Two new crystalline forms of nilotinib free base and preparation methods thereof

Abstract

The present invention discloses two new nilotinib free base crystal forms and preparation methods thereof, wherein the two nilotinib free base crystal forms are free base crystal form X and free base crystal form Y. In the X-ray powder diffraction spectrum, the free base crystal form X has diffraction peaks at diffraction angles 2θ of 6.31°, 8.62°, 12.63°, 13.32°, 14.39°, 15.30°, 17.28°, 18.12°, 18.99°, 19.46°, 20.88°, 21.51°, 22.57°, 23.02°, 24.47°, 25.13°, 27.72°, and 33.16°. The free base crystal form Y also provides diffraction peaks at corresponding diffraction angles in the X-ray powder diffraction spectrum. The solubility of the two free base crystal forms X and Y provided by the present invention in sodium dihydrogen phosphate buffer solution is respectively increased by 4.01 times and 1.07 times compared with the free base crystal form A, which is conducive to the absorption of the drug in the gastrointestinal tract, and has good stability, a simple preparation process and no need for solvents, and has the potential to become a pharmaceutical crystal form.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, relates to the preparation of raw materials, and specifically relates to two new free base crystal forms of nilotinib and preparation methods thereof. Background Art

[0002] Nilotinib, chemical name is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]-benzamide, also known as nilotinib free base, chemical structure is shown in formula (I):

[0003]

[0004] Nilotinib was developed by Novartis AG and approved by the U.S. Food and Drug Administration (FDA) in 2007 for the treatment of chronic myeloid leukemia (CML) that has become resistant to imatinib. It is a potent Bcr-Abl tyrosine kinase inhibitor and has been shown to have inhibitory activity against KIT and PDEFR kinases.

[0005] Nilotinib has poor solubility in water and low bioavailability, and is a BSC IV class drug. Patent WO2007015870 describes several polymorphs of nilotinib free base and its salts. In an aqueous buffer solution with a pH of 6.8, the solubility of free base crystal form A is 2 μg / mL, and the solubility of free base crystal form B is only 0.2 μg / mL. Patent CN109020954 discloses a new crystal form of nilotinib with a solubility of 0.36 μg / mL. At present, research on the solid form of nilotinib is mostly focused on nilotinib salt forms and their cocrystal forms. Patent WO 2010054056 discloses several crystalline forms of nilotinib hydrochloride. Patent WO 2011163222 discloses the preparation of nilotinib salts and their crystalline forms, including nilotinib hydrochloride, nilotinib fumarate, nilotinib succinate, nilotinib glutarate, etc. However, drug salt formation may produce physiological toxicity due to the additional introduction of anions and cations used for salt formation. In addition, the increased polarity of the drug caused by salt formation leads to a decrease in its lipophilicity, which hinders the penetration process and may affect the final efficacy. Patent WO 2014060449 discloses a multi-component crystal system of nilotinib or nilotinib hydrohalide and a cocrystal former. Patent CN 114133378 describes a nilotinib hydrochloride L-tartaric acid cocrystal and a preparation method thereof, and the results show that it has a significant solubility advantage. However, long-term storage of the cocrystal system easily leads to the precipitation of a single component, causing the crystal form to change. Therefore, the art urgently needs to develop a nilotinib free base crystal form with high solubility and good stability, which is conducive to improving the bioavailability of the drug and is of great significance for improving the efficacy and safety of the drug. Summary of the invention

[0006] The purpose of the present invention is to provide two new crystalline forms of nilotinib free base and preparation methods thereof, so as to improve the solubility of the drug and thus improve the bioavailability. The obtained two new crystalline forms of nilotinib free base have good stability, significantly improved solubility, simple preparation process and no need to use solvents, and have the potential to become pharmaceutical crystalline forms.

[0007] On the one hand, the present invention provides a new crystalline form X of nilotinib free base, whose X-ray powder diffraction (PXRD) spectrum has diffraction peaks at the following 2θ angles: 6.31°, 8.62°, 12.63°, 13.32°, 14.39°, 15.30°, 17.28°, 18.12°, 18.99°, 19.46°, 20.88°, 21.51°, 22.57°, 23.02°, 24.47°, 25.13°, 27.72°, 33.16°, and the 2θ value accuracy is ±0.2°. Further, the differential scanning calorimetry curve of the nilotinib free base crystalline form X has a melting peak at 224±2°C; the thermogravimetric analysis curve shows that it starts to decompose at 290±2°C, and loses 80.66±2% of its weight in the range of 290-446°C.

