Crystalline solid of azd9291

Abstract

This invention relates to the field of crystalline drug molecule technology, and particularly to the field of crystal preparation technology for the cancer treatment drug AZD9291. This invention provides a novel crystalline solid of AZD9291, specifically: osimertinib-adipic acid crystals, whose X-ray diffraction pattern (denoted by 2θ) shows characteristic peaks at least at 6.60±0.2, 15.65±0.2, 19.73±0.2, 19.80±0.2, 20.41±0.2, 21.01±0.2, 21.32±0.2, 24.86±0.2, and 26.18±0.2°; and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, whose X-ray diffraction pattern (denoted by 2θ) shows characteristic peaks at at least 6.00±0.2°, 8.52±0.2°, 11.85±0.2°, 16.45±0.2°, 19.75±0.2°, and 23.66±0.2°. The crystalline form of AZD9291 provided by this invention has improved physicochemical properties such as solubility and stability.

Description

Technical Field

[0001] This invention relates to the field of crystalline drug molecule technology, and particularly to the field of crystal preparation technology for the cancer treatment drug AZD9291. Background Technology

[0002] AZD9291, Chinese name Osimertinib, chemical name: N-[2-[[2-(dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)pyrimidinyl]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. Its structural formula is shown below:

[0003]

[0004] Lung cancer patients with EGFR or ALK gene mutations can achieve good survival benefits with targeted therapy. However, the efficacy of these drugs is generally short-lived, with resistance developing within 9-11 months. This is because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and altering their growth patterns.

[0005] AstraZeneca's ADZ9291 is a third-generation, oral, irreversible, selective EGFR mutation inhibitor. It can be used for both activating and resistant EGFR mutations. This means that in patients with advanced non-small cell lung cancer (NSCLC), 50% of acquired resistance to anti-EGFR therapy is caused by the T790M mutation, and ADZ9291 can render this challenging mutation ineffective. ADZ9291 has shown better therapeutic efficacy in NSCLC patients with existing epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and T790M mutations.

[0006] Patent CN103702990A discloses the structure of the compound. This patent also discloses the polymorphs of this compound and its mesylate. Patent CN104961731A discloses osimertinib phosphate; patent CN106432231A discloses pharmaceutical-grade osimertinib sulfate, p-toluenesulfonate, tartrate, acetate, and citrate; patent CN107915725A discloses its new pharmaceutical-grade maleate, fumarate, gluconate, malonate, succinate, and lactate.

[0007] The original manufacturer used osimertinib mesylate in clinical trials. However, mesylate has high biotoxicity and is unsuitable for drug development under selective conditions. Furthermore, mesylate is highly hygroscopic and prone to deliquescence in high humidity. Therefore, developing other salts with high bioavailability, low toxicity, and pharmaceutical suitability is essential. Although numerous osimertinib crystal forms have been published in the existing literature, systematic studies of these crystal forms are still needed, especially comprehensive studies of osimertinib cocrystals. While there are many reports on other salts, their drug-likeness requires further investigation.

[0008] This invention provides a simple and easy-to-operate method for preparing high-purity osimertinib crystals, providing a better basis for the application of osimertinib in drug therapy, thereby maximizing the medicinal value of osimertinib. Summary of the Invention

[0009] In view of the shortcomings of the existing crystalline form of osimertinib in terms of physicochemical properties, the purpose of this invention is to provide a new crystalline form of osimertinib that improves and enhances physicochemical properties such as solubility and stability.

[0010] On the one hand, the present invention provides a new crystalline solid of AZD9291, specifically osimertinib-adipic acid crystals and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate.

[0011] Preferably, the osimertinib-adipic acid crystal, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 6.60±0.2°, 15.65±0.2°, 19.73±0.2°, 19.80±0.2°, 20.41±0.2°, 21.01±0.2°, 21.32±0.2°, 24.86±0.2°, and 26.18±0.2°.

[0012] Preferably, the osimertinib-adipic acid crystal, when subjected to Cu-Kα radiation, exhibits an X-ray diffraction pattern (denoted as 2θ) at at least 6.60±0.2°, 8.64±0.2°, 10.15±0.2°, 10.65±0.2°, 11.29±0.2°, 13.60±0.2°, 14.13±0.2°, 15.65±0.2°, and 19. Characteristic peaks are observed at 02±0.2°, 19.73±0.2°, 19.80±0.2°, 20.41±0.2°, 21.01±0.2°, 21.32±0.2°, 22.55±0.2°, 23.64±0.2°, 23.98±0.2°, 24.86±0.2°, 26.18±0.2°, and 28.37±0.2°.

