salt provided by the present invention.
图2为本发明提供的巴瑞克替尼三氟乙酸盐A晶型五天高温稳定性的XRPD图谱。Fig. 2 is the XRPD spectrum of the five-day high-temperature stability of baricitinib trifluoroacetate salt A crystal form provided by the present invention.
图3为本发明提供的巴瑞克替尼三氟乙酸盐A晶型十天高温稳定性的XRPD图谱。Fig. 3 is the XRPD spectrum of the ten-day high-temperature stability of baricitinib trifluoroacetate salt A crystal form provided by the present invention.
图4为本发明提供的巴瑞克替尼三氟乙酸盐A晶型五天高湿稳定性的XRPD图谱。Fig. 4 is the XRPD spectrum of the five-day high-humidity stability of baricitinib trifluoroacetate salt A crystal form provided by the present invention.
图5为本发明提供的巴瑞克替尼三氟乙酸盐A晶型十天高湿稳定性的XRPD图谱。Fig. 5 is the XRPD spectrum of the 10-day high-humidity stability of baricitinib trifluoroacetate salt A crystal form provided by the present invention.
图6为本发明提供的巴瑞克替尼三氟乙酸盐A晶型五天光照稳定性的XRPD图谱。Fig. 6 is the XRPD spectrum of the five-day light stability of baricitinib trifluoroacetate salt A crystal form provided by the present invention.
图7为本发明提供的巴瑞克替尼三氟乙酸盐A晶型十天光照稳定性的XRPD图谱。Fig. 7 is the XRPD spectrum of the ten-day light stability of baricitinib trifluoroacetate salt A crystal form provided by the present invention.
图8为本发明提供的巴瑞克替尼三氟乙酸盐B晶型的XRPD图谱。Fig. 8 is the XRPD pattern of the crystal form B of baricitinib trifluoroacetate salt provided by the present invention.
图9为本发明提供的巴瑞克替尼三氟乙酸盐B晶型五天高温稳定性的XRPD图谱。Fig. 9 is the XRPD spectrum of the five-day high-temperature stability of baricitinib trifluoroacetate salt B crystal form provided by the present invention.
图10为本发明提供的巴瑞克替尼三氟乙酸盐B晶型十天高温稳定性的XRPD图谱。Fig. 10 is the XRPD spectrum of the ten-day high-temperature stability of baricitinib trifluoroacetate salt B crystal form provided by the present invention.
图11为本发明提供的巴瑞克替尼三氟乙酸盐B晶型五天高湿稳定性的XRPD图谱。Figure 11 is the XRPD spectrum of the five-day high-humidity stability of baricitinib trifluoroacetate salt form B provided by the present invention.
图12为本发明提供的巴瑞克替尼三氟乙酸盐B晶型十天高湿稳定性的XRPD图谱。Figure 12 is the XRPD spectrum of the 10-day high-humidity stability of baricitinib trifluoroacetate salt form B provided by the present invention.
图13为本发明提供的巴瑞克替尼三氟乙酸盐B晶型五天光照稳定性的XRPD图谱。Figure 13 is the XRPD spectrum of the five-day light stability of baricitinib trifluoroacetate salt B crystal form provided by the present invention.
图14为本发明提供的巴瑞克替尼三氟乙酸盐B晶型十天光照稳定性的XRPD图谱。Figure 14 is the XRPD spectrum of the ten-day light stability of baricitinib trifluoroacetate salt B crystal form provided by the present invention.
图15为现有的巴瑞克替尼三氟乙酸盐半晶体的XRPD图谱。Figure 15 is the XRPD pattern of the existing semi-crystal of baricitinib trifluoroacetate.
图16为现有的巴瑞克替尼三氟乙酸盐半晶体五天高温稳定性的XRPD图谱。Figure 16 is the XRPD pattern of the five-day high temperature stability of the existing baricitinib trifluoroacetate semi-crystal.
