技术领域technical field
本发明涉及药物化学领域，具体涉及能够抑制酪氨酸激酶的药物阿法替尼的晶型及其制备方法。The invention relates to the field of medicinal chemistry, in particular to a crystal form of afatinib capable of inhibiting tyrosine kinase and a preparation method thereof.
背景技术Background technique
阿法替尼二马来酸盐(Afatinib dimaleate)，是表皮生长因子受体(EGFR)和人表皮生长因子受体2(HER2)酪氨酸激酶的不可逆抑制剂，被批准用于治疗晚期非小细胞肺癌(NSCLC)等疾病，其化学名为(2E)-4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉二马来酸盐；其结构如式(1)所示：Afatinib dimaleate, an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, is approved for the treatment of advanced Diseases such as small cell lung cancer (NSCLC), whose chemical name is (2E)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino) -1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate; its structure is as formula (1) Shown:
PCT申请WO2005037824和WO2013052157等文献公开了阿法替尼二马来酸盐的晶型A、晶型B等多种晶型、用途等；但晶型是影响药品质量的重要因素，同一药物的不同晶型在外观、流动性、溶解度、储存稳定性等理化性质方面可能会存在极大差异，从而对药物的储存转移、应用、稳定性、生物利用度、疗效等产生影响；因此，为了得到有效的晶型，需要对阿法替尼二马来酸盐的结晶行为进行全面的考察，以得到满足生产要求的晶型。Documents such as PCT applications WO2005037824 and WO2013052157 disclose various crystal forms and uses of afatinib dimaleate, such as crystal form A and crystal form B; Crystal forms may have great differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, etc., which will affect the storage transfer, application, stability, bioavailability, and curative effect of drugs; therefore, in order to obtain effective In order to obtain the crystal form that meets the production requirements, it is necessary to conduct a comprehensive investigation on the crystallization behavior of afatinib dimaleate.
发明内容Contents of the invention
发明概述Summary of the invention
第一方面提供了阿法替尼二马来酸盐的晶型I。The first aspect provides the crystalline form I of afatinib dimaleate.
第二方面提供了阿法替尼二马来酸盐的晶型I的制备方法。The second aspect provides a method for preparing the crystal form I of afatinib dimaleate.
第三方面提供了阿法替尼二马来酸盐的晶型I在制备治疗非小细胞肺癌的药物中的应用。The third aspect provides the application of the crystal form I of afatinib dimaleate in the preparation of a medicament for treating non-small cell lung cancer.
第四方面提供了包含阿法替尼二马来酸盐的晶型I的药物组合物。The fourth aspect provides a pharmaceutical composition comprising Form I of afatinib dimaleate.
术语定义Definition of Terms
“晶型”是指化合物在晶格中的分子的独特的有序排列和/或构象。"Crystal form" refers to the unique ordered arrangement and/or conformation of the molecules of a compound in a crystal lattice.
在本发明中，X-射线粉末衍射图中的2θ值均以度(°)为单位。In the present invention, the 2θ values in the X-ray powder diffraction pattern are all in degrees (°).
X-射线粉末衍射“基本上如图所示”是指X-射线粉末衍射图中至少90％，或至少95％，或至少99％的峰显示在图中。X-ray powder diffraction "substantially as shown" means that at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the pattern.
“相对强度”是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。"Relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first strong peak when the intensity of the first strong peak is 100% among all the diffraction peaks of the X-ray powder diffraction pattern (XRPD).
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。"Peak" when referring to a spectrum and/or data appearing in a graph refers to a feature that one skilled in the art would recognize and would not attribute to background noise.
“良溶剂”是指在该溶剂中，阿法替尼二马来酸盐的溶解度大于1克/升，或者大于2克/升，或者大于3克/升，或者大于4克/升，或者大于5克/升，或者大于6克/升，或者大于7克/升，或者大于8克/升，或者大于9克/升，或者大于10克/升，或者大于15克/升，或者大于20克/升，或者大于30克/升，或者大于40克/升，或者大于50克/升，或者大于60克/升，或者大于70克/升，或者大于80克/升，或者大于90克/升，或者大于100克/升。"Good solvent" means that in the solvent, the solubility of afatinib dimaleate is greater than 1 g/L, or greater than 2 g/L, or greater than 3 g/L, or greater than 4 g/L, or Greater than 5 g/L, or greater than 6 g/L, or greater than 7 g/L, or greater than 8 g/L, or greater than 9 g/L, or greater than 10 g/L, or greater than 15 g/L, or greater than 20 g/L, or greater than 30 g/L, or greater than 40 g/L, or greater than 50 g/L, or greater than 60 g/L, or greater than 70 g/L, or greater than 80 g/L, or greater than 90 g/L, or greater than 100 g/L.
