Osimertinib Medicinal Cocrystal and Its Preparation Method

Abstract

The present invention relates to the technical field of crystalline drug molecules, and specifically provides osimertinib cocrystals, a preparation method thereof, and applications. The pharmaceutical cocrystals of the present invention are osimertinib - malic acid cocrystals, osimertinib - malonic acid cocrystals, osimertinib - vanillic acid cocrystals, or osimertinib - sorbic acid cocrystals. The preparation method of the pharmaceutical cocrystals of the present invention is simple to operate, and the prepared crystals have high purity. Compared with the existing osimertinib crystal forms, they have better solubility and lower hygroscopicity, and are more suitable for drug development.

Description

Technical Field

[0001] The present invention relates to the technical field of crystalline pharmaceutical molecules, and particularly relates to osimertinib cocrystals and their preparation methods and applications. Background Art

[0002] Osimertinib, chemical name: N-[2-[[2-(dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide, English name: N-(2-{[2-(Dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino}phenyl)acrylamide. CAS No.: 1421373-65-0, and its structural formula is shown as follows:

[0003]

[0004] Lung cancer patients with EGFR or ALK gene mutations can benefit from targeted drugs in terms of survival. However, the efficacy of these drugs is generally very short-lived, and drug resistance occurs within 9 - 11 months. This is because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing their growth patterns.

[0005] ADZ9291 developed by AstraZeneca is a third-generation oral, irreversible selective EGFR mutation inhibitor, which can be used for both activating and resistant mutant EGFRs. That is to say, for advanced non-small cell lung cancer patients, 50% of the acquired resistance to anti-EGFR therapy is caused by the T790M mutation, and ADZ9291 can render this challenging mutation ineffective. ADZ9291 has a better therapeutic effect on NSCLC patients with resistance to existing epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the T790M mutation.

[0006] Patent CN103702990A discloses the compound structure of AZD9291. This patent also discloses the polymorphs of this compound and its mesylate, including osimertinib mesylate polymorph A and osimertinib mesylate polymorph B. The original research company uses the mesylate of osimertinib for clinical research. However, methanesulfonic acid has high biological toxicity and is not suitable for drug development when there are alternatives. And the mesylate has problems of high hygroscopicity and easy deliquescence in high humidity. Improving the solubility of candidate compounds by salting has become an important means in drug research and development. Compared with the free form of the drug, a suitable salt form of the drug can improve the solubility of the drug, increase physical and chemical stability, and after the drug is salted, its physical properties such as melting point, hygroscopicity, and crystal type can also be improved.

[0007] Patent CN104961731A discloses osimertinib phosphate; Patent CN106432231A discloses osimertinib pharmaceutical salts sulfate, p-toluenesulfonate, tartrate, acetate, and citrate; which overcomes the problems of high toxicity and high hygroscopicity of the mesylate, and the solubility is greatly improved compared with osimertinib. Patent CN107915725A discloses new pharmaceutical salts of osimertinib maleate, fumarate, gluconate, malonate, succinate, and lactate, and Patent CN110483486A discloses osimertinib ketorolac salt, which improves the problem of high hygroscopicity of the mesylate.

[0008] Although numerous osimertinib crystal forms have been disclosed in the existing literature, the systematic research on its crystal forms still needs to be improved, especially for osimertinib cocrystals. There are many reports on other salts now, but their drug-forming properties need to be further studied. Summary of the Invention

[0009] The present invention provides osimertinib cocrystals and their preparation methods, providing a better basis for the application of osimertinib in drug treatment, so as to more efficiently exert the medicinal value of osimertinib.

[0010] The technical solution of the present invention is as follows:

[0011] The osimertinib pharmaceutical cocrystal of the present invention, the cocrystal ligand of the pharmaceutical cocrystal is malic acid, malonic acid, vanillic acid, or sorbic acid.

