CN116751204A - 一种巴瑞克替尼-没食子酸共晶及其制备方法和应用 - Google Patents
一种巴瑞克替尼-没食子酸共晶及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种巴瑞克替尼‑没食子酸共晶及其制备方法和应用,巴瑞克替尼‑没食子酸共晶以巴瑞克替尼和没食子酸为原料反应得到,巴瑞克替尼和没食子酸的摩尔比为1:1.0~1.3,应用于制备治疗自身免疫疾病药物。本发明巴瑞克替尼‑没食子酸共晶具有较好的化学稳定性和较高的溶解度,形成的共晶体药效协同作用有可能减少药物的剂量,也可有效避免现有晶型的转晶现象,具有很强的成药价值,有助于提高临床疗效,适合药物制剂的制造及长期储存;制备方法重现性好,操作方便,收率高;有效避免了单一药物晶型含有有机溶剂残留的问题,保持了较好的用药安全性。
Description
技术领域
本发明属于晶型药物分子技术领域,具体涉及一种巴瑞克替尼-没食子酸共晶及其制备方法和应用。
背景技术
巴瑞替尼(baricitinib,商品名为Olumiant),化学名称为:{ 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,英文名为:2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile,其结构式如下所示。巴瑞替尼为Janus 激酶(JAK)1和JAK2抑制剂,由礼来和因赛特制药公司研制。作为一种单药或联合甲氨蝶呤,用于对一种或多种疾病修饰抗风湿药物(DMARD)缓解不足或不耐受的中度至重度活动性类风湿性关节炎成人患者的治疗,这也是欧盟批准治疗类风湿性关节炎的首个JAK抑制剂。
没食子酸(Gallic acid),化学名称为3,4,5-三羟基苯甲酸,是一种多酚类有机化合物如下所示,广泛存在于掌叶大黄、大叶桉、山茱萸等植物中,在食品、生物、医药、化工等领域有广泛的应用。没食子酸具有抗炎、抗突变、抗氧化、抗自由基等多种生物学活性,同时没食子酸具有抗肿瘤作用,可以抑制肥大细胞瘤的转移,从而延长生存期,也是相对适宜的杀锥虫候选药物,对肝脏具有保护作用。
目前很多文献报道了巴瑞克替尼多晶型及其共晶问题,由于药物的不同晶型会直接影响药物在体内的溶解度、溶出度、与靶点的作用等进而影响药效的发挥,虽然药用的巴瑞克替尼已经上市多年,但是对其药用晶型的研究报道从未间断。
专利CN105924444A公开了巴瑞替尼晶型I、晶型II、磷酸盐晶型A、磷酸盐晶型B和磷酸盐晶型C的制备方法;CRYSTAL GROWTH&DESIGN杂志中一篇文章Similarity andDiversity: Cocrystallization of Baricitinib with Four C4-Dicarboxylic Acids中报道了巴瑞克替尼-马来酸、富马酸、琥珀酸和l -酒石酸共晶;专利WO2020163431A1公开了巴瑞克替尼-乳清酸、巴瑞克替尼-萘-2-磺酸、巴瑞克替尼-樟脑酸、巴瑞克替尼-富马酸、巴瑞克替尼-酒石酸和巴瑞克替尼-琥珀酸共晶及其制备方法;专利WO2019003249A1公开了巴瑞克替尼丙酸溶剂合物和巴瑞克替尼甲酸溶剂合物新晶型及其制备方法;专利WO2018233437A1公开了巴瑞克替尼晶型G、晶型D、晶型E和晶型F新晶型及其制备方法;专利WO2018113801A1公开了磷酸巴瑞克替尼结晶形式A、形式B、形式C、形式D、形式E、形式F、结晶形式G以及半磷酸巴瑞克替尼结晶形式I和形式II及其制备方法;专利EP3321267A1公开了巴瑞克替尼氢溴酸盐、巴瑞克替尼盐酸盐、巴瑞克替尼硫酸盐、巴瑞克替尼甲磺酸盐、巴瑞克替尼乙烷磺酸盐、巴瑞克替尼对甲苯磺酸盐、巴瑞克替尼富马酸盐和巴瑞克替尼酒石酸盐新晶型及其制备方法。上述方法制备的巴瑞克替尼多晶型溶解度和稳定性仍不理想。
虽然现有文献已经公开了众多的巴瑞克替尼晶型,但是以上文献和专利都没有报道巴瑞克替尼-没食子酸共晶新晶型和具有潜在协同抗菌消炎作用的化合物,所以本发明开发的新晶型可以在药物协同方面研究发挥更大的优势,开发出生物利用度高的药物新晶型,减少患者的用药量和药物副作用。
发明内容
针对现有技术中存在的问题,本发明提供了一种巴瑞克替尼-没食子酸共晶及其制备方法和应用,巴瑞克替尼-没食子酸共晶具有较高溶解性和稳定性,且简单易得,具有较高的成药价值。
本发明通过以下技术方案实现:
一种巴瑞克替尼-没食子酸共晶,以巴瑞克替尼和没食子酸为原料反应得到,巴瑞克替尼和没食子酸的摩尔比为1:1.0~1.3。
进一步地,所述的巴瑞克替尼-没食子酸共晶XRPD图谱在2θ=13.83,17.23,20.25,23.99,26.19,27.29,28.30,29.20,33.83处有衍射峰,2θ误差范围为±0.2。
进一步地,所述的巴瑞克替尼-没食子酸共晶XRPD图谱在2θ=12.34,13.83,14.84,15.26,16.56,17.23,18.99,20.25,22.25,23.99,25.26,26.19,27.29,28.30,29.20,29.78,33.83,35.10,37.00,39.60,41.57处有衍射峰,2θ误差范围为±0.2。
本发明公开了巴瑞克替尼-没食子酸共晶的制备方法,包括以下步骤:
(1)将巴瑞克替尼溶于三氟乙醇中,得巴瑞克替尼溶液;
