Osimertinib pharmaceutical salt and preparation method thereof

Abstract

The present invention relates to the technical field of crystal form drug molecules, and specifically provides a pharmaceutical salt of osimertinib, a preparation method thereof, and an application thereof. The pharmaceutical salt disclosed in the present invention is a pharmaceutical salt formed by osimertinib and hydroxybenzoic acid or dihydroxybenzoic acid, wherein the hydroxybenzoic acid is 3-hydroxybenzoic acid or 4-hydroxybenzoic acid; and the dihydroxybenzoic acid is 1,2-dihydroxybenzoic acid, 1,3-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, or 3,5-dihydroxybenzoic acid. Compared with existing osimertinib crystal forms, the pharmaceutical salt of the present invention has lower hygroscopicity and higher solubility, and is more suitable for drug development.

Description

Technical Field

[0001] The present invention relates to the field of crystalline drug molecule technology, in particular to the field of osimertinib crystalline technology, specifically to osimertinib pharmaceutical salt and its preparation method and application.

[0002] Background technology

[0003] 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 number: 1421373-65-0, its structural formula is shown below:

[0004]

[0005] Lung cancer patients with EGFR or ALK gene mutations can benefit from targeted drugs to improve survival. However, the efficacy of these drugs is generally short-lived, with resistance developing within 9-11 months. This occurs because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing their growth patterns.

[0006] ADZ9291, developed by AstraZeneca, is a third-generation, oral, irreversible, selective EGFR mutation inhibitor that can be used against both activating and resistant EGFR mutations. Specifically, for patients with advanced non-small cell lung cancer, 50% of acquired resistance to anti-EGFR therapy is caused by the T790M mutation. ADZ9291 can render this challenging mutation ineffective. ADZ9291 has demonstrated a superior therapeutic effect in NSCLC patients who are resistant to existing epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and have the T790M mutation.

[0007] The original research patent CN103702990A discloses the structure of the ADZ9291 compound. The patent also discloses the polymorphic forms of this compound and its mesylate salt, including osimertinib mesylate Form A and osimertinib mesylate Form B. The original research company used the mesylate salt of osimertinib for clinical research. However, methanesulfonic acid has high biological toxicity and is not suitable for drug development under selective conditions. In addition, the mesylate salt has the problem of high hygroscopicity and easy deliquesce in high humidity. Patent CN104961731A discloses osimertinib phosphate; Patent CN106432231A discloses osimertinib pharmaceutical salts sulfate, p-toluenesulfonate, tartrate, acetate, and citrate; these overcome the high toxicity and high hygroscopicity of the mesylate salt. Patent CN107915725A discloses new pharmaceutical salts of osimertinib, including maleate, fumarate, gluconate, malonate, succinate, and lactate. Patent CN110483486A discloses osimertinib ketorolac, which improves the high hygroscopicity problem of the mesylate.

[0008] Although numerous osimertinib crystalline forms have been disclosed in existing literature, systematic research on their crystalline forms remains to be completed. The present invention provides a simple and easy-to-operate method for preparing high-purity osimertinib crystalline forms, providing a better basis for the application of osimertinib in drug therapy, thereby more effectively realizing the medicinal value of osimertinib. Summary of the Invention

[0009] In view of the deficiencies of the prior art, one object of the present invention is to provide a new pharmaceutical salt of osimertinib to improve the problems of high hygroscopicity and low solubility in the prior art.

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

[0011] The pharmaceutical salt of osimertinib provided by the present invention is a pharmaceutical salt formed by osimertinib and hydroxybenzoic acid or dihydroxybenzoic acid, wherein the hydroxybenzoic acid is 3-hydroxybenzoic acid or 4-hydroxybenzoic acid; the dihydroxybenzoic acid is 1,2-dihydroxybenzoic acid, 1,3-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, or 3,5-dihydroxybenzoic acid.