[0013] Preferably, the osimertinib-adipic acid crystal, when subjected to Cu-Kα radiation, exhibits characteristic peaks with... Figure 1 Or the X-ray powder diffraction patterns or data shown in Table 2.

[0014] Further preferably, in a preferred embodiment of the present invention, the osimertinib-adipic acid crystals, as detected by differential scanning calorimetry (DSC), show that the starting point of the first endothermic peak is at 137.02℃, and the peak value appears at 145.33℃, as detailed in the attached figure. Figure 2 As shown.

[0015] Preferably, the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 6.00±0.2°, 8.52±0.2°, 11.85±0.2°, 16.45±0.2°, 19.75±0.2°, and 23.66±0.2°.

[0016] Preferably, the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (represented by 2θ) at at least 6.00±0.2°, 8.52±0.2°, 11.85±0.2°, 12.32±0.2°, 13.14±0.2°, 13.45±0.2°, 13.78±0.2°, 16.45±0.2°, 17.18±0.2°, 18.40±0.2°, 19.75±0.2°, 20.42±0.2°, 22.12±0.2°, and 23.66±0.2°.

[0017] Preferably, the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits an X-ray diffraction pattern (denoted as 2θ) at at least 6.00±0.2°, 8.52±0.2°, 11.85±0.2°, 12.32±0.2°, 13.14±0.2°, 13.45±0.2°, 13.78±0.2°, 15.30±0.2°, and 16. Characteristic peaks are observed at 45±0.2°, 17.18±0.2°, 18.40±0.2°, 19.75±0.2°, 20.42±0.2°, 21.75±0.2°, 22.12±0.2°, 22.95±0.2°, 23.66±0.2°, 24.08±0.2°, 24.65±0.2°, 25.64±0.2°, and 26.51±0.2°.

[0018] Preferably, the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits characteristic peaks with... Figure 5Or the X-ray powder diffraction patterns or data shown in Table 3.

[0019] Preferably, in a preferred embodiment of the present invention, the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, as detected by differential scanning calorimetry (DSC), has a first endothermic peak at 63.71℃, a second endothermic peak at 153.04℃, and a third endothermic peak at 213.63℃, as specifically... Figure 6 As shown.

[0020] In a second aspect, the present invention provides a method for preparing the aforementioned AZD929 crystalline solid. The osimertinib-adipic acid crystals can be prepared by the following method:

[0021] Osimertinib and adipic acid were dissolved in organic solvent A, heated to dissolve, and after the solution became clear, it was cooled to crystallize. The crystals were then filtered and dried to obtain osimertinib-adipic acid crystals.

[0022] Preferably, the organic solvent A is selected from one or a mixture of at least two of acetone, methanol, ethanol, and acetonitrile; more preferably, it is one or two of acetone and ethanol.

[0023] Preferably, the molar ratio of osimertinib to adipic acid is 1:0.8 to 1.5; more preferably, it is 1:0.9 to 1.1.

[0024] Preferably, the mass-to-volume ratio of osimertinib to organic solvent A in the system is 5–40:1, where the mass is in mg and the volume is in ml; more preferably, it is 15–20:1, where the mass is in mg and the volume is in ml.

[0025] Preferably, the melting and heating temperature is 40–60°C; the cooling and crystallization temperature is 0–30°C; more preferably 5–20°C; and the crystallization time is 24–36 hours.

[0026] The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate can be prepared by the following method: osimertinib and 3,5-dihydroxybenzoic acid are dissolved in a mixed solvent, heated to dissolve, and after the solution is clarified, it is cooled to crystallize, filtered and dried to obtain osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate crystals.

[0027] Preferably, the mixed solvent is a mixture of ethanol and purified water.

[0028] Preferably, in the mixed solvent, purified water accounts for 15% to 30% of the volume of the mixed solvent; more preferably, it accounts for 20%.