图17为现有的巴瑞克替尼三氟乙酸盐半晶体十天高温稳定性的XRPD图谱。Figure 17 is the XRPD pattern of the ten-day high temperature stability of the existing baricitinib trifluoroacetate salt semi-crystal.
图18为现有的巴瑞克替尼三氟乙酸盐半晶体五天高湿稳定性的XRPD图谱。Figure 18 is the XRPD pattern of the five-day high-humidity stability of the existing baricitinib trifluoroacetate semi-crystal.
图19为现有的巴瑞克替尼三氟乙酸盐半晶体十天高湿稳定性的XRPD图谱。Figure 19 is the XRPD pattern of the existing baricitinib trifluoroacetate salt semi-crystal ten-day high-humidity stability.
图20为现有的巴瑞克替尼三氟乙酸盐半晶体五天光照稳定性的XRPD图谱。Figure 20 is the XRPD pattern of the five-day light stability of the existing baricitinib trifluoroacetate salt semi-crystal.
图21为现有的巴瑞克替尼三氟乙酸盐半晶体十天光照稳定性的XRPD图谱。Figure 21 is the XRPD spectrum of the ten-day light stability of the existing baricitinib trifluoroacetate semi-crystal.
具体实施方式detailed description
从下文的详细描述中，本发明的上述方面和本发明的其他方面将是明显的。The above aspects of the invention and other aspects of the invention will be apparent from the following detailed description.
实施例1巴瑞克替尼三氟乙酸盐A晶型的制备Example 1 Preparation of crystal form A of baricitinib trifluoroacetate
将巴瑞克替尼三氟乙酸盐半晶体400mg加入4mL丙酮中，配制成50℃下的溶液，将该溶液在超声条件下快速冷却至15℃后过滤，干燥得到固体，称量固体重量为106mg。Add 400 mg of baricitinib trifluoroacetate semi-crystals into 4 mL of acetone to prepare a solution at 50 ° C, and the solution is rapidly cooled to 15 ° C under ultrasonic conditions, then filtered, dried to obtain a solid, and the weight of the solid is weighed is 106mg.
实施例2巴瑞克替尼三氟乙酸盐A晶型的制备Example 2 Preparation of crystal form A of baricitinib trifluoroacetate
将巴瑞克替尼三氟乙酸盐半晶体400mg加入3.3mL丙酮中，配制成54℃下的溶液，将该溶液在超声条件下快速冷却至0℃后过滤，干燥得到固体，称量固体重量为113mg。Add 400 mg of baricitinib trifluoroacetate semi-crystals into 3.3 mL of acetone to prepare a solution at 54°C. The solution is rapidly cooled to 0°C under ultrasonic conditions, filtered, and dried to obtain a solid. Weigh the solid The weight is 113mg.
实施例3巴瑞克替尼三氟乙酸盐A晶型的制备Example 3 Preparation of crystal form A of baricitinib trifluoroacetate
将巴瑞克替尼三氟乙酸盐半晶体400mg加入5mL丙酮中，配制成52℃下的溶液，将该溶液在超声条件下快速冷却至20℃后过滤，干燥得到固体，称量固体重量为97mg。Add 400 mg of baricitinib trifluoroacetate semi-crystals into 5 mL of acetone to prepare a solution at 52 °C, and then quickly cool the solution to 20 °C under ultrasonic conditions, then filter, dry to obtain a solid, and weigh the weight of the solid is 97mg.
实施例4通过XRPD图来表征巴瑞克替尼三氟乙酸盐A晶型Example 4 Characterization of baricitinib trifluoroacetate A crystal form by XRPD pattern
X射线粉末衍射(XRPD)图谱的测量，使用Rigaku Ultima IV型号组合式多功能X射线衍射仪进行，具体采集信息如下：Cu阳极(40kV，40mA)，扫描速度20°/分钟、扫描范围(2θ范围)3～45°、扫描步长0.02、狭缝宽度0.01。采用载玻片直接在测试板压制对样品进行处理。其后的XRPD图谱均采用类似的测量方法。The measurement of the X-ray powder diffraction (XRPD) pattern was carried out using the Rigaku Ultima IV model combined multifunctional X-ray diffractometer. The specific collection information is as follows: Cu anode (40kV, 40mA), scanning speed 20°/min, scanning range (2θ Range) 3～45°, scan step size 0.02, slit width 0.01. Samples were processed using glass slides pressed directly onto the test plate. Subsequent XRPD patterns all adopt similar measurement methods.