[0012] Preferably, the pharmaceutically acceptable salt of osimertinib is a pharmaceutically acceptable salt formed by osimertinib and 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid or 3,5-dihydroxybenzoic acid, which are osimertinib-3-hydroxybenzoate, osimertinib-4-hydroxybenzoate, osimertinib-2,3-dihydroxybenzoate or osimertinib-3,5-dihydroxybenzoate, respectively.

[0013] The osimertinib-3-hydroxybenzoate salt uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 5.78±0.2°, 12.05±0.2°, 13.72±0.2°, 16.27±0.2°, 16.51±0.2°, 20.09±0.2°, 21.44±0.2°, and 23.83±0.2°. Preferably, the osimertinib-3-hydroxybenzoate, using Cu-Kα radiation, has an X-ray diffraction spectrum expressed in 2θ at 5.78±0.2°, 9.36±0.2°, 12.05±0.2°, 13.72±0.2°, 16.27±0.2°, 16.51±0.2°, 18.12±0.2°, 20.09±0.2°, 21.44±0.2°, 21.82±0.2°, 23.83±0.2°, and 32.20±0.2°. Further, the osimertinib-3-hydroxybenzoate, using Cu-Kα radiation, has Figure 1 The X-ray powder diffraction pattern is shown.

[0014] The osimertinib-4-hydroxybenzoate salt uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.05±0.2°, 9.60±0.2°, 12.05±0.2°, 14.00±0.2°, 20.29±0.2°, and 23.99±0.2°. Preferably, the osimertinib-4-hydroxybenzoate, using Cu-Kα radiation, has an X-ray diffraction spectrum expressed in 2θ at 8.66±0.2°, 10.04±0.2°, 15.58±0.2°, 16.76±0.2°, 18.08±0.2°, 18.72±0.2°, 21.79±0.2°, 22.24±0.2°, 24.82±0.2°, 25.78±0.2°, 26.32±0.2°, 27.86±0.2°, and 32.58±0.2°. Further, the osimertinib-4-hydroxybenzoate, using Cu-Kα radiation, has Figure 5 The X-ray powder diffraction pattern is shown.

[0015] The osimertinib-2,3-dihydroxybenzoate uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 4.46±0.2°, 12.03±0.2°, 13.36±0.2°, 17.26±0.2°, 20.07±0.2°, and 25.00±0.2°. Preferably, the osimertinib-2,3-dihydroxybenzoate, using Cu-Kα radiation, has an X-ray diffraction spectrum expressed in 2θ at 4.46±0.2°, 6.53±0.2°, 12.03±0.2°, 13.36±0.2°, 15.64±0.2, 17.26±0.2°, 17.82±0.2°, 20.07±0.2°, 21.09±0.2°, 23.26±0.2°, 24.16±0.2°, 25.00°±0.2°, 26.82±0.2°, and 28.40±0.2°. Further, the osimertinib-2,3-dihydroxybenzoate, using Cu-Kα radiation, has Figure 9 The X-ray powder diffraction pattern is shown.

[0016] The osimertinib-3,5-dihydroxybenzoate uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 4.00±0.2°, 5.65±0.2°, 11.53±0.2°, 11.93±0.2°, 16.79±0.2°, 19.38±0.2°, 20.04±0.2°, and 21.79±0.2°. Preferably, the osimertinib-3,5-dihydroxybenzoate has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation at 4.00±0.2°, 5.65±0.2°, 11.53±0.2°, 11.93±0.2°, 13.09±0.2°, 13.39±0.2°, 16.79±0.2°, 19.38±0.2°, 20.04±0.2°, 21.39±0.2°, and 21.79±0.2°. Further preferably, the osimertinib-3,5-dihydroxybenzoate uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is 4.00±0.2°, 5.65±0.2°, 11.53±0.2°, 11.93±0.2°, 12.82±0.2°, 13.09±0.2°, 13.39±0.2°, 16.79±0.2°, There are characteristic peaks at 17.44±0.2°, 19.38±0.2°, 20.04±0.2°, 21.39±0.2°, 21.79±0.2°, 22.40±0.2°, 23.34±0.2°, 24.93±0.2°, 24.25±0.2°, 25.27±0.2°, 25.71±0.2°, and 26.09±0.2°. Furthermore, the osimertinib-3,5-dihydroxybenzoate, using Cu-Kα radiation, has Figure 13 The X-ray powder diffraction pattern is shown.