[0029] Preferably, the molar ratio of osimertinib to 3,5-dihydroxybenzoic acid is 1:0.8 to 1.5; more preferably, the molar ratio is 1:0.9 to 1.1.

[0030] Preferably, the mass-to-volume ratio of osimertinib to the mixed solvent is 5–25:1, wherein the mass is in mg and the volume is in ml; more preferably, it is 8–15:1, wherein the mass is in mg and the volume is in ml.

[0031] Preferably, the melting and heating temperature is 40–60°C; the cooling and crystallization temperature is 0–30°C, preferably 0–15°C; and the crystallization time is 24 hours or more.

[0032] In another aspect, the present invention provides a pharmaceutical composition, with the AZD9291 crystalline solid described in the present invention as the active ingredient and other pharmaceutically acceptable components; more preferably, in addition to the aforementioned components, the composition also contains other active ingredients that can be used in combination.

[0033] Preferably, the other components include other active ingredients, excipients, fillers, etc., that can be used in combination.

[0034] Preferably, the pharmaceutical composition can be formulated into sprays, tablets, capsules, powder injections, liquid injections, etc., using standard and conventional techniques.

[0035] Structural confirmation:

[0036] Osimertinib-Adipic Acid Crystals

[0037] X-ray crystal data were collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K using CuKa radiation. Data were collected in ω-scan mode and Lp correction was performed. The structure was resolved using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. Hydrogen atoms on all carbon and nitrogen atoms were obtained by theoretical hydrogenation. The structure was refined using the least squares method.

[0038] The crystallographic data obtained from testing and analyzing the osimertinib-adipic acid crystals prepared in this invention are as follows (see Table 1 for details): Its crystallographic parameters are: monoclinic system, chiral space group P2 / C The unit cell parameters are: α = 94.956(2)°, β = 106.305(2)°, γ = 103.030(2)°, cell volume The molecular formula is: C 34 H 43 N7O6, molecular weight: 645.75. The structural diagram of the osimertinib-adipic acid crystal of this invention shows that the crystal is solvent-free, specifically as follows... Figure 4As shown. The hydrogen bond packing diagram of the osimertinib-adipic acid crystal of the present invention is as follows. Figure 3 As shown.

[0039] Table 1. Main crystallographic data of osimertinib-adipic acid crystals

[0040]

[0041]

[0042] The X-ray powder diffraction testing instrument and conditions for the osimertinib-adipic acid crystal test described in this invention are as follows: PANalytical Empyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PLXCEL, voltage 45KV, current 40mA, divergence slit 1 / 4°, anti-scattering slit 1°, Solar slit 0.04rad, counting time per step 0.5s, scanning range 3~50°.

[0043] Based on crystallographic data, the characteristic peaks in its corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed below. Figure 1 And Table 2.

[0044] Table 2. Main PXRD peaks of osimertinib-adipic acid crystals

[0045]

[0046]

[0047] All osimertinib-adipic acid crystal samples prepared in the examples had the same crystallographic parameters and X-ray powder diffraction patterns.

[0048] The TGA / DSC thermal analysis instrument and test conditions in this invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC3+; dynamic temperature range: 30~300℃; heating rate: 10℃ / min; program segment: gas N2; gas flow rate: 50mL / min; crucible: aluminum crucible 40μl.

[0049] The differential scanning calorimetry (DSC) results of the osimertinib-adipic acid crystals prepared by the method described in this invention are as follows: Figure 2 As shown, the differential scanning calorimetry (DSC) curve shows only one endothermic peak at 145.33℃, which is the melting point of the osimertinib-adipic acid crystal; its thermogravimetric analysis (TGA) shows only one weight loss step, indicating that the osimertinib-adipic acid crystal is solvent-free and structurally stable. The osimertinib-adipic acid crystal exhibits the following characteristics: Figure 2 The DSC / TGA spectrum shown.

[0050] Osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solution

[0051] X-ray crystal data were collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K using CuKa radiation. Data were collected in ω-scan mode and Lp correction was performed. The structure was resolved using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. Hydrogen atoms on all carbon and nitrogen atoms were obtained by theoretical hydrogenation. The structure was refined using the least squares method.