“不良溶剂”是指能够促进溶液过饱和和/或结晶化的溶剂。在一些实施例中，阿法替尼二马来酸盐在不良溶剂中的溶解度小于0.001克/升，小于0.1克/升，小于0.0克/升，小于0.3克/升，小于0.4克/升，小于0.5克/升，小于0.6克/升，小于0.7克/升，小于0.8克/升，小于1克/升，小于2克/升，小于3克/升，小于4克/升，小于5克/升，小于6克/升，小于7克/升，小于8克/升，小于9克/升，或小于10克/升。"Poor solvent" refers to a solvent capable of promoting supersaturation and/or crystallization of a solution. In some embodiments, the solubility of afatinib dimaleate in a poor solvent is less than 0.001 g/L, less than 0.1 g/L, less than 0.0 g/L, less than 0.3 g/L, less than 0.4 g/L , less than 0.5 g/l, less than 0.6 g/l, less than 0.7 g/l, less than 0.8 g/l, less than 1 g/l, less than 2 g/l, less than 3 g/l, less than 4 g/l, less than 5 g/L, less than 6 g/L, less than 7 g/L, less than 8 g/L, less than 9 g/L, or less than 10 g/L.
在一些实施例中，阿法替尼二马来酸盐在良溶剂中的溶解度大于其在不良溶剂中的溶解度，因此良溶剂和不良溶剂在体系中是相对而言的。在某些实施例中，以在良溶剂中的溶解度为计算基础，阿法替尼二马来酸盐在良溶剂和不良溶剂中的溶解度相差大约10％，或20％，或30％，或40％，或50％，或60％，或70％，或80％，或90％。在某些实施例中，阿法替尼二马来酸盐在良溶剂中的溶解度比在不良溶剂中的溶解度大约高10％，或20％，或30％，或40％，或50％，或60％，或70％，或80％，或90％。In some embodiments, the solubility of afatinib dimaleate in a good solvent is greater than that in a poor solvent, so the good solvent and the poor solvent are relative in the system. In certain embodiments, based on the solubility in the good solvent, the solubility of afatinib dimaleate in the good solvent and the poor solvent differs by about 10%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%. In certain embodiments, the solubility of afatinib dimaleate in a good solvent is about 10%, or 20%, or 30%, or 40%, or 50% higher than that in a poor solvent, Or 60%, or 70%, or 80%, or 90%.
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示每一个数字的数值有可能会出现1％、2％、5％、7％、8％、或10％的差异。In the context of the present invention, when or whether the words "about" or "approximately" are used, it means that each numerical value may appear 1%, 2%, 5%, 7%, 8%, or 10% difference.
发明详述Detailed description of the invention
第一方面，发明人通过研究开发了阿法替尼二马来酸盐的晶型I。In the first aspect, the inventors developed the crystal form I of afatinib dimaleate through research.
阿法替尼二马来酸盐的晶型I的X-射线粉末衍射图中在2θ为5.45度的位置有峰，其相对强度大于90％，或者大于99％，或者为100％。In the X-ray powder diffraction pattern of the crystal form I of afatinib dimaleate, there is a peak at the position where 2θ is 5.45 degrees, and its relative intensity is greater than 90%, or greater than 99%, or 100%.
一些实施例中，阿法替尼二马来酸盐的晶型I的X-射线粉末衍射图中在2θ为5.45度的位置有峰，其相对强度大于99％。In some embodiments, in the X-ray powder diffraction pattern of the crystalline form I of afatinib dimaleate, there is a peak at a position where 2θ is 5.45 degrees, and its relative intensity is greater than 99%.
