A crystalline form of loperamide and a process for its preparation

Abstract

The application provides a new crystal form of (7S, 13R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenobridged pyrazolo[4,3-f][1,4,8,10]-benzoxatriazacyclotridecine-4(5H)-one (formula I), and in another aspect, the application provides a preparation method of the crystal form. Compared with the prior art, the crystal form prepared by the application has high stability, low hygroscopicity, simple preparation method, good solubility, and is suitable for subsequent preparation research and industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a new crystalline form of (7S,13R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-etheno pyrazolo[4,3-f][1,4,8,10]-benzoxatricyclotridecine-4(5H)-one and a method for preparing the same. BACKGROUND

[0002] Lorlatinib (TPX-0005) is a potent small molecule multi-target kinase inhibitor, which shows activity against wild-type and mutant ALK (anaplastic lymphoma kinase), wild-type and mutant ROS1 (ROS1 proto-oncogene receptor tyrosine kinase), TRK family kinases (myo-inositol-related receptor tyrosine kinases), JAK2 of the Janus family kinases, SRC (Src family protein tyrosine kinases (SFK)) and FAK (adhesion plaque kinase). It is the fourth generation ALK inhibitor developed by TP Therapeutics. On June 28, 2017, TP Therapeutics announced that the FDA had granted its new clinical drug compound TPX-0005 orphan drug status for the treatment of NSCLC (non-small cell lung cancer) patients carrying ALK, ROS1 or NTRK oncogene rearrangements.

[0003] It has a compact three-dimensional macrocyclic molecular structure, and the molecular weight is 355.4, which is smaller than all existing ALK and ROS1 inhibitor molecules. It is known that there are several mechanisms of ALK inhibitor resistance, including secondary drug resistance mutations in ALK kinase domains, amplification of ALK fusion gene copy numbers, activation of bypass and downstream pathways, and epithelial mesenchymal transition. The compact small molecular structure of TPX-0005 binds to the central binding site inside ATP and avoids steric hindrance caused by mutations outside the ATP binding site, i.e. avoids interference of clinical drug resistance mutations. The chemical name of lorlatinib (TPX-0005) is (7S,13R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-etheno pyrazolo[4,3-f][1,4,8,10]-benzoxatricyclotridecine-4(5H)-one, and its molecular structure formula is as follows:

[0004]

[0005] WO2017007759 reported one crystal form of the compound of formula (I) - Form 1, but did not disclose any of the physicochemical properties of the crystal form, such as stability, solubility, hygroscopicity, powder properties, etc., which are of great significance for product development. The preparation method reported therein is concentration crystallization, which has unpredictable scale-up effect, i.e. it is difficult to control the particle size and crystal habit of the crystal during scale-up production, resulting in batch inconsistency and affecting the subsequent preparation process. In addition, dichloromethane and methanol are required in the above preparation method, which are carcinogenic to animals and have low environmental friendliness.

[0006] For drug research and development, the study of polymorphism is a crucial content. Different crystal forms can cause differences in solubility, stability and flowability of drugs, thereby affecting the safety and effectiveness of drugs and leading to different clinical effects. In order to obtain stable and suitable dosage forms for drug use, it is necessary to provide a crystal form with high stability and suitable for industrial production. Therefore, there is still a need in the art to develop a crystal form with good stability under different temperature, humidity and grinding conditions to meet the needs of drug development, preparation of formulation and industrial production. SUMMARY

[0007] The purpose of the present application is to provide a new crystal form of the compound of formula (I) which is easy to prepare and has high stability, so as to meet the needs of drug research and industrial production.

[0008] In a first aspect, the present application provides a crystal form of the compound of formula (I):

[0009]

[0010] Preferably, the crystal form is selected from the group consisting of crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form CM-V, crystal form CM-VI, crystal form CM-VII and / or crystal form CM-VIII.

[0011] The XRPD pattern of the crystal form CM-I includes two or more 2θ values selected from the group consisting of 7.7°±0.2°, 8.9°±0.2°, 11.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°;

[0012] The XRPD of the crystal form CM-II includes three or more 2θ values selected from the group consisting of 10.7°±0.2°, 12.4°±0.2°, 19.1°±0.2°, 22.8°±0.2°;

[0013] The XRPD pattern of said crystalline form CM-III comprises 3 or more 2Θ values selected from the group consisting of: 7.9°±0.2°, 9.1°±0.2°, 9.7°±0.2°, 18.9°±0.2°.

[0014] Preferably, said crystalline form is crystalline form CM-I, wherein the XRPD pattern of said crystalline form CM-I comprises 2 or more (such as 2, 3, 4) 2Θ values selected from the group consisting of: 7.7°±0.2°, 8.9°±0.2°, 11.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°.

[0015] Preferably, said crystalline form is crystalline form CM-II, wherein the XRPD of said crystalline form CM-II comprises 3 or more (such as 3, 4, 5) 2Θ values selected from the group consisting of: 10.7°±0.2°, 12.4°±0.2°, 19.1°±0.2°, 22.8°±0.2°.

[0016] Preferably, said crystalline form is crystalline form CM-III, wherein the XRPD pattern of said crystalline form CM-III comprises 3 or more (such as 3, 4, 5) 2Θ values selected from the group consisting of: 7.9°±0.2°, 9.1°±0.2°, 9.7°±0.2°, 18.9°±0.2°.

[0017] Preferably, said crystalline form CM-I has one or more characteristics selected from the group consisting of:

[0018] 1) The XRPD pattern of said crystalline form CM-I comprises 6 or more (such as 6, 7, 8, 9, 10) 2Θ values selected from the group consisting of: 3.9°±0.2°, 7.7°±0.2°, 8.9°±0.2°, 11.3°±0.2°, 14.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°, 20.0°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 25.1°±0.2°, 28.9°±0.2°.

[0019] 2) Said crystalline form CM-I has an XRPD pattern substantially as shown in Figure 1 ;

[0020] 3) Said crystalline form CM-I has a TGA pattern substantially as shown in Figure 2 ;

[0021] 4) Said crystalline form CM-I has a DSC pattern substantially as shown in Figure 3 ;

[0022] 5) Said crystalline form CM-I has an H NMR pattern substantially as shown in Figure 4 ; 1 H NMR pattern.

[0023] Preferably, said crystalline Form CM-II has one or more characteristics selected from the group consisting of:

[0024] 1) The XRPD pattern of said crystalline Form CM-II comprises 6 or more (such as 6, 7, 8, 9, 10) 2Θ values selected from the group consisting of: 6.2°±0.2°, 8.8°±0.2°, 10.7°±0.2°, 12.4°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 20.2°±0.2°, 21.4°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 24.5°±0.2°, 26.8°±0.2°, 27.0°±0.2°, 27.5°±0.2°.