[0008] Furthermore, the Fourier transform infrared spectrum of nilotinib free base form X is at 3550 cm -1 ,3414cm -1 , 3233cm -1 , 2917cm -1 , 1733cm -1 , 1669cm -1 , 1617cm -1 , 1592cm -1 , 1563cm -1 , 1447cm -1 , 1406cm -1 It has a characteristic absorption peak.

[0009] Furthermore, the preparation method of nilotinib free base crystal form X adopts a polymer-induced melt cooling crystallization method.

[0010] Furthermore, the preparation method of nilotinib free base crystal form X, the polymer-induced melt cooling crystallization method comprises the following steps:

[0011] 1) Weighing a certain amount of nilotinib free base crystal form A, and then weighing a small amount of polymer, grinding and mixing them evenly to obtain a mixture;

[0012] 2) placing the mixture of step 1) on a hot plate and heating it until it melts;

[0013] 3) The melt of step 2) is cooled to a certain temperature for isothermal crystallization until the crystallization is complete to obtain the nilotinib free base crystal form X.

[0014] The polymer in step 1) is one of hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), and Soluplus, and the amount of the polymer is 5% to 20% of the mass of nilotinib;

[0015] The melting temperature in step 2) is 240-270°C;

[0016] The isothermal crystallization temperature in step 3) is 180-205°C.

[0017] On the other hand, the present invention provides a new crystal form Y of nilotinib free base, whose X-ray powder diffraction (PXRD) spectrum has diffraction peaks at the following 2θ angles: 7.06°, 8.32°, 8.82°, 13.73°, 14.24°, 15.74°, 16.79°, 17.78°, 18.97°, 20.08°, 20.51°, 21.55°, 21.87°, 22.01°, 22.42°, 22.74°, 24.46°, 24.77°, 25.46°, 25.77°, 26.71°, 27.11°, 27.99°, 28.83°, 29.83°, 31.05°, 34.12°, and the 2θ value accuracy is ±0.2°.

[0018] Furthermore, the differential scanning calorimetry curve of the nilotinib free base crystal form Y showed a melting peak at 244±1°C; thermogravimetric analysis showed that it began to decompose at 297±2°C, and lost 63.29±2% of its weight in the range of 297-441°C.

[0019] Furthermore, the Fourier transform infrared spectrum (FT-IR) of nilotinib free base form Y is at 3474 cm -1 , 3415cm -1 , 3235cm -1 , 3122cm -1 , 3028cm -1 , 1671cm -1 , 1617cm -1 , 1569cm -1 , 1543cm -1 , 1435cm -1 It has a characteristic absorption peak.

[0020] Furthermore, the preparation method of nilotinib free base crystal form Y can adopt a secondary melt cooling crystallization method.

[0021] Furthermore, the preparation method of nilotinib free base crystal form Y, the secondary melt cooling crystallization method comprises the following steps:

[0022] 1) Weigh a certain amount of nilotinib and place it on an aluminum crucible or hot plate, and heat the nilotinib until it melts;

[0023] 2) Cool down to T 1 , the melt of step 1) is isothermally crystallized for a period of time (t 1 ), to obtain a recrystallized solid;

[0024] 3) The solid in step 2) is heated and melted again, and then cooled to T 2 , for a period of time (t 2 ) to obtain Nilotinib free base Form Y.

[0025] The melting temperature in step 1) is 240-270°C;

[0026] The isothermal crystallization temperature T in step 2) 1 is 150~205℃, crystallization time t 1 10 to 30 minutes;

[0027] The melting temperature in step 3) is 240°C and the isothermal crystallization temperature T 2 is 220~225℃, crystallization time t 2 30 to 60 minutes.

