WO2019034048A1

WO2019034048A1 - Crystal form of vegfr inhibitor and preparation method thereof

Info

Publication number: WO2019034048A1
Application number: PCT/CN2018/100413
Authority: WO
Inventors: 杨俊然; 李俊明; 王立坤; 杜振兴
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2017-08-15
Filing date: 2018-08-14
Publication date: 2019-02-21
Also published as: CN110637010A

Abstract

Provided are a crystal form of a VEGFR inhibitor and a preparation method thereof. In particular, provided are crystal forms A-J of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) and a preparation method thereof.

Description

一种VEGFR抑制剂晶型及其制备方法Crystal form of VEGFR inhibitor and preparation method thereof

本申请要求申请日为2017年8月15日的中国专利申请CN201710698282.0的优先权。本申请要求申请日为2017年8月16日的中国专利申请CN201710701633.9的优先权。本申请引用上述中国专利申请的全文。This application claims priority from Chinese patent application CN201710698282.0 on August 15, 2017. This application claims priority from Chinese patent application CN201710701633.9, filed on August 16, 2017. This application cites the entire text of the above-mentioned Chinese patent application.

技术领域Technical field

本发明涉及一种VEGFR抑制剂晶型及其制备方法。The invention relates to a crystal form of a VEGFR inhibitor and a preparation method thereof.

背景技术Background technique

近年来，VEGFR的小分子抑制剂日渐成为一种非常具有应用前景的新型非细胞毒抗肿瘤药物。与抑制肿瘤生长的传统细胞毒药物相比，靶向新生血管生成的治疗药物具有更高的特异性、更低的毒性，以及有利于克服肿瘤的耐药性，并且可用于多种肿瘤的治疗。N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)是新一代VEGFR的小分子抑制剂，具有如下结构：In recent years, small molecule inhibitors of VEGFR have become a very promising new non-cytotoxic antitumor drug. Compared with traditional cytotoxic drugs that inhibit tumor growth, therapeutic drugs targeting neovascularization have higher specificity, lower toxicity, and help overcome tumor resistance, and can be used for the treatment of various tumors. . N-[4-(1-Cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) is a small molecule inhibitor of a new generation of VEGFR having the following structure:

多晶型现象是指固态物质存在两种或两种以上不同的空间排列方式，从而具有不同物理、化学性质。同种药物不同晶型之间由于排列方式的不同，其生物利用度也可能会存在差别。同时，鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，药物研究人员开展了N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)多种晶型的研究是非常有必要。Polymorphism refers to the presence of two or more different spatial arrangements of solid materials, which have different physical and chemical properties. There may be differences in bioavailability between different crystal forms of the same drug due to their different arrangement. At the same time, in view of the importance of solid drug crystal form and its stability in clinical treatment, drug researchers have developed N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridine The study of various crystal forms of methyl)amino-3-pyridinecarboxamide (Formula I) is highly desirable.

发明内容Summary of the invention

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型A，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在11.5,12.6,15.9,17.0,20.5,21.7,22.0处有特征峰，其中，每个特征峰2θ的误差范围为 ±0.2，The present invention provides a crystalline form A of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 11.5, 12.6, 15.9, 17.0, 20.5, 21.7, 22.0, wherein the error range of each characteristic peak 2θ Is ±0.2,

进一步地，在优选实施方案中，所述式I化合物的晶型A，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在7.6,11.5,12.6,15.9,17.0,20.5,21.7,22.0,23.4,23.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, Form A of the compound of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern at an angle of diffraction 2θ, which is at 7.6, 11.5, 12.6, 15.9, There are characteristic peaks at 17.0, 20.5, 21.7, 22.0, 23.4, and 23.9, wherein the error range of each characteristic peak 2θ is ±0.2.

更进一步地，所述式I化合物的晶型A，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.6,11.5,12.6,15.9,17.0,17.8,18.1,19.7,20.5,21.7,22.0,23.4,23.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, the crystal form A of the compound of the formula I, using Cu-Kα radiation, gives an X-ray powder diffraction pattern expressed by the angle of diffraction 2θ, at 7.6, 11.5, 12.6, 15.9, 17.0, 17.8, 18.1, There are characteristic peaks at 19.7, 20.5, 21.7, 22.0, 23.4, and 23.9, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型A的制备方法，包括：The invention also provides a process for the preparation of crystalline form A of the compound of formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(I)中，所述溶剂(I)于室温下对式I的溶解度不大于20mg/ml，可为20mg/ml、19mg/ml、18mg/ml、17mg/ml、16mg/ml、15mg/ml、14mg/ml、13mg/ml、12mg/ml、11mg/ml、10mg/ml、9mg/ml、8mg/ml、7mg/ml、6mg/ml、5mg/ml、4mg/ml、3mg/ml、2mg/ml、1mg/ml，优选自水、乙腈、正庚烷、环已烷、叔丁基甲醚、乙酸丁酯、乙酸异丙酯中至少一种；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (I), The solubility of the solvent (I) to the formula I at room temperature is not more than 20 mg/ml, and may be 20 mg/ml, 19 mg/ml, 18 mg/ml, 17 mg/ml, 16 mg/ml, 15 mg/ml, 14 mg/ml, 13 mg. /ml, 12mg/ml, 11mg/ml, 10mg/ml, 9mg/ml, 8mg/ml, 7mg/ml, 6mg/ml, 5mg/ml, 4mg/ml, 3mg/ml, 2mg/ml, 1mg/ml , preferably from at least one of water, acetonitrile, n-heptane, cyclohexane, tert-butyl methyl ether, butyl acetate, isopropyl acetate;

(b)室温打浆，过滤得式I化合物晶体。(b) Room temperature beating and filtering to obtain crystals of the compound of formula I.

本法所述溶剂(I)所用体积可以为式I重量的50～500倍，更优选50～200倍，在非限制性实施方案中可以为50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、150、200、250、300、350、400、450、500倍。The solvent (I) used in the present process may have a volume of 50 to 500 times, more preferably 50 to 200 times the weight of the formula I, and in a non-limiting embodiment may be 50, 55, 60, 65, 70, 75, 80. 85, 90, 95, 100, 105, 110, 115, 120, 150, 200, 250, 300, 350, 400, 450, 500 times.

制备式I化合物晶型A的方法二，包括： Method 2 for preparing Form A of the compound of Formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(II)中，搅拌溶解或加热溶解，所述溶剂(II)于室温下对式I的溶解度大于10mg/ml，可为10mg/ml、11mg/ml、12mg/ml、13mg/ml、14mg/ml、15mg/ml、16mg/ml、17mg/ml、18mg/ml、19mg/ml、20mg/ml、21mg/ml、22mg/ml、23mg/ml、24mg/ml、25mg/ml、26mg/ml、27mg/ml、28mg/ml、29mg/ml、30mg/ml、31mg/ml、33mg/ml、34mg/ml等，优选自乙酸乙酯、四氢呋喃、丙酮、甲基异丁基酮、10％水/丙酮、四氢呋喃/乙醇(2:1，v/v)、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、硝基甲烷、1,2-二氯乙烷、2-丁酮中至少一种；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (II), stirring Dissolved or dissolved by heating, the solubility of the solvent (II) to the formula I at room temperature is greater than 10 mg / ml, may be 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ Ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 33 mg/ml, 34 mg/ml, etc., preferably from ethyl acetate, tetrahydrofuran, acetone, methyl isobutyl ketone, 10% water/acetone, tetrahydrofuran/ethanol ( 2:1, v/v), dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, nitromethane, 1,2-dichloroethane, 2-butyl At least one of the ketones;

(b)室温挥发得式I化合物晶体。(b) Crystallization of the compound of formula I at room temperature.

本法所述溶剂(II)所用体积可以为式I重量的1～500倍，更优选1～200倍，在非限制性实施方案中可以为1、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、150、200、250、300、350、400、450、500倍。The solvent (II) used in the present process may be used in a volume of from 1 to 500 times, more preferably from 1 to 200 times, by weight of the formula I, and in the non-limiting embodiment may be 1, 10, 15, 20, 25, 30, 35. 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 150, 200, 250, 300, 350, 400, 450, 500 Times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型B，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.8,11.7,14.5,16.1,17.7,20.7,25.8处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form B of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 5.8, 11.7, 14.5, 16.1, 17.7, 20.7, 25.8, wherein the error range of each characteristic peak 2θ Is ±0.2.