[0017] A second object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical salt of osimertinib, comprising the following steps: adding osimertinib and hydroxybenzoic acid or dihydroxybenzoic acid to a solvent, heating or ultrasonically dissolving them, and cooling to crystallize them.

[0018] In one embodiment, the preparation method of osimertinib-3-hydroxybenzoate comprises the following steps:

[0019] Osimertinib and 3-hydroxybenzoic acid were added to organic solvent A, heated to dissolve, and after the solution was clarified, the temperature was lowered for crystallization, and the solution was filtered and dried to obtain osimertinib-3-hydroxybenzoate.

[0020] The organic solvent A is selected from one or more mixed solvents of acetone, methanol, ethanol, and acetonitrile.

[0021] Preferably, the organic solvent A is selected from one or both of acetone and methanol.

[0022] The molar ratio of osimertinib to 3-hydroxybenzoic acid is 1:1 to 1.5; preferably, the molar ratio of osimertinib to 3-hydroxybenzoic acid is 1:1 to 1.05.

[0023] The mass-to-volume ratio of osimertinib to organic solvent A in the system is 10-25:1, where the mass is measured in mg and the volume is measured in mL.

[0024] The dissolving and heating temperature is 40-60°C.

[0025] The cooling and crystallization temperature is 0-30°C, preferably, the cooling and crystallization temperature is 5-20°C.

[0026] The crystallization time is 45 to 72 hours.

[0027] The drying temperature is 45-70° C., and the drying time is 8-12 hours.

[0028] Confirmation of the crystal structure of osimertinib-3-hydroxybenzoate

[0029] X-ray crystallography data were collected on a Rigaku XtaLAB Synergy instrument at 293(2)K using CuKa radiation. Data were collected in an ω scan mode and Lp correction was performed. The structure was solved by direct analysis, with the difference Fourier transform method identifying all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined using the least squares method.

[0030] The X-ray powder diffraction test instrument and test conditions of the present invention are: PANalytical Empyrean X-ray powder diffractometer; light source: Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PIXCEL, voltage 45 kV, current 40 mA, divergence slit of 1 / 4°, anti-scattering slit of 1°, Soller slit of 0.04 rad, counting time per step of 0.5 s, scanning range of 3-50°.

[0031] The TGA / DSC thermal analysis tester and test conditions in the present invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature range: 30-300°C; heating rate: 10°C / min; program gas N2; gas flow rate: 50 mL / min; crucible: aluminum crucible 40 μl.

[0032] The crystallographic data obtained by testing and analyzing the osimertinib-3-hydroxybenzoate prepared by the present invention (see Table 1) show that the crystallographic parameters are: monoclinic system, chiral space group P21 / c; unit cell parameters are: α=90.00°,β=98.082(2)°,γ=90.00°,unit cell volume The molecular formula is: C 35 H 39 N7O5, molecular weight is: 637.73. The structural analysis photo of osimertinib-3-hydroxybenzoate of the present invention shows that the crystal contains one molecule of osimertinib and one molecule of 3-hydroxybenzoic acid, as shown in the attached figure. Figure 3 The stacking diagram of osimertinib-3-hydroxybenzoate of the present invention is shown in the attached Figure 2 shown.

[0033] Table 1 Main crystallographic data of osimertinib-3-hydroxybenzoate

[0034]

[0035]

[0036] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) corresponding to osimertinib-3-hydroxybenzoate prepared by the present invention are shown in the attached Figure 1 And Table 2. The differential scanning calorimetry (DSC) results of the osimertinib-3-hydroxybenzoate are as follows Figure 4 As shown, the differential scanning calorimetry (DSC) curve has an endothermic peak at 165.8°C; the osimertinib-3-hydroxybenzoate salt exists as shown in FIG. Figure 4 DSC / TGA spectra shown.

