Osimertinib-terephthalic acid crystal and its preparation method

Abstract

The present invention provides osimertinib-terephthalic acid crystal A and osimertinib-terephthalic acid crystal B with excellent physicochemical properties. The crystal A has characteristic peaks in the X-ray diffraction pattern expressed in 2θ at least at 5.72±0.2°, 6.10±0.2°, 10.23±0.2°, 12.24±0.2°, 21.80±0.2°, 23.00±0.2°, 26.22±0.2° using Cu-Kα radiation; the crystal B has characteristic peaks in the X-ray diffraction pattern expressed in 2θ at least at 5.59±0.2°, 6.32±0.2°, 10.54±0.2°, 11.14±0.2°, 16.68±0.2°, 18.67±0.2°, 25.07±0.2° using Cu-Kα radiation. The crystals of the present invention can effectively improve the disadvantages of low solubility, high hygroscopicity and easy deliquescence of osimertinib; and the preparation method of the crystals is simple and convenient to operate.

Description

Technical Field

[0001] The present invention relates to the technical field of crystalline pharmaceutical molecules, particularly to the technical field of osimertinib series compounds, and specifically provides osimertinib-terephthalic acid crystals, as well as a preparation method and application thereof. 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] For lung cancer patients with EGFR or ALK gene mutations, the use of targeted drugs can achieve better survival benefits. However, the efficacy of these drugs is generally very short-lived, and drug resistance will occur after 9-11 months of medication. This is because cancer cells can reduce the cytotoxic activity of EGFR or ALK inhibitors against cancer cells through gene mutations and growth variations.

[0005] ADZ9291 developed by AstraZeneca is a third-generation oral, irreversible selective EGFR mutation inhibitor, which can be used for activated and resistant mutant EGFR. 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 structure of osimertinib compound. The patent also discloses the polymorphs and hydrates of the compound and its mesylate, but the series of crystal forms provided do not significantly improve the physical and chemical properties of osimertinib mesylate used in existing preparations, such as solubility, hygroscopicity, stability, etc. Patent CN104961731A discloses osimertinib phosphate. Although it has some improvements in solubility and hygroscopicity compared with osimertinib, it still has the disadvantage of easily absorbing water when placed in a conventional environment; Patent CN106432231A discloses osimertinib pharmaceutical salts of sulfate, p-toluenesulfonate, tartrate, acetate and citrate and preparation methods thereof; Patent CN107915725A discloses its new pharmaceutical salts of maleate, fumarate, gluconate, malonate, succinate and lactate. Although the studied combination of osimertinib and salts has improved the physicochemical properties of osimertinib to a certain extent, the disclosed salt compounds are still hygroscopic, and the product purity needs to be improved. The solubility of osimertinib still needs to be improved, and whether the various crystal forms of osimertinib salts provided in the existing literature are suitable for clinical application also needs to be verified.

[0007] The active ingredient raw material currently used in clinical treatment and clinical research is still the mesylate of osimertinib. However, it is well known that the biological toxicity of methanesulfonic acid is relatively high, and the mesylate has the problem of high hygroscopicity and easy deliquesce at high humidity. Therefore, it is still necessary to continuously develop other forms of osimertinib raw materials with high bioavailability, low biological toxicity and suitable for pharmaceutical use. Although the existing literature has disclosed a large number of osimertinib series salts and their crystal forms, the systematic study of their crystal forms needs to be improved, and their drugability needs further study, especially the comprehensive study of osimertinib crystalline compounds has not been reported.

[0008] The present invention provides a simple and easy-to-operate method for preparing high-purity osimertinib crystals, which provides better raw materials for the application of osimertinib drugs in disease treatment, thereby more efficiently exerting the clinical medicinal value of osimertinib. Summary of the invention

[0009] In view of the current problems of high hygroscopicity, easy deliquesce and low solubility of osimertinib, the present invention provides osimertinib-terephthalic acid crystals A and crystals B with excellent physical and chemical properties, which can effectively improve the disadvantages of low solubility, high hygroscopicity and easy deliquesce of osimertinib; and the preparation method of the crystals is simple, easy to operate, and easy to prepare.

[0010] The specific technical contents of the present invention are as follows:

[0011] On the one hand, the present invention provides an osimertinib-terephthalic acid crystal, wherein the molar ratio of osimertinib to terephthalic acid in the crystal structure of crystal A is 1:1; the molar ratio of osimertinib, terephthalic acid to water in the crystal structure of crystal B is 1:1.5:2.