[0025] 2) Said crystalline Form CM-II has an XRPD pattern substantially as shown in Figure 6 ;

[0026] 3) Said crystalline Form CM-II has a TGA pattern substantially as shown in Figure 7 ;

[0027] 4) Said crystalline Form CM-II has a DSC pattern substantially as shown in Figure 8 ;

[0028] 5) Said crystalline Form CM-II has a H NMR pattern substantially as shown in Figure 9 ; 1

[0029] Preferably, said crystalline Form CM-III has one or more characteristics selected from the group consisting of:

[0030] 1) The XRPD pattern of said crystalline Form CM-III comprises 6 or more (such as 6, 7, 8, 9, 10) 2Θ values selected from the group consisting of: 6.5°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 9.7°±0.2°, 15.3°±0.2°, 18.8°±0.2°, 18.9°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 23.3°±0.2°, 23.8°±0.2°, 26.1°±0.2°, 28.9°±0.2°.

[0031] 2) Said crystalline Form CM-III has an XRPD pattern substantially as shown in Figure 13 ;

[0032] 3) Said crystalline Form CM-III has a TGA pattern substantially as shown in Figure 14 ;

[0033] ​4) said crystalline Form CM-III has a DSC pattern substantially as shown in Figure 15

[0034] 5) said crystalline Form CM-III has a H NMR pattern substantially as shown in Figure 16 1

[0035] Preferably, said crystalline form is crystalline Form CM-IV, wherein said crystalline Form CM-IV has an XRPD pattern comprising 2 or more (e.g. 2, 3, 4) 2-theta values selected from the group consisting of: 7.1 °±0.2°, 19.6°±0.2°, 21.5°±0.2°, 28.9°±0.2°.

[0036] Preferably, said crystalline Form CM-IV has one or more characteristics selected from the group consisting of:

[0037] 1) said crystalline Form CM-IV has an XRPD pattern comprising 4 or more (e.g. 5, 6, 7, 8) 2-theta values selected from the group consisting of: 7.1 °±0.2°, 9.7°±0.2°, 18.6°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 28.9°±0.2°;

[0038] 2) said crystalline Form CM-IV has an XRPD pattern substantially as shown in Figure 18

[0039] Preferably, said crystalline form is crystalline Form CM-V, wherein said crystalline Form CM-V has an XRPD pattern comprising 2 or more (e.g. 2, 3, 4) 2-theta values selected from the group consisting of: 6.9°±0.2°, 9.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 28.1 °±0.2°.

[0040] Preferably, said crystalline Form CM-V has one or more characteristics selected from the group consisting of:

[0041] 1) said crystalline Form CM-V has an XRPD pattern comprising 6 or more (e.g. 6, 7, 8, 9) 2-theta values selected from the group consisting of: 6.9°±0.2°, 9.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 28.1 °±0.2°, 28.8°±0.2°;

[0042] 2) said crystalline Form CM-V has an XRPD pattern substantially as shown in Figure 19

[0043] ​​​​​Preferably, the crystalline form is crystalline form CM-VI, wherein the XRPD pattern of the crystalline form CM-VI comprises 2 or more (such as 2, 3, 4) 2θ values ​​selected from the following group: 7.4°±0.2°, 9.0°±0.2°, 15.1°±0.2°, 22.5°±0.2°.

[0044] Preferably, the crystalline form CM-VI has one or more characteristics selected from the following group:

[0045] 1) the XRPD pattern of the crystalline form CM-VI comprises 4 or more (e.g., 5, 6, 7, or 8) 2θ values ​​selected from the group consisting of 7.4°±0.2°, 9.0°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 18.2°±0.2°, 22.5°±0.2°, and 30.7°±0.2°;

[0046] 2) The crystalline form CM-VI has substantially the following Figure 20 The XRPD pattern shown.

[0047] Preferably, the crystalline form is crystalline form CM-VII, wherein the XRPD pattern of the crystalline form CM-VII comprises 3 or more (such as 3, 4, 5) 2θ values ​​selected from the following group: 8.4°±0.2°, 13.6°±0.2°, 15.3°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 23.0°±0.2°.

[0048] Preferably, the crystalline form CM-VII has one or more characteristics selected from the following group:

[0049] 1) the XRPD pattern of the crystalline form CM-VII comprises 6 or more (e.g., 6, 7, 8, or 9) 2θ values ​​selected from the group consisting of 8.4°±0.2°, 13.6°±0.2°, 15.3°±0.2°, 16.5°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.0°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 21.2°±0.2°, 23.0°±0.2°, 23.9°±0.2°, and 26.9°±0.2°;

[0050] 2) The crystalline form CM-VII has substantially the following Figure 21 The XRPD pattern shown;

[0051] 3) The crystalline form CM-VII has substantially the following Figure 22 TGA graph shown.

[0052] Preferably, the crystalline form is crystalline form CM-VIII, wherein the XRPD pattern of the crystalline form CM-VIII comprises 2 or more (such as 2, 3, 4) 2-theta values selected from the group consisting of: 7.4°±0.2°, 8.2°±0.2°, 8.9°±0.2°, 10.4°±0.2°.

[0053] Preferably, the crystalline form CM-VIII has one or more of the following characteristics selected from the group consisting of:

[0054] 1) the XRPD pattern of the crystalline form CM-VIII comprises 4 or more (such as 5, 6, 7) 2-theta values selected from the group consisting of: 7.4°±0.2°, 8.2°±0.2°, 8.9°±0.2°, 10.4°±0.2°, 16.3°±0.2°, 18.3°±0.2°, 25.2°±0.2°;

[0055] 2) the crystalline form CM-VIII has an XRPD pattern substantially as shown in Figure 2. Figure 26

[0056] In a second aspect of the present application, there is provided a method for preparing the crystalline form of the first aspect, comprising the step of: crystallizing a compound of formula (I) in an inert solvent, or treating a solid form of a compound of formula (I), wherein the treating comprises one or more steps selected from the group consisting of: stirring, heating, placing under certain temperature and humidity conditions.

[0057] Preferably, the method for preparing comprises the step of: a) providing a solution of a compound of formula (I) in a first solvent, adding a second solvent to the solution to crystallize, and collecting the precipitated solid to obtain the crystalline form.

[0058] Preferably, the step a) comprises: dissolving a compound of formula (I) in a first solvent, filtering, and then adding a second solvent to the obtained filtrate to crystallize, and collecting the precipitated solid to obtain the crystalline form.

[0059] Preferably, in step a), the adding is dropwise or slow adding.

[0060] Preferably, in step a), the crystallization comprises stirring crystallization or standing crystallization.

[0061] Preferably, the method for preparing comprises the step of: b) providing a solution of a compound of formula (I) in a first solvent, adding the solution to a second solvent to crystallize, and collecting the precipitated solid to obtain the crystalline form.