[0037] Table 2 Main PXRD peaks of osimertinib-3-hydroxybenzoate

[0038]

[0039]

[0040] All osimertinib-3-hydroxybenzoate samples prepared in the present invention have the same crystallographic parameters, X-ray powder diffraction spectra and DSC / TGA spectra as those described above.

[0041] In one embodiment, the preparation method of osimertinib-4-hydroxybenzoate comprises the following steps:

[0042] Osimertinib and 4-hydroxybenzoic acid were added to organic solvent B, followed by sonication until completely dissolved, and filtered. The filtrate was placed in an evaporator, allowed to stand at room temperature for natural volatilization, filtered, and dried to obtain osimertinib-4-hydroxybenzoate.

[0043] Wherein, the molar ratio of osimertinib to 4-hydroxybenzoic acid is 1:1-2.

[0044] The room temperature is 10-30°C.

[0045] The time for natural volatilization by standing at room temperature is 2 to 8 days.

[0046] The drying temperature is 40-70°C.

[0047] The drying time is 2 to 6 hours.

[0048] The organic solvent B is a mixed solvent of methanol and other organic solvents, wherein the other organic solvents are one or a combination of acetone, ethanol, acetonitrile or tetrahydrofuran.

[0049] The mass volume ratio of osimertinib to the organic solvent is 20-60:1, mg / ml.

[0050] The volume ratio of the methanol to the other organic solvents is 1:0-1.

[0051] Confirmation of the crystal structure of osimertinib-4-hydroxybenzoate

[0052] The crystallographic data obtained by testing and analyzing the osimertinib-4-hydroxybenzoate prepared by the present invention (see Table 3) show that its crystallographic parameters are: monoclinic system, space group P21 / c; unit cell parameters are: α=90°,β=99.9430(10)°,γ=90°,unit cell volume The ORTEP diagram of osimertinib-4-hydroxybenzoate prepared by the present invention shows that one molecule of osimertinib is combined with one molecule of 4-hydroxybenzoic acid and one molecule of methanol, as shown in FIG. Figure 6 shown.

[0053] Table 3 Main crystallographic data of osimertinib-4-hydroxybenzoate

[0054]

[0055]

[0056] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) corresponding to osimertinib-4-hydroxybenzoate prepared by the present invention are shown in the attached Figure 5 And Table 4. The osimertinib-4-hydroxybenzoate was detected by differential scanning calorimetry (DSC) at the starting point of the first endothermic peak at 161.20 ° C, and the peak appeared at 169.10 ° C. The osimertinib-4-hydroxybenzoate exists as follows Figure 8 DSC / TGA spectra shown.

[0057] Table 4 Main XRD peaks of osimertinib-4-hydroxybenzoate

[0058]

[0059]

[0060] All osimertinib-4-hydroxybenzoate samples prepared in the present invention have the same crystallographic parameters, X-ray powder diffraction spectra and DSC / TGA spectra as those described above.

[0061] In one embodiment, the method for preparing osimertinib-2,3-dihydroxybenzoate comprises the following steps:

[0062] Osimertinib and 2,3-dihydroxybenzoic acid are dissolved in organic solvent C, heated to dissolve, and after the solution is clarified, cooled for crystallization, filtered, washed, and dried to obtain osimertinib-2,3-dihydroxybenzoate.

[0063] The organic solvent C is a mixed solvent of one or more solvents selected from acetone, methanol, ethanol, and acetonitrile.

[0064] The molar ratio of osimertinib to 2,3-dihydroxybenzoic acid is 1:1-2; preferably, the molar ratio of osimertinib to 2,3-dihydroxybenzoic acid crystals is 1:1-1.5.

[0065] The mass-to-volume ratio of osimertinib to the organic solvent C in the system is 10-25:1, where the mass is measured in mg and the volume is measured in mL.

[0066] The dissolving and heating temperature is 40-60°C.