一些实施例中，阿法替尼二马来酸盐的晶型I的X-射线粉末衍射图中在2θ为5.45,10.92,19.85度的位置有峰，其中衍射角2θ为5.45度的峰的相对强度大于90％，或者大于99％，或者为100％。In some embodiments, the X-ray powder diffraction pattern of the crystal form I of afatinib dimaleate has peaks at 2θ of 5.45, 10.92, and 19.85 degrees, where the diffraction angle 2θ is 5.45 degrees. The relative intensity is greater than 90%, or greater than 99%, or 100%.
一些实施例中，阿法替尼二马来酸盐的晶型I的X-射线粉末衍射图中在2θ为5.45,10.92,19.85,22.05,25.57度的位置有峰，其中衍射角2θ为5.45度的峰的相对强度大于90％，或者大于99％，或者为100％。In some embodiments, in the X-ray powder diffraction pattern of the crystal form I of afatinib dimaleate, there are peaks at 2θ of 5.45, 10.92, 19.85, 22.05, and 25.57 degrees, wherein the diffraction angle 2θ is 5.45 The relative intensity of the peak is greater than 90%, or greater than 99%, or 100%.
一些实施例中，阿法替尼二马来酸盐晶型I的X-射线粉末衍射图中在2θ为5.45,10.92,11.39,17.52,19.85,22.05,25.57,26.14,27.93度的位置有峰，其中衍射角2θ为5.45度的峰的相对强度大于90％，或者大于99％，或者为100％。In some embodiments, the X-ray powder diffraction pattern of Afatinib dimaleate crystal form I has peaks at the positions of 5.45, 10.92, 11.39, 17.52, 19.85, 22.05, 25.57, 26.14, and 27.93 degrees in 2θ , wherein the relative intensity of the peak at a diffraction angle 2θ of 5.45 degrees is greater than 90%, or greater than 99%, or 100%.
一些实施例中，阿法替尼二马来酸盐晶型I的X-射线粉末衍射图中在2θ为5.45,6.22,7.32,10.92,11.39,13.05,14.92,17.52,19.85,22.05,25.57,26.14,27.93度的位置的一处或多处有峰，其中衍射角2θ为5.45度的峰的相对强度大于90％，或者大于99％，或者为100％。In some embodiments, the X-ray powder diffraction pattern of Afatinib dimaleate salt crystal form I is 5.45, 6.22, 7.32, 10.92, 11.39, 13.05, 14.92, 17.52, 19.85, 22.05, 25.57, There are peaks at one or more positions at 26.14, 27.93 degrees, and the relative intensity of the peaks whose diffraction angle 2θ is 5.45 degrees is greater than 90%, or greater than 99%, or 100%.
一些实施例中，阿法替尼二马来酸盐晶型I的X-射线粉末衍射图中在2θ为5.45,6.22,7.32,10.92,11.39,13.05,14.92,16.82,17.52,19.85,22.05,25.57,26.14,27.93,29.64度的位置的一处或多处有峰，其中衍射角2θ为5.45度的峰的相对强度大于90％，或者大于99％，或者为100％。In some embodiments, the X-ray powder diffraction pattern of Afatinib dimaleate salt crystal form I is 5.45, 6.22, 7.32, 10.92, 11.39, 13.05, 14.92, 16.82, 17.52, 19.85, 22.05, There are peaks at one or more positions at 25.57, 26.14, 27.93, and 29.64 degrees, wherein the relative intensity of the peak with a diffraction angle 2θ of 5.45 degrees is greater than 90%, or greater than 99%, or 100%.
一些实施例中，阿法替尼二马来酸盐晶型I的X-射线粉末衍射图基本上如图1所示，其中衍射角2θ为5.45度的峰的相对强度大于90％，或者大于99％，或者为100％。In some embodiments, the X-ray powder diffraction pattern of Afatinib dimaleate crystalline form I is basically as shown in Figure 1, wherein the relative intensity of the peak whose diffraction angle 2θ is 5.45 degrees is greater than 90%, or greater than 99%, or 100%.
阿法替尼二马来酸盐晶型I还可以用其它方式表征，例如，在一些实施方式中，阿法替尼二马来酸盐的晶型I的热重分析(TGA)中在50℃-125℃间有失重，失重4.41％；在一些实施例中，其TGA如图2所示。Afatinib dimaleate crystal form I can also be characterized in other ways, for example, in some embodiments, in the thermogravimetric analysis (TGA) of the crystal form I of afatinib dimaleate at 50 There is weight loss between ℃ and 125 ℃, and the weight loss is 4.41%. In some embodiments, its TGA is shown in FIG. 2 .