(2)将没食子酸溶于醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶。
进一步地,步骤(1)中所述的巴瑞克替尼与三氟乙醇的比例为20mg:0.2~0.4mL。
进一步地,步骤(2)中所述的没食子酸与醇溶剂的比例为30 mg:0.2~0.4 mL。
进一步地,所述的醇溶剂为乙醇、甲醇、异丙醇和叔丁醇中的一种以上。
进一步地,步骤(3)中所述的超声加热反应温度为55~65℃,超声加热反应时间为16~24h。
本发明中,公开了巴瑞克替尼-没食子酸共晶在制备治疗自身免疫疾病药物中的应用。
进一步地,所述的巴瑞克替尼-没食子酸共晶在制备治疗类风湿性关节炎药物中的应用
有益效果
(1)本发明巴瑞克替尼-没食子酸共晶具有较好的化学稳定性和较高的溶解度,形成的共晶体药效协同作用有可能减少药物的剂量,也可有效避免现有晶型的转晶现象,具有很强的成药价值,有助于提高临床疗效,适合药物制剂的制造及长期储存;
(2)本发明巴瑞克替尼-没食子酸共晶制备方法重现性好,操作方便,收率高;
(3)本发明制备方法得到的巴瑞克替尼-没食子酸共晶共晶体有效避免了单一药物晶型含有有机溶剂残留的问题,保持了较好的用药安全性。
附图说明
图1为巴瑞克替尼-没食子酸共晶的X射线粉末衍射图谱;
图2为巴瑞克替尼-没食子酸共晶的DSC/TGA图,
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
实施例1
(1)将1.0 g巴瑞克替尼溶于10 mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将458 mg没食子酸溶于3 mL甲醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为55℃,反应时间为16h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率85.6%,纯度99.94%。
实施例2
(1)将1.0 g巴瑞克替尼溶于15mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将595mg没食子酸溶于5mL甲醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为55℃,反应时间为16h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率86.6%,纯度99.93%。
实施例3
(1)将1.0 g巴瑞克替尼溶于10mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将504mg没食子酸溶于4.5mL异丙醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为65℃,反应时间为16h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率86.8%,纯度99.95%。
实施例4
(1)将1.0 g巴瑞克替尼溶于15mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将458mg没食子酸溶于4.5mL甲醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为55℃,反应时间为20h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率89.9%,纯度99.96%。
实施例5
(1)将1.0 g巴瑞克替尼溶于20mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将503mg没食子酸溶于5mL甲醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为60℃,反应时间为16h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率84.6%,纯度99.95%。
实施例6
(1)将1.0 g巴瑞克替尼溶于15mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将458mg没食子酸溶于6mL甲醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为55℃,反应时间为18h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率84.6%,纯度99.94%。
实施例7
(1)将1.0 g巴瑞克替尼溶于10mL三氟乙醇中,得巴瑞克替尼溶液;
(2)将458mg没食子酸溶于6mL甲醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应温度为55℃,反应时间为20h,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶,收率78.2%,纯度99.96%。
性能检测:
(1)实施例1~7制备的巴瑞克替尼-没食子酸共晶的晶型相同