[0012] Preferably, the pharmaceutical cocrystal is osimertinib-malic acid cocrystal or osimertinib-malonic acid cocrystal.

[0013] Preferably, the osimertinib pharmaceutical cocrystal is osimertinib - malic acid cocrystal. Using Cu - Kα radiation, the X - ray diffraction pattern expressed in 2θ has characteristic peaks at 3.68±0.2°, 6.87±0.2°, 10.55±0.2°, 14.86±0.2°, 21.37±0.2°, 25.57±0.2°. Further preferably, for the osimertinib - malic acid cocrystal, using Cu - Kα radiation, the X - ray diffraction pattern expressed in 2θ has characteristic peaks at 3.68±0.2°, 4.85±0.2°, 5.22±0.2°, 6.23±0.2, 6.87±0.2°, 8.32±0.2°, 10.55±0.2°, 12.74±0.2°, 14.86±0.2°, 15.34±0.2°, 19.17±0.2°, 21.37±0.2°, 25.57±0.2°. Still further, for the osimertinib - malic acid cocrystal, using Cu - Kα radiation, it has the X - ray diffraction pattern as shown in Figure 1.

[0014] Preferably, the osimertinib pharmaceutical cocrystal is osimertinib - malonic acid cocrystal. Using Cu - Kα radiation, the X - ray diffraction pattern expressed in 2θ has characteristic peaks at 4.54±0.2°, 5.52±0.2°, 13.43±0.2°, 17.33±0.2°, 17.90±0.2°, 21.11±0.2°, 25.02±0.2°. Further preferably, for the osimertinib - malonic acid cocrystal, using Cu - Kα radiation, the X - ray diffraction pattern expressed in 2θ has characteristic peaks at 4.54±0.2°, 5.52±0.2°, 5.94±0.2°, 6.63±0.2°, 12.15±0.2, 13.43±0.2°, 17.33±0.2°, 17.90±0.2°, 19.84±0.2°, 21.11±0.2°, 22.40±0.2°, 24.27±0.2°, 25.02±0.2°, 28.44±0.2°. Still further, for the osimertinib - malonic acid cocrystal, using Cu - Kα radiation, it has the X - ray diffraction pattern as shown in Figure 5.

[0015] The present invention provides a method for preparing the osimertinib pharmaceutical cocrystal, comprising the following steps:

[0016] Dissolve osimertinib and the cocrystal ligand in a solvent, heat to dissolve, cool to crystallize, and filter and dry to obtain.

[0017] In one embodiment, the present invention provides a method for preparing the osimertinib - malic acid cocrystal, which comprises the following steps:

[0018] Osimertinib and malic acid are dissolved in a mixed solvent of an organic solvent and purified water, heated for dissolution. After the solution becomes clear, it is cooled for crystallization, and then filtered and dried to obtain the osimertinib-malic acid co-crystal.

[0019] The organic solvent is selected from one or at least two of acetone, methanol, ethanol, and acetonitrile; preferably, the organic solvent is selected from one or two of acetone and methanol.

[0020] The molar ratio of osimertinib to malic acid is 1:1 to 2: preferably, the molar ratio of osimertinib to malic acid is 1:1 to 1.2.

[0021] The mass-volume ratio of osimertinib to the organic solvent in the system is 10 - 25:1, where the mass is in mg and the volume is in mL.

[0022] The volume ratio of the organic solvent to purified water is 10 - 15:1.

[0023] The temperature for dissolving and heating is 40 - 60 °C.

[0024] The temperature for cooling and crystallization is 0 - 30 °C, preferably 5 - 20 °C.

[0025] The crystallization time is 45 - 72 hours.

[0026] The drying temperature is 45 - 70 °C, and the drying time is 8 - 12 hours.

[0027] Confirmation of the structure of osimertinib-malic acid co-crystal

[0028] The X-ray crystal data of the present invention was collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K, using CuKa radiation, collecting data in the ω-scan mode and performing Lp correction. The structure was solved by the direct method, and all non-hydrogen atoms were found by the difference Fourier method. The hydrogen atoms on all carbons and nitrogens were obtained by theoretical hydrogenation, and the structure was refined by the least squares method.