进一步地，在优选实施方案中，所述式I的晶型B，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.8,11.7,14.5,16.1,17.7,20.7,24.2,25.2,25.8,28.6处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, Form B of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at an angle of diffraction 2θ of 5.8, 11.7, 14.5, 16.1, 17.7 There are characteristic peaks at 20.7, 24.2, 25.2, 25.8, and 28.6, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型B的制备方法，包括：The invention also provides a process for the preparation of crystalline form B of the compound of formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(III)中，搅拌溶解或加热溶解，所述溶剂(III)于室温下对式I的溶解度大于10mg/ml，可为10mg/ml、11mg/ml、12mg/ml、13mg/ml、14mg/ml、15mg/ml、16mg/ml、17mg/ml、18mg/ml、19mg/ml、20mg/ml、21mg/ml、22mg/ml、23mg/ml、24mg/ml、25mg/ml、26mg/ml、27mg/ml、28mg/ml、29mg/ml、30mg/ml、31mg/ml、33mg/ml、34mg/ml等，优选自但不限于二氯甲烷；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (III), stirring Dissolved or dissolved by heating, the solubility of the solvent (III) to the formula I at room temperature is greater than 10 mg / ml, may be 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ Ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 33 mg/ml, 34 mg/ml, etc., preferably but not limited to dichloromethane;

本法所述溶剂(III)所用体积可以为式I重量的1～200倍，更优选1～100倍，在非限制性实施方案中可以为1、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100倍。The solvent (III) used in the present process may be used in a volume of from 1 to 200 times, more preferably from 1 to 100 times by weight of the formula I, and in the non-limiting embodiment may be 1, 10, 15, 20, 25, 30, 35. 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型C，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.2,6.0,12.1,15.6,18.3,20.0,24.3处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form C of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 5.2, 6.0, 12.1, 15.6, 18.3, 20.0, 24.3, wherein the error range of each characteristic peak 2θ Is ±0.2.

进一步地，在优选实施方案中，所述式I的晶型C，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.2,6.0,12.1,14.7,15.6,18.3,20.0,22.9,24.3,30.0处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, the Form C of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at an angle of diffraction 2θ of 5.2, 6.0, 12.1, 14.7, 15.6 There are characteristic peaks at 18.3, 20.0, 22.9, 24.3, and 30.0, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型C的制备方法，包括：The invention also provides a process for the preparation of crystalline form C of the compound of formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(IV)中，所述溶剂(IV)于室温下对式I的溶解度不大于20mg/ml，可为20mg/ml、19mg/ml、18mg/ml、17mg/ml、16mg/ml、15mg/ml、14mg/ml、13mg/ml、12mg/ml、11mg/ml、10mg/ml、9mg/ml、8mg/ml、7mg/ml、6mg/ml、5mg/ml、4mg/ml、3mg/ml、2mg/ml、1mg/ml，优选自但不限于异丙醇；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (IV), The solubility of the solvent (IV) to the formula I at room temperature is not more than 20 mg/ml, and may be 20 mg/ml, 19 mg/ml, 18 mg/ml, 17 mg/ml, 16 mg/ml, 15 mg/ml, 14 mg/ml, 13 mg. /ml, 12mg/ml, 11mg/ml, 10mg/ml, 9mg/ml, 8mg/ml, 7mg/ml, 6mg/ml, 5mg/ml, 4mg/ml, 3mg/ml, 2mg/ml, 1mg/ml , preferably but not limited to isopropanol;

本法所述溶剂(IV)所用体积可以为式I重量的50～500倍，更优选50～200倍，在非限制性实施方案中可以为50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、150、200、250、300、350、400、450、500倍。The solvent (IV) used in the present process may have a volume of 50 to 500 times, more preferably 50 to 200 times the weight of the formula I, and in a non-limiting embodiment may be 50, 55, 60, 65, 70, 75, 80. 85, 90, 95, 100, 105, 110, 115, 120, 150, 200, 250, 300, 350, 400, 450, 500 times.

制备式I化合物晶型C的方法二，包括： Method 2 for preparing Form C of the compound of Formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(V)中，搅拌溶解或加热溶解，所述溶剂(V)于室温下对式I的溶解度大于10mg/ml，可为10mg/ml、11mg/ml、12mg/ml、13mg/ml、14mg/ml、15mg/ml、16mg/ml、17mg/ml、18mg/ml、19mg/ml、20mg/ml、21mg/ml、22mg/ml、23mg/ml、24mg/ml、25mg/ml、26mg/ml、27mg/ml、28mg/ml、29mg/ml、30mg/ml、31mg/ml、33mg/ml、34mg/ml等，优选自但不限于水/异丙醇；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (V) and stirring Dissolved or dissolved by heating, the solvent (V) has a solubility in formula I of more than 10 mg/ml at room temperature, and may be 10 mg/ml, 11 mg/ml, 12 mg/ml, 13 mg/ml, 14 mg/ml, 15 mg/ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ Ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 33 mg/ml, 34 mg/ml, etc., preferably but not limited to water/isopropanol;

本法所述溶剂(V)所用体积可以为式I重量的1～500倍，更优选1～200倍，在非限制性实施方案中可以为1、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、150、200、250、300、350、400、450、500倍。The volume of the solvent (V) used in the present process may be from 1 to 500 times, more preferably from 1 to 200 times the weight of the formula I, and in the non-limiting embodiment may be 1, 10, 15, 20, 25, 30, 35. 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 150, 200, 250, 300, 350, 400, 450, 500 Times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型D，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,12.2,15.7,16.1,18.5,20.2,21.3处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form D of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 6.0, 12.2, 15.7, 16.1, 18.5, 20.2, 21.3, wherein the error range of each characteristic peak 2θ Is ±0.2.

进一步地，在优选实施方案中，所述式I化合物的晶型D，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,10.6,12.2,15.7,16.1,18.5,20.2,20.3,21.3,25.4处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, Form D of the compound of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at a diffraction angle 2θ angle of 6.0, 10.6, 12.2, 15.7, There are characteristic peaks at 16.1, 18.5, 20.2, 20.3, 21.3, and 25.4, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型D的制备方法，包括：The invention also provides a process for the preparation of the crystalline form D of the compound of the formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(VI)中，所述溶剂(VI)于室温下对式I的溶解度不大于20mg/ml，可为20mg/ml、 19mg/ml、18mg/ml、17mg/ml、16mg/ml、15mg/ml、14mg/ml、13mg/ml、12mg/ml、11mg/ml、10mg/ml、9mg/ml、8mg/ml、7mg/ml、6mg/ml、5mg/ml、4mg/ml、3mg/ml、2mg/ml、1mg/ml，优选自但不限于甲醇、10％水/甲醇；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (VI), The solubility of the solvent (VI) to the formula I at room temperature is not more than 20 mg/ml, and may be 20 mg/ml, 19 mg/ml, 18 mg/ml, 17 mg/ml, 16 mg/ml, 15 mg/ml, 14 mg/ml, 13 mg. /ml, 12mg/ml, 11mg/ml, 10mg/ml, 9mg/ml, 8mg/ml, 7mg/ml, 6mg/ml, 5mg/ml, 4mg/ml, 3mg/ml, 2mg/ml, 1mg/ml , preferably but not limited to methanol, 10% water/methanol;

本法所述溶剂(VI)所用体积可以为式I重量的1～500倍，更优选1～200倍，在非限制性实施方案中可以为1、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、150、200、250、300、350、400、450、500倍。The solvent (VI) used in the present process may have a volume of from 1 to 500 times, more preferably from 1 to 200 times the weight of the formula I, and in a non-limiting embodiment may be 1, 10, 15, 20, 25, 30, 35. 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 150, 200, 250, 300, 350, 400, 450, 500 Times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型E，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,5.9,11.5,12.0,17.3,18.2,20.9,处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form E of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction 2θ is obtained, which has characteristic peaks at 5.7, 5.9, 11.5, 12.0, 17.3, 18.2, 20.9, wherein the error of each characteristic peak 2θ The range is ±0.2.

进一步地，在优选实施方案中，所述式I化合物的晶型E，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,5.9,11.5,12.0,14.1,17.3,18.2,19.0,20.9,22.7,处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, the Form E of the compound of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at a diffraction angle 2θ angle of 5.7, 5.9, 11.5, 12.0, 14.1, 17.3, 18.2, 19.0, 20.9, 22.7, with characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型E的制备方法，包括：The invention also provides a process for the preparation of the crystalline form E of the compound of formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(VII)中，所述溶剂(VII)于室温下对式I的溶解度不大于20mg/ml，可为20mg/ml、19mg/ml、18mg/ml、17mg/ml、16mg/ml、15mg/ml、14mg/ml、13mg/ml、12mg/ml、11mg/ml、10mg/ml、9mg/ml、8mg/ml、7mg/ml、6mg/ml、5mg/ml、4mg/ml、3mg/ml、2mg/ml、1mg/ml，优选自但不限于乙醇。(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to the solvent (VII), The solubility of the solvent (VII) to the formula I at room temperature is not more than 20 mg/ml, and may be 20 mg/ml, 19 mg/ml, 18 mg/ml, 17 mg/ml, 16 mg/ml, 15 mg/ml, 14 mg/ml, 13 mg. /ml, 12mg/ml, 11mg/ml, 10mg/ml, 9mg/ml, 8mg/ml, 7mg/ml, 6mg/ml, 5mg/ml, 4mg/ml, 3mg/ml, 2mg/ml, 1mg/ml Preferably, but not limited to, ethanol.