[0028] The nilotinib free base crystal form X and free base crystal form Y provided by the present invention have the following characteristics:

[0029] Beneficial effects:

[0030] 1) The nilotinib free base crystal form X and the free base crystal form Y of the present invention are polymorphs of nilotinib free base, which improve the problem of low solubility of nilotinib. The equilibrium solubilities in 0.1M sodium dihydrogen phosphate buffer (pH=6.8) containing 0.1% SDS are 39.90±6.55 μg / mL and 10.63±3.04 μg / mL, respectively, which are 4.01 times and 1.07 times that of nilotinib free base crystal form A, respectively, which are beneficial to the absorption of the drug in the gastrointestinal tract and have better bioavailability.

[0031] 2) The nilotinib free base crystal form X and the free base crystal form Y of the present invention were placed at 40° C., 75% RH and 60° C., 0% RH for 90 days and 30 days respectively, and the crystal form did not change, indicating that they have good stability, are suitable for drug production and storage, and have great potential for development into pharmaceutical preparations.

[0032] 3) The preparation process of the nilotinib free base crystal form X and the free base crystal form Y of the present invention is simple and green, does not require a solvent, and the conditions are easy to control, which is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is the PXRD pattern of the nilotinib free base crystal form X of Example 1;

[0034] Figure 2 is the DSC curve of the nilotinib free base crystal form X of Example 1;

[0035] Figure 3 is the TGA curve of the nilotinib free base crystal form X of Example 1;

[0036] Figure 4 is the FT-IR spectrum of the Nilotinib free base crystal form X of Example 1;

[0037] Figure 5 The PXRD pattern of the physical stability comparison of the Nilotinib free base Form X of Example 1;

[0038] Figure 6 is the PXRD pattern of the nilotinib free base crystal form Y of Example 8;

[0039] Figure 7 is the DSC curve of the nilotinib free base crystal form Y of Example 8;

[0040] Figure 8 is the TGA curve of the nilotinib free base crystal form Y of Example 8;

[0041] Fig. 9 is the FT-IR spectrum of the nilotinib free base crystal form Y of Example 8;

[0042] Fig.10 The PXRD spectrum of the physical stability comparison of the nilotinib free base form Y of Example 8. DETAILED DESCRIPTION

[0043] The present invention is further described below in conjunction with specific examples, so that professionals in the field can more fully understand the present invention, but the protection scope of the present invention is not limited thereto. The raw materials and reagents used in the examples can all be obtained from conventional commercial channels.

[0044] Raw materials of the present invention and their sources:

[0045] Nilotinib free base form A was sourced from Yangzhou Qinyuan Pharmaceutical Co., Ltd. with a purity of 99%; hydroxypropyl methylcellulose acetate succinate (HPMCAS) was sourced from Ashland (China) Co., Ltd., polyvinyl pyrrolidone (PVP) was sourced from Sinopharm Chemical Reagent Co., Ltd., and Soluplus was sourced from BASF (China) Co., Ltd., all of which were analytical grade.

[0046] The instruments and methods used in the present invention to collect data are:

[0047] The instrument used for the powder X-ray diffraction (PXRD) pattern was a Bruker D42Advance diffractometer. The samples were tested at room temperature, and the detection conditions were: 2θ angle range 3-50°; step length 0.02° / step; speed 0.2s / step.

[0048] Differential scanning calorimetry (DSC) analysis data were collected on a TADSC 250. The detection process was as follows: 1 to 5 mg of sample was taken with a 40°C equilibrium temperature, and the sample was heated from 40°C to 260°C at a heating rate of 10°C / min under the protection of a 50 mL / min dry nitrogen atmosphere.

[0049] Thermogravimetric analysis (TGA) data were collected on TGA Q200. The detection process was as follows: 1-10 mg of sample was placed in a sample pan, with 40 °C as the equilibrium temperature, and the sample was heated from 40 °C to 500 °C at a heating rate of 10 °C / min under the protection of a dry nitrogen atmosphere at 40 mL / min.

[0050] Fourier transform infrared spectroscopy (FT-IR) spectra are from Nicolet Avatar 370. The test method is: using KBr pellet method, at 500-4000 cm -1 The scanning range is used for detection to obtain an infrared spectrum.

[0051] The solubility data were detected using an Agilent 1260 high performance liquid chromatograph and a Welch Welchrom-C18 (250×4.6mm, 5μm) column. The detection conditions were as follows:

[0052] Detection temperature: 30℃;

[0053] Detection wavelength: 260nm;

[0054] Mobile phase: methanol: ammonium acetate solution = 80:20 (v / v);

[0055] Flow rate: 1mL / min.