[0062] ​Preferably, the step b) comprises: dissolving the compound of formula (I) in a first solvent, filtering, and then adding the obtained filtrate into a second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form.

[0063] Preferably, in the step b), the adding is dropwise or slowly.

[0064] Preferably, in the step b), the crystallization comprises stirring crystallization or standing crystallization.

[0065] Preferably, the preparation method comprises a step c) of providing a solution or slurry of the compound of formula (I) in a first solvent, treating the solution or slurry to obtain a solid, and collecting the obtained solid to obtain the crystal form; wherein the treating comprises stirring or evaporation.

[0066] Preferably, the preparation method comprises a step d) of providing a solid form of the compound of formula (I), and treating the solid form to obtain the crystal form; wherein the solid form is a crystal form or an amorphous form, and the treating comprises one or more steps of heating or placing under certain temperature and humidity conditions.

[0067] Preferably, the first solvent comprises an alcohol solvent, a ketone solvent, an amide solvent, an ester solvent, an ether solvent, an acid solvent, a nitrile, water, or a combination thereof.

[0068] Preferably, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or a combination thereof.

[0069] Preferably, the ketone solvent is selected from the group consisting of acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.

[0070] Preferably, the amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.

[0071] Preferably, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, or a combination thereof.

[0072] Preferably, the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or a combination thereof.

[0073] Preferably, the acid solvent is selected from the group consisting of formic acid, acetic acid, lactic acid, or a combination thereof.

[0074] Preferably, the nitrile solvent is selected from the group consisting of acetonitrile.

[0075] Preferably, the second solvent comprises a hydrocarbon, an ester, water, or a combination thereof.

[0076] Preferably, the hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or a combination thereof.

[0077] Preferably, the ester solvent is selected from the group consisting of butyl acetate, n-propyl acetate, or a combination thereof.

[0078] In the step a) or the step b), after the precipitated solid is collected, the solid is treated to obtain the crystal form, wherein the treatment comprises vacuum drying.

[0079] In a third aspect of the present application, a pharmaceutical composition is provided, which comprises:

[0080] 1) the crystal form according to the first aspect; and 2) a pharmaceutically acceptable carrier.

[0081] In a fourth aspect of the present application, a use of the pharmaceutical composition according to the third aspect for preparing a medicament for treating NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement is provided.

[0082] In a fifth aspect of the present application, a use of the crystal form according to the first aspect is provided, which comprises: 1) preparing the compound of formula (I) or a salt thereof; and 2) preparing a medicament for treating NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement.

[0083] In a fifth aspect of the present application, a use of the crystal form according to the first aspect is provided, which comprises: 1) preparing the compound of formula (I) or a salt thereof; and 2) preparing a medicament for treating NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement.

[0084] Compared with the prior art, the present application has the following advantages:

[0085] (1) The crystal form of the present application has good stability and mechanical stability, thereby reducing the risk of crystal transformation in the preparation process, and reducing the risk of changes in dissolution rate and bioavailability of the drug due to crystal form changes, which is beneficial to the control of crystal form in crystallization and preparation process.

[0086] (2) The crystal form of the present application has low hygroscopicity, and the requirements for packaging and storage conditions are not strict, and no special drying conditions are required in the preparation process, which simplifies the preparation and post-processing process of the drug, is beneficial to industrialized production, and significantly reduces the cost of drug production, transportation and storage.

[0087] (3) The preparation method of the crystal form provided by the present application is safe and reliable. At the same time, the operation is simple and easy to operate, the cost is low, and it is suitable for drug research and development and industrialized production.

[0088] (4) The crystal form provided by the present application has good solubility and high bioavailability, and can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug while ensuring the efficacy of the drug.

[0089] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0090] Figure 1 is the XRPD pattern of the crystal form CM-I of the present application.

[0091] Figure 2 is the TGA pattern of the crystal form CM-I of the present application.

[0092] Figure 3 is the DSC pattern of the crystal form CM-I of the present application.

[0093] Figure 4 is the XRPD pattern of the crystal form CM-I of the present application. 1 H NMR spectrum.

[0094] Figure 5 is the XRPD comparison pattern of the crystal form CM-I of the present application after being placed at 25℃ / 60%RH and 40℃ / 75%RH for one month (from top to bottom in the figure, the patterns after being placed at 40℃ / 75%RH, 25℃ / 60%RH for one month and before being placed are shown respectively).

[0095] Figure 6 is the XRPD pattern of the crystal form CM-II of the present application.

[0096] Figure 7 is the TGA pattern of the crystal form CM-II of the present application.

[0097] Figure 8 is the DSC pattern of the crystal form CM-II of the present application.

[0098] Figure 9 is the XRPD pattern of the crystal form CM-II of the present application. 1 H NMR spectrum.

[0099] Figure 10 is the XRPD comparison pattern of the crystal form CM-II of the present application after being placed at 25℃ / 60%RH and 40℃ / 75%RH for one month (from top to bottom in the figure, the patterns after being placed at 40℃ / 75%RH, 25℃ / 60%RH for one month and before being placed are shown respectively).

[0100] Figure 11is the XRPD pattern of the crystalline form CM-II of the present application before and after milling (the upper figure is the XRPD pattern after milling, and the lower figure is the XRPD pattern before milling).

[0101] Figure 12 is the DVS pattern of the crystalline form CM-II of the present application.

[0102] Figure 13 is the XRPD pattern of the crystalline form CM-III of the present application.

[0103] Figure 14 is the TGA pattern of the crystalline form CM-III of the present application.

[0104] Figure 15 is the DSC pattern of the crystalline form CM-III of the present application.

[0105] Figure 16 is the 1 H NMR pattern of the crystalline form CM-III of the present application.

[0106] Figure 17 is the XRPD pattern of the crystalline form CM-III of the present application before and after milling (the upper figure is the XRPD pattern after milling, and the lower figure is the XRPD pattern before milling).

[0107] Figure 18 is the XRPD pattern of the crystalline form CM-IV of the present application.

[0108] Figure 19 is the XRPD pattern of the crystalline form CM-V of the present application.

[0109] Figure 20 is the XRPD pattern of the crystalline form CM-VI of the present application.

[0110] Figure 21 is the XRPD pattern of the crystalline form CM-VII of the present application.

[0111] Figure 22 is the TGA pattern of the crystalline form CM-VII of the present application.

[0112] Figure 23 is the XRPD pattern of the amorphous form of the present application.

[0113] Figure 24 is the XRPD comparison pattern of the crystalline form CM-III of the present application after being stored at 25°C / 60%RH and 40°C / 75%RH for one month (from top to bottom, the figures are after being stored at 40°C / 75%RH, 25°C / 60%RH for one month and before storage).

[0114] Figure 25 is the XRPD pattern of Form 1 prepared according to the method of patent WO2017007759.