本法所述溶剂(VII)所用体积可以为式I重量的1～500倍，更优选1～200倍，在非限制性实施方案中可以为1、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、150、200、250、300、350、400、450、500倍。The solvent (VII) used in the present process may have a volume of from 1 to 500 times, more preferably from 1 to 200 times the weight of the formula I, and in a non-limiting embodiment may be 1, 10, 15, 20, 25, 30, 35. 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 150, 200, 250, 300, 350, 400, 450, 500 Times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型F，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,11.3,11.6,16.0,17.1,17.6,20.6处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form F of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 5.7, 11.3, 11.6, 16.0, 17.1, 17.6, 20.6, wherein the error range of each characteristic peak 2θ Is ±0.2.

进一步地，在优选实施方案中，所述式I化合物的晶型F，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,11.3,11.6,16.0,17.1,17.6,19.7, 20.6,21.7,22.0处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, the Form F of the compound of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at a diffraction angle 2θ angle of 5.7, 11.3, 11.6, 16.0, 17.1, 17.6, 19.7, 20.6, 21.7, 22.0 have characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型F的制备方法，包括：The invention also provides a process for the preparation of the crystalline form F of the compound of the formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(IX)中，搅拌溶解或加热溶解，所述溶剂(IX)于室温下对式I的溶解度大于10mg/ml，可为10mg/ml、11mg/ml、12mg/ml、13mg/ml、14mg/ml、15mg/ml、16mg/ml、17mg/ml、18mg/ml、19mg/ml、20mg/ml、21mg/ml、22mg/ml、23mg/ml、24mg/ml、25mg/ml、26mg/ml、27mg/ml、28mg/ml、29mg/ml、30mg/ml、31mg/ml、33mg/ml、34mg/ml等，优选自但不限于1,4-二氧六环；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (IX), stirring Dissolved or dissolved by heating, the solubility of the solvent (IX) to the formula I at room temperature is greater than 10 mg / ml, may be 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ Ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 33 mg/ml, 34 mg/ml, etc., preferably but not limited to 1,4-dioxane;

本法所述溶剂(IX)所用体积可以为式I重量的1～100倍，更优选1～80倍，在非限制性实施方案中可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、55、58、60、62、65、68、70、72、75、78、80倍。The solvent (IX) used in the present process may be used in a volume of from 1 to 100 times, more preferably from 1 to 80 times by weight of the formula I, and in the non-limiting embodiment may be 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 58, 60, 62 65, 68, 70, 72, 75, 78, 80 times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型G，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在4.9,9.9,10.6,15.0,16.5,20.1,20.7处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form G of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 4.9, 9.9, 10.6, 15.0, 16.5, 20.1, 20.7, wherein the error range of each characteristic peak 2θ Is ±0.2.

进一步地，在优选实施方案中，所述式I化合物的晶型G，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在4.9,9.9,10.6,15.0,16.0,16.5,19.8,20.1,20.7,25.0处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, the crystalline form G of the compound of formula I, using Cu-Kα radiation, results in an X-ray powder diffraction pattern at an angle of diffraction 2θ, which is at 4.9, 9.9, 10.6, 15.0, There are characteristic peaks at 16.0, 16.5, 19.8, 20.1, 20.7, and 25.0, wherein the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型G的制备方法，包括：The invention also provides a preparation method of the crystalline form G of the compound of the formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(X)中，搅拌溶解或加热溶解，所述溶剂(X)于室温下对式I的溶解度大于10mg/ml，可为10mg/ml、11mg/ml、12mg/ml、13mg/ml、14mg/ml、15mg/ml、16mg/ml、17mg/ml、18mg/ml、19mg/ml、20mg/ml、21mg/ml、22mg/ml、23mg/ml、24mg/ml、25mg/ml、26mg/ml、27mg/ml、28mg/ml、29mg/ml、30mg/ml、31mg/ml、33mg/ml、34mg/ml等，优选自但不限于丙二醇甲醚；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (X) and stirring Dissolved or dissolved by heating, the solubility of the solvent (X) to the formula I at room temperature is greater than 10 mg / ml, may be 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ Ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 33 mg/ml, 34 mg/ml, etc., preferably but not limited to propylene glycol methyl ether;

本法所述溶剂(X)所用体积可以为式I重量的1～100倍，更优选1～80倍，在非限制性实施方案中可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、 37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、55、58、60、62、65、68、70、72、75、78、80倍。The solvent (X) used in the present process may be used in a volume of from 1 to 100 times, more preferably from 1 to 80 times by weight of the formula I, and in the non-limiting embodiment may be 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 58, 60, 62 65, 68, 70, 72, 75, 78, 80 times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型I，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,12.2,18.4,23.0,24.2,25.1,29.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystalline form I of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 6.0, 12.2, 18.4, 23.0, 24.2, 25.1, 29.9, wherein the error range of each characteristic peak 2θ Is ±0.2.

进一步地，在优选实施方案中，所述式I化合物的晶型I，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,6.0,12.2,16.7,18.4,23.0,24.2,25.1,25.9,29.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, Form I of the compound of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at a diffraction angle 2θ angle of 5.7, 6.0, 12.2, 16.7, There are characteristic peaks at 18.4, 23.0, 24.2, 25.1, 25.9, and 29.9, where the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型I的制备方法，包括：The invention also provides a process for the preparation of the crystalline form I of the compound of formula I, comprising:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(XI)中，搅拌溶解或加热溶解，所述溶剂(XI)于室温下对式I的溶解度大于10mg/ml，可为10mg/ml、11mg/ml、12mg/ml、13mg/ml、14mg/ml、15mg/ml、16mg/ml、17mg/ml、18mg/ml、19mg/ml、20mg/ml、21mg/ml、22mg/ml、23mg/ml、24mg/ml、25mg/ml、26mg/ml、27mg/ml、28mg/ml、29mg/ml、30mg/ml、31mg/ml、33mg/ml、34mg/ml等，优选自但不限于7％水/乙醇；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (XI), stirring Dissolved in dissolved or heated, the solvent (XI) has a solubility in formula I of more than 10 mg/ml at room temperature, and may be 10 mg/ml, 11 mg/ml, 12 mg/ml, 13 mg/ml, 14 mg/ml, 15 mg/ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ Ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 33 mg/ml, 34 mg/ml, etc., preferably but not limited to 7% water/ethanol;

本法所述溶剂(X)所用体积可以为式I重量的1～100倍，更优选1～80倍，在非限制性实施方案中可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、55、58、60、62、65、68、70、72、75、78、80倍。The solvent (X) used in the present process may be used in a volume of from 1 to 100 times, more preferably from 1 to 80 times by weight of the formula I, and in the non-limiting embodiment may be 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 58, 60, 62 65, 68, 70, 72, 75, 78, 80 times.

本发明提供了一种N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)的晶型J，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,12.1,16.6,17.7,18.4,24.3,25.1,25.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The present invention provides a crystal form J of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I), used Cu-Kα radiation, an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained, which has characteristic peaks at 6.0, 12.1, 16.6, 17.7, 18.4, 24.3, 25.1, 25.9, wherein each characteristic peak is 2θ The error range is ±0.2.

进一步地，在优选实施方案中，所述式I化合物的晶型J，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,6.1,11.7,12.1,15.5,16.6,17.7,18.4,24.3,25.1,25.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Further, in a preferred embodiment, the Form J of the compound of Formula I, using Cu-Kα radiation, yields an X-ray powder diffraction pattern expressed at a diffraction angle 2θ angle of 6.0, 6.1, 11.7, 12.1, There are characteristic peaks at 15.5, 16.6, 17.7, 18.4, 24.3, 25.1, and 25.9, where the error range of each characteristic peak 2θ is ±0.2.