[0056] Example 1

[0057] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 2 mg of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS), grind and mix gently, heat the mixture to 260° C. on a hot plate to melt, then lower the temperature to 195° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0058] Example 2

[0059] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 1 mg of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS), grind and mix gently, heat the mixture to 240° C. on a hot plate to melt, then lower the temperature to 205° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0060] Example 3

[0061] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 2 mg of polyvinyl pyrrolidone (PVP K30), grind and mix gently, heat the mixture to 250° C. on a hot plate to melt, then lower the temperature to 195° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0062] Example 4

[0063] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 3 mg of polyvinyl pyrrolidone (PVP K30), grind and mix gently, heat the mixture to 270° C. on a hot plate to melt, then lower the temperature to 190° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0064] Example 5

[0065] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 2 mg of Soluplus, grind and mix gently, heat the mixture to 270° C. on a hot plate to melt, then lower the temperature to 195° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0066] Example 6

[0067] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 3 mg of Soluplus, grind and mix gently, heat the mixture to 260° C. on a hot plate to melt, then lower the temperature to 190° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0068] Example 7

[0069] Preparation of Nilotinib Free Base Form X: Weigh 20 mg of Nilotinib Free Base Form A and 4 mg of Soluplus, grind and mix gently, heat the mixture to 270° C. on a hot plate to melt, then lower the temperature to 180° C. for isothermal crystallization until crystallization is complete, to obtain Nilotinib Free Base Form X.

[0070] Example 8

[0071] Preparation of Nilotinib Free Base Form Y: Weigh 6 mg of Nilotinib Free Base Form A and place it in an aluminum crucible of a differential scanning calorimeter for heating. After heating to 240°C to melt, cool it to 150°C and allow the melt to crystallize at this temperature for 10 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 220°C for isothermal crystallization for 30 minutes, and naturally cool it to room temperature to obtain Nilotinib Free Base Form Y.

[0072] Example 9

[0073] Preparation of Nilotinib Free Base Form Y: Weigh 6 mg of Nilotinib Free Base Form A and place it in an aluminum crucible of a differential scanning calorimeter for heating. After heating to 250°C to melt, cool it to 170°C and allow the melt to crystallize at this temperature for 15 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 223°C for isothermal crystallization for 40 minutes, and naturally cool it to room temperature to obtain Nilotinib Free Base Form Y.

[0074] Example 10

[0075] Preparation of Nilotinib Free Base Form Y: Weigh 6 mg of Nilotinib Free Base Form A and place it in an aluminum crucible of a differential scanning calorimeter for heating. After heating to 260°C to melt, cool it to 195°C and allow the melt to crystallize at this temperature for 25 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 225°C for isothermal crystallization for 50 minutes, and naturally cool it to room temperature to obtain Nilotinib Free Base Form Y.

[0076] Embodiment 11

[0077] Preparation of Nilotinib Free Base Form Y: Weigh 6 mg of Nilotinib Free Base Form A and place it in an aluminum crucible of a differential scanning calorimeter for heating. After heating to 270°C to melt, cool it to 205°C and allow the melt to crystallize at this temperature for 30 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 225°C for isothermal crystallization for 60 minutes, and naturally cool it to room temperature to obtain Nilotinib Free Base Form Y.

[0078] Example 12

[0079] Preparation of Nilotinib Free Base Form Y: Weigh 20 mg of Nilotinib Free Base Form A and heat it on a hot plate. After heating to 240°C and melting, cool it to 150°C and allow the melt to crystallize at this temperature for 10 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 225°C for isothermal crystallization for 60 minutes, and cool it naturally to room temperature to obtain Nilotinib Free Base Form Y.

[0080] Embodiment 13

[0081] Preparation of Nilotinib Free Base Form Y: Weigh 20 mg of Nilotinib Free Base Form A and heat it on a hot plate. After heating to 250°C and melting, cool it to 190°C and allow the melt to crystallize at this temperature for 20 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 225°C for isothermal crystallization for 40 minutes, and naturally cool it to room temperature to obtain Nilotinib Free Base Form Y.