所述晶型的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是大约+/-0.2个单位，或大约+/-0.1个单位，因此所述2θ或衍射峰的数值不能视为绝对的。The X-ray powder diffraction peak of the crystal form, the 2θ of its X-ray powder diffraction pattern or the measurement of the diffraction peak have experimental errors, between one machine and another machine and between one sample and another sample , the measurement of the 2θ or diffraction peaks of the X-ray powder diffraction pattern may be slightly different, and the value of the experimental error or difference may be about +/-0.2 units, or about +/-0.1 units, so the said Values for 2Θ or diffraction peaks are not to be considered absolute.
所述晶型的热重分析(TGA)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，失重温度和失重的量可能会略有差别，实验误差或差别的数值可能是大约+/-0.1个单位，大约+/-0.05个单位，或者大约+/-0.01个单位，因此所述失重温度和失重的量的数值不能视为绝对的。The thermogravimetric analysis (TGA) of described crystalline form has experimental error, between one machine and another machine and between one sample and another sample, the weight loss temperature and the amount of weight loss may have slight difference, experimental error Or the value of the difference may be about +/-0.1 unit, about +/-0.05 unit, or about +/-0.01 unit, so the values of the weight loss temperature and the amount of weight loss cannot be regarded as absolute.
经过观察，本发明提供的阿法替尼二马来酸盐的晶型I具有良好的流动性，不易结块，易于转移；另一方面，晶型I还具有较低的引湿性，有利于生产工艺中操作，可用于药物制剂。After observation, the crystal form I of afatinib dimaleate provided by the present invention has good fluidity, is not easy to agglomerate, and is easy to transfer; on the other hand, the crystal form I also has lower hygroscopicity, which is beneficial to Operated in the production process, it can be used in pharmaceutical preparations.
第二方面，这里还提供了所述阿法替尼二马来酸盐晶型I的制备方法。In the second aspect, a method for preparing the crystal form I of afatinib dimaleate is also provided herein.
一种制备阿法替尼二马来酸盐晶型I的方法包括：将阿法替尼二马来酸盐溶解于良溶剂中，降温，析出晶体，收集晶体，除去溶剂，得到产物。A method for preparing crystal form I of afatinib dimaleate comprises: dissolving afatinib dimaleate in a good solvent, lowering the temperature to precipitate crystals, collecting the crystals, and removing the solvent to obtain a product.
在一些实施方式中，所述溶解于良溶剂中包括加热溶解于良溶剂中；所述加热温度为室温至溶剂的回流温度的任一值；在一些实施方式中，加热回流将阿法替尼二马来酸盐溶解于良溶剂中。In some embodiments, the dissolving in a good solvent includes heating and dissolving in a good solvent; the heating temperature is any value from room temperature to the reflux temperature of the solvent; in some embodiments, heating to reflux will dissolve Afatinib The dimaleate is dissolved in a good solvent.
在一些实施方式中，所述降温还包括加入不良溶剂。In some embodiments, the temperature reduction also includes adding a poor solvent.
所述良溶剂选自：醇类溶剂，酮类溶剂，酯类溶剂，烷烃类溶剂，醚类溶剂，N,N-二甲基甲酰胺，水，或其组合；所述醇类溶剂选自甲醇、乙醇、其组合；所述酮类溶剂选自丙酮、丁酮、其组合；所述酯类溶剂选自乙酸乙酯、乙酸异丙酯、或其组合；所述烷烃类溶剂选自二氯甲烷、三氯甲烷、甲苯、或其组合；所述醚类溶剂选自四氢呋喃、二氧六环、或其组合。The good solvent is selected from: alcohol solvents, ketone solvents, ester solvents, alkane solvents, ether solvents, N,N-dimethylformamide, water, or combinations thereof; the alcohol solvents are selected from Methanol, ethanol, and its combination; the ketone solvent is selected from acetone, butanone, and its combination; the ester solvent is selected from ethyl acetate, isopropyl acetate, or its combination; the alkane solvent is selected from two Chloromethane, chloroform, toluene, or a combination thereof; the ether solvent is selected from tetrahydrofuran, dioxane, or a combination thereof.