[0029] The X-ray powder diffraction test instrument and test conditions of the present invention are as follows: PANalytical Empyrean X-ray powder diffractometer; Cu target for the light source, flat sample stage, incident optical path: BBHD, diffraction optical path: PIXCEL, voltage 45 KV, current 40 mA, divergence slit 1 / 4°, anti-scattering slit 1°, Soller slit 0.04 rad, counting time per step 0.5 s, scanning range 3 - 50°.

[0030] TGA / DSC Thermal Analyzer and Test Conditions in the Present Invention: TGA / DSC Thermal Analyzer: METTLER TOLEDOTGA / DSC3+; Dynamic Temperature Range: 30 - 300 °C; Heating Rate: 10 °C / min; Gas in Program Segment: N2; Gas Flow Rate: 50 mL / min; Crucible: 40 μl Aluminum Crucible.

[0031] Testing and Analyzing the Crystallographic Data (see Table 1) of the Osimertinib-Malic Acid Cocrystal Prepared in the Present Invention. Its crystallographic parameters are: Monoclinic System, chiral space group is P2 / n ; Cell Parameters are: α = 90.00°, β = 100.1040(10)°, γ = 90.00°, Cell Volume Molecular Formula is: C 32 H 43 N7O9, Molecular Weight is: 669.74. The ORTEP diagram of the structure of the osimertinib-malic acid cocrystal in the present invention shows that the crystal includes one molecule of osimertinib, one molecule of malic acid and two molecules of water, as shown in the appendix Figure 3 Shown. The packing diagram of the osimertinib-malic acid cocrystal in the present invention is shown in the appendix Figure 2 Shown.

[0032] Table 1 Main Crystallographic Data of Osimertinib-Malic Acid Cocrystal

[0033]

[0034]

[0035] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) corresponding to the osimertinib-malic acid cocrystal prepared in the present invention are shown in detail in the appendix Figure 1 And Table 2.

[0036] Table 2 Main PXRD Peaks of Osimertinib-Malic Acid Cocrystal

[0037]

[0038] For the osimertinib-malic acid cocrystal prepared in the present invention, the results of its differential scanning calorimetry curve (DSC) are as shown in Figure 4 Shown. There are two endothermic peaks, 103.88 °C and 145.01 °C, in the differential scanning calorimetry curve (DSC). The first absorption peak is the endothermic peak for the osimertinib-malic acid cocrystal to lose two water molecules, and the second absorption peak is the melting point of the osimertinib-malic acid cocrystal; its thermogravimetric analysis (TGA) only has two weight loss steps, indicating that the osimertinib-malic acid cocrystal corresponds to the DSC curve and has a stable structure. The osimertinib-malic acid cocrystal in the present invention exists as shown in Figure 4The DSC / TGA spectra shown

[0039] All osimertinib - malic acid cocrystal samples prepared by the present invention have the same crystallographic parameters, X - ray powder diffraction patterns and TGA / DSC thermal analysis diagrams as described above.

[0040] In one embodiment, the present invention provides a method for preparing the osimertinib - malonic acid cocrystal, which method comprises the following steps:

[0041] Dissolve osimertinib and malonic acid in an organic solvent, heat to dissolve, after the solution becomes clear, cool down for crystallization, filter and dry to obtain the osimertinib - malonic acid cocrystal.

[0042] The organic solvent is selected from one or at least two of acetone, methanol, ethanol, and acetonitrile; preferably, the organic solvent is selected from one or two of acetone and methanol.

[0043] The molar ratio of osimertinib to malonic acid is 1:1 - 2; preferably, the molar ratio of osimertinib to malonic acid is 1:1 - 1.2.