[0082] Embodiment 14

[0083] Preparation of Nilotinib Free Base Form Y: Weigh 20 mg of Nilotinib Free Base Form A and heat it on a hot plate. After heating to 270°C and melting, cool it to 205°C and allow the melt to crystallize at this temperature for 30 minutes to obtain a recrystallized solid. Heat it again to 240°C to melt the solid, then cool it to 220°C for isothermal crystallization for 30 minutes, and naturally cool it to room temperature to obtain Nilotinib Free Base Form Y.

[0084] The prepared samples were characterized by powder X-ray diffractometer, differential scanning calorimeter, thermogravimetric analyzer and infrared spectroscopy.

[0085] The solid sample of the nilotinib free base crystal form X obtained in Example 1 was subjected to powder X-ray diffraction analysis, and the results are as follows: Figure 1 The diffraction data are shown in Table 1.

[0086] Table 1 Powder diffraction data of Nilotinib free base Form X

[0087]

[0088]

[0089] Differential scanning calorimetry analysis was performed on the nilotinib free base crystal form X obtained in Example 1. The results are as follows: Figure 2 As shown, Nilotinib free base Form X exhibits a melting peak at 224°C.

[0090] Thermogravimetric analysis of the nilotinib free base crystal form X obtained in Example 1 was performed, and the results are shown in Figure 3 Nilotinib free base crystal form X begins to decompose when heated to around 290°C, and the TGA spectrum shows no weight loss before this temperature. The weight loss is 80.66% in the range of 290-446°C.

[0091] The nilotinib free base crystal form X obtained in Example 1 was subjected to infrared spectroscopy analysis, and the results are shown in Figure 4 The characteristic peak position of the X-ray spectrum of the nilotinib free base crystal form is (cm -1): 3550, 3414, 3233, 2917, 1733, 1669, 1617, 1592, 1563, 1447, 1406, 1324, 1108, 1078, 924, 853, 800, 797, 554.

[0092] Equilibrium solubility experiment: The powder solubility data of the nilotinib free base crystal form X prepared in Example 1 and the commercially available nilotinib free base crystal form A were compared and studied.

[0093] Equilibrium solubility test method: The powder samples of nilotinib free base crystal form X and nilotinib free base crystal form A were respectively passed through a 60-mesh standard sieve. The excess sample after the sieve was placed in a vial, and sodium dihydrogen phosphate buffer (pH=6.8) containing 0.1% SDS was added, and after stirring at 37°C and 200 rpm for 24 hours, it was filtered through a 0.22 μm microporous membrane, and the drug concentration in the filtrate was detected by high performance liquid chromatography.

[0094] In sodium dihydrogen phosphate buffer (pH = 6.8) containing 0.1% SDS, the equilibrium solubility of nilotinib free base form X and nilotinib free base form A were 39.90 ± 6.55 μg / mL and 9.96 ± 7.41 μg / mL, respectively. It can be seen that compared with nilotinib free base form A, the equilibrium solubility of nilotinib free base form X is increased by 4.0 times.

[0095] Stability experiment: Nilotinib free base crystal form X prepared in Example 1 was evenly distributed in an open vial, placed at 40°C, 75±5% RH, and PXRD was performed on the 30th and 90th days; placed at 60°C, 0% RH, and PXRD was performed on the 30th day. The PXRD results of Nilotinib crystal form X are shown in Figure 2. Figure 5 As shown, it is shown that the crystal form of Nilotinib free base Form X has not changed.

[0096] The samples of Examples 2 to 7 have the same or similar PXRD spectra, DSC curves, TGA curves and FT-IR spectra as those of Example 1, indicating that the samples of Examples 2 to 7 and the sample of Example 1 are of the same crystal form.

[0097] The solid sample of the nilotinib free base crystal form Y prepared in Example 8 was subjected to powder X-ray diffraction analysis, and the results are as follows: Figure 6 The diffraction data are shown in Table 2.

[0098] Table 2 Powder diffraction data of Nilotinib free base Form Y

[0099]

[0100]

[0101]

[0102] Differential scanning calorimetry analysis was performed on the nilotinib free base crystal form Y obtained in Example 8. The results are as follows: Figure 7 As shown, Nilotinib free base Form Y shows a melting peak at 244°C.