[0115] Figure 26 is the XRPD pattern of the crystalline form CM-VIII of the present application.

[0116] Figure 27 is the XRPD pattern of the crystalline form CM-II of the present application before and after the test of DVS (the upper figure is the XRPD pattern after the test, and the lower figure is the XRPD pattern before the test).

[0117] Figure 28 is the XRPD pattern of the crystalline form CM-I of the present application containing excipients before and after the compression of tablets (the upper figure is the XRPD pattern after the compression of tablets, and the lower figure is the XRPD pattern before the compression of tablets).

[0118] Figure 29 is the XRPD pattern of the crystalline form CM-II of the present application containing excipients before and after the compression of tablets (the upper figure is the XRPD pattern after the compression of tablets, and the lower figure is the XRPD pattern before the compression of tablets).

[0119] Figure 30 is the XRPD pattern of the crystalline form CM-III of the present application containing excipients before and after the compression of tablets (the upper figure is the XRPD pattern after the compression of tablets, and the lower figure is the XRPD pattern before the compression of tablets).

[0120] Figure 31 is the XRPD pattern of the Form 1 in WO2017007759 of the present application containing excipients before and after the compression of tablets (the upper figure is the XRPD pattern after the compression of tablets, and the lower figure is the XRPD pattern before the compression of tablets). DETAILED DESCRIPTION

[0121] The inventors of the present application surprisingly found a series of new crystalline forms of the compound of formula (I) in the course of research. These crystalline forms are simple to prepare, low in cost, have advantages in crystalline form stability, solubility, hygroscopicity, tabletting stability, mechanical stability, preparation stability, process developability and powder processing performance, and are of great significance to the optimization and development of the drug. And after using the crystalline forms of the present application and pharmaceutically acceptable excipients to prepare tablets, the tablets do not stick during tabletting, so the tablets prepared from the crystalline forms of the present application have excellent tabletting stability.

[0122] TERMS

[0123] In the present text, unless otherwise specified, each abbreviation has the conventional meaning understood by one skilled in the art.

[0124] As used herein, unless otherwise specified, the term "compound of formula (I) raw material" refers to the amorphous form and / or various crystalline forms of the compound of formula (I) (including various crystalline forms and amorphous forms mentioned herein, crystalline forms or amorphous forms mentioned in various literatures or patents disclosed or not disclosed, for example, Form 1 of the compound of formula (I) prepared according to the method described in WO2017007759.

[0125] As used herein, "crystal forms of the present invention" refers to crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form CM-V, crystal form CM-VI, crystal form CM-VII and crystal form CM-VIII as described herein.

[0126] As used herein, unless otherwise specified, the manner of adding solvent or solution is by pouring directly or adding uniformly, etc.

[0127] As used herein, the manner of "slowly adding" includes, but is not limited to, dropwise adding, slowly adding along the wall of a container, etc.

[0128] General methods

[0129] The present application is further described in conjunction with the following examples. It is to be understood that these examples are merely illustrative of the present application and do not limit the scope of the application. Unless otherwise indicated, the methods of the experiments in the following examples were carried out in accordance with conventional procedures or as otherwise described. Unless otherwise indicated, all percentages and parts are by weight.

[0130] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs. Also, any methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials are described herein.

[0131] All solvents used in the present application are of analytical purity, and the water content is about 0.1%. The compound of formula (I) used as raw material in the examples is purchased. All test methods of the present application are general methods, and the test parameters are as follows:

[0132] XRPD chart determination method:

[0133] X-ray powder diffraction instrument: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; initial 2θ: 2.000°, scanning range: 2.0000-35.000°, scanning step 0.02°, scanning speed 0.1s / step.

[0134] TGA chart determination method:

[0135] Thermogravimetric analysis (TGA) instrument: TGA55 of TA Corporation of USA; heating rate: 10°C / min; nitrogen flow rate: 40mL / min.

[0136] DSC chart determination method:

[0137] Differential scanning calorimetry (DSC) instrument: TA Q2000, TA Instruments; heating rate: 10°C / min, nitrogen flow rate: 50 mL / min.

[0138] Nuclear magnetic resonance hydrogen spectrum data 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 2 mg of sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a nuclear magnetic tube for testing.

[0139] DVS graph determination method:

[0140] Dynamic vapor sorption instrument (DVS): TA Q5000 SA, TA Instruments; temperature: 25°C; nitrogen flow rate: 50 mL / min; mass change per unit time: 0.002% / min; relative humidity range: 0% RH to 90% RH.

[0141] Bulk density test:

[0142] Particle and powder property analyzer: FT-2000A / B, Ningbo Ruikeweiye Instrument Co., Ltd.

[0143] Tabletting:

[0144] Single-punch manual tablet press, model: ENERPAC, die: Round.

[0145] In the present application, unless otherwise specified, the method used for drying is a conventional drying method in the art, for example, in the examples of the present application, drying refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, the drying is performed for 0.1 to 50 h or 1 to 30 h.

[0146] Pharmaceutical composition and administration method

[0147] Since the crystal form of the present application or the crystalline form of the present application has excellent therapeutic effect on patients carrying ALK, ROS1 or NTRK oncogene rearrangement NSCLC, the crystal form of the present application or the crystalline form of the present application and the pharmaceutical composition containing the crystal form of the present application or the crystalline form of the present application as the main active ingredient can be used for treating cancer patients or patients carrying ALK, ROS1 or NTRK oncogene rearrangement NSCLC. Therefore, the crystal form of the present application or the crystalline form of the present application can be used for preparing a drug for treating cancer patients (such as patients carrying ALK, ROS1 or NTRK oncogene rearrangement NSCLC), which can be prepared by the methods commonly used in the art.

[0148] The pharmaceutical composition of the present application comprises a safe and effective amount of the crystalline form of the present application or loperamide prepared from the crystalline form of the present application (amorphous) and a pharmaceutically acceptable excipient or carrier.

[0149] wherein "safe and effective amount" means an amount of the compound (or crystalline form or amorphous) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the crystalline form of the present application per dose, more preferably, 10-200 mg of the crystalline form of the present application per dose. Preferably, the "dose" is one capsule or tablet.

[0150] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid filler or gel materials which are suitable for human use and which are nontoxic under the conditions of administration. "Compatible" means that the carrier does not significantly interact with the active ingredient of the present application or with other components of the composition. Examples of suitable pharmaceutically acceptable carriers are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0151] The mode of administration of the polymorph or pharmaceutical composition of the present application is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0152] ​Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) humectants, e.g., hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) moistening agents, e.g., glycerol, (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, e.g., paraffin, (f) absoφtion accelerators, e.g., quaternary ammonium compounds, (g) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (h) respiration agents, e.g., kaolin, and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents.