本发明还提供了式I化合物晶型J的制备方法，包括：The invention also provides a process for the preparation of the crystalline form J of the compound of formula I, comprising:

本发明还提供一种药物组合物，其含有前述式I化合物的晶型A，优选所述式I化合物的粒径D90值小于约10μm。The present invention also provides a pharmaceutical composition comprising Form A of the compound of Formula I above, preferably wherein the compound of Formula I has a particle size D90 of less than about 10 μm.

在可选实施例中，本发明药物组合物中式I化合物的晶型A的粒径D90值可选自小于约10μm，小于约9μm，小于约8μm，小于约7μm，小于约6μm，小于约5μm，小于约4μm，小于约3μm，小于约2μm，小于约1μm，小于约5000nm，小于约4800nm，小于约4500nm，小于约4200nm，小于约4000nm，小于约3800nm，小于约3500nm，小于约3200nm，小于约3000nm，小于约2800nm，小于约2500nm，小于约2200nm，小于约2000nm，小于约1900nm，小于约1800nm，小于约1700nm，小于约1600nm，小于约1500nm，小于约1400nm，小于约1300nm，小于约1200nm，小于约1100nm，小于约1000nm，小于约900nm，小于约800nm，小于约700nm，小于约600nm，小于约500nm，小于约400nm，小于约300nm，小于约200nm，小于约100nm，小于约50nm或更小，优选小于约5000nm，更优选小于约3000nm，最优选小于约2000nm。In an alternative embodiment, the crystalline form A of the compound of formula I in the pharmaceutical composition of the invention may have a particle size D90 value selected from less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm. Less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm, less than about 5000 nm, less than about 4800 nm, less than about 4500 nm, less than about 4200 nm, less than about 4000 nm, less than about 3800 nm, less than about 3500 nm, less than about 3200 nm, less than about 3200 nm. About 3000 nm, less than about 2800 nm, less than about 2500 nm, less than about 2200 nm, less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm. Less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, less than about 50 nm or more. Small, preferably less than about 5000 nm, more preferably less than about 3000 nm, and most preferably less than about 2000 nm.

进一步地，本发明药物组合物中式I化合物的晶型A的粒径D50值小于约1μm，所述D50值优选自小于约1μm，小于约900nm、小于约800nm，小于约700nm，小于约600nm，小于约500nm，小于约450nm，小于约400nm，小于约350nm，小于约300nm，小于约250nm，小于约200nm，小于约150nm，小于约100nm或更小，优选小于约500nm，更优选小于约300nm，最优选小于约150nm。Further, the crystalline form A of the compound of formula I in the pharmaceutical composition of the invention has a particle size D50 value of less than about 1 μm, preferably from less than about 1 μm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, Less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm or less, preferably less than about 500 nm, more preferably less than about 300 nm, Most preferably less than about 150 nm.

更进一步地，本发明药物组合物中式I化合物的晶型A的粒径D10值小于约300nm，所述D50值优选自小于约300nm，小于约280nm，小于约250nm，小于约220nm，小于约200nm，小于约180nm，小于约150nm，小于约120nm，小于约100nm，小于约90nm，小于约80nm，小于约70nm，小于约60nm，小于约50nm，小于约40nm，小于约30nm，小于约20nm，小于约10nm，小于约5nm或更小，优选小于约50nm，最优选小于30nm。Further, the crystalline form A of the compound of formula I in the pharmaceutical composition of the invention has a particle size D10 value of less than about 300 nm, preferably from less than about 300 nm, less than about 280 nm, less than about 250 nm, less than about 220 nm, less than about 200 nm. Less than about 180 nm, less than about 150 nm, less than about 120 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, less than about 20 nm. About 10 nm, less than about 5 nm or less, preferably less than about 50 nm, and most preferably less than 30 nm.

进一步地，本发明所述药物组合物还含有至少一种表面稳定剂。Further, the pharmaceutical composition of the present invention further contains at least one surface stabilizer.

本发明所述表面稳定剂是那些通过物理作用吸附在N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺的表面，但不与N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺形成化学键结合的物质。表面稳定剂包括非离子型、阴离子型、阳离子型、离子型和两性离子型表面稳定剂。The surface stabilizers of the present invention are those which are adsorbed on the surface of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide by physical action. However, it does not form a chemical bond with N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide. Surface stabilizers include nonionic, anionic, cationic, ionic and zwitterionic surface stabilizers.

进一步地，所述表面稳定剂选自聚乙烯吡咯烷酮、羟丙甲基纤维素、羟丙基纤维素、多库脂钠、胆酸钠、脱氧胆酸钠、泊洛沙姆、吐温、十二烷基硫酸钠、聚乙烯醇(PVA)、聚乙烯吡洛烷酮(PVP)、甲基纤维素、D-Α琥珀酸生育酚聚乙二醇酯(TPGS)、醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、Soluplus(聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物)、羟乙基纤维素中至少一种。本发明所述的药物组合物可以同时包含1至10种表面稳定剂，优选2至5种表面稳定剂。在可选实施例中，本发明所述的药物组合物含有至少两种或三种表面稳定剂。Further, the surface stabilizer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium docusate, sodium cholate, sodium deoxycholate, poloxamer, Tween, ten Sodium dialkyl sulfate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl cellulose, tocopheryl tocopheryl D-succinic acid (TPGS), hypromellose acetate At least one of succinate (HPMCAS), Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), and hydroxyethyl cellulose. The pharmaceutical composition of the present invention may comprise from 1 to 10 surface stabilizers, preferably from 2 to 5 surface stabilizers. In an alternative embodiment, the pharmaceutical compositions of the present invention contain at least two or three surface stabilizers.

在非限制实施例中，本发明所述的药物组合物含有表面稳定剂组合包括但不限于十二烷基硫酸钠与羟丙甲基纤维素，十二烷基硫酸钠与羟丙基纤维素，十二烷基硫酸钠与聚乙烯醇(PVA)，十二烷基硫酸钠与聚乙烯吡洛烷酮(PVP，Plasdone)，羟丙甲基纤维素(HPMC)与多库脂钠，泊洛沙姆与共聚维酮，聚乙烯吡洛烷酮(PVP)与多库脂钠，共聚维酮与多库脂钠，D-Α琥珀酸生育酚聚乙二醇酯(TPGS)与羟丙甲基纤维素，泊洛沙姆与吐温-80(Tween80)，吐温-20与十二烷基硫酸钠(SDS)、羟丙基纤维素(HPC)等。In a non-limiting embodiment, the pharmaceutical compositions of the present invention comprise a surface stabilizer combination including, but not limited to, sodium lauryl sulfate and hydroxypropylmethylcellulose, sodium lauryl sulfate and hydroxypropyl cellulose. , sodium lauryl sulfate and polyvinyl alcohol (PVA), sodium lauryl sulfate and polyvinylpyrrolidone (PVP, Plasdone), hydroxypropylmethylcellulose (HPMC) and sodium docusate, moor Losamm and copolyvidone, polyvinylpyrrolidone (PVP) and sodium docusate, copovidone and sodium docusate, tocopheryl tocopheryl D-succinic acid (TPGS) and hydroxypropyl Methylcellulose, poloxamer and Tween 80, Tween-20 with sodium dodecyl sulfate (SDS), hydroxypropyl cellulose (HPC), and the like.

本发明所述的药物组合物可以中间制剂进一步制备成注射液或固体制剂，所述固体制剂选自但不限于片剂、丸剂、颗粒剂、冻干粉针剂或胶囊剂。The pharmaceutical composition of the present invention may be further prepared as an injection or a solid preparation by an intermediate preparation selected from the group consisting of, but not limited to, tablets, pills, granules, lyophilized powders or capsules.

进一步地，所述固体制剂中包含一种或多种药学上可接受的赋形剂，所述赋形剂为本领域技术人员所熟知或可以确定的，选自但不限于崩解剂、填充剂、粘合剂、润滑剂中的至少一种；所述注射液，包括一种或多种药学上可接受的赋形剂，如无毒性的生理学可接受的液体载体、pH调节剂或防腐剂。Further, the solid preparation comprises one or more pharmaceutically acceptable excipients which are well known or determinable by those skilled in the art and are selected from, but not limited to, disintegrants, fillings At least one of a agent, a binder, a lubricant; the injection comprising one or more pharmaceutically acceptable excipients, such as a non-toxic physiologically acceptable liquid carrier, pH adjuster or preservative Agent.

本发明所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，

衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。 The "X-ray powder diffraction pattern or XRPD" according to the present invention means that according to the Bragg formula 2d sin θ = nλ (where λ is the wavelength of the X-ray,

The order of diffraction n is any positive integer, generally taking the first-order diffraction peak, n=1), when the X-ray is incident on the crystal or part of the crystal sample with the sweep angle θ (the angle of incidence angle, also called the Bragg angle) When a certain atomic plane with d-plane plane spacing is used, the Bragg equation can be satisfied, and the X-ray powder diffraction pattern is measured.