[0052] The crystallographic data obtained from testing and analyzing the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate prepared in this invention are shown in Table 3: its crystallographic parameters are: monoclinic system, chiral space group P21 / C The unit cell parameters are: α = 90.00°, β = 115.9728(11)°, γ = 90.00°, cell volume The molecular formula is: C 37 H 47 N7O8, with a molecular weight of 717.81. The structural diagram of the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate of this invention shows that the crystal contains one molecule of ethanol and one molecule of water, specifically as follows... Figure 8 As shown. The hydrogen bond diagram of the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate of the present invention is specifically shown below. Figure 7 As shown.

[0053] Table 3. Main crystallographic data of osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate

[0054]

[0055] The X-ray powder diffraction test instrument and test conditions for the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate test described in this invention are as follows: PANalytical Empyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1 / 4°, anti-scattering slit 1°, Solar slit 0.04rad, counting time per step 0.5s, scanning range 3~50°.

[0056] Based on crystallographic data, the characteristic peaks in its corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed below. Figure 5 And Table 4.

[0057] Table 4. Main PXRD peaks of osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate

[0058]

[0059]

[0060] All osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate samples prepared in the examples had the same crystallographic parameters and X-ray powder diffraction patterns.

[0061] The TGA / DSC thermal analysis instrument and test conditions in this invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC3+; dynamic temperature range: 30~300℃; heating rate: 10℃ / min; program segment: gas N2; gas flow rate: 50mL / min; crucible: aluminum crucible 40μl.

[0062] The differential scanning calorimetry (DSC) results of the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate prepared by the method of the present invention are as follows: Figure 6 As shown, the differential scanning calorimetry (DSC) curve shows three endothermic peaks: the first endothermic peak starts at 63.71℃, the second at 153.04℃, and the third at 213.63℃, corresponding to the absorption peaks of the water solvent, ethanol, and the melting point of the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, respectively. Thermogravimetric analysis (TGA) shows only three weight loss steps, indicating that the osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate exists in two different solvents and has a stable structure. The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate exhibits the following characteristics: Figure 6 The DSC / TGA spectrum shown.

[0063] Compared with existing technologies, the method for preparing osimertinib-adipic acid crystals and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate provided by the present invention is simple to operate and produces crystals with high purity. The AZD9291 crystalline solid osimertinib-adipic acid crystals and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate provided by the present invention have good chemical stability and good solubility, providing a better crystalline form for osimertinib to exert its role in cancer treatment. Attached Figure Description

[0064] Figure 1 X-ray powder diffraction pattern of osimertinib-adipic acid.

[0065] Figure 2 Differential scanning calorimetry (DSC) curve of osimertinib-adipic acid.

[0066] Figure 3Stacking diagram of osimertinib-adipic acid.

[0067] Figure 4 ORTEP plot of osimertinib-adipic acid.

[0068] Figure 5 X-ray powder diffraction pattern of osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate.

[0069] Figure 6 Differential scanning calorimetry (DSC) curve of osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate.

[0070] Figure 7 Packing diagram of osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate.

[0071] Figure 8 ORTEP plot of osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate. Detailed Implementation

[0072] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0073] Example 1: Osimertinib-Adipic Acid Crystals

[0074] 1.7 g of osimertinib and 0.5 g of adipic acid were added to 110 ml of ethanol, heated to 60 °C and stirred to dissolve. The mixture was refluxed for 0.5 hours, then slowly cooled to 5–10 °C and allowed to stand for crystallization for 30 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 50 °C for 10 hours to obtain osimertinib-adipic acid eutectic crystals with a yield of 92.68% and a purity of 99.95%.

[0075] Example 2 Osimertinib-Adipic Acid Crystals

[0076] 1.7 g of osimertinib and 0.45 g of adipic acid were added to 85 ml of ethanol, heated to 50 °C and stirred to dissolve. The mixture was refluxed for 0.5 hours, then slowly cooled to 5–10 °C and allowed to stand for crystallization for 36 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 50 °C for 10 hours to obtain osimertinib-adipic acid eutectic crystals with a yield of 91.56% and a purity of 99.95%.

[0077] Example 3 Osimertinib-Adipic Acid Crystals

[0078] 1.7 g of osimertinib and 0.55 g of adipic acid were added to 170 ml of ethanol, heated to 40 °C and stirred to dissolve. The mixture was refluxed for 0.5 hours, then slowly cooled to 5–10 °C and allowed to stand for crystallization for 30 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 50 °C for 12 hours to obtain osimertinib-adipic acid eutectic with a yield of 92.28% and a purity of 99.94%.