测定根据实施例1所述方法制备的巴瑞克替尼三氟乙酸盐A晶型的XRPD图谱，在2θ＝8.60，10.12，10.72，14.02，16.66，17.24，17.84，18.90，19.54，20.26，21.54，21.94，23.40，23.78，24.66，25.64，25.98，26.32，27.12，28.16，30.34，31.12处有衍射峰，如图1所示。其中2θ值误差范围为±0.2。经检测，2θ值误差范围也可以为±0.15。根据实施例2-3的方法制备的巴瑞克替尼三氟乙酸盐B晶型，其XRPD的结果也具有上述衍射峰，XRPD图谱与附图图8所示图谱基本相同。Determination of the XRPD pattern of the baricitinib trifluoroacetate salt A crystal form prepared according to the method described in Example 1, at 2θ=8.60, 10.12, 10.72, 14.02, 16.66, 17.24, 17.84, 18.90, 19.54, 20.26, There are diffraction peaks at 21.54, 21.94, 23.40, 23.78, 24.66, 25.64, 25.98, 26.32, 27.12, 28.16, 30.34, and 31.12, as shown in Figure 1. The error range of 2θ value is ±0.2. After testing, the error range of 2θ value can also be ±0.15. The XRPD result of baricitinib trifluoroacetate B crystal form prepared according to the method of Example 2-3 also has the above-mentioned diffraction peaks, and the XRPD pattern is basically the same as that shown in Figure 8 of the attached drawing.
本领域技术人员应理解，这些衍射峰不代表巴瑞克替尼三氟乙酸盐A晶型所显示衍射峰的详尽情况。X射线粉末衍射图的2θ值是可以随着机器以及随着样品制备中的变化和批次间变化而轻微变化，所引用的值不视为绝对值。还应理解的是，峰的相对强度可能随取向效应而变，因此本发明所含的XRPD迹线中所示的强度是示例性的，并不用于绝对比较。Those skilled in the art should understand that these diffraction peaks do not represent the detailed information of the diffraction peaks displayed by the A crystal form of baricitinib trifluoroacetate. The 2Θ values for the X-ray powder diffraction patterns are subject to slight variation with machine as well as with variations in sample preparation and batch-to-batch variation and quoted values are not to be considered absolute. It should also be understood that the relative intensities of peaks may vary with orientation effects, therefore the intensities shown in the XRPD traces contained herein are exemplary and not intended for absolute comparison.
实施例5巴瑞克替尼三氟乙酸盐A晶型的高温稳定性考察Example 5 Investigation of the High Temperature Stability of Baricitinib Trifluoroacetate A Crystal Form
取适量巴瑞克替尼三氟乙酸盐A晶型样品置于60℃烘箱内，5天和10天后将样品取出进行XPRD测试(如图2和图3所示)，以考察样品对温度的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐A晶型在高温条件下稳定。Take an appropriate amount of baricitinib trifluoroacetate salt A crystal sample and place it in an oven at 60°C. After 5 days and 10 days, take out the sample for XPRD test (as shown in Figure 2 and Figure 3) to investigate the effect of the sample on temperature. crystal stability. The results showed that the A crystal form of baricitinib trifluoroacetate was stable under high temperature conditions.