[0012] Specifically, for the osimertinib-terephthalic acid crystal A, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 5.72±0.2°, 6.10±0.2°, 10.23±0.2°, 12.24±0.2°, 21.80±0.2°, 23.00±0.2°, 26.22±0.2°.

[0013] Preferably, for the osimertinib-terephthalic acid crystal A, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 4.03±0.2°, 5.72±0.2°, 6.10±0.2°, 10.23±0.2°, 11.23±0.2°, 12.24±0.2°, 12.69±0.2°, 16.14±0.2°, 16.94±0.2°, 17.28±0.2°, 20.94±0.2°, 21.31±0.2°, 21.80±0.2°, 23.00±0.2°, 26.22±0.2°, 27.85±0.2°.

[0014] Preferably, for the osimertinib-terephthalic acid crystal A, using Cu-Kα radiation, its characteristic peaks conform to Figure 1 the X-ray powder diffraction pattern shown.

[0015] Preferably, for the osimertinib-terephthalic acid crystal A, its crystallographic parameters are: triclinic system, space group is P -1 ; the unit cell parameters are: α = 100.4168(13), β = 94.0240(14), γ = 99.4698(15), unit cell volume

[0016] Preferably, for the osimertinib-terephthalic acid crystal A, there is an endothermic peak in the differential scanning calorimetry curve (DSC), and the corresponding temperature range is 203.54 - 233.42 °C.

[0017] For the osimertinib-terephthalic acid crystal B, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 5.59±0.2°, 6.32±0.2°, 10.54±0.2°, 11.14±0.2°, 16.68±0.2°, 18.67±0.2°, 25.07±0.2°.

[0018] Preferably, for the osimertinib-terephthalic acid crystal B, in the X-ray diffraction pattern represented by 2θ using Cu-Kα radiation, characteristic peaks are present at least at 4.01±0.2°, 5.59±0.2°, 6.32±0.2°, 6.87±0.2°, 9.32±0.2°, 10.54±0.2°, 11.14±0.2°, 12.97±0.2°, 14.39±0.2°, 15.75±0.2°, 16.68±0.2°, 18.67±0.2°, 18.97±0.2°, 21.21±0.2°, 23.26±0.2°, 25.07±0.2°.

[0019] Preferably, for the osimertinib-terephthalic acid crystal B, using Cu-Kα radiation, its characteristic peaks conform to Figure 4 the X-ray powder diffraction pattern shown.

[0020] Preferably, for the osimertinib-terephthalic acid crystal B, its crystallographic parameters are: triclinic system, space group P -1 ; the unit cell parameters are: α = 101.537(4), β = 103.951(4), γ = 96.717(4), unit cell volume

[0021] Preferably, for the osimertinib-terephthalic acid crystal B, there is an endothermic peak in the differential scanning calorimetry curve (DSC), and the corresponding temperature range is 205.09 - 232.10 °C.

[0022] The second aspect of the present invention provides a preparation method for osimertinib-terephthalic acid crystals;

[0023] The specific preparation steps for the crystal A include: dissolving osimertinib in acetone, dissolving terephthalic acid in solution A, then adding the osimertinib solution to the terephthalic acid solution, stirring for a moment, filtering, collecting the filtrate, allowing it to crystallize by volatilization at room temperature, filtering, and drying under reduced pressure to obtain osimertinib-terephthalic acid crystal A.

[0024] Preferably, the mass-volume ratio of osimertinib to acetone is 100 - 150, mg / ml; preferably 125, mg / ml.

[0025] Preferably, the molar ratio of osimertinib to terephthalic acid is 1:1.8 - 2.5; preferably 1:2.

[0026] Preferably, the solution A is a mixed solution of methanol and ethanol; the volume ratio of methanol to ethanol is 0.5 - 1:1; preferably 1:1.

[0027] Preferably, the mass-to-volume ratio of terephthalic acid to Solution A is 80 - 90 mg / ml; preferably 83 mg / ml.

[0028] The specific preparation steps of Crystal B are as follows: Dissolve osimertinib in acetone and terephthalic acid in a mixed solvent of methanol, ethanol and purified water. Then add the osimertinib solution to the terephthalic acid solution, mix the two, filter, seal with a sealing film, pierce several holes, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain osimertinib-terephthalic acid Crystal B.

[0029] Preferably, the mass-to-volume ratio of osimertinib to acetone is 100 - 150 mg / ml; preferably 125 mg / ml.