(2)X-射线粉末衍射测试仪器及测试条件:X-射线粉末衍射仪:PANalyticalEMPYREAN;Cu-Kα;样品台:平板;入射光路:BBHD;衍射光路:PLXCEL;电压45 kv,电流40 mA;发散狭缝:1/4;防散射狭缝:1;索拉狭缝:0.04 rad;步长:0.5 s;扫描范围:3~50 °;实施例1中制备的巴瑞克替尼-没食子酸共晶的X射线粉末衍射图谱如图1所示,X射线粉末衍射图(Cu-Kα)中特征峰如表1所示:
表1巴瑞克替尼-没食子酸共晶的主要X射线粉末衍射特征峰
(3)TGA/DSC热分析测试仪及测试条件:TGA/DSC热分析仪:METTLER TOLEDO TGA/DSC3+;动态温度段:30~300℃;加热速率:10℃/min;程序段气体N2;气体流量:50 mL/min;坩埚:铝坩埚40 μL;对实施例1中制备的巴瑞克替尼-没食子酸共晶进行TGA/DSC测试,结果如图2所示,由图2可知,DSC检测谱图显示该共晶有一个吸热峰,温度范围为170.02~206.29℃,其峰值为198.13℃。
(4)稳定性实验:影响因素试验参照《中国药典》第四部有关稳定性考察的指导方法进行(光照4500±500lx、高温60℃、高湿90±5%RH),纯度(%)检测用HPLC法进行检测,对实施例1~3制备的巴瑞克替尼-没食子酸共晶进行稳定性测试,不同条件下巴瑞克替尼-没食子酸共晶纯度检测结果如下表2所示。
表2不同条件下巴瑞克替尼-没食子酸共晶纯度检测结果表
由表2可知,巴瑞克替尼-没食子酸共晶,在光照、高温及高湿的条件下,总杂含量没有发生显著变化,可见本发明制备的巴瑞克替尼-没食子酸共晶具有较高的稳定性,适合药物制剂的制造及长期储存。
在40℃,不同相对湿度(RH)条件(75%,92.5%)下,测定实施例1~3中巴瑞克替尼-没食子酸共晶中水分含量,具体的试验结果见表3:
表3不同湿度条件下巴瑞克替尼-没食子酸共晶水分含量试验结果
由表3可知,本发明制备得到的巴瑞克替尼-没食子酸共晶,在不同湿度条件(RH75%,RH92.5%)下,水分含量保持恒定,说明其稳定性好,适合制药用途。
(5)溶解性实验:
按照EP3327020A1所述方法制备巴瑞克替尼单柠檬酸盐、巴瑞克替尼双柠檬酸盐,按照US20220135566A1所述的方法制备巴瑞克替尼-萘磺酸晶型I,按照专利WO2019121290A1所述的方法制备巴瑞克替尼-乳酸共晶,对实施例1中制备的巴瑞克替尼-没食子酸共晶、巴瑞克替尼单柠檬酸盐、巴瑞克替尼双柠檬酸盐巴瑞克替尼-萘磺酸晶型I巴瑞克替尼-乳酸共晶在pH6.5磷酸盐缓冲液和纯水中的溶解度进行测试,分别量取10mL的pH6.5磷酸盐缓冲液和纯水两种介质于西林瓶中,分别加入过量的待测样品,密封西林瓶置于25℃恒温水浴中搅拌24小时,经滤膜过滤,取滤液通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量,结果如下表4所示。
表4巴瑞克替尼共晶产品溶解度测试结果
由表4可知,本发明制备的巴瑞克替尼-没食子酸具有较好的溶解性,优于现有溶解度较高的晶型,有助于改善巴瑞克替尼的生物利用度。
Claims (10)
1.一种巴瑞克替尼-没食子酸共晶,其特征在于,以巴瑞克替尼和没食子酸为原料反应得到,巴瑞克替尼和没食子酸的摩尔比为1:1.0~1.3。
2.根据权利要求1所述的巴瑞克替尼-没食子酸共晶,其特征在于,所述的巴瑞克替尼-没食子酸共晶XRPD图谱在2θ=13.83,17.23,20.25,23.99,26.19,27.29,28.30,29.20,33.83处有衍射峰,2θ误差范围为±0.2。
3.根据权利要求1所述的巴瑞克替尼-没食子酸共晶,其特征在于,所述的巴瑞克替尼-没食子酸共晶XRPD图谱在2θ=12.34,13.83,14.84,15.26,16.56,17.23,18.99,20.25,22.25,23.99,25.26,26.19,27.29,28.30,29.20,29.78,33.83,35.10,37.00,39.60,41.57处有衍射峰,2θ误差范围为±0.2。
4.一种权利要求1~3任一项所述的巴瑞克替尼-没食子酸共晶的制备方法,其特征在于,包括以下步骤:
(1)将巴瑞克替尼溶于三氟乙醇中,得巴瑞克替尼溶液;
(2)将没食子酸溶于醇溶剂中,得没食子酸溶液;
(3)将步骤(1)和步骤(2)中的巴瑞克替尼溶液和没食子酸溶液混合,超声加热反应,反应结束后,自然降温析晶,过滤,真空干燥得巴瑞克替尼-没食子酸共晶。
5.根据权利要求4所述的巴瑞克替尼-没食子酸共晶的制备方法,其特征在于,步骤(1)中所述的巴瑞克替尼与三氟乙醇的比例为20mg:0.2~0.4mL。
6.根据权利要求4所述的巴瑞克替尼-没食子酸共晶的制备方法,其特征在于,步骤(2)中所述的没食子酸与醇溶剂的比例为30mg:0.2~0.4mL。
7.根据权利要求4所述的巴瑞克替尼-没食子酸共晶的制备方法,其特征在于,所述的醇溶剂为乙醇、甲醇、异丙醇和叔丁醇中的一种以上。
8.根据权利要求4所述的巴瑞克替尼-没食子酸共晶的制备方法,其特征在于,步骤(3)中所述的超声加热反应温度为55~65℃,超声加热反应时间为16~24h。
9.一种权利要求1~3任一项所述的巴瑞克替尼-没食子酸共晶在制备治疗自身免疫疾病药物中的应用。
10.根据权利要求9所述的巴瑞克替尼-没食子酸共晶在制备治疗类风湿性关节炎药物中的应用。
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