实施例6巴瑞克替尼三氟乙酸盐A晶型的高湿稳定性考察Example 6 Investigation of the high-humidity stability of baricitinib trifluoroacetate salt A crystal form
取适量巴瑞克替尼三氟乙酸盐A晶型样品置于92.5％湿度条件下，5天和10天后将样品取出进行XPRD测试(如图4和图5所示)，以考察样品对湿度的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐A晶型在高湿条件下稳定。Take an appropriate amount of baricitinib trifluoroacetate salt A crystal sample and place it under 92.5% humidity conditions, take out the sample after 5 days and 10 days and carry out XPRD test (as shown in Figure 4 and Figure 5), to investigate the effect of the sample on Crystalline stability to humidity. The results showed that the crystal form A of baricitinib trifluoroacetate was stable under high humidity conditions.
实施例7巴瑞克替尼三氟乙酸盐A晶型的光照稳定性考察Example 7 Investigation of Light Stability of Baricitinib Trifluoroacetate A Crystal Form
取适量巴瑞克替尼三氟乙酸盐A晶型样品置于4500lux光照强度下，5天和10天后将样品取出进行XPRD测试(如图6和图7所示)，以考察样品对光照的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐A晶型在光照条件下稳定。Take an appropriate amount of baricitinib trifluoroacetate A crystal sample and place it under the light intensity of 4500lux, take out the sample after 5 days and 10 days for XPRD test (as shown in Figure 6 and Figure 7), to investigate the effect of the sample on light intensity. crystal stability. The results showed that the A crystal form of baricitinib trifluoroacetate was stable under light conditions.
实施例8巴瑞克替尼三氟乙酸盐B晶型的制备Example 8 Preparation of crystal form B of baricitinib trifluoroacetate
将2g巴瑞克替尼三氟乙酸盐半晶体置于10mL丙酮中，得到巴瑞克替尼三氟乙酸盐半晶体的悬浮物，于50℃条件下搅拌悬浮8小时，再次加入5mL丙酮继续悬浮0.5小时，然后冷却至室温，将冷却后的悬浮物过滤并在室温下真空干燥，得到固体，称量固体重量为51mg。Put 2 g of baricitinib trifluoroacetate semi-crystals in 10 mL of acetone to obtain a suspension of baricitinib trifluoroacetate semi-crystals, stir and suspend at 50°C for 8 hours, then add 5 mL The acetone was continued to suspend for 0.5 hour, and then cooled to room temperature. The cooled suspension was filtered and vacuum-dried at room temperature to obtain a solid, which weighed 51 mg.
实施例9巴瑞克替尼三氟乙酸盐B晶型的制备Example 9 Preparation of crystal form B of baricitinib trifluoroacetate
将2.5g巴瑞克替尼三氟乙酸盐半晶体置于10mL丙酮中，得到巴瑞克替尼三氟乙酸盐半晶体的悬浮物，于52℃条件下搅拌悬浮8小时，再次加入5mL丙酮继续悬浮0.5小时，然后冷却至室温，将冷却后的悬浮物过滤并在室温下真空干燥，得到固体，称量固体重量为98mg。Put 2.5 g of baricitinib trifluoroacetate semi-crystals in 10 mL of acetone to obtain a suspension of baricitinib trifluoroacetate semi-crystals, stir and suspend at 52°C for 8 hours, then add Continue to suspend 5 mL of acetone for 0.5 hour, then cool to room temperature, filter the cooled suspension and vacuum-dry at room temperature to obtain a solid, which weighs 98 mg.
实施例10巴瑞克替尼三氟乙酸盐B晶型的制备Example 10 Preparation of Baricitinib Trifluoroacetate Salt Form B
将2.4g巴瑞克替尼三氟乙酸盐半晶体置于8mL丙酮中，得到巴瑞克替尼三氟乙酸盐半晶体的悬浮物，于54℃条件下搅拌悬浮8小时，再次加入5mL丙酮继续悬浮0.5小时，然后冷却至室温，将冷却后的悬浮物过滤并在室温下真空干燥，得到固体，称量固体重量为86mg。Put 2.4 g of baricitinib trifluoroacetate semi-crystals in 8 mL of acetone to obtain a suspension of baricitinib trifluoroacetate semi-crystals, stir and suspend at 54°C for 8 hours, then add Continue to suspend 5 mL of acetone for 0.5 hour, then cool to room temperature, filter the cooled suspension and vacuum-dry at room temperature to obtain a solid, which weighs 86 mg.