[0030] Preferably, the mass-to-volume ratio of terephthalic acid to the mixed solvent is 65 - 80 mg / ml; preferably 74 mg / ml.

[0031] Preferably, the volume ratio of methanol, ethanol to water in the mixed solvent is 3 - 5:3 - 5:1.

[0032] Preferably, the molar ratio of osimertinib to terephthalic acid is 1:1.8 - 2.5; preferably 1:2.

[0033] In the third aspect of the present invention, there is provided a pharmaceutical composition containing the osimertinib-terephthalic acid crystal of the present invention and the use of the crystal in the preparation of drugs for treating diseases such as cancer.

[0034] The preparation method of the pharmaceutical composition of the present invention can be as follows: The compound of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally combined with a pharmaceutically acceptable adjuvant and excipient to prepare a usable dosage form.

[0035] The pharmaceutical composition of the present invention can be tablets, capsules, powder injections, liquid injections, lyophilized powder injections and other pharmaceutically usable dosage forms.

[0036] Confirmation of the crystal structure of Crystal A

[0037] In the test of osimertinib-terephthalic acid Crystal A of the present invention, the X-ray diffraction test instrument and test conditions are: PANalytical Empyrean X-ray powder diffractometer; Cu target light source, flat sample stage, incident light path: BBHD, diffraction light path: PLXCEL, voltage 45KV, current 40mA, divergence slit 1 / 4°, anti-scattering slit 1°, Soller slit 0.04rad, counting time per step 0.5s, scanning range 3 - 50°, and the test results are shown in Table 1 and Figure 1 。

[0038] Table 1 Main XRD Peaks of Osimertinib-Terephthalic Acid Crystal A

[0039]

[0040]

[0041] For the Osimertinib-Terephthalic Acid Crystal A provided by the present invention, X-ray single crystal diffraction test analysis was carried out. The X-ray single crystal diffraction instrument and test conditions involved were: Rigaku XtaLAB Synergy X-ray single crystal diffractometer, test temperature 293(2)K, using CuKa radiation, collecting data in ω scan mode and performing Lp correction. The structure was solved by the direct method, and all non-hydrogen atoms were located 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.

[0042] The crystallographic data obtained from testing and analyzing the Osimertinib-Terephthalic Acid Crystal A prepared by the present invention are shown in Table 2, and its crystallographic parameters are: triclinic system, space group P -1 ; The unit cell parameters are: α = 100.4168(13), β = 94.0240(14), γ = 99.4698(15), unit cell volume The ORTEP diagram of the Osimertinib-Terephthalic Acid Crystal A of the present invention shows that the molar ratio of osimertinib to terephthalic acid is 1:1, as Figure 2 shown.

[0043] Table 2 Main Crystallographic Data of Osimertinib-Terephthalic Acid Crystal A

[0044]

[0045]

[0046] The TGA / DSC thermal analysis test conditions for the Osimertinib-Terephthalic Acid Crystal A described in the present invention are: METTLE TOLEDO TGA / DSC3+ thermal analyzer, dynamic temperature range: 30 - 300 °C, heating rate: 10 °C / min, program segment gas N2, flow rate: 50 ml / min, crucible: aluminum crucible 40 μl.

[0047] The TGA / DSC test results of the Osimertinib-Terephthalic Acid Crystal A provided by the present invention are as Figure 3 shown. The DSC detection spectrum shows that the crystal has an endothermic peak, corresponding to a temperature range of 203.54 - 233.42 °C, and the peak value is 223.36 °C.

[0048] Confirmation of the Crystal Structure of Crystal B

[0049] In the X-ray diffraction test of osimertinib-terephthalic acid crystal B of the present invention, the test instrument and test conditions are as follows: PANalytical Empyrean X-ray powder diffractometer; Cu target as the light source, flat sample stage, incident light path: BBHD, diffraction light path: PLXCEL, 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°, and the test results are shown in Table 3 and Figure 4 .

[0050] Table 3 Main XRD peaks of osimertinib-terephthalic acid crystal B

[0051]

[0052]

[0053] For the osimertinib-terephthalic acid crystal B provided by the present invention, X-ray single crystal diffraction test and analysis are carried out. The X-ray single crystal diffraction instrument and test conditions involved are: Rigaku XtaLAB Synergy X-ray single crystal diffractometer, test temperature 293(2) K, using CuKa radiation, collecting data in ω scan mode and performing Lp correction. The structure is solved by the direct method, and all non-hydrogen atoms are found by the difference Fourier method. The hydrogen atoms on all carbons and nitrogens are obtained by theoretical hydrogenation, and the structure is refined by the least squares method.