本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。The "differential scanning calorimetry or DSC" described in the present invention refers to measuring the temperature difference and the heat flow difference between the sample and the reference during the temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase change information of the sample.

本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度。The "2θ or 2θ angle" as used in the present invention means a diffraction angle, and θ is a Bragg angle in units of ° or degree.

本发明所述干燥温度一般为30℃～100℃，优选40℃～70℃，可以常压干燥，也可以减压干燥。优选的，干燥在减压下干燥。The drying temperature of the present invention is generally from 30 ° C to 100 ° C, preferably from 40 ° C to 70 ° C, and can be dried at normal pressure or dried under reduced pressure. Preferably, the drying is dried under reduced pressure.

本发明所用N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)可以外购或按照CN201610595409.1所述方法制备获得。N-[4-(1-Cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) as used in the present invention may be purchased or in accordance with CN201610595409.1 The method is prepared and obtained.

本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为

或埃。 The "plane spacing or interplanar spacing (d value)" according to the present invention means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points. The parallelepiped unit, which is divided into juxtapositions, is called the interplanar spacing. The spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice. The lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different;

Or ang.

本发明实验所用仪器的测试条件：Test conditions for the instruments used in the experiments of the present invention:

1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)1. Differential Scanning Calorimeter (DSC)

仪器型号：Mettler Toledo DSC 3 ⁺STAR ^e System Instrument model: Mettler Toledo DSC 3 ⁺ STAR ^e System

吹扫气：氮气Purge gas: nitrogen

升温速率：10.0℃/minHeating rate: 10.0 ° C / min

温度范围：25-250℃Temperature range: 25-250 ° C

2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)2. X-ray Powder Diffraction (XRPD)

(1)仪器型号：Bruker D8 Discover A25X-射线粉末衍射仪(1) Instrument model: Bruker D8 Discover A25X-ray powder diffractometer

射线：单色Cu-Kα射线(λ＝1.5406)Ray: Monochrome Cu-Kα ray (λ=1.5406)

扫描方式：θ/2θ，扫描范围：10-48 ^o Scanning method: θ/2θ, scanning range: 10-48 ^o

电压：40KV，电流：40mAVoltage: 40KV, current: 40mA

3、热重分析仪(Thermogravimetric Analysis,TGA)3. Thermogravimetric Analysis (TGA)

仪器型号：Mettler Toledo DSC1/TG209F3Instrument model: Mettler Toledo DSC1/TG209F3

吹扫气：氮气Purge gas: nitrogen

升温速率：10.0℃/minHeating rate: 10.0 ° C / min

温度范围：25-250℃Temperature range: 25-250 ° C

本发明研磨设备可采用德国Retsch PM100行星球磨机The grinding equipment of the invention can adopt German Retsch PM100 planetary ball mill

本发明所述“含量”或有关物质检测采用高效液相法(HPLC)。The "content" or related substances detected in the present invention are detected by a high performance liquid phase (HPLC) method.

附图说明DRAWINGS

图1：式I化合物晶型A的XRPD图谱。Figure 1: XRPD pattern of Form A of the compound of Formula I.

图2：式I化合物晶型A的DSC谱图。Figure 2: DSC spectrum of Form A of the compound of Formula I.

图3：式I化合物晶型A的TGA谱图。Figure 3: TGA spectrum of Form A of the compound of Formula I.

图4：式I化合物晶型B的XRPD图谱。Figure 4: XRPD pattern of Form B of the compound of Formula I.

图5：式I化合物晶型B的DSC谱图。Figure 5: DSC spectrum of Form B of the compound of Formula I.

图6：式I化合物晶型B的TGA谱图。Figure 6: TGA spectrum of Form B of the compound of Formula I.

图7：式I化合物晶型C的XRPD图谱。Figure 7: XRPD pattern of Form C of the compound of Formula I.

图8：式I化合物晶型C的DSC谱图。Figure 8: DSC spectrum of Form C of the compound of Formula I.

图9：式I化合物晶型C的TGA谱图。Figure 9: TGA spectrum of Form C of the compound of Formula I.

图10：式I化合物晶型D的XRPD图谱。Figure 10: XRPD pattern of Form D of the compound of Formula I.

图11：式I化合物晶型D的DSC谱图。Figure 11: DSC spectrum of Form D of the compound of Formula I.

图12：式I化合物晶型D的TGA谱图。Figure 12: TGA spectrum of Form D of the compound of Formula I.

图13：式I化合物晶型E的XRPD图谱。Figure 13: XRPD pattern of Form E of the compound of Formula I.

图14：式I化合物晶型E的DSC谱图。Figure 14: DSC spectrum of Form E of the compound of Formula I.

图15：式I化合物晶型E的TGA谱图。Figure 15: TGA spectrum of Form E of the compound of Formula I.

图16：式I化合物晶型F的XRPD图谱。Figure 16: XRPD pattern of Form F of the compound of Formula I.

图17：式I化合物晶型F的DSC谱图。Figure 17: DSC spectrum of Form F of the compound of Formula I.

图18：式I化合物晶型F的TGA谱图。Figure 18: TGA spectrum of Form F of the compound of Formula I.

图19：式I化合物晶型G的XRPD图谱。Figure 19: XRPD pattern of Form G of the compound of Formula I.

图20：式I化合物晶型G的DSC谱图。Figure 20: DSC spectrum of Form G of the compound of Formula I.

图21：式I化合物晶型G的TGA谱图。Figure 21: TGA spectrum of Form G of the compound of Formula I.

图22：式I化合物晶型I的XRPD图谱。Figure 22: XRPD pattern of Form I of the compound of Formula I.

图23：式I化合物晶型I的DSC谱图。Figure 23: DSC spectrum of Form I of the compound of Formula I.

图24：式I化合物晶型I的TGA谱图。Figure 24: TGA spectrum of Form I of the compound of Formula I.

图25：式I化合物晶型J的XRPD图谱。Figure 25: XRPD pattern of Form J of the compound of Formula I.

图26：式I化合物晶型J的DSC谱图。Figure 26: DSC spectrum of Form J of the compound of Formula I.

图27：式I化合物晶型J的TGA谱图。Figure 27: TGA spectrum of Form J of the compound of Formula I.

图28：式I化合物晶型A研磨前XRPD图。Figure 28: XRPD pattern of Form A of the compound of Formula I prior to milling.

图29：式I化合物晶型A研磨后XRPD图。Figure 29: XRPD pattern after grinding of Form A of the compound of Formula I.

具体实施方式Detailed ways

以下将结合实施例或实验例更详细地解释本发明，本发明的实施例或实验例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。The invention is explained in more detail below with reference to the examples or the experimental examples, which are intended to illustrate the technical solutions of the invention and not to limit the scope and scope of the invention.

实施例1：晶型A的制备Example 1: Preparation of Form A

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入3ml水中，室温打浆5天，过滤，干燥得固体，该结晶样品的XRPD图谱见图1，其DSC图谱见图2，TGA图谱见图3，熔点在163.69℃附近，起始熔化温度为162.25℃，其特征峰位置如下表1所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 3 ml of water and beaten at room temperature for 5 days. The solid is dried. The XRPD pattern of the crystal sample is shown in Fig. 1. The DSC spectrum is shown in Fig. 2. The TGA spectrum is shown in Fig. 3. The melting point is around 163.69 °C. The initial melting temperature is 162.25 °C. The characteristic peak positions are as shown in Table 1 below. Show:

表1Table 1

实施例2：晶型A的制备Example 2: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl乙酸乙酯中，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 500 μl of ethyl acetate and evaporated at room temperature. solid.

实施例3：晶型A的制备Example 3: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl四氢呋喃中，溶解后，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 500 μl of tetrahydrofuran, dissolved, and volatilized at room temperature. Get a solid.

实施例4：晶型A的制备Example 4: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl乙腈中，样品部分溶解，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 500 μl of acetonitrile, and the sample was partially dissolved at room temperature. It was beaten for 13 days, filtered and dried to give a solid.

实施例5：晶型A的制备Example 5: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入250μl丙酮中，溶解后，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 250 μl of acetone, dissolved, and volatilized at room temperature. Get a solid.

实施例6：晶型A的制备Example 6: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl正庚烷中，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 500 μl of n-heptane, and beaten at room temperature 13 Day, filter, dry to a solid.