实施例11通过XRPD图来表征巴瑞克替尼三氟乙酸盐B晶型Example 11 Characterization of baricitinib trifluoroacetate B crystal form by XRPD pattern
以与实施例2相同的方式，测定根据实施例8所述方法制备的巴瑞克替尼三氟乙酸盐B晶型的XRPD图谱，在2θ＝5.34，9.00，10.08，10.70，16.12，17.44，17.80，18.92，19.48，20.22，21.56，22.68，23.42，23.98，25.84，27.22，28.76，29.46，32.66处有衍射峰，如图8所示。其中2θ值误差范围为±0.2。经检测，2θ值误差范围也可以为±0.15。根据实施例9-10的方法制备的巴瑞克替尼三氟乙酸盐B晶型，其XRPD的结果也具有上述衍射峰，XRPD图谱与附图图8所示图谱基本相同。In the same manner as in Example 2, determine the XRPD pattern of the baricitinib trifluoroacetate salt B crystal form prepared according to the method described in Example 8, at 2θ=5.34, 9.00, 10.08, 10.70, 16.12, 17.44 , 17.80, 18.92, 19.48, 20.22, 21.56, 22.68, 23.42, 23.98, 25.84, 27.22, 28.76, 29.46, 32.66 have diffraction peaks, as shown in Figure 8. The error range of 2θ value is ±0.2. After testing, the error range of 2θ value can also be ±0.15. The XRPD results of the crystal form B of baricitinib trifluoroacetate prepared according to the method of Examples 9-10 also have the above-mentioned diffraction peaks, and the XRPD pattern is basically the same as that shown in Figure 8 of the accompanying drawings.
本领域技术人员应理解，这些衍射峰不代表巴瑞克替尼三氟乙酸盐B晶型所显示衍射峰的详尽情况。X射线粉末衍射图的2θ值是可以随着机器以及随着样品制备中的变化和批次间变化而轻微变化，所引用的值不视为绝对值。还应理解的是，峰的相对强度可能随取向效应而变，因此本发明所含的XRPD迹线中所示的强度是示例性的，并不用于绝对比较。Those skilled in the art should understand that these diffraction peaks do not represent the detailed information of the diffraction peaks displayed by the crystal form B of baricitinib trifluoroacetate salt. The 2Θ values for the X-ray powder diffraction patterns are subject to slight variation with machine as well as with variations in sample preparation and batch-to-batch variation and quoted values are not to be considered absolute. It should also be understood that the relative intensities of peaks may vary with orientation effects, therefore the intensities shown in the XRPD traces contained herein are exemplary and not intended for absolute comparison.
实施例12巴瑞克替尼三氟乙酸盐B晶型的高温稳定性考察Example 12 Investigation of the High Temperature Stability of Baricitinib Trifluoroacetate Salt B Crystal Form
取适量巴瑞克替尼三氟乙酸盐B晶型样品置于60℃烘箱内，5天和10天后将样品取出进行XPRD测试(如图9和图10所示)，以考察样品对温度的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐B晶型在高温条件下稳定。Take an appropriate amount of baricitinib trifluoroacetate salt B crystal sample and place it in an oven at 60°C. After 5 days and 10 days, take out the sample for XPRD test (as shown in Figure 9 and Figure 10) to investigate the temperature of the sample. crystal stability. The results showed that the B crystal form of baricitinib trifluoroacetate was stable under high temperature conditions.