[0054] The crystallographic data obtained by testing and analyzing the osimertinib-terephthalic acid crystal B prepared by the present invention are shown in Table 4, and its crystallographic parameters are: triclinic system, space group P -1 ; The unit cell parameters are as follows: α = 101.537(4), β = 103.951(4), γ = 96.717(4), unit cell volume The ORTEP diagram of the osimertinib-terephthalic acid crystal B of the present invention shows that 1 molecule of osimertinib in the crystal binds 1.5 molecules of terephthalic acid and two molecules of water, as Figure 5 shown.

[0055] Table 4 Main crystallographic data of osimertinib-terephthalic acid crystal B

[0056]

[0057]

[0058] The TGA / DSC thermal analysis test conditions for the osimertinib-terephthalic acid crystal B of the present invention are as follows: METTLE TOLEDO TGA / DSC3+ thermal analyzer, dynamic temperature range: 30 - 300 °C, heating rate: 10 °C / min, gas in the program segment: N2, flow rate: 50 ml / min, crucible: 40 μl aluminum crucible.

[0059] The TGA / DSC test results of the osimertinib-terephthalic acid crystal B provided by the present invention are as Figure 6 shown. The DSC detection spectrum shows that the crystal has an endothermic peak, corresponding to a temperature of 205.09 - 232.10 °C and a peak value of 222.38 °C.

[0060] Compared with the prior art, the technical effects achieved by the present invention are:

[0061] Firstly, the present invention provides new crystal forms of osimertinib, namely osimertinib-terephthalic acid crystal A and osimertinib-terephthalic acid crystal B. The crystals have a unique crystal structure, significantly improving the problems of high hygroscopicity and easy deliquescence of osimertinib, showing good stability, and increasing the solubility of osimertinib. Secondly, the preparation methods of the osimertinib crystals and hydrates provided by the present invention are simple, convenient, safe, environmentally friendly, and suitable for industrial production. Description of the Drawings

[0062] Figure 1 : X-ray powder diffraction pattern of osimertinib-terephthalic acid crystal A.

[0063] Figure 2 : ORTEP diagram of osimertinib-terephthalic acid crystal A.

[0064] Figure 3 : TGA / DSC thermal analysis diagram of osimertinib-terephthalic acid crystal A.

[0065] Figure 4 : X-ray powder diffraction pattern of osimertinib-terephthalic acid crystal B.

[0066] Figure 5 : ORTEP diagram of osimertinib-terephthalic acid crystal B.

[0067] Figure 6 : TGA / DSC thermal analysis diagram of osimertinib-terephthalic acid crystal B. Detailed Embodiments

[0068] The present invention will be further described below through examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention fall within the scope of protection required by the present invention.

[0069] The osimertinib raw material used in the present invention was prepared in the laboratory with a purity of 99.56%; the osimertinib mesylate crystal form A used in the property investigation experiment was prepared with reference to Patent CN103702990B with a purity of 99.32%; the osimertinib fumarate was prepared with reference to Patent CN107915725A with a purity of 99.46%. The myricetin mesylate hydrate was prepared with reference to Patent CN107778296A with a purity of 99.87%.

[0070] Preparation of osimertinib terephthalate crystal A

[0071] Example 1

[0072] Dissolve 1 g of osimertinib in 8 ml of acetone, and dissolve 664 mg of terephthalic acid in a mixed solution of 8 ml of methanol and ethanol. Then add the osimertinib solution to the terephthalic acid solution, stir for a moment, filter, collect the filtrate, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.53 g of osimertinib terephthalate crystal A with a purity of 99.94%.

[0073] Example 2

[0074] Dissolve 1 g of osimertinib in 8 ml of acetone, and dissolve 830 mg of terephthalic acid in a mixed solution of 8 ml of methanol and ethanol. Then add the osimertinib solution to the terephthalic acid solution, stir for a moment, filter, collect the filtrate, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.51 g of osimertinib terephthalate crystal A with a purity of 99.93%.

[0075] Example 3

[0076] Dissolve 1 g of osimertinib in 10 ml of acetone, and dissolve 664 mg of terephthalic acid in a mixed solution of 7.5 ml of methanol and ethanol. Then add the osimertinib solution to the terephthalic acid solution, stir for a moment, filter, collect the filtrate, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.48 g of osimertinib terephthalate crystal A with a purity of 99.93%.