[0153] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other coatings and shells well known in the art. They can optionally contain opacifying agents, and can have one or more layers treating agents, shelf life extender agents, and the like. Dosage forms, wherein the active ingredients' release is delayed in the gastrointestinal tract, can be used. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient, if in solid form, can also be in micro-encapsulated form, if so desired.

[0154] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0155] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0156] Suspensions, in addition to the active ingredient, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0157] Compositions suitable for parenteral injection include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and / or solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and / or thickening agents.

[0158] Dosage forms of the crystalline polymorphs of the present application for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which can be required.

[0159] The crystalline polymorphs of the present application or lopatinib (amorphous) prepared from the crystalline polymorphs of the present application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0160] When used as pharmaceutical compositions, safe and effective amounts of the crystalline polymorphs of the present application or lopatinib (amorphous) prepared from the crystalline polymorphs of the present application are administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is pharmaceutically effective, and for a 60 kg body weight human, the daily dosage is usually 1-2000 mg, preferably 20-500 mg. Of course, the specific dose will also depend on the route of administration, the health condition of the patient, and the like, which are within the skill of the skilled practitioner.

[0161] The main advantages of the present application are:

[0162] (1) Good stability and mechanical stability. The crystalline polymorph CM-I is stable for at least 30 days at 25℃ / 60%RH. The crystalline polymorphs CM-II and CM-III are stable for at least 30 days at 25℃ / 60%RH and 40℃ / 75%RH. The crystalline polymorphs CM-II and CM-III do not change before and after grinding, indicating that they have good mechanical stability, which can reduce the risk of crystallization during the crushing of the raw material during the preparation process. The crystalline polymorphs CM-I, CM-II and CM-III do not change before and after tabletting with excipients, indicating that they have good tabletting stability. Good crystalline polymorph stability can reduce the risk of changes in dissolution rate and bioavailability due to changes in crystalline polymorphs, and is beneficial for crystallization and control of crystalline polymorphs in the preparation process, and is also of great benefit to the production and storage of products.

[0163] (2) Low hygroscopicity. The crystalline polymorph CM-II has low hygroscopicity, with a weight gain of 0.12% at 40%RH-80%RH. Low hygroscopicity indicates that the crystalline polymorph does not have strict requirements for packaging and storage conditions, and does not require special drying conditions during preparation, simplifying the preparation and post-processing process of the drug, facilitating industrial production, and significantly reducing the cost of drug production, transportation and storage.

[0164] (3) Compared with the prior art, the preparation method of the crystal form provided by the present application is safer and more reliable. At the same time, the operation is simple and easy to implement, the cost is low, and it is suitable for drug research and development and industrial production. The crystal form provided by the present application can be prepared using low-toxicity or non-toxic solvents such as ethanol, acetic acid and water. At the same time, the preparation method is a conventional and industrialized production crystallization method, which can control the particle size, crystal habit and crystal form by controlling the process parameters, thereby obtaining stable and high-quality products.

[0165] (4) Compared with the prior art, the crystal form provided by the present application has good solubility, which is beneficial to improve the absorption of the drug in the human body, improve the bioavailability, and make the drug play a better therapeutic effect. In addition, better solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

[0166] (5) Compared with the prior art, the crystal form provided by the present application has better flowability and does not stick during tabletting. It is beneficial to the transportation and transfer of the drug and the development of the preparation process.

[0167] The present application will be further described below through specific examples, but it is not used to limit the protection scope of the present application. Therefore, the protection scope of the present application patent should be subject to the appended claims.

[0168] Comparative Example 1: Form 1 in patent WO2017007759

[0169] According to the method described in patent WO2017007759, the preparation of the form 1 is as follows: 5.55 g of the compound of formula (I) is dissolved in ethyl acetate: dichloromethane: methanol (200:150:40), and the solution is concentrated to a volume of about 70 mL, and a white solid is precipitated, which is filtered. The white solid is form 1 in patent WO2017007759. The XRPD pattern of the obtained solid is shown in Figure 25 .

[0170] Example 1: Preparation of crystal form CM-I

[0171] 500 mg of the compound of formula (I) is dissolved in 27 mL of ethanol at 50°C, and filtered. The filtrate is added dropwise to 200 mL of water at 20°C, stirred for 2 h, and filtered. The wet filter cake is dried under vacuum at 25°C for 24 h, and the obtained solid is crystal form CM-I of the compound of formula (I). The X-ray powder diffraction data of the obtained solid is shown in Table 1, and the XRPD pattern is shown in Figure 1 . The TGA spectrum of the obtained solid is shown in Figure 2As shown, about 10.5% weight loss was observed at 25-100°C; the obtained solid was subjected to DSC test, two endothermic peaks were observed at 60-92°C and one exothermic peak was observed at 170-185°C, and the spectrum was as shown in Figure 3 As shown, the obtained solid was subjected to 1H NMR test, and the spectrum was as shown in Figure 4 As shown, the nuclear magnetic data was as follows: 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.81 (d, J = 6.7 Hz, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.13 (dd, J = 9.5, 3.0 Hz, 1H), 7.00 (ddd, J = 10.9, 8.5, 3.8 Hz, 2H), 6.36 (d, J = 7.6 Hz, 1H), 5.75 - 5.35 (m, 1H), 4.49 (t, J = 9.0 Hz, 1H), 3.91 (ddd, J = 12.1, 8.1, 3.7 Hz, 1H), 3.14 (dd, J = 11.5, 8.6 Hz, 1H), 2.50 (s, 6H), 1.45 (t, J = 6.8 Hz, 6H).

[0172] Table 1

[0173] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 3.8 1.1 20.0 2.9 7.7 8.8 22.7 1.4 8.9 100.0 22.7 1.1 11.3 3.7 23.3 1.1 14.3 0.8 25.1 3.0 15.5 1.8 28.9 1.4 17.8 5.7

[0174] Example 2: Preparation of crystal form CM-I

[0175] 9 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of formic acid / water (4:1, v / v) at room temperature, and filtered. The filtrate was added dropwise into 4 mL of water at 28°C, stirred for 2 h, and filtered. The solid was dried under vacuum at 25°C for 24 h, and the obtained solid was crystal form CM-I of the compound of formula (I). The obtained solid was subjected to XRPD test, and the X-ray powder diffraction data was as shown in Table 2.

[0176] Table 2

[0177] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 3.7 1.9 17.6 4.2 7.5 11.4 20.0 3.2 8.7 100.0 24.9 2.4 11.1 3.8 28.7 1.7

[0178] Example 3: Preparation of crystal form CM-I

[0179] 10 mg of the compound of formula (I) was weighed and dissolved in 0.5 mL of tetrahydrofuran at room temperature, and filtered. 1 mL of water was slowly added dropwise into the filtrate, stirred for 2 h, and filtered. The solid was dried under vacuum at 25°C for 24 h, and the obtained solid was crystal form CM-I of the compound of formula (I). The obtained solid was subjected to XRPD test, and the X-ray powder diffraction data was as shown in Table 3.