[0079] Example 4: Osimertinib-Adipic Acid Crystals

[0080] 1.7 g of osimertinib and 0.5 g of adipic acid were added to 110 ml of acetone, heated to 40 °C and stirred to dissolve. The mixture was refluxed for 0.5 hours, then slowly cooled to 5–10 °C and allowed to stand for crystallization for 24 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 50 °C for 10 hours to obtain osimertinib-adipic acid eutectic crystals with a yield of 91.26% and a purity of 99.94%.

[0081] Example 5: Osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate

[0082] 666.8 mg of osimertinib and 205.7 mg of 3,5-dihydroxybenzoic acid were added to a mixed solution of 54 ml ethanol and 13 ml purified water. The mixture was heated to 50 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then slowly cooled to 5 °C and allowed to stand for crystallization for 30 hours. The crystals were filtered, washed with ethanol, and dried under vacuum at 60 °C for 8 hours to obtain osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, with a yield of 90.56% and a purity of 99.96%.

[0083] Example 6 Osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate

[0084] 666.8 mg of osimertinib and 226.27 mg of 3,5-dihydroxybenzoic acid were added to a mixed solution of 66 ml of ethanol and 16 ml of purified water. The mixture was heated to 40 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then slowly cooled to 10 °C and allowed to stand for crystallization for 36 hours. The crystals were filtered, washed with ethanol, and dried under vacuum at 60 °C for 10 hours to obtain osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, with a yield of 89.78% and a purity of 99.95%.

[0085] Example 7 Osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate

[0086] 666.8 mg of osimertinib and 185.1 mg of 3,5-dihydroxybenzoic acid were added to 38 mL of ethanol and 7 mL of purified water. The mixture was heated to 60 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then slowly cooled to 0 °C and allowed to stand for crystallization for 24 hours. The crystals were filtered, washed with ethanol, and dried under vacuum at 60 °C for 10 hours to obtain osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, with a yield of 89.86% and a purity of 99.96%.

[0087] Example 8 Osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate

[0088] 666.8 mg of osimertinib and 205.7 mg of 3,5-dihydroxybenzoic acid were added to 57 ml of ethanol and 10 ml of purified water. The mixture was heated to 60 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then slowly cooled to 15 °C and allowed to stand for crystallization for 48 hours. The crystals were filtered, washed with ethanol, and dried under vacuum at 60 °C for 12 hours to obtain osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, with a yield of 87.56% and a purity of 99.94%.

[0089] Stability test

[0090] The specific stability test methods were carried out in accordance with the guidelines for stability studies in Part IV of the 2015 edition of the Chinese Pharmacopoeia. Purity was detected by HPLC, and the specific test results are shown in Table 5.

[0091] Table 5. Stability test results under light, high temperature, and high humidity conditions.

[0092]

[0093]

[0094] The results in the table above show that the purity of the new AZD9291 crystalline solid osimertinib-adipic acid crystal and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate prepared in this invention did not change significantly under strong light, high temperature or high humidity conditions, and both have good stability.

[0095] Solubility test

[0096] Standard method determination: Measure 10 ml of the medium (water, 0.1 mol / L HCl solution, and phosphate buffer solution with pH=6.8) into a vial, add an excess of the test sample, seal the vial and place it in a constant temperature water bath at 25℃ and stir for 1 hour. Filter through a 0.45 μm filter membrane and collect the filtrate. Measure the absorbance at a wavelength of 210 nm. Calculate the solubility by measuring the absorbance of the standard reference.

[0097] Table 6. Solubility in different media (mg / ml)

[0098]

[0099] As can be seen from the results in the table above, the solubility of the osimertinib-adipic acid crystals and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate prepared by this invention is improved compared with the existing crystal forms. They have relatively high solubility and exhibit good solubility characteristics in both water and acidic environments, providing a new crystalline form for solving the solubility problem of osimertinib.