实施例13巴瑞克替尼三氟乙酸盐B晶型的高湿稳定性考察Example 13 Investigation of the high-humidity stability of baricitinib trifluoroacetate salt B crystal form
取适量巴瑞克替尼三氟乙酸盐B晶型样品置于92.5％湿度条件下，5天和10天后将样品取出进行XPRD测试(如图11和图12所示)，以考察样品对湿度的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐B晶型在高湿条件下稳定。Take an appropriate amount of baricitinib trifluoroacetate salt B crystal sample and place it under 92.5% humidity conditions, take out the sample after 5 days and 10 days and carry out XPRD test (as shown in Figure 11 and Figure 12), to investigate the effect of the sample on Crystalline stability to humidity. The results showed that the crystal form B of baricitinib trifluoroacetate was stable under high humidity conditions.
实施例14巴瑞克替尼三氟乙酸盐B晶型的光照稳定性考察Example 14 Investigation of Light Stability of Baricitinib Trifluoroacetate Salt B Crystal Form
取适量巴瑞克替尼三氟乙酸盐B晶型样品置于4500lux光照强度下，5天和10天后将样品取出进行XPRD测试(如图13和图14所示)，以考察样品对光照的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐B晶型在光照条件下稳定。Take an appropriate amount of baricitinib trifluoroacetate salt B crystal sample and place it under the light intensity of 4500lux, take out the sample after 5 days and 10 days for XPRD test (as shown in Figure 13 and Figure 14), to investigate the effect of the sample on light intensity. crystal stability. The results showed that the crystal form B of baricitinib trifluoroacetate was stable under light conditions.
比较例1通过XRPD图来表征巴瑞克替尼三氟乙酸盐半晶体Comparative Example 1 Characterizes Baricitinib Trifluoroacetate Semi-Crystal by XRPD Pattern
根据中国发明专利CN 102026999(WO 2009/114512)中所公开的方法制备巴瑞克替尼三氟乙酸盐半晶体。如图15所示，经XRPD测定，所得的最终产物为半晶型。According to the method disclosed in Chinese invention patent CN 102026999 (WO 2009/114512), baricitinib trifluoroacetate semi-crystals were prepared. As shown in Figure 15, the final product obtained was determined by XRPD to be semi-crystalline.
比较例2巴瑞克替尼三氟乙酸盐半晶体的高温稳定性考察Comparative Example 2 Investigation of High Temperature Stability of Baricitinib Trifluoroacetate Semi-Crystal
取适量巴瑞克替尼三氟乙酸盐半晶体样品置于60℃烘箱内，5天和10天后将样品取出进行XPRD测试(如图16和图17所示)，以考察样品对温度的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐半晶体在高温条件下不稳定，在5天和10天时晶型均发生转变。Take an appropriate amount of baricitinib trifluoroacetate semi-crystalline samples and place them in an oven at 60°C. After 5 days and 10 days, the samples are taken out for XPRD testing (as shown in Figures 16 and 17) to investigate the effect of the samples on temperature. Crystal stability. The results showed that the semi-crystal of baricitinib trifluoroacetate was unstable under high temperature conditions, and the crystal form changed at both 5 days and 10 days.
比较例3巴瑞克替尼三氟乙酸盐半晶体的高湿稳定性考察Comparative Example 3 Investigation of High Humidity Stability of Baricitinib Trifluoroacetate Semi-Crystal
取适量巴瑞克替尼三氟乙酸盐半晶体样品置于92.5％湿度条件下，5天和10天后将样品取出进行XPRD测试(如图18和图19所示)，以考察样品对湿度的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐半晶体在高湿条件下不稳定，在5天和10天时晶型均发生转变。Take an appropriate amount of baricitinib trifluoroacetate semi-crystalline samples and place them under 92.5% humidity conditions. After 5 days and 10 days, the samples are taken out and carried out XPRD test (as shown in Figure 18 and Figure 19), to investigate the effect of the samples on humidity. crystal stability. The results showed that the semi-crystal of baricitinib trifluoroacetate was unstable under high humidity conditions, and the crystal form changed at both 5 days and 10 days.