[0067] The cooling and crystallization temperature is 0-30°C, and more preferably, the cooling and crystallization temperature is 5-20°C.

[0068] The crystallization time is 45 to 72 hours.

[0069] The drying temperature is 45-70° C., and the drying time is 8-12 hours.

[0070] Confirmation of the crystal structure of osimertinib-2,3-dihydroxybenzoate

[0071] The crystallographic data obtained by testing and analyzing the osimertinib-2,3-dihydroxybenzoate prepared by the present invention (see Table 5) show that its crystallographic parameters are: orthorhombic system, chiral space group Pbca; unit cell parameters are: α=90.00°,β=90°,γ=90.00°,unit cell volume The molecular formula is: C 35 H 39N7O6, molecular weight is: 653.73. The ORTEP diagram of the structure of osimertinib-2,3-dihydroxybenzoate prepared by the present invention shows that the crystal contains one molecule of osimertinib and one molecule of 2,3-dihydroxybenzoic acid, as shown in the attached figure. Figure 11 The stacking diagram of osimertinib-2,3-dihydroxybenzoate is shown in the attached Figure 10 shown.

[0072] Table 5 Main crystallographic data of osimertinib-2,3-dihydroxybenzoate

[0073]

[0074]

[0075] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) corresponding to the osimertinib-2,3-dihydroxybenzoate prepared by the present invention are shown in the attached Figure 9 And Table 6. The differential scanning calorimetry (DSC) results of the osimertinib-2,3-dihydroxybenzoate are as follows Figure 12 As shown, the differential scanning calorimetry (DSC) curve has an endothermic peak at 195.13°C; its thermogravimetric analysis (TGA) has only one weight loss step, indicating that the osimertinib-2,3-dihydroxybenzoic acid crystals do not contain solvent and have a stable structure. The osimertinib-2,3-dihydroxybenzoic acid salt exists as follows Figure 12 DSC / TGA spectra shown.

[0076] Table 6 Main PXRD peaks of osimertinib-2,3-dihydroxybenzoate

[0077]

[0078]

[0079] All osimertinib-2,3-dihydroxybenzoate samples prepared in the present invention have the same crystallographic parameters, X-ray powder diffraction spectra and DSC / TGA spectra as those described above.

[0080] In one embodiment, the preparation method of osimertinib-3,5-dihydroxybenzoate comprises the following steps:

[0081] Osimertinib and 3,5-dihydroxybenzoic acid are added to a mixed solvent of an organic solvent D containing methanol and purified water, and heated to dissolve. After the solution is clarified, the temperature is lowered for crystallization, and the solution is filtered and dried to obtain osimertinib 3,5-dihydroxybenzoate.

[0082] The organic solvent D is selected from one of acetone, ethanol, isopropanol and acetonitrile; preferably, the organic solvent D is selected from one of acetone and ethanol.

[0083] The molar ratio of osimertinib to 3,5-dihydroxybenzoic acid is 1:1 to 1.5; preferably, the molar ratio of osimertinib to 3,5-dihydroxybenzoic acid is 1:1 to 1.1.

[0084] The mass ratio of osimertinib and 3,5-dihydroxybenzoic acid to the volume ratio of the organic solvent D is 10 to 30:1, where the mass is measured in mg and the volume is measured in mL.

[0085] The volume ratio of the methanol to the organic solvent D is 1:0-15.

[0086] The volume ratio of the organic solvent D to purified water is 10-20:1.

[0087] The dissolving and heating temperature is 50-70°C.

[0088] The cooling and crystallization temperature is 0-30°C; more preferably, the cooling and crystallization temperature is 10-20°C.

[0089] The crystallization time is 48 to 72 hours.

[0090] The drying temperature is 20-30° C., and the drying time is 8-12 hours.