[0044] The mass - volume ratio of osimertinib to the organic solvent in the system is 10 - 25:1, where the mass is in mg and the volume is in mL.

[0045] The temperature for dissolving and heating is 40 - 60 °C.

[0046] The temperature for cooling and crystallization is 0 - 30 °C; preferably, the temperature for cooling and crystallization is 5 - 20 °C.

[0047] The crystallization time is 45 - 72 hours.

[0048] The drying temperature is 45 - 70 °C and the drying time is 8 - 12 hours.

[0049] Structure confirmation of osimertinib - malonic acid cocrystal

[0050] Testing and analyzing the crystallographic data (see Table 3) of the osimertinib - malonic acid cocrystal prepared by the present invention, its crystallographic parameters are: monoclinic system, chiral space group is P2 / n ; the unit cell parameters are: α = 90.00°, β = 103.5400(10)°, γ = 90.00°, unit cell volume The molecular formula is: C 31 H 37 N7O6, and the molecular weight is: 603.67. The ORTEP diagram of the structure of the osimertinib - malonic acid cocrystal prepared by the present invention shows that there is one molecule of osimertinib and one molecule of malonic acid in the crystal, as shown in the appendixFigure 7 As shown. The packing diagram of the osimertinib-malonic acid co-crystal prepared by the present invention is shown in the appendix Figure 6 as shown.

[0051] Table 3 Main crystallographic data of osimertinib-malonic acid co-crystal

[0052]

[0053]

[0054] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) corresponding to the osimertinib-malonic acid co-crystal prepared by the present invention are shown in detail in the appendix Figure 5 and Table 4.

[0055] Table 4 Main PXRD peaks of osimertinib-malonic acid co-crystal

[0056]

[0057]

[0058]

[0059] For the osimertinib-malonic acid co-crystal prepared by the present invention, the result of its differential scanning calorimetry curve (DSC) is as Figure 8 shown. The differential scanning calorimetry curve (DSC) has an endothermic peak at 165.05 °C; there is only one weight loss step in its thermogravimetric analysis (TGA), indicating that the osimertinib-malonic acid co-crystal has no solvent and has a stable structure. The osimertinib-malonic acid co-crystal of the present invention has a DSC / TGA spectrum as Figure 8 shown.

[0060] All osimertinib-malonic acid co-crystal samples prepared by the present invention have the same crystallographic parameters, X-ray powder diffraction pattern and TGA / DSC thermal analysis pattern as described above.

[0061] The osimertinib-malic acid co-crystal and osimertinib-malonic acid co-crystal prepared by the present invention have good solubility and low hygroscopicity, and are suitable for drug development. The osimertinib-malic acid co-crystal and osimertinib-malonic acid co-crystal prepared by the present invention can be combined with other active ingredients and / or pharmaceutically acceptable excipient components to form a pharmaceutical preparation; the other components include other active ingredients, excipients, fillers, etc. that can be combined; the preparation can be a spray, tablet, capsule, powder injection, liquid injection, etc. The osimertinib-malic acid co-crystal and osimertinib-malonic acid co-crystal prepared by the present invention can be used as active ingredients for the preparation of anti-cancer drugs.

[0062] The present invention also provides a pharmaceutical composition, which comprises the osimertinib pharmaceutical cocrystal prepared as described above, and contains other active ingredients that can be used in combination and / or excipients acceptable in pharmacy.

[0063] Preferably, the other components include other active ingredients, excipients, fillers, etc. that can be used in combination.

[0064] Preferably, the pharmaceutical composition can be made into sprays, tablets, capsules, powder injections, liquid injections, etc. using standard and conventional techniques.

[0065] The present application also provides the use of the above osimertinib pharmaceutical cocrystal as an active ingredient in the preparation of anti-cancer drugs.