实施例7：晶型A的制备Example 7: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl环已烷中，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 500 μl of cyclohexane and beaten at room temperature 13 Day, filter, dry to a solid.

实施例8：晶型A的制备Example 8: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl甲基叔丁基醚(MTBE)中，室温打浆13天，过滤，干燥得固体。Add 5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to 500 μl of methyl tert-butyl ether (MTBE) The mixture was beaten at room temperature for 13 days, filtered, and dried to give a solid.

实施例9：晶型A的制备Example 9: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500 μl甲基异丁基酮(MIBK)中，溶解后，室温挥发得固体。Add 5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to 500 μl of methyl isobutyl ketone ( In MIBK), after dissolution, it evaporates at room temperature to obtain a solid.

实施例10：晶型A的制备Example 10: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl乙酸丁酯中，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 500 μl of butyl acetate and beaten at room temperature 13 Day, filter, dry to a solid.

实施例11：晶型A的制备Example 11: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入500μl乙酸异丙酯中，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 500 μl of isopropyl acetate and beaten at room temperature. After 13 days, it was filtered and dried to give a solid.

实施例12：晶型A的制备Example 12: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入70μl四氢呋喃/甲醇(2:1，v/v)中，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 70 μl of tetrahydrofuran/methanol (2:1, In v/v), it was beaten at room temperature for 13 days, filtered and dried to give a solid.

实施例13：晶型A的制备Example 13: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入10％H ₂O/丙酮120μl中，溶解后，室温挥发得固体。 Add 5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to 10% H ₂ O/acetone 120 μl After dissolution, it evaporates at room temperature to obtain a solid.

实施例14：晶型A的制备Example 14: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入N,N-二甲基甲酰胺20μl中，溶解后，室温挥发得固体。Add 5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to N,N-dimethylformamide In 20 μl, after dissolution, it was evaporated to a solid at room temperature.

实施例15：晶型A的制备Example 15: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入N,N-二甲基乙酰胺20μl中，溶解后，室温挥发得固体。Add 5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to N,N-dimethylacetamide In 20 μl, after dissolution, it was evaporated to a solid at room temperature.

实施例16：晶型A的制备Example 16: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入二甲亚砜20μl中，溶解后，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 20 μl of dimethyl sulfoxide and dissolved. It evaporates at room temperature to give a solid.

实施例17：晶型A的制备Example 17: Preparation of Form A

实施例18：晶型A的制备Example 18: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入硝基甲烷450μl中，溶解后，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 450 μl of nitromethane, and after dissolution, It evaporates at room temperature to give a solid.

实施例19：晶型A的制备Example 19: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入1,2-二氯甲烷200μl中，溶解后，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 1,2-dichloromethane 200 μl After dissolution, it evaporates at room temperature to obtain a solid.

实施例20：晶型A的制备Example 20: Preparation of Form A

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入2-丁酮200μl中，溶解后，室温挥发得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 2-butanone 200 μl, dissolved It evaporates at room temperature to give a solid.

实施例21：晶型B的制备Example 21: Preparation of Form B

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入二氯甲烷17ml中，溶解后，室温挥发得固体。该结晶样品的XRPD图谱见图4，其DSC图谱见图5，TGA图谱见图6，熔点在162.41℃附近，起始熔化温度为159.63℃，其特征峰位置如下表2所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 17 ml of dichloromethane and dissolved. It evaporates at room temperature to give a solid. The XRPD pattern of the crystal sample is shown in Fig. 4. The DSC spectrum is shown in Fig. 5. The TGA spectrum is shown in Fig. 6. The melting point is around 162.41 °C. The initial melting temperature is 159.63 °C. The characteristic peak positions are shown in Table 2 below:

表2Table 2

实施例22：晶型C的制备Example 22: Preparation of Form C

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入10ml异丙醇中，室温打浆13天，过滤，干燥得固体。该结晶样品的XRPD图谱见图7，DSC图谱见图8，TGA图谱见图9，熔点在163.87℃附近，起始熔化温度为162.45℃，其特征峰位置如下表3所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 10 ml of isopropanol and beaten at room temperature 13 Day, filter, dry to a solid. The XRPD pattern of the crystal sample is shown in Fig. 7, the DSC spectrum is shown in Fig. 8, the TGA spectrum is shown in Fig. 9, the melting point is around 163.87 °C, and the initial melting temperature is 162.45 °C. The characteristic peak positions are shown in Table 3 below:

表3table 3

实施例23：晶型C的制备Example 23: Preparation of Form C

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入10％H ₂O/异丙醇450μl中，溶解后，室温挥发得固体。 Add 5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to 10% H ₂ O/isopropanol In 450 μl, after dissolution, it was evaporated to a solid at room temperature.

实施例24：晶型D的制备Example 24: Preparation of Form D

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入6ml甲醇中，室温打浆13天，过滤，干燥得固体。该结晶样品的XRPD图谱见图10，DSC图谱见图11，TGA图谱见图12，熔点在163.59℃附近，起始熔化温度为162.01℃，其特征峰位置如下表4所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 6 ml of methanol and beaten at room temperature for 13 days. Filter and dry to a solid. The XRPD pattern of the crystal sample is shown in Fig. 10. The DSC spectrum is shown in Fig. 11. The TGA spectrum is shown in Fig. 12. The melting point is around 163.59 °C. The initial melting temperature is 162.01 °C. The characteristic peak positions are shown in Table 4 below:

表4Table 4

实施例25：晶型D的制备Example 25: Preparation of Form D

将5mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入10％水/甲醇500μl中，室温打浆13天，过滤，干燥得固体。5 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 10% water/methanol 500 μl at room temperature It was beaten for 13 days, filtered and dried to give a solid.

实施例26：晶型E的制备Example 26: Preparation of Form E

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入乙醇12ml中，室温打浆13天，过滤，干燥得固体。该结晶样品的XRPD图谱见图13，DSC图谱见图14，TGA图谱见图15，熔点在163.31℃附近，起始熔化温度为161.83℃，其特征峰位置如下表5所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 12 ml of ethanol and beaten at room temperature for 13 days. Filter and dry to a solid. The XRPD pattern of the crystal sample is shown in Fig. 13, the DSC spectrum is shown in Fig. 14, the TGA spectrum is shown in Fig. 15, the melting point is around 163.31 °C, and the initial melting temperature is 161.83 °C. The characteristic peak positions are shown in Table 5 below:

表5table 5

实施例27：晶型F的制备Example 27: Preparation of Form F

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入1,4-二氧六环9ml中，溶解后，室温挥发得固体。该结晶样品的XRPD图谱见图16，DSC图谱见图17，TGA图谱见图18，熔点在160.64℃附近，起始熔化温度为156.13℃，其特征峰位置如下表6所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) was added to 1,4-dioxane 9 ml After dissolving, it evaporates at room temperature to obtain a solid. The XRPD pattern of the crystal sample is shown in Fig. 16, the DSC spectrum is shown in Fig. 17, the TGA spectrum is shown in Fig. 18, the melting point is around 160.64 ° C, and the initial melting temperature is 156.13 ° C. The characteristic peak positions are shown in Table 6 below:

表6Table 6

实施例28：晶型G的制备Example 28: Preparation of Form G

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入丙二醇甲醚6ml中，溶解后，室温挥发得固体。该结晶样品的XRPD图谱见图19，DSC图谱见图20，TGA图谱见图21，熔点在163.94℃附近，起始熔化温度为162.39℃，其特征峰位置如下表7所示：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 6 ml of propylene glycol methyl ether, and after dissolution, It evaporates at room temperature to give a solid. The XRPD pattern of the crystal sample is shown in Fig. 19, the DSC spectrum is shown in Fig. 20, the TGA spectrum is shown in Fig. 21, the melting point is around 163.94 ° C, and the initial melting temperature is 162.39%, and the characteristic peak positions are as shown in Table 7 below:

表7Table 7

实施例29：晶型I的制备Example 29: Preparation of Form I

将200mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入7％水/乙醇10ml中，溶解后，室温挥发得固体。该结晶样品的XRPD图谱见图22，DSC图谱见图23，TGA图谱见图24，熔点在163.59℃附近，起始熔化温度为162.54℃，其特征峰位置如下表8所示：200 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 7% water/ethanol 10 ml, dissolved After that, it was evaporated to a solid at room temperature. The XRPD pattern of the crystal sample is shown in Fig. 22, the DSC spectrum is shown in Fig. 23, the TGA spectrum is shown in Fig. 24, the melting point is around 163.59 ° C, and the initial melting temperature is 162.54 ° C. The characteristic peak positions are shown in Table 8 below:

表8Table 8

实施例30：晶型J的制备Example 30: Preparation of Form J

将300mg N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入7％水/乙醇10ml中，加热至50℃溶解后，室温挥发得固体。该结晶样品的XRPD图谱见图25，DSC图谱见图26，TGA图谱见图27，熔点在164.56℃附近，起始熔化温度为163.00℃，其特征峰位置如下所示表9：300 mg of N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (formula I) was added to 7% water/ethanol 10 ml and heated After dissolving at 50 ° C, it evaporates at room temperature to give a solid. The XRPD pattern of the crystal sample is shown in Fig. 25, the DSC spectrum is shown in Fig. 26, the TGA spectrum is shown in Fig. 27, the melting point is around 164.56 ° C, and the initial melting temperature is 163.00 ° C. The characteristic peak positions are shown in Table 9 below:

表9Table 9

实施例31：晶型稳定性研究Example 31: Crystal Stability Study

纳米混悬剂的制备Preparation of nanosuspensions

称取约1.25g HPMC，加入50ml的纯化水，搅拌分散并逐渐溶解，加入0.125g SDS，搅拌溶解；Weigh about 1.25g of HPMC, add 50ml of purified water, stir to disperse and gradually dissolve, add 0.125g SDS, stir and dissolve;

称取约200mg式I加至10ml载体溶液中，搅拌30min混匀，式I大致浓度为100mg/ml；Weigh about 200mg of formula I to 10ml carrier solution, stir for 30min to mix, the approximate concentration of formula I is 100mg / ml;

采用12ml的球磨罐，加入载药混悬液及6ml体积量的小球，研磨速度为200rpm，研磨1小时，于12000rpm高速离心，干燥得固体。A 12 ml ball mill jar was used, a drug-loaded suspension and a 6 ml volume of pellets were added, the milling speed was 200 rpm, and the mixture was ground for 1 hour, centrifuged at 12,000 rpm, and dried to obtain a solid.

实验结果：Experimental results:

比较式I化合物晶型A研磨前后的XRPD图，其衍射角2θ角数据无明显差异，研磨前后晶型A未发生变化，晶型A具有较好稳定，可适用于制备纳米混悬剂。具体XRPD对比数据见表10，XRPD图见图28和图29。Compared with the XRPD pattern before and after the polishing of the crystal form A of the compound of the formula I, there is no significant difference in the diffraction angle 2θ angle data, and the crystal form A does not change before and after the polishing, and the crystal form A has good stability and is suitable for preparing the nanosuspension. The specific XRPD comparison data is shown in Table 10, and the XRPD diagram is shown in Figure 28 and Figure 29.

表10Table 10

Claims

一种式I化合物的晶型A，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.5,12.6,15.9,17.0,20.5,21.7,22.0处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，Form A of a compound of formula I, characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 11.5, 12.6, 15.9, 17.0, 20.5, 21.7, 22.0 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2,
如权利要求1所述的晶型A，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在7.6,11.5,12.6,15.9,17.0,20.5,21.7,22.0,23.4,23.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form A according to claim 1, wherein an X-ray powder diffraction pattern expressed by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 7.6, 11.5, 12.6, 15.9, 17.0, 20.5, There are characteristic peaks at 21.7, 22.0, 23.4, and 23.9, wherein the error range of each characteristic peak 2θ is ±0.2.
如权利要求1或2所述的晶型A，其特征在于：使用Cu-Ka辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.6,11.5,12.6,15.9,17.0,17.8,18.1,19.7,20.5,21.7,22.0,23.4,23.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form A according to claim 1 or 2, wherein an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Ka radiation at 7.6, 11.5, 12.6, 15.9, 17.0, 17.8. There are characteristic peaks at 18.1, 19.7, 20.5, 21.7, 22.0, 23.4, and 23.9, wherein the error range of each characteristic peak 2θ is ±0.2.
一种制备如权利要求1-3中任意一项所述的晶型A的方法，其包括：A method of preparing Form A according to any one of claims 1 to 3, comprising:

方法1：method 1:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(I)中，所述的溶剂(I)于室温下对式I化合物的溶解度不大于20mg/ml，优选自水、乙腈、正庚烷、环已烷、叔丁基甲醚、乙酸丁酯、乙酸异丙酯中至少一种；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (I), The solvent (I) has a solubility in the compound of the formula I at room temperature of not more than 20 mg/ml, preferably at least one of water, acetonitrile, n-heptane, cyclohexane, tert-butyl methyl ether, butyl acetate and isopropyl acetate. Species

(b)室温打浆，过滤得式I化合物晶体；(b) beating at room temperature, filtering the crystal of the compound of formula I;

或者，方法2：Or, Method 2:

(a)将N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺(式I)加入溶剂(II)中，搅拌溶解或加热溶解，所述的溶剂(II)于室温下对式I化合物的溶解度大于10mg/ml，优选自乙酸乙酯、四氢呋喃、丙酮、甲基异丁基酮、10％水/丙酮、四氢呋喃/乙醇＝2:1(v/v)、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、硝基甲烷、1,2-二氯乙烷、2-丁酮中至少一种；(a) adding N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide (Formula I) to solvent (II), stirring Dissolved in dissolved or heated, the solvent (II) has a solubility in the compound of formula I at room temperature of greater than 10 mg/ml, preferably from ethyl acetate, tetrahydrofuran, acetone, methyl isobutyl ketone, 10% water/acetone, tetrahydrofuran. /ethanol = 2:1 (v / v), dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, nitromethane, 1,2-dichloroethane, At least one of 2-butanone;

(b)室温挥发得式I化合物晶体。(b) Crystallization of the compound of formula I at room temperature.
一种式I化合物的晶型B，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.8,11.7,14.5,16.1,17.7,20.7,25.8处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，Form B of a compound of formula I, characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 5.8, 11.7, 14.5, 16.1, 17.7, 20.7, 25.8 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2.
如权利要求5所述的晶型B，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.8,11.7,14.5,16.1,17.7,20.7,24.2,25.2,25.8,28.6处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form B according to claim 5, wherein an X-ray powder diffraction pattern expressed by an angle of diffraction angle 2θ is obtained using Cu-Kα radiation at 5.8, 11.7, 14.5, 16.1, 17.7, 20.7, There are characteristic peaks at 24.2, 25.2, 25.8, and 28.6, where the error range of each characteristic peak 2θ is ±0.2.
一种制备如权利要求5或6所述的晶型B的方法，其包括：A method of preparing Form B according to claim 5 or 6, comprising:

a)将式I化合物加入溶剂(III)中，搅拌溶解或加热溶解，所述的溶剂(III)于室温下对式I的溶解度大于10mg/ml，优选自但不限于二氯甲烷；a) adding a compound of the formula I to the solvent (III), dissolved or dissolved by heating, the solvent (III) having a solubility in the formula I at room temperature of more than 10 mg/ml, preferably but not limited to dichloromethane;

(b)室温挥发得式I化合物晶体。(b) Crystallization of the compound of formula I at room temperature.
一种式I化合物的晶型C，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.2,6.0,12.1,15.6,18.3,20.0,24.3处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，Form C of a compound of formula I, characterized in that an X-ray powder diffraction pattern at an angle of diffraction 2θ is obtained using Cu-Kα radiation at 5.2, 6.0, 12.1, 15.6, 18.3, 20.0, 24.3 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2,
如权利要求8所述的晶型C，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.2,6.0,12.1,14.7,15.6,18.3,20.0,22.9,24.3,30.0处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form C according to claim 8, wherein an X-ray powder diffraction pattern expressed by an angle of diffraction angle 2θ is obtained using Cu-Kα radiation at 5.2, 6.0, 12.1, 14.7, 15.6, 18.3, There are characteristic peaks at 20.0, 22.9, 24.3, and 30.0, wherein the error range of each characteristic peak 2θ is ±0.2.
一种制备如权利要求8或9所述的晶型C的方法，其包括：A method of preparing Form C according to claim 8 or 9, comprising:

方法一：method one:

(a)将式I化合物加入溶剂(IV)中，所述的溶剂(IV)于室温下对式I的溶解度不大于20mg/ml，优选自但不限于异丙醇；(a) adding a compound of formula I to solvent (IV), said solvent (IV) having a solubility in formula I of not more than 20 mg/ml at room temperature, preferably but not limited to isopropanol;

(b)室温打浆，过滤得化合物C晶体；(b) beating at room temperature, filtering to obtain a crystal of compound C;

或方法二：Or method two:

(a)将式I化合物加入溶剂(V)中，搅拌溶解或加热溶解，所述的溶剂(V)于室温下对式I化合物的溶解度大于10mg/ml，优选自但不限于水/异丙醇；(a) adding a compound of the formula I to the solvent (V), dissolved or dissolved by heating, the solvent (V) having a solubility in the compound of the formula I at room temperature of more than 10 mg/ml, preferably but not limited to water/isopropyl alcohol;

(b)室温挥发得式I化合物晶体。(b) Crystallization of the compound of formula I at room temperature.
一种式I化合物的晶型D，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.0,12.2,15.7,16.1,18.5,20.2,21.3处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，A crystalline form D of a compound of formula I characterized by the use of Cu-Kα radiation to obtain an X-ray powder diffraction pattern at an angle of diffraction angle 2θ, at 6.0, 12.2, 15.7, 16.1, 18.5, 20.2, 21.3 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2,
如权利要求11所述的晶型D，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,10.6,12.2,15.7,16.1,18.5,20.2,20.3,21.3,25.4处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form D according to claim 11, wherein an X-ray powder diffraction pattern expressed by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 6.0, 10.6, 12.2, 15.7, 16.1, 18.5, There are characteristic peaks at 20.2, 20.3, 21.3, and 25.4, wherein the error range of each characteristic peak 2θ is ±0.2.
一种制备权利要求11或12所述的晶型D的方法，其包括：A method of preparing the crystalline form D of claim 11 or 12, comprising:

方法一：method one:

(a)将式I化合物加入溶剂(IV)中，所述的溶剂(IV)于室温下对式I化合物的溶解度不大于20mg/ml，优选自但不限于甲醇、10％水/甲醇；(a) adding a compound of formula I to solvent (IV), said solvent (IV) having a solubility in the compound of formula I at room temperature of not more than 20 mg/ml, preferably but not limited to methanol, 10% water/methanol;

(b)室温打浆，过滤得式I化合物晶体。(b) Room temperature beating and filtering to obtain crystals of the compound of formula I.
一种式I化合物的晶型E，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.7,5.9,11.5,12.0,17.3,18.2,20.9,处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，Form E of a compound of formula I characterized by the use of Cu-Kα radiation to obtain an X-ray powder diffraction pattern at an angle of diffraction angle 2θ, at 5.7, 5.9, 11.5, 12.0, 17.3, 18.2, 20.9, There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2.
如权利要求14所述的晶型E，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ 角度表示的X-射线粉末衍射图谱，其在5.7,5.9,11.5,12.0,14.1,17.3,18.2,19.0,20.9,22.7处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。Crystal Form E according to claim 14 wherein an X-ray powder diffraction pattern at an angle of diffraction angle 2θ is obtained using Cu-Kα radiation at 5.7, 5.9, 11.5, 12.0, 14.1, 17.3, There are characteristic peaks at 18.2, 19.0, 20.9, and 22.7, where the error range of each characteristic peak 2θ is ±0.2.
一种式I化合物的晶型F，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.7,11.3,11.6,16.0,17.1,17.6,20.6处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，Form F of a compound of formula I characterized by the use of Cu-Kα radiation to obtain an X-ray powder diffraction pattern at an angle of diffraction angle 2θ, at 5.7, 11.3, 11.6, 16.0, 17.1, 17.6, 20.6 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2,
如权利要求16所述的晶型F，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,11.3,11.6,16.0,17.1,17.6,19.7,20.6,21.7,22.0处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form F according to claim 16, wherein an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 5.7, 11.3, 11.6, 16.0, 17.1, 17.6, There are characteristic peaks at 19.7, 20.6, 21.7, and 22.0, wherein the error range of each characteristic peak 2θ is ±0.2.
一种式I化合物的晶型G，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.9,9.9,10.6,15.0,16.5,20.1,20.7处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，A crystalline form G of a compound of formula I, characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 4.9, 9.9, 10.6, 15.0, 16.5, 20.1, 20.7 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2,
如权利要求18所述的晶型G，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,6.0,12.2,16.7,18.4,23.0,24.2,25.1,25.9,29.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form G according to claim 18, wherein an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 5.7, 6.0, 12.2, 16.7, 18.4, 23.0, There are characteristic peaks at 24.2, 25.1, 25.9, and 29.9, where the error range of each characteristic peak 2θ is ±0.2.
一种式I化合物的晶型I，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.0,12.2,18.4,23.0,24.2,25.1,29.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，Form I of a compound of formula I, characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 6.0, 12.2, 18.4, 23.0, 24.2, 25.1, 29.9 There are characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2,
如权利要求20所述的晶型I，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在5.7,6.0,12.2,16.7,18.4,23.0,24.2,25.1,25.9,29.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form I according to claim 20, wherein an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 5.7, 6.0, 12.2, 16.7, 18.4, 23.0, There are characteristic peaks at 24.2, 25.1, 25.9, and 29.9, where the error range of each characteristic peak 2θ is ±0.2.
一种式I化合物的晶型J，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.0,12.1,16.6,17.7,18.4,24.3,25.1,25.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，A crystalline form J of a compound of formula I, characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 6.0, 12.1, 16.6, 17.7, 18.4, 24.3, 25.1, There are characteristic peaks at 25.9, where the error range of each characteristic peak 2θ is ±0.2.
如权利要求22所述的晶型J，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在6.0,6.1,11.7,12.1,15.5,16.6,17.7,18.4,24.3,25.1,25.9处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。The crystal form J according to claim 22, wherein an X-ray powder diffraction pattern expressed by a diffraction angle 2θ angle is obtained using Cu-Kα radiation at 6.0, 6.1, 11.7, 12.1, 15.5, 16.6, There are characteristic peaks at 17.7, 18.4, 24.3, 25.1, and 25.9, where the error range of each characteristic peak 2θ is ±0.2.
一种药物组合物，其含有权利要求1所述的晶型A，优选所述的晶型A的粒径D90值小于约10μm。A pharmaceutical composition comprising the crystalline form A of claim 1 wherein preferably the crystalline form A has a particle size D90 value of less than about 10 μm.
如权利要求24所述的药物组合物，其特征在于，所述的晶型A的粒径D90值小于5000nm，优选小于约3000nm，最优选小于约2000nm。The pharmaceutical composition according to claim 24, wherein said Form A has a particle size D90 value of less than 5000 nm, preferably less than about 3000 nm, and most preferably less than about 2000 nm.
如权利要求24或25所述的药物组合物，其特征在于，所述的晶型A的粒径D50值小于约1μm，优选小于约800nm，更优选小于约700nm，最优选小于约600nm。The pharmaceutical composition according to claim 24 or 25, wherein said Form A has a particle size D50 value of less than about 1 μm, preferably less than about 800 nm, more preferably less than about 700 nm, and most preferably less than about 600 nm.
如权利要求24-26中任意一项所述的药物组合物，其特征在于，所述的晶型A的粒径D10值小于约300nm，优选小于约200nm，最优选小于100nm。The pharmaceutical composition according to any one of claims 24 to 26, wherein the crystalline form A has a particle size D10 value of less than about 300 nm, preferably less than about 200 nm, and most preferably less than 100 nm.
如权利要求24-27中任意一项所述的药物组合物，其特征在于，其还含有至少一种表面稳定剂。The pharmaceutical composition according to any one of claims 24 to 27, which further comprises at least one surface stabilizer.
如权利要求24-28中任意一项所述的药物组合物，其特征在于：所述的表面稳定剂选自阴离子型表面稳定剂、阳离子型表面稳定剂、两性表面稳定剂、非离子表面稳定剂和离子表面稳定剂。The pharmaceutical composition according to any one of claims 24 to 28, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, an amphoteric surface stabilizer, and a nonionic surface stabilization. Agent and ionic surface stabilizer.
如权利要求28或29所述的药物组合物，其特征在于：所述的表面稳定剂选自聚乙烯吡咯烷酮、羟丙甲基纤维素、羟丙基纤维素、多库脂钠、胆酸钠、脱氧胆酸钠、泊洛沙姆、吐温、十二烷基硫酸钠、聚乙烯醇(PVA)、聚乙烯吡洛烷酮(PVP)、甲基纤维素、D-Α琥珀酸生育酚聚乙二醇酯(TPGS)、醋酸羟丙甲纤维素琥珀酸酯、Soluplus、羟乙基纤维素中至少一种。The pharmaceutical composition according to claim 28 or 29, wherein the surface stabilizer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium docusate, sodium cholate , sodium deoxycholate, poloxamer, Tween, sodium lauryl sulfate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl cellulose, tocopheryl succinate At least one of polyethylene glycol ester (TPGS), hypromellose acetate succinate, Soluplus, and hydroxyethyl cellulose.