[0103] Thermogravimetric analysis of the nilotinib free base crystal form Y obtained in Example 8 was performed, and the results are shown in Figure 8 Nilotinib free base crystal form Y begins to decompose when heated to around 297°C, and the TGA spectrum shows no weight loss before this temperature. The weight loss is 63.29% in the range of 297-441°C.

[0104] The nilotinib free base crystal form Y obtained in Example 8 was subjected to infrared spectroscopy analysis, and the results are shown in Fig. 9 The characteristic peak position of nilotinib free base crystal form Y infrared spectrum is (cm -1 ): 3474, 3415, 3235, 3122, 3028, 1671, 1617, 1569, 1543, 1435, 1342, 1233, 1114, 1079, 920, 840, 793, 710, 536.

[0105] Equilibrium solubility experiment: The powder solubility data of the nilotinib free base crystal form Y prepared in Example 8 and the commercially available nilotinib free base crystal form A were compared and studied.

[0106] Equilibrium solubility test method: The powder samples of nilotinib free base crystal form Y and nilotinib free base crystal form A were respectively passed through a 60-mesh standard sieve. The excess sample after sieving was placed in a 20 mL vial, and sodium dihydrogen phosphate buffer (pH = 6.8) containing 0.1% SDS was added, and after stirring at 37°C and 200 rpm for 24 hours, it was filtered through a 0.22 μm microporous membrane, and the drug concentration in the filtrate was detected by high performance liquid chromatography.

[0107] In sodium dihydrogen phosphate buffer (pH=6.8) containing 0.1% SDS, the equilibrium solubility of nilotinib free base form Y is 10.63±3.04 μg / mL, which is 1.07 times that of form X.

[0108] Stability experiment: Nilotinib free base crystal form Y prepared in Example 8 was evenly distributed in an open vial, placed at 40°C, 75±5% RH, and PXRD was performed on the 30th and 90th days; placed at 60°C, 0% RH, and PXRD was performed on the 30th day. The PXRD results of Nilotinib free base crystal form Y are shown in Figure 1. Fig.10As shown, it is shown that the crystal form of nilotinib free base form Y has not changed.

[0109] The samples of Examples 9 to 14 have the same or similar PXRD spectra, DSC curves, TGA curves and FT-IR spectra as those of Example 8, indicating that the samples of Examples 9 to 14 and the sample of Example 1 are of the same crystal form.

Claims

1. A nilotinib free base crystal form, characterized in that: The nilotinib free base crystal form is free base crystal form X; The free base crystal form X has diffraction peaks at diffraction angles 2θ of 6.31°, 8.62°, 12.63°, 13.32°, 14.39°, 15.30°, 17.28°, 18.12°, 18.99°, 19.46°, 20.88°, 21.51°, 22.57°, 23.02°, 24.47°, 25.13°, 27.72°, and 33.16° in the X-ray powder diffraction pattern; The differential scanning calorimetry curve of the free base crystal form X has a melting peak at 224±2°C. The thermogravimetric analysis curve of the free base crystal form X shows that it starts to decompose at 290±2°C and loses 80.66±2% of its weight in the range of 290~446°C. The Fourier transform infrared spectrum of the free base crystal form X shows a peak at 3550 cm -1 , 3414 cm -1 , 3233 cm -1 , 2917 cm -1 , 1733 cm -1 , 1669 cm -1 , 1617cm -1 , 1592 cm -1 , 1563 cm -1 , 1447 cm -1 , 1406 cm -1 It has a characteristic absorption peak.

2. The method for preparing a nilotinib free base crystal form according to claim 1, characterized in that: The preparation method of the free base crystal form X is to adopt a polymer-induced melt cooling crystallization method, which specifically comprises the following steps: 1) Weigh a certain amount of nilotinib free base crystal form A, and then weigh a small amount of polymer, grind and mix them evenly to obtain a mixture; 2) placing the mixture of step 1) on a hot plate and heating it until it melts; 3) cooling the melt of step 2) to a certain temperature for isothermal crystallization until the crystallization is complete to obtain nilotinib free base crystal form X; The polymer in step 1) is one of hydroxypropylmethylcellulose acetate succinate, polyvinyl pyrrolidone, and Soluplus, and the amount of the polymer is 5% to 20% of the mass of the nilotinib free base crystal form A; The melting temperature in step 2) is 240-270°C; The isothermal crystallization temperature in step 3) is 180~205℃.

Images