[0180] Table 3

[0181]

[0182]

[0183] Example 4: Preparation of crystalline form CM-I

[0184] Weigh 10 mg of the compound of formula (I) and dissolve it in 0.5 mL of acetone at room temperature, and filter. Slowly drop 1 mL of water into the filtrate, stir for 2 h, and filter. Dry the solid at 25 °C under vacuum for 24 h, and the obtained solid is crystalline form CM-I of the compound of formula (I). The X-ray powder diffraction data of the obtained solid are shown in Table 4.

[0185] Table 4

[0186] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 7.5 4.4 17.6 4.0 8.7 100.0 19.8 2.1 11.1 2.3 24.8 1.3 14.1 0.5 28.7 0.7

[0187] Example 5: Preparation of crystalline form CM-I

[0188] Weigh 5 mg of the compound of formula (I) and dissolve it in 5 mL of acetonitrile at room temperature, and filter. Evaporate the solvent at 23 °C under open evaporation, and the obtained solid is crystalline form CM-I of the compound of formula (I). The X-ray powder diffraction data of the obtained solid are shown in Table 5.

[0189] Table 5

[0190] 2 theta (°) Relative intensity (%) 7.6 14.5 8.9 100.0 15.3 3.0

[0191] Example 6: Preparation of crystalline form CM-I

[0192] Place the crystalline form CM-II obtained in Example 9 in water, and stir at 5 °C for 1 day, and the obtained solid is crystalline form CM-I of the compound of formula (I). The X-ray powder diffraction data of the obtained solid are shown in Table 6.

[0193] Table 6

[0194] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 7.5 2.1 17.6 4.0 8.7 100.0 19.8 1.9 11.1 2.1 28.7 1.0

[0195] Example 7: Preparation of crystalline form CM-I

[0196] Place the crystalline form CM-IV obtained in Example 11 in water, and stir at 5 °C for 1 day, and the obtained solid is crystalline form CM-I of the compound of formula (I). The X-ray powder diffraction data of the obtained solid are shown in Table 7.

[0197] Table 7

[0198] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 7.5 2.6 17.6 2.6 8.7 100.0 19.8 1.2 11.1 1.4

[0199] Example 8: Preparation of crystalline form CM-I

[0200] The crystalline form obtained in Example 10 was placed in water, stirred at 5°C for 1 day, and the obtained solid was Form CM-I of the compound of Formula (I). The obtained solid was tested by XRPD, and the X-ray powder diffraction data thereof are shown in Table 8.

[0201] Table 8

[0202] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 7.5 11.1 17.7 3.2 8.8 100.0 19.8 1.4 11.1 3.2 22.7 0.7 14.2 0.9 24.9 1.1 15.3 1.1

[0203] Example 9: Preparation of crystalline form CM-II

[0204] The crystalline form CM-I obtained in Example 1 was weighed at 12 mg, and heated to 200°C under normal pressure under nitrogen protection, and the obtained solid was Form CM-II of the compound of Formula (I). The obtained solid was tested by XRPD, and the X-ray powder diffraction data thereof are shown in Table 9, and the XRPD pattern thereof is shown in Figure 6 The obtained solid was tested by TGA, and the spectrum thereof is shown in Figure 7 , and the weight loss was about 0.8% at 25-100°C; the obtained solid was tested by DSC, and the spectrum thereof is shown in Figure 8 The obtained solid was tested by 1 H NMR, and the spectrum thereof is shown in Figure 9 The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (d, J = 6.3 Hz, 1H), 8.81 (d, J = 6.7 Hz, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.13 (dd, J = 9.5, 3.0 Hz, 1H), 7.06 - 6.91 (m, 2H), 6.36 (d, J = 7.6 Hz, 1H), 5.60 - 5.48 (m, 1H), 4.54 - 4.43 (m, 1H), 3.91 (ddd, J = 12.3, 8.1, 3.8 Hz, 1H), 3.14 (dd, J = 11.3, 8.5 Hz, 1H), 1.45 (t, J = 6.9 Hz, 6H).

[0205] Table 9

[0206]

[0207]

[0208] Example 10: Preparation of crystalline form CM-III

[0209] Take 8 mg of the compound of formula (I) and dissolve it in 0.4 mL of acetic acid at room temperature, filter, and drop the filtrate into 4 mL of water at 28°C, stir for 2 h, and filter. Dry the solid at 25°C under vacuum for 24 h, and the obtained solid is the crystal form CM-III of the compound of formula (I). The obtained solid is tested by XRPD, and the X-ray powder diffraction data thereof are shown in Table 10, and the XRPD pattern thereof is shown in Figure 13 The obtained solid is tested by TGA, and the spectrum thereof is shown in Figure 14 The weight loss is about 8.6% at 25-100°C. The obtained solid is tested by DSC, and the spectrum thereof is shown in Figure 15 The obtained solid is tested by 1H NMR, and the spectrum thereof is shown in Figure 16 The nuclear magnetic resonance data are as follows: 1H NMR (400 MHz, DMSO-d6) δ 9.81 (d, J = 6.6 Hz, 1H), 8.80 (d, J = 6.7 Hz, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.13 (dd, J = 9.5, 3.1 Hz, 1H), 7.08 - 6.91 (m, 2H), 6.36 (d, J = 7.6 Hz, 1H), 5.61 - 5.45 (m, 1H), 4.54 - 4.43 (m, 1H), 3.90 (ddd, J = 12.3, 8.4, 4.0 Hz, 1H), 3.14 (dd, J = 11.4, 8.5 Hz, 1H), 1.45 (t, J = 7.0 Hz, 6H).

[0210] Table 10

[0211] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 6.5 33.4 20.3 11.9 7.9 46.8 21.1 15.9 9.1 100.0 23.3 12.2 9.7 40.8 23.8 10.3 15.3 8.4 26.1 5.7 18.8 25.2 28.9 6.1 18.9 29.1

[0212] Example 11: Preparation of crystal form CM-IV

[0213] Take 196 mg of the compound of formula (I) and dissolve it in 8 mL of 95% ethanol at room temperature, filter, and drop the filtrate into 80 mL of water, and solid precipitates. The obtained solid is the crystal form CM-IV of the compound of formula (I). The obtained solid is tested by XRPD, and the X-ray powder diffraction data thereof are shown in Table 11, and the XRPD pattern thereof is shown in Figure 18

[0214] Table 11

[0215] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 6.0 0.5 21.5 14.4 7.1 100.0 22.9 0.6 7.8 0.6 23.9 0.3 9.7 0.8 24.5 0.2 12.6 0.4 25.6 0.2 18.6 0.9 28.9 5.5 19.6 1.5 30.0 0.4 21.0 0.5 31.5 0.4

[0216] Example 12: Preparation of crystal form CM-V

[0217] ​Take 12 mg of the compound of formula (I) and dissolve it in 1 mL of 1,4-dioxane / water (1:1, v / v) at room temperature, filter, and place the filtrate into a 10 mL glass vial, slowly add 3 mL of water, cap the vial, and stand at 25 °C until solid precipitates. The obtained solid is the crystal form CM-V of the compound of formula (I). The X-ray powder diffraction data of the obtained solid are shown in Table 12, and the XRPD pattern thereof is shown in Figure 19 .