所述降温指将温度较低至析出晶体温度，在一些实施方式中，将温度降低至30℃-零下5℃；在一些实施方式中，将温度降低至25℃-15℃；在一些实施方式中，将温度降低至25℃-20℃；在一些实施方式中，将温度降低至15℃-5℃；在一些实施方式中，将温度降低至5℃-零下5℃；在一些实施方式中，将温度降低至-5℃-0℃。The temperature reduction refers to lowering the temperature to the crystal precipitation temperature. In some embodiments, the temperature is reduced to 30°C-minus 5°C; in some embodiments, the temperature is reduced to 25°C-15°C; in some embodiments In some embodiments, reduce the temperature to 25°C-20°C; in some embodiments, reduce the temperature to 15°C-5°C; in some embodiments, reduce the temperature to 5°C-minus 5°C; in some embodiments , lower the temperature to -5°C-0°C.
在一些实施方式中，将阿法替尼二马来酸盐加热回流溶于二氯甲烷，然后降温至25℃-20℃，析出晶体，除去溶剂，得到晶型I。In some embodiments, afatinib dimaleate is dissolved in dichloromethane under reflux, and then cooled to 25°C-20°C to precipitate crystals, and the solvent is removed to obtain Form I.
在一些实施方式中，将阿法替尼二马来酸盐加热回流溶于二氯甲烷中，然后降温至25℃-20℃，析出晶体，然后固液分离，所得固体在空气中放置12小时-18小时风干溶剂，得到晶型I。In some embodiments, afatinib dimaleate is heated to reflux and dissolved in dichloromethane, then cooled to 25°C-20°C, crystals are precipitated, and then solid-liquid separation is performed, and the obtained solid is placed in air for 12 hours -18 hours air-dried the solvent to obtain Form I.
第三方面，这里提供了阿法替尼二马来酸盐的晶型I在制备治疗非小细胞肺癌的药物中的应用。In the third aspect, the application of the crystal form I of afatinib dimaleate in the preparation of a drug for treating non-small cell lung cancer is provided.
第四方面，这里提供了包含阿法替尼二马来酸盐的晶型I的药物组合物。In the fourth aspect, there is provided a pharmaceutical composition comprising the crystal form I of afatinib dimaleate.
所述的阿法替尼二马来酸盐晶型I可以与至少一种药学上可接受的惰性赋形剂或载体混合，制备成口服药物的各种固体剂型，包括胶囊，片剂等；还可以与各种赋形剂或载体制备成固体分散体等，然后制备成各种固体制剂。The crystalline form I of afatinib dimaleate can be mixed with at least one pharmaceutically acceptable inert excipient or carrier to prepare various solid dosage forms of oral medicine, including capsules, tablets, etc.; It can also be prepared into solid dispersion with various excipients or carriers, and then prepared into various solid preparations.
在一些实施方式中，所述惰性赋形剂或载体包括微晶纤维素、乳糖、或聚维酮。In some embodiments, the inert excipient or carrier includes microcrystalline cellulose, lactose, or povidone.
在一些实施方式中，阿法替尼二马来酸盐的晶型I的药物组合物含有硬脂酸镁。In some embodiments, the pharmaceutical composition of Form I of afatinib dimaleate contains magnesium stearate.
在一些实施方式中，阿法替尼二马来酸盐的晶型I的药物组合物含有胶体二氧化硅。In some embodiments, the pharmaceutical composition of Form I of afatinib dimaleate contains colloidal silicon dioxide.
阿法替尼二马来酸盐晶型I的治疗有效量重量百分比在整个混合物占约0.1％至99.5％，在一些实施例中为约0.5％至95％重量的重量百分比存在于上述药物制剂中。Therapeutically effective amount of Afatinib dimaleate crystal form I is present in the above pharmaceutical preparation in a weight percentage of about 0.1% to 99.5% in the whole mixture, and in some embodiments, in a weight percentage of about 0.5% to 95% by weight middle.
附图说明Description of drawings
图1示阿法替尼二马来酸盐的晶型I的X-射线粉末衍射图(XRPD)；Fig. 1 shows the X-ray powder diffraction pattern (XRPD) of the crystal form I of Afatinib dimaleate;
图2示阿法替尼二马来酸盐的晶型I的TGA图。Figure 2 shows the TGA diagram of the crystal form I of afatinib dimaleate.