[0066] The preparation method of the osimertinib pharmaceutical cocrystal of the present invention is simple to operate, and the prepared crystal has high purity. Compared with the existing osimertinib crystal forms, it has better solubility and lower hygroscopicity. In particular, the osimertinib-malate cocrystal and the osimertinib-malonic acid cocrystal are more suitable for drug development. Description of the Drawings

[0067] Figure 1 : X-ray powder diffraction pattern of osimertinib-malate cocrystal;

[0068] Figure 2 : Packing diagram of osimertinib-malate cocrystal;

[0069] Figure 3 : ORTEP diagram of osimertinib-malate cocrystal;

[0070] Figure 4 : Differential scanning calorimetry (DSC) curve of osimertinib-malate cocrystal;

[0071] Figure 5 : X-ray powder diffraction pattern of osimertinib-malonic acid cocrystal;

[0072] Figure 6 : Packing diagram of osimertinib-malonic acid cocrystal;

[0073] Figure 7 : ORTEP diagram of osimertinib-malonic acid cocrystal;

[0074] Figure 8 : Differential scanning calorimetry (DSC) curve of osimertinib-malonic acid cocrystal. Detailed Embodiments

[0075] The present invention will be further illustrated by the following examples. It should be understood correctly that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, any simple improvement to the present invention under the premise of the method of the present invention falls within the scope of protection of the present invention.

[0076] Example 1

[0077] 2.0 g of osimertinib and 0.65 g of malic acid were added to a mixed solvent of 100 mL of methanol and 8 mL of purified water, heated to 50 °C and stirred until dissolved, refluxed for 1 hour, slowly cooled to 5 °C, and then crystallized by controlled-temperature static standing for 60 hours. After filtration, the filter cake was washed with methanol and dried in vacuo at 50 °C for 10 h to obtain the osimertinib-malic acid co-crystal, with a yield of 95.33% and a purity of 99.97%.

[0078] Example 2

[0079] 2.0 g of osimertinib and 0.80 g of malic acid were added to a mixed solvent of 130 mL of acetone and 10 mL of purified water, heated to 55 °C and stirred until dissolved, refluxed for 1 hour, slowly cooled to 10 °C, and then crystallized by controlled-temperature static standing for 65 hours. After filtration, the filter cake was washed with acetone and dried in vacuo at 60 °C for 8 h to obtain the osimertinib-malic acid co-crystal, with a yield of 93.67% and a purity of 99.95%.

[0080] Example 3

[0081] 2.0 g of osimertinib and 1.07 g of malic acid were added to a mixed solvent of 80 mL of ethanol and 6 mL of purified water, heated to 60 °C and stirred until dissolved, refluxed for 1 hour, slowly cooled to 15 °C, and then crystallized by controlled-temperature static standing for 50 hours. After filtration, the filter cake was washed with ethanol and dried in vacuo at 50 °C for 12 h to obtain the osimertinib-malic acid co-crystal, with a yield of 91.77% and a purity of 99.92%.

[0082] Example 4

[0083] 2.0 g of osimertinib and 0.54 g of malic acid were added to a mixed solvent of 200 mL of acetonitrile and 20 mL of purified water, heated to 45 °C and stirred until dissolved, refluxed for 1 hour, slowly cooled to 20 °C, and then crystallized by controlled-temperature static standing for 45 hours. After filtration, the filter cake was washed with acetonitrile and dried in vacuo at 70 °C for 8 h to obtain the osimertinib-malic acid co-crystal, with a yield of 88.77% and a purity of 99.92%.

[0084] Example 5

[0085] 2.0 g of osimertinib and 1.34 g of malic acid were added to a mixed solvent of 100 mL of methanol and 7 mL of purified water, heated to 40 °C and stirred until dissolved, refluxed for 1 hour, slowly cooled to 30 °C, then temperature-controlled and allowed to crystallize statically for 72 hours, filtered, the filter cake was washed with methanol, and dried in vacuo at 45 °C for 9 h to obtain the osimertinib-malic acid co-crystal, with a yield of 77.77% and a purity of 99.90%.