[0077] Example 4

[0078] Dissolve 1.2 g of osimertinib in 8 ml of acetone, and dissolve 797 mg of terephthalic acid in a mixed solution of 9 ml of methanol and ethanol. Then add the osimertinib solution to the terephthalic acid solution, stir for a moment, filter, collect the filtrate, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.50 g of osimertinib terephthalate crystal A with a purity of 99.92%.

[0079] Example 5

[0080] Dissolve 1 g of osimertinib in 12 ml of acetone, dissolve 664 mg of terephthalic acid in a mixed solution of 10 ml of methanol and ethanol, then add the osimertinib solution to the terephthalic acid solution, stir for a while, filter, collect the filtrate, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.33 g of osimertinib-terephthalic acid crystal A with a purity of 99.89%.

[0081] Example 6

[0082] Dissolve 1 g of osimertinib in 8 ml of acetone, dissolve 1 g of terephthalic acid in a mixed solution of 12 ml of methanol and ethanol, then add the osimertinib solution to the terephthalic acid solution, stir for a while, filter, collect the filtrate, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.35 g of osimertinib-terephthalic acid crystal A with a purity of 99.88%.

[0083] Preparation of osimertinib-terephthalic acid crystal B

[0084] Example 7

[0085] Dissolve 1 g of osimertinib in 8 ml of acetone, dissolve 664 mg of terephthalic acid in 9 ml of a mixed solvent, then add the osimertinib solution to the terephthalic acid solution, mix the two, filter, seal with a sealing film, pierce several holes, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.58 g of crystal B with a purity of 99.94%.

[0086] Example 8

[0087] Dissolve 1 g of osimertinib in 10 ml of acetone, dissolve 664 mg of terephthalic acid in 10 ml of a mixed solvent, then add the osimertinib solution to the terephthalic acid solution, mix the two, filter, seal with a sealing film, pierce several holes, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.56 g of crystal B with a purity of 99.93%.

[0088] Example 9

[0089] Dissolve 1.2 g of osimertinib in 8 ml of acetone, dissolve 797 mg of terephthalic acid in 10 ml of a mixed solvent, then add the osimertinib solution to the terephthalic acid solution, mix the two, filter, seal with a sealing film, pierce several holes, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.56 g of crystal B with a purity of 99.92%.

[0090] Example 10

[0091] Dissolve 1 g of osimertinib in 8 ml of acetone, dissolve 830 mg of terephthalic acid in 11 ml of a mixed solvent, then add the osimertinib solution to the terephthalic acid solution, mix the two, filter, seal with a sealing film, punch several holes, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.53 g of crystal B with a purity of 99.92%.

[0092] Example 11

[0093] Dissolve 1 g of osimertinib in 12 ml of acetone, dissolve 664 mg of terephthalic acid in 11 ml of a mixed solvent, then add the osimertinib solution to the terephthalic acid solution, mix the two, filter, seal with a sealing film, punch several holes, volatilize and crystallize at room temperature, filter, and dry under reduced pressure to obtain 1.37 g of crystal B with a purity of 99.87%.

[0094] Stability experiment

[0095] The specific stability test method was carried out with reference to the guiding method for stability investigation in the fourth part of the Chinese Pharmacopoeia 2015 edition. The purity was detected by HPLC method, and the specific detection results are shown in Table 3.

[0096] Table 3 Stability test results of osimertinib series crystal forms under light, high temperature and high humidity conditions

[0097]

[0098] It can be seen from the experimental results that the purity of osimertinib-terephthalic acid crystal A and crystal B prepared by the present invention has no significant change under light, high temperature and high humidity environments, showing good stability.

[0099] Solubility experiment

[0100] Method: Measure 10 ml of media (water, 0.1 mol / L HCl solution and phosphate buffer solution with pH = 6.8) into vials, add an excessive amount of the sample to be tested, seal the vials and place them in a constant temperature water bath at 25 °C and stir for 1 hour, filter through a 0.45 μm filter membrane, and take the filtrate; measure the absorbance at a wavelength of 210 nm, and calculate its solubility by measuring the absorbance of the standard reference substance.

[0101] Table 4 Solubility (mg / ml) of osimertinib series crystal forms in different media

[0102]

[0103] From the solubility test results, it can be seen that the solubility of osimertinib-terephthalic acid crystal A and osimertinib-terephthalic acid crystal B prepared by the present invention has been greatly improved compared with the existing osimertinib mesylate crystal form A or the crystal forms of other salts, showing relatively high solubility, reflecting good dissolution characteristics, and providing a new API form for solving the solubility of osimertinib.