具体实施方式Detailed ways
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.
本发明中，g表示克，mL表示毫升。In the present invention, g means gram, and mL means milliliter.
本发明中，X-射线粉末衍射检测条件为：仪器型号：PANalytical Empyrean；Cu靶kα，波长扫描范围：3°-40°；在X-射线粉末衍射图中，纵坐标为用计数(counts)表示的衍射强度(Intensity)，横坐标为用度(°)表示的衍射角2θ(2Theta)。Among the present invention, X-ray powder diffraction detection condition is: instrument model: PANalytical Empyrean; Cu target kα, wavelength Scanning range: 3°-40°; in the X-ray powder diffraction pattern, the ordinate is the diffraction intensity (Intensity) expressed in counts, and the abscissa is the diffraction angle 2θ (2Theta) expressed in degrees (°) .
热重分析(TGA)检测条件为：仪器型号：TA Q500；氮气氛下，以10℃/分钟升温，温度范围为25℃至300℃。The detection conditions of thermogravimetric analysis (TGA) are: instrument model: TA Q500; under nitrogen atmosphere, the temperature is raised at 10°C/min, and the temperature range is from 25°C to 300°C.
实施例1Example 1
将1.0g阿法替尼二马来酸盐加入到8mL二氯甲烷中，40℃加热45分钟，缓慢降温至23℃，保温23℃-20℃搅拌30分钟后过滤，滤饼在空气中放置12小时-18小时风干溶剂，得产物0.86g，其XRPD图、TGA图分别见图1、图2，命名为晶型I。Add 1.0g of afatinib dimaleate into 8mL of dichloromethane, heat at 40°C for 45 minutes, slowly cool down to 23°C, keep warm at 23°C-20°C and stir for 30 minutes, then filter, and put the filter cake in the air The solvent was air-dried for 12 hours to 18 hours to obtain 0.86 g of the product, whose XRPD pattern and TGA pattern are shown in Fig. 1 and Fig. 2 respectively, and named as crystal form I.
实施例2Example 2
将取部分预先混匀的乳糖与微晶纤维素，加入阿法替尼二马来酸盐晶型I，加适量水，混匀，过筛；然后加入聚维酮，加入适量水，混匀，过筛，并且进一步混匀30分钟，60℃干燥；然后加入硬脂酸镁，胶体二氧化硅，混匀；然后将混合物压片，包衣。Take part of the pre-mixed lactose and microcrystalline cellulose, add afatinib dimaleate crystal form I, add appropriate amount of water, mix well, and sieve; then add povidone, add appropriate amount of water, mix well , sieved, and further mixed for 30 minutes, and dried at 60°C; then magnesium stearate and colloidal silicon dioxide were added, and mixed; then the mixture was compressed into tablets and coated.
胶囊组成Capsule Composition
实施例3Example 3
引湿性测试：Humidity test:
按照现行中国药典的规定，设计实验，考察晶型I的引湿性；结果表明晶型I的引湿性极低，如下表1所示：According to the provisions of the current Chinese Pharmacopoeia, an experiment was designed to investigate the hygroscopicity of the crystal form I; the results showed that the hygroscopicity of the crystal form I was extremely low, as shown in Table 1 below:
表1：晶型I的引湿性考察结果Table 1: Investigation results of hygroscopicity of crystal form I
测试结果：晶型I的引湿性较低。Test results: Form I has low hygroscopicity.
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410839991.2ACN104744445A (en) | 2013-12-30 | 2014-12-29 | Crystal form of tyrosine kinase inhibitor |
| Application Number | Priority Date | Filing Date | Title |
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| CN2013107510053 | 2013-12-30 | ||
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| CN201410839991.2ACN104744445A (en) | 2013-12-30 | 2014-12-29 | Crystal form of tyrosine kinase inhibitor |
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| CN104744445Atrue CN104744445A (en) | 2015-07-01 |
| Application Number | Title | Priority Date | Filing Date |
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| CN201410839991.2APendingCN104744445A (en) | 2013-12-30 | 2014-12-29 | Crystal form of tyrosine kinase inhibitor |
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