Claims

1. A crystalline solid of AZD9291 characterized by, The crystalline solids are specifically osimertinib-adipic acid crystals and osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate; the osimertinib-adipic acid crystals, when subjected to Cu-Kα radiation, exhibit X-ray diffraction patterns (expressed as 2θ) at at least 6.60±0.2°, 15.65±0.2°, 19.73±0.2°, 19.80±0.2°, 20.41±0.2°, 21.01±0.2°, 21.32±0.2°, 24.86±0.2°, and 26°. A characteristic peak is present at 0.18±0.2°. Its crystallographic parameters are: monoclinic system, chiral space group P2 / c; cell parameters are: a=9.4483(2)Å, b=13.5894(4)Å, c=14.2594(3)Å, α=94.956(2)°, β=106.305(2)°, γ=103.030(2)°, cell volume V=1689.90(7)Å. 3 The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits an X-ray diffraction pattern (expressed as 2θ) at at least 6.00±0.2°, 8.52±0.2°, 11.85±0.2°, 16.45±0.2°, 19.75±0.2°, and 23.66±0. A characteristic peak is present at 0.2°. Its crystallographic parameters are: monoclinic system, chiral space group P21 / c; cell parameters are: a=16.82545(16)Å, b=14.34169(10)Å, c=17.25087(16)Å, α=90.00(2)°, β=115.9728(11)°, γ=90.00°, cell volume V=3742.30(6)Å. 3 .

2. The crystalline solid as described in claim 1, characterized in that, The osimertinib-adipic acid crystals, when subjected to Cu-Kα radiation, exhibit X-ray diffraction patterns (expressed as 2θ) at at least 6.60±0.2°, 8.64±0.2°, 10.15±0.2°, 10.65±0.2°, 11.29±0.2°, 13.60±0.2°, 14.13±0.2°, 15.65±0.2°, 19.02±0.2°, 19.73±0.2°, 19.80±0.2°, 20.41±0.2°, 21.01±0.2°, 21.32±0.2°, 22.55±0.2°, 23.64±0.2°, and 23.98±0.2°. Characteristic peaks are observed at 0.2°, 24.86±0.2°, 26.18±0.2°, and 28.37±0.2°.

3. The crystalline solid as described in claim 1, characterized in that, The osimertinib-adipic acid crystal, when subjected to Cu-Kα radiation, exhibits the X-ray powder diffraction pattern shown in Figure 1.

4. The crystalline solid as described in claim 1, characterized in that, The osimertinib-adipic acid crystals described herein, when subjected to Cu-Kα radiation, exhibit characteristic peaks as shown in Table 2 of the X-ray powder diffraction data.

5. The crystalline solid of claim 1, wherein, The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits characteristic peaks at least at 6.00±0.2°, 8.52±0.2°, 11.85±0.2°, 12.32±0.2°, 13.14±0.2°, 13.45±0.2°, 13.78±0.2°, 16.45±0.2°, 17.18±0.2°, 18.40±0.2°, 19.75±0.2°, 20.42±0.2°, 22.12±0.2°, and 23.66±0.2° in its X-ray diffraction pattern (represented by 2θ).

6. The crystalline solid of claim 1, wherein, The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα radiation, exhibits the X-ray powder diffraction pattern shown in Figure 5.

7. The crystalline solid of claim 1, wherein, The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate, when subjected to Cu-Kα irradiation, exhibits characteristic peaks as shown in Table 4 of the X-ray powder diffraction data.

8. A process for preparing the crystalline solid of claim 1, characterized in that, The osimertinib-adipic acid crystals are prepared by the following method: osimertinib and adipic acid are dissolved in organic solvent A, heated to dissolve, and after the solution is clarified, the solution is cooled to crystallize, filtered and dried to obtain osimertinib-adipic acid crystals; wherein the organic solvent A is selected from one or a mixture of at least two of acetone, methanol, ethanol and acetonitrile.

9. A process for preparing the crystalline solid of claim 1, characterized in that, The osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate is prepared by the following method: osimertinib and 3,5-dihydroxybenzoic acid are dissolved in a mixed solvent, heated to dissolve, and after the solution is clarified, it is cooled to crystallize, filtered and dried to obtain osimertinib-3,5-dihydroxybenzoic acid ethanol aqueous solvate; wherein the mixed solvent is a mixture of ethanol and purified water.

10. A pharmaceutical composition, characterized by, The active ingredient is the crystalline solid as described in any one of claims 1 to 7, and other pharmaceutically acceptable components.

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