[0086] Example 6

[0087] 1.5 g of osimertinib and 0.38 g of malonic acid were dissolved in 80 mL of acetone by heating at 50 °C, stirred and refluxed for 0.5 hour, cooled to 5 °C and crystallized for 60 hours, filtered, the filter cake was washed with acetone, and dried at 65 °C for 10 h to obtain the osimertinib-malonic acid co-crystal, with a yield of 93.68% and a purity of 99.96%.

[0088] Example 7

[0089] 1.5 g of osimertinib and 0.47 g of malonic acid were dissolved in 100 mL of methanol by heating at 55 °C, stirred and refluxed for 0.5 hour, cooled to 10 °C and crystallized for 65 hours, filtered, the filter cake was washed with methanol, and dried at 60 °C for 12 h to obtain the osimertinib-malonic acid co-crystal, with a yield of 91.30% and a purity of 99.95%.

[0090] Example 8

[0091] 1.5 g of osimertinib and 0.62 g of malonic acid were dissolved in a mixed solvent of 30 mL of methanol and 30 mL of ethanol by heating at 45 °C, stirred and refluxed for 0.5 hour, cooled to 15 °C and crystallized for 50 hours, filtered, the filter cake was washed with methanol, and dried at 50 °C for 9 h to obtain the osimertinib-malonic acid co-crystal, with a yield of 89.24% and a purity of 99.92%.

[0092] Example 9

[0093] 1.5 g of osimertinib and 0.31 g of malonic acid were dissolved in 150 mL of acetonitrile by heating at 60 °C, stirred and refluxed for 0.5 hour, cooled to 20 °C and crystallized for 45 hours, filtered, the filter cake was washed with acetonitrile, and dried at 70 °C for 8 h to obtain the osimertinib-malonic acid co-crystal, with a yield of 85.69% and a purity of 99.90%.

[0094] Example 10

[0095] 1.5 g of osimertinib and 0.78 g of malonic acid were dissolved in 75 mL of ethanol by heating at 40 °C, stirred and refluxed for 0.5 hour, cooled to 30 °C and crystallized for 72 hours, filtered, the filter cake was washed with ethanol, and dried at 45 °C for 10 h to obtain the osimertinib-malonic acid co-crystal, with a yield of 67.43% and a purity of 99.91%.

[0096] Osimertinib mesylate polymorph A was prepared according to the prior art patent CN103702990A, and AZD9291 malonate was prepared according to the prior art patent CN107915725A.

[0097] I. Solubility test

[0098] The solubility comparison study was carried out on osimertinib - malic acid cocrystal, osimertinib - malonic acid cocrystal prepared according to the methods of Example 1 and Example 6 of the present invention, and osimertinib mesylate polymorph A and AZD9291 malonate in the prior art. Method: 10 ml of media (water, 0.1 mol / L HCl solution and phosphate buffer solution with pH = 6.8) were respectively measured and placed in a vial, an excessive amount of the sample to be tested was added, the vial was sealed and placed in a constant temperature water bath at 25 °C and stirred for 1 hour, filtered through a 0.45 μm filter membrane, and the filtrate was taken; the absorbance was measured at a wavelength of 210 nm, and the solubility was calculated by measuring the absorbance of the standard reference substance.

[0099] Table 5 Solubility of osimertinib polymorphs in different media (mg / ml)

[0100]

[0101]

[0102] From the above test data, it can be seen that compared with osimertinib mesylate polymorph A and AZD9291 malonate, the polymorphs of Example 1 and Example 6 of the present invention have significantly improved solubility in three different media, especially in 0.1 mol / L HCl, indicating that the osimertinib - malic acid cocrystal and osimertinib - malonic acid cocrystal prepared by the present invention have good solubility, and it is beneficial for human absorption when made into pharmaceutical preparations.