[0104] Hygroscopicity study

[0105] A comparative study on the hygroscopicity of osimertinib-terephthalic acid crystals and various pharmaceutical salts of osimertinib was carried out according to the method in Appendix 9103 of Part IV of the Chinese Pharmacopoeia 2015 Edition. The specific experimental method is as follows:

[0106] Take a dry stoppered glass weighing bottle, place it in a suitable constant temperature dryer at 25°C ± 1°C one day before the test, and weigh its weight m1; take 1.0 g of the test sample and spread it evenly in the above-mentioned weighing bottle, and accurately weigh the weight m2; open the weighing bottle and place the bottle cap in the same test environment, and place it for 24 hours under constant temperature and humidity conditions; cover the weighing bottle cap and weigh the weight to get m3, and calculate the hygroscopicity result according to the formula.

[0107] Table 5 Hygroscopicity study of osimertinib series crystal forms

[0108]

[0109] From the hygroscopicity experiment, it can be seen that the hygroscopicity of osimertinib-terephthalic acid crystal A and osimertinib-terephthalic acid crystal B has been greatly improved compared with osimertinib mesylate crystal form A, and there is also a certain improvement compared with the existing crystal forms of other salts, providing a better solution for solving the problem of easy deliquescence of osimertinib API.

Claims

1. An osimertinib-terephthalic acid crystal, characterized in that, The molar ratio of osimertinib to terephthalic acid in the crystal structure of crystal A is 1:1, or the molar ratio of osimertinib, terephthalic acid to water in the crystal structure of crystal B is 1:1.5:2; for the said crystal A, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 5.72±0.2°, 6.10±0.2°, 10.23±0.2°, 12.24±0.2°, 21.80±0.2°, 23.00±0.2°, 26.22±0.2°, and for the said crystal B, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 5.59±0.2°, 6.32±0.2°, 10.54±0.2°, 11.14±0.2°, 16.68±0.2°, 18.67±0.2°, 25.07±0.2°.

2. The osimertinib-terephthalic acid crystal according to claim 1, characterized in that, For the said crystal A, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 4.03±0.2°, 5.72±0.2°, 6.10±0.2°, 10.23±0.2°, 11.23±0.2°, 12.24±0.2°, 12.69±0.2°, 16.14±0.2°, 16.94±0.2°, 17.28±0.2°, 20.94±0.2°, 21.31±0.2°, 21.80±0.2°, 23.00±0.2°, 26.22±0.2°, 27.85±0.2°.

3. The osimertinib-terephthalic acid crystal according to claim 1, characterized in that, For the said crystal A, using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

4. The osimertinib-terephthalic acid crystal according to claim 1, wherein For the said crystal B, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 4.01±0.2°, 5.59±0.2°, 6.32±0.2°, 6.87±0.2°, 9.32±0.2°, 10.54±0.2°, 11.14±0.2°, 12.97±0.2°, 14.39±0.2°, 15.75±0.2°, 16.68±0.2°, 18.67±0.2°, 18.97±0.2°, 21.21±0.2°, 23.26±0.2°, 25.07±0.2°.

5. The osimertinib-terephthalic acid crystal according to claim 1, wherein, For the said crystal B, using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 4.

6. A method for preparing crystal A as described in claim 1, characterized in that, The specific preparation steps include: dissolving osimertinib in acetone and terephthalic acid in solution A, then adding the osimertinib solution to the terephthalic acid solution, stirring for a moment, filtering, collecting the filtrate, volatilizing and crystallizing at room temperature, filtering, and drying under reduced pressure to obtain osimertinib-terephthalic acid crystals; the said solution A is a mixed solution of methanol and ethanol.

7. A method for preparing crystal B as described in claim 1, characterized in that, The specific preparation steps include: dissolving osimertinib in acetone and terephthalic acid in a mixed solvent of methanol, ethanol and purified water, then adding the osimertinib solution to the terephthalic acid solution, mixing the two, filtering, sealing with a sealing film, making several holes, volatilizing and crystallizing at room temperature, filtering, and drying under reduced pressure to obtain osimertinib terephthalate hydrate.

8. A pharmaceutical composition, characterized in that, The composition comprises the osimertinib-terephthalic acid crystal according to any one of claims 1 to 5 and other pharmaceutically acceptable components.

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