[0091] Confirmation of the crystal structure of osimertinib-3,5-dihydroxybenzoate

[0092] The crystallographic data obtained by testing and analyzing the osimertinib-3,5-dihydroxybenzoate prepared by the present invention (see Table 7) show that the crystallographic parameters are: monoclinic system, chiral space group P21 / c; unit cell parameters are: b=14.4833(2) α=90°,β=114.867(2)°,γ=90°,unit cell volume The structural analysis photos of osimertinib 3,5-dihydroxybenzoate show that the crystal contains one osimertinib molecule, one 3,5-dihydroxybenzoic acid, two water molecules, and one methanol molecule. Figure 15 The stacking diagram of osimertinib-3,5-dihydroxybenzoate of the present invention is shown in the attached Figure 14 shown.

[0093] Table 7 Main crystallographic data of osimertinib-3,5-dihydroxybenzoate

[0094]

[0095]

[0096] According to the crystallographic data, the corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 13 and Table 8.

[0097] Table 8 Main PXRD peaks of osimertinib-3,5-dihydroxybenzoate

[0098]

[0099]

[0100] All osimertinib-3,5-dihydroxybenzoate samples prepared in the present invention have the same crystallographic parameters and X-ray powder diffraction spectra as those described above.

[0101] The osimertinib-3-hydroxybenzoate, osimertinib-4-hydroxybenzoate, osimertinib-2,3-dihydroxybenzoate, and osimertinib-3,5-dihydroxybenzoate prepared by the present invention have excellent hygroscopicity, improve the solubility of osimertinib, and thus more efficiently exert the medicinal value of osimertinib.

[0102] The third object of the present invention is to provide a pharmaceutical composition comprising the pharmaceutically acceptable salt of osimertinib prepared as described above, and other active ingredients and / or pharmaceutically acceptable excipient components that can be used in combination.

[0103] Preferably, the other components include other active ingredients, excipients, fillers, etc. that can be used in combination.

[0104] Preferably, the pharmaceutical composition can be prepared into sprays, tablets, capsules, powder injections, liquid injections, etc. using standard and conventional techniques.

[0105] The fourth objective of the present application is to provide the use of the above-mentioned pharmaceutical salt of osimertinib as an active ingredient in the preparation of therapeutic anticancer drugs.

[0106] The beneficial effects of the present invention are:

[0107] The new pharmaceutical salt of osimertinib provided by the present invention overcomes the problem of high toxicity of mesylate, has lower hygroscopicity and improved solubility compared with the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0108] Figure 1 X-ray powder diffraction pattern of osimertinib-3-hydroxybenzoate;

[0109] Figure 2 Stacking diagram of osimertinib-3-hydroxybenzoate;

[0110] Figure 3 ORTEP diagram of osimertinib-3-hydroxybenzoate;

[0111] Figure 4 Differential scanning calorimetry (DSC) curve of osimertinib-3-hydroxybenzoate;

[0112] Figure 5 X-ray powder diffraction pattern of osimertinib-4-hydroxybenzoate;

[0113] Figure 6 ORTEP diagram of osimertinib-4-hydroxybenzoate;

[0114] Figure 7 Unit cell stacking diagram of osimertinib-4-hydroxybenzoate;

[0115] Figure 8 TGA / DSC thermogram of osimertinib-4-hydroxybenzoate;

[0116] Figure 9 X-ray powder diffraction pattern of osimertinib-2,3-dihydroxybenzoate;

[0117] Figure 10 Stacking diagram of osimertinib-2,3-dihydroxybenzoate;

[0118] Figure 11 ORTEP diagram of osimertinib-2,3-dihydroxybenzoate;

[0119] Figure 12 Differential scanning calorimetry (DSC) curve of osimertinib-2,3-dihydroxybenzoate;

[0120] Figure 13 X-ray powder diffraction pattern of osimertinib-3,5-dihydroxybenzoate;

[0121] Figure 14 Stacking diagram of osimertinib-3,5-dihydroxybenzoate;

[0122] Figure 15 ORTEP diagram of osimertinib-3,5-dihydroxybenzoate. Specific embodiments