[0103] II. Hygroscopicity test

[0104] The hygroscopicity comparison study was carried out on osimertinib - malic acid cocrystal, osimertinib - malonic acid cocrystal prepared according to the methods of Example 1 and Example 6 of the present invention, and osimertinib mesylate polymorph A, and the test was carried out according to the method of Appendix 9103 of the Fourth Part of Chinese Pharmacopoeia 2015 Edition.

[0105] Table 6 Hygroscopicity results of osimertinib polymorphs

[0106]

[0107] From the above test data, it can be seen that compared with osimertinib mesylate polymorph A and AZD9291 malonate, the polymorphs of Example 1 and Example 6 of the present invention have less hygroscopicity and good stability, and are more suitable for drug development.

[0108] After testing, the hygroscopicity and solubility effects of the osimertinib-malate cocrystals prepared in Examples 2-5 of the present invention can all reach those similar to the osimertinib-malate cocrystal prepared in Example 1, and the hygroscopicity and solubility effects of the osimertinib-malonic acid cocrystals prepared in Examples 7-10 of the present invention can all reach those similar to the osimertinib-malonic acid cocrystal prepared in Example 6. Therefore, compared with the existing crystal forms, the osimertinib-malate cocrystals and osimertinib-malonic acid cocrystals provided by the present invention have less hygroscopicity, good stability, and are more suitable for drug development.

Claims

1. The osimertinib pharmaceutical cocrystal is characterized in that: The pharmaceutical cocrystal is osimertinib-malic acid cocrystal or osimertinib-malonic acid cocrystal; for the osimertinib-malic acid cocrystal, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 3.68±0.2°, 6.87±0.2°, 10.55±0.2°, 14.86±0.2°, 21.37±0.2°, 25.57±0.2°; for the osimertinib-malonic acid cocrystal, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 4.54±0.2°, 5.52±0.2°, 13.43±0.2°, 17.33±0.2°, 17.90±0.2°, 21.11±0.2°, 25.02±0.2°.

2. The osimertinib pharmaceutical cocrystal according to claim 1, characterized in that: The osimertinib pharmaceutical cocrystal is osimertinib-malic acid cocrystal. Using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 3.68±0.2°, 4.85±0.2°, 5.22±0.2°, 6.23±0.2, 6.87±0.2°, 8.32±0.2°, 10.55±0.2°, 12.74±0.2°, 14.86±0.2°, 15.34±0.2°, 19.17±0.2°, 21.37±0.2°, 25.57±0.2°.

3. The osimertinib pharmaceutical cocrystal according to claim 1, wherein: For the osimertinib-malonic acid cocrystal, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 4.54±0.2°, 5.52±0.2°, 5.94±0.2°, 6.63±0.2°, 12.15±0.2, 13.43±0.2°, 17.33±0.2°, 17.90±0.2°, 19.84±0.2°, 21.11±0.2°, 22.40±0.2°, 24.27±0.2°, 25.02±0.2°, 28.44±0.2°.

4. A method for preparing the osimertinib pharmaceutical cocrystal according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: Dissolve osimertinib and the cocrystal ligand in a solvent, heat for dissolution, cool for crystallization, and filter and dry to obtain the product; the solvent is an organic solvent or a mixed solvent of an organic solvent and water; the organic solvent is selected from one of acetone, methanol, ethanol, acetonitrile or a mixed solvent of at least two of them; the heating dissolution temperature is 40-60°C; the cooling crystallization temperature is 0-30°C; the crystallization time is 45-72 hours; the molar ratio of osimertinib to malic acid or malonic acid is 1:1-1.2; the volume ratio of the organic solvent to purified water is 10-15:

1.

5. A pharmaceutical composition comprising the osimertinib pharmaceutical cocrystal according to any one of claims 1 to 4, and containing other active ingredients that can be used in combination and / or pharmaceutically acceptable excipient components.

6. Use of the osimertinib pharmaceutical cocrystal according to any one of claims 1 to 3 as an active ingredient in the preparation of an anticancer drug; the cancer is lung cancer.

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