比较例4巴瑞克替尼三氟乙酸盐半晶体的光照稳定性考察Comparative Example 4 Investigation of Light Stability of Baricitinib Trifluoroacetate Semi-Crystal
取适量巴瑞克替尼三氟乙酸盐半晶体样品置于4500lux光照强度下，5天和10天后将样品取出进行XPRD测试(如图20和图21所示)，以考察样品对光照的晶型稳定性。结果显示，巴瑞克替尼三氟乙酸盐半晶体在光照条件下不稳定，在5天和10天时晶型均发生转变。Take an appropriate amount of baricitinib trifluoroacetate semi-crystalline sample and place it under the light intensity of 4500lux, take out the sample after 5 days and 10 days for XPRD test (as shown in Figure 20 and Figure 21), to investigate the effect of the sample on light Crystal stability. The results showed that the semi-crystal of baricitinib trifluoroacetate was unstable under light conditions, and the crystal form changed at both 5 days and 10 days.
综上所述，巴瑞克替尼三氟乙酸盐A晶型和B晶型在高温、高湿及光照条件下都能够保持稳定，优于半晶体产物。如本领域技术人员已知的，化合物半晶体理化性能不稳定，因此稳定的晶型在药物制剂的生产过程中具有优势。由于巴瑞克替尼三氟乙酸盐A晶型和B晶型具有的稳定性，其在各种固态剂型的药物加工过程中能够保持稳定，能够确定最终获得的药物中的药物活性成分的晶型，能够确保已知的生物利用度，不会发生因为晶型转变而带来的药效差异。To sum up, the crystal forms A and B of baricitinib trifluoroacetate can remain stable under high temperature, high humidity and light conditions, which are better than semi-crystalline products. As known to those skilled in the art, semi-crystalline compounds have unstable physical and chemical properties, so stable crystal forms have advantages in the production process of pharmaceutical preparations. Due to the stability of baricitinib trifluoroacetate salt A crystal form and B crystal form, they can remain stable during the pharmaceutical processing of various solid dosage forms, and the identity of the pharmaceutically active ingredients in the final obtained medicine can be determined. The crystal form can ensure the known bioavailability, and there will be no difference in drug effect due to the change of the crystal form.
本领域的技术人员应当明了，尽管为了举例说明的目的，本文描述了本发明的具体实施方式，但可以对其进行各种修改而不偏离本发明的精神和范围。因此，本发明的具体实施方式和实施例不应当视为限制本发明的范围。本发明仅受所附权利要求的限制。本申请中引用的所有文献均完整地并入本文作为参考。Those skilled in the art will appreciate that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications can be made thereto without departing from the spirit and scope of the invention. Therefore, the detailed description and examples of the present invention should not be considered as limiting the scope of the present invention. The invention is limited only by the appended claims. All documents cited in this application are hereby incorporated by reference in their entirety.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610064221.4ACN105566332B (en) | 2016-01-29 | 2016-01-29 | Baricitinib trifluoroacetate A crystal form and B crystal form and preparation method thereof |
| CN201710747417.8ACN107573348B (en) | 2016-01-29 | 2016-01-29 | Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof |
| Application Number | Priority Date | Filing Date | Title |
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| CN201610064221.4ACN105566332B (en) | 2016-01-29 | 2016-01-29 | Baricitinib trifluoroacetate A crystal form and B crystal form and preparation method thereof |
| Application Number | Title | Priority Date | Filing Date |
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| CN201710747417.8ADivisionCN107573348B (en) | 2016-01-29 | 2016-01-29 | Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof |
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| CN105566332A CN105566332A (en) | 2016-05-11 |
| CN105566332Btrue CN105566332B (en) | 2018-01-16 |
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| CN201610064221.4AActiveCN105566332B (en) | 2016-01-29 | 2016-01-29 | Baricitinib trifluoroacetate A crystal form and B crystal form and preparation method thereof |
| CN201710747417.8AActiveCN107573348B (en) | 2016-01-29 | 2016-01-29 | Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof |
| Application Number | Title | Priority Date | Filing Date |
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| CN201710747417.8AActiveCN107573348B (en) | 2016-01-29 | 2016-01-29 | Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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