[0123] The present invention is further illustrated by the following examples. It should be understood that the examples of the present invention are merely for illustrating the present invention, rather than for limiting the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0124] (1) Preparation of osimertinib-3-hydroxybenzoate

[0125] Example 1

[0126] 1.5 g of osimertinib and 0.44 g of 3-hydroxybenzoic acid were added to 75 mL of methanol, heated to 55°C with stirring to dissolve, heated to reflux, reacted for 1 hour, slowly cooled to 0°C, and allowed to stand at controlled temperature for 60 hours for crystallization. The mixture was filtered, and the filter cake was washed with methanol. The filter cake was dried in vacuo at 60°C for 10 hours to obtain osimertinib-3-hydroxybenzoate with a yield of 97.74% and a purity of 99.97%.

[0127] Example 2

[0128] 1.5 g of osimertinib and 0.50 g of 3-hydroxybenzoic acid were added to 40 mL of methanol and 60 mL of acetonitrile, heated to 45°C with stirring to dissolve, heated to reflux, reacted for 1 hour, slowly cooled to 5°C, and allowed to stand at controlled temperature for crystallization for 65 hours. The mixture was filtered, and the filter cake was washed with methanol. The filter cake was dried under vacuum at 65°C for 12 hours to obtain osimertinib-3-hydroxybenzoate with a yield of 96.67% and a purity of 99.94%.

[0129] Example 3

[0130] 1.5 g of osimertinib and 0.54 g of 3-hydroxybenzoic acid were added to 30 mL of acetone and 30 mL of ethanol, heated to 50°C with stirring to dissolve, heated to reflux, reacted for 1 hour, slowly cooled to 10°C, and allowed to stand at controlled temperature for crystallization for 50 hours. The mixture was filtered, the filter cake was washed with ethanol, and vacuum dried at 50°C for 10 hours to obtain osimertinib-3-hydroxybenzoate with a yield of 96.33% and a purity of 99.92%.

[0131] Example 4

[0132] 1.5 g of osimertinib and 0.62 g of 3-hydroxybenzoic acid were added to 150 mL of ethanol, heated to 60°C with stirring to dissolve, heated to reflux, reacted for 1 hour, slowly cooled to 15°C, and allowed to stand at controlled temperature for 72 hours for crystallization. The mixture was filtered, and the filter cake was washed with ethanol. The filter cake was dried under vacuum at 70°C for 8 hours to obtain osimertinib-3-hydroxybenzoate with a yield of 95.32% and a purity of 99.92%.

[0133] Example 5

[0134] 1.5 g of osimertinib and 0.41 g of 3-hydroxybenzoic acid were added to 80 mL of acetone, heated to 40°C with stirring to dissolve, heated to reflux, reacted for 1 hour, slowly cooled to 20°C, and allowed to stand at controlled temperature for 45 hours for crystallization. The mixture was filtered, and the filter cake was washed with acetone. The filter cake was vacuum dried at 45°C for 12 hours to obtain osimertinib-3-hydroxybenzoate with a yield of 93.08% and a purity of 99.90%.

[0135] Example 6

[0136] 1.5 g of osimertinib and 0.83 g of 3-hydroxybenzoic acid were added to 150 mL of acetone, heated to 50°C with stirring to dissolve, heated to reflux, reacted for 1 hour, slowly cooled to 30°C, and allowed to stand at controlled temperature for 50 hours for crystallization. The mixture was filtered, and the filter cake was washed with acetone. The filter cake was vacuum dried at 60°C for 10 hours to obtain osimertinib-3-hydroxybenzoate with a yield of 81.20% and a purity of 99.86%.

[0137] (II) Preparation of osimertinib-4-hydroxybenzoate

[0138] Example 7

[0139] 499 mg of osimertinib and 207 mg of 4-hydroxybenzoic acid were added to 12 mL of methanol, and then sonicated at 200 W using an ultrasonicator until completely dissolved. The mixture was filtered and the filtrate was placed in an evaporator with a small-pore membrane seal. The mixture was allowed to evaporate naturally at 15°C for 5 days. The mixture was filtered to obtain light pink block crystals, which were dried in an oven at 50°C for 2 h to obtain osimertinib-4-hydroxybenzoate with a yield of 96.54% and a purity of 99.98%.