[0218] Table 12

[0219] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 6.9 100.0 23.6 1.7 7.6 1.1 25.6 0.5 9.4 1.7 28.1 2.9 19.3 0.9 28.8 1.8 21.0 8.1 30.8 0.7 21.5 3.2 22.2 0.5 23.2 1.5

[0220] Example 13: Preparation of crystal form CM-VI

[0221] Take 20 mg of the compound of formula (I) and dissolve it in 1 mL of formic acid at room temperature, filter, and place the filtrate into a 10 mL glass vial. Slowly add 4 mL of water along the vial wall, cap the vial, and stand at 25 °C until solid precipitates. The obtained solid is the crystal form CM-VI. The X-ray powder diffraction data of the obtained solid are shown in Table 13, and the XRPD pattern thereof is shown in Figure 20 .

[0222] Table 13

[0223] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 6.6 0.2 16.1 0.1 7.4 100.0 18.2 0.9 9.0 7.6 22.5 3.5 9.6 0.2 22.8 0.4 13.6 0.1 30.4 0.1 14.9 1.7 30.7 0.8 15.1 5.1 32.4 0.1

[0224] Example 14: Preparation of crystal form CM-VII

[0225] Take 36 mg of the compound of formula (I) and dissolve it in 0.2 mL of N,N-dimethylacetamide at room temperature, filter, and drop the filtrate into 2 mL of butyl acetate at 28 °C. Continue stirring until solid precipitates. The obtained solid is the crystal form CM-VII. The X-ray powder diffraction data of the obtained solid are shown in Table 14, and the XRPD pattern thereof is shown in Figure 21 . Figure 22 .

[0226] Table 14

[0227] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 6.8 1.6 20.6 4.4 7.7 1.1 21.2 17.1 8.4 100.0 21.6 5.1 9.4 2.0 22.1 4.9 10.6 2.0 22.6 7.1 11.8 4.1 23.0 14.1 12.9 1.5 23.5 3.9 13.3 2.7 23.9 10.3 13.6 6.7 24.8 9.1 13.9 4.4 25.4 2.4 14.2 3.1 25.7 7.7 14.5 2.2 26.9 11.6 15.3 15.5 28.0 2.8 16.5 7.5 28.5 4.7 16.8 30.4 29.0 6.6 17.3 8.0 29.6 6.7 18.0 12.0 30.7 3.7 18.9 41.5 31.0 3.3 19.8 6.9

[0228] Example 15: Preparation of amorphous form

[0229] Take 15 mg of the crystal form CM-I obtained in Example 1, and heat it to 100 °C under nitrogen protection. The obtained solid is the amorphous form of the compound of formula (I). The XRPD pattern of the obtained solid is shown in Figure 23 .

[0230] Example 16: Preparation of Form CM-VIII

[0231] Weigh 15 mg of the amorphous form obtained in Example 15 and place it open at 25°C / 92.5% RH for 2 weeks. The resulting solid is Form CM-VIII. The obtained solid was subjected to XRPD testing. Its X-ray powder diffraction data are shown in Table 15. Its XRPD pattern is shown in Table 15. Figure 26 shown.

[0232] Table 15

[0233] 2 theta (°) Relative intensity (%) 2 theta (°) Relative intensity (%) 7.4 9.9 16.3 3.7 8.2 100.0 18.3 3.3 8.9 27.3 25.2 3.6 10.4 6.6

[0234] Test Case

[0235] Test Example 1: Crystal Stability

[0236] Crystalline Forms CM-I and CM-II prepared according to the present invention were each exposed for 30 days under different conditions. XRPD patterns of the crystals before and after exposure were analyzed, and the XRPD patterns of the crystals before and after exposure were compared. The specific results are shown in Table 16.

[0237] By comparing the XRPD patterns before and after placement in each figure, it can be seen that the crystal forms CM-I, CM-II, and CM-III provided by the present invention do not change in crystal form after being exposed to the conditions of 25°C / 60% RH and 40°C / 75% RH for 30 days, indicating that the crystal forms of the present invention have good stability under different temperatures / humidities.

[0238] Table 16

[0239]

[0240] Test Example 2: Mechanical Stability

[0241] 50 mg of crystal form CM-II and crystal form CM-III were weighed and ground in a mortar for 10 min. The ground solids were tested by XRPD. The XRPD comparison diagrams of the crystal forms before and after grinding are shown in Figure 2. Figure 11 and Figure 17 , the grinding results are shown in Table 17.

[0242] By comparing the XRPD patterns before and after grinding in each figure, it can be seen that the crystal forms CM-II and CM-III provided by the present invention do not change in crystal form before and after grinding, indicating that the crystal forms CM-II and CM-III provided by the present invention have good mechanical stability.

[0243] Table 17

[0244]

[0245] Test Example 3: hygroscopicity

[0246] About 20 mg of the crystal form CM-II obtained in Example 9 of the present application was subjected to a dynamic vapor sorption (DVS) test to test its hygroscopicity, and the DVS graph thereof is shown in Figure 12 In addition, the solid before and after the DVS test was subjected to XRPD test, and the XRPD graph thereof is shown in Figure 27 The overall test results are shown in Table 18.

[0247] From the DVS test results, it can be seen that the crystal form CM-II provided by the present application has lower hygroscopicity; from the XRPD results, it can be seen that the crystal form does not change before and after the DVS test. It can be seen that the crystal form CM-II of the present application has the ability to resist high humidity environment.

[0248] Table 18

[0249]

[0250] Test Example 4: solubility

[0251] 5 mg of the crystal form CM-I prepared in Example 1 of the present application, the crystal form CM-II prepared in Example 9, the crystal form CM-III prepared in Example 10 and the crystal form of Comparative Example 1 (Form 1 prepared according to the method described in patent WO2017007759) were respectively stirred in solvents of different pH at 37℃ for 24 hours, the dissolution phenomenon was observed, and the corresponding solubility was calculated, and the specific data are shown in Table 19.

[0252] It can be seen that the solubility of the crystal form CM-I, the crystal form CM-II and the crystal form CM-III provided by the present application are all greater than that of Form 1 in patent WO2017007759, and have good solubility.

[0253] Table 19

[0254]

[0255] Test Example 5: bulk density

[0256] The bulk densities of the crystal form CM-I, the crystal form CM-III and Form 1 in WO2017007759 were tested, and the specific data are shown in Table 20. It can be seen that the crystal form CM-I and the crystal form CM-III provided by the present application have better flowability than Form 1 in WO2017007759.

[0257] Table 20

[0258] Crystal form Bulk density (g / mL) Tapped density (g / mL) Hausner ratio Form 1 0.22 0.35 1.59 Crystal form CM-I 0.28 0.33 1.18 Crystal form CM-III 0.27 0.33 1.22

[0259] Test Example 6: tabletting stability with excipients

[0260] The tabletting stability of crystal form CM-I, crystal form CM-II, crystal form CM-III and Form 1 in WO2017007759 with excipients was tested, the pressure was 10 kN, and the preparation prescription was shown in Table 21. The crystal form change before and after tabletting was shown in Table 22. From the tabletting data, it could be seen that the crystal form CM-I, crystal form CM-II and crystal form CM-III provided by the application had excellent tabletting stability when containing excipients. And there was no sticking phenomenon during tabletting.

[0261] Table 21

[0262] Class mg / tablet %(w / w) Crystal form provided by the present invention 30.0 30.0 Microcrystalline cellulose 50.0 50.0 Hydroxypropyl methylcellulose 9.0 9.0 Pre-gelatinized starch 9.0 9.0 Crospovidone 1.0 1.0 Magnesium stearate 1.0 1.0

[0263] Table 22

[0264]

[0265] All the documents mentioned in the present application are incorporated herein by reference. In addition, it should be understood that various modifications can be made to the present application by those skilled in the art, which are within the scope of the appended claims, after reading the above teaching of the present application.

Claims

1. A crystalline form of a compound represented by formula (I): (I) It is characterized by: The crystal form is selected from the group consisting of crystal form CM-I, crystal form CM-II, and crystal form CM-III; Wherein, the crystalline form CM-1 has an XRPD pattern substantially as shown in FIG1 ; The crystalline form CM-II has an XRPD pattern substantially as shown in FIG6 ; The Form CM-III has an XRPD pattern substantially as shown in FIG13 .

2. The crystal form according to claim 1, wherein The crystalline form CM-1 has one or more characteristics selected from the following group: 1) The crystalline form CM-I has a TGA graph substantially as shown in FIG2 ; 2) the crystalline form CM-I has a DSC pattern substantially as shown in FIG3 ; 3) The crystal form CM-I has the following characteristics: 1 H NMR spectrum.

3. The crystal form according to claim 1, wherein The crystalline form CM-II has one or more characteristics selected from the following group: 1) The crystalline form CM-II has a TGA graph substantially as shown in FIG7 ; 2) the crystalline form CM-II has a DSC pattern substantially as shown in FIG8 ; 3) The crystal form CM-II has the following characteristics: 1 H NMR spectrum.

4. The crystal form according to claim 1, wherein The crystalline form CM-III has one or more characteristics selected from the following group: The crystalline form CM-III has a TGA pattern substantially as shown in FIG14 ; The crystalline form CM-III has a DSC pattern substantially as shown in FIG15 ; The crystal form CM-III has a substantially 1 H NMR spectrum.

5. A method for preparing the crystal form according to any one of claims 1 to 4, characterized in that: The preparation method of the crystalline form CM-I is any one of method (a) to method (g): (a) 500 mg of the compound of formula (I) was weighed and dissolved in 27 mL of ethanol at 50°C. The mixture was filtered. The filtrate was added dropwise to 200 mL of water at 20°C, stirred for 2 h, filtered, and the wet cake was dried under vacuum at 25°C for 24 h. The resulting solid was the crystalline form CM-I of the compound of formula (I). (b) 9 mg of the compound of formula (I) was dissolved in 0.4 mL of formic acid / water (4:1 by volume) at room temperature, filtered, and the filtrate was added dropwise to 4 mL of water at 28°C, stirred for 2 h, filtered, and the solid was dried under vacuum at 25°C for 24 h. The resulting solid is the crystalline form CM-I of the compound of formula (I). (c) 10 mg of the compound of formula (I) was dissolved in 0.5 mL of tetrahydrofuran at room temperature and filtered. 1 mL of water was slowly added dropwise to the filtrate, stirred for 2 h, filtered, and the solid was dried under vacuum at 25°C for 24 h. The resulting solid was the crystalline form CM-I of the compound of formula (I). (d) 10 mg of the compound of formula (I) was dissolved in 0.5 mL of acetone at room temperature and filtered. 1 mL of water was slowly added dropwise to the filtrate, stirred for 2 h, filtered, and the solid was dried under vacuum at 25°C for 24 h. The resulting solid was the crystalline form CM-I of the compound of formula (I). (e) Weigh 5 mg of the compound of formula (I) and dissolve it in 5 mL of acetonitrile at room temperature. Filter the solution and evaporate it open at 23°C until the solvent is evaporated to dryness. The resulting solid is the crystalline form CM-I of the compound of formula (I). (f) placing the crystalline form CM-II in water and stirring at 5°C for 1 day to obtain a solid which is the crystalline form CM-I of the compound of formula (I); (g) The crystalline form CM-IV was placed in water and stirred at 5°C for 1 day to obtain a solid, which is the crystalline form CM-I of the compound of formula (I). The preparation method of the crystalline form CM-IV is as follows: 196 mg of the compound of formula (I) was dissolved in 8 mL of 95% ethanol at room temperature, filtered, and the filtrate was added dropwise to 80 mL of water. A solid precipitated, and the obtained solid is the crystalline form CM-IV of the compound of formula (I). Alternatively, the preparation method of the crystal form CM-II is as follows: weigh 12 mg of the crystal form CM-I, heat it to 200° C. at normal pressure under nitrogen protection, and the resulting solid is the crystal form CM-II of the compound of formula (I); Alternatively, the preparation method of the crystalline form CM-III is as follows: 8 mg of the compound of formula (I) is weighed and dissolved in 0.4 mL of acetic acid at room temperature, filtered, the filtrate is dropped into 4 mL of water at 28 ° C, stirred for 2 h, filtered, and the solid is vacuum dried at 25 ° C for 24 h. The resulting solid is the crystalline form CM-III of the compound of formula (I).

6. A pharmaceutical composition, characterized in that The composition comprises: 1) the crystalline form according to any one of claims 1 to 4; 2) a pharmaceutically acceptable carrier.

7. Use of the pharmaceutical composition according to claim 6 for preparing a medicament for treating NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangements.

8. The use of the crystalline form according to any one of claims 1 to 4, characterized in that The uses include: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a drug for treating NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangements.

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