[0140] Example 8

[0141] 499 mg of osimertinib and 249 mg of 4-hydroxybenzoic acid were added to 10 mL of methanol, and then sonicated at 250 W using an ultrasonicator until completely dissolved. The mixture was filtered, and the filtrate was placed in an evaporator with a small-pore membrane seal and allowed to evaporate naturally at 20°C for 4 days. The mixture was filtered to obtain light pink block crystals, which were dried in an oven at 60°C for 5 h to obtain osimertinib-4-hydroxybenzoate with a yield of 94.69% and a purity of 99.97%.

[0142] Example 9

[0143] 499 mg of osimertinib and 166 mg of 4-hydroxybenzoic acid were added to a mixed solvent of 6 mL of acetone and 10 mL of methanol, and then sonicated at 150 W using an ultrasonicator until completely dissolved. The mixture was filtered and the filtrate was placed in an evaporator with a small-pore membrane seal. The mixture was allowed to evaporate naturally at 23°C for 6 days and filtered to obtain light pink block crystals. The crystals were dried in an oven at 42°C for 4.5 h to obtain osimertinib-4-hydroxybenzoate with a yield of 91.70% and a purity of 99.97%.

[0144] Example 10

[0145] 499 mg of osimertinib and 276 mg of 4-hydroxybenzoic acid were added to a mixed solvent of 4 mL of methanol and 4 mL of acetonitrile, and then sonicated at 300 W using an ultrasonicator until completely dissolved. The mixture was filtered and the filtrate was placed in an evaporator with a small-pore membrane seal and allowed to evaporate naturally at 25°C for 8 days. The mixture was filtered to obtain light pink block crystals, which were dried in an oven at 70°C for 6 h to obtain osimertinib-4-hydroxybenzoate with a yield of 86.54% and a purity of 99.96%.

[0146] Example 11

[0147] 499 mg of osimertinib and 138 mg of 4-hydroxybenzoic acid were added to a mixed solvent of 15 mL of methanol and 10 mL of tetrahydrofuran, and then sonicated at 150 W using an ultrasonicator until completely dissolved. The mixture was filtered and the filtrate was placed in an evaporator with a small-pore membrane seal and allowed to evaporate naturally at 25°C for 2 days. The mixture was filtered to obtain light pink block crystals, which were dried in an oven at 40°C for 2 h to obtain osimertinib-4-hydroxybenzoate with a yield of 81.32% and a purity of 99.95%.

[0148] Example 12

[0149] 249.5 mg of osimertinib and 172.5 mg of 4-hydroxybenzoic acid were added to a mixed solvent of 10 mL of methanol and 6.5 mL of acetonitrile, and then sonicated at 250 W using an ultrasonicator until completely dissolved. The mixture was filtered, and the filtrate was placed in an evaporator with a small-pore membrane seal, allowed to stand at 30°C for natural volatilization, and filtered to obtain light pink block crystals. The crystals were dried in an oven at 55°C for 3 h to obtain osimertinib-4-hydroxybenzoate with a yield of 74.54% and a purity of 99.93%.

[0150] (III) Preparation of osimertinib-2,3-dihydroxybenzoate

[0151] Example 13

[0152] Dissolve 2.0 g of osimertinib and 0.74 g of 2,3-dihydroxybenzoic acid in 100 mL of acetone and heat to 50°C for dissolution. After the solution is clarified, cool to 15°C for crystallization for 60 hours, filter, wash the filter cake with acetone, and dry at 65°C for 10 hours to obtain osimertinib-2,3-dihydroxybenzoic acid crystals with a yield of 95.8% and a purity of 99.8%.

[0153] Example 14

[0154] 2.0 g of osimertinib and 0.93 g of 2,3-dihydroxybenzoic acid were dissolved in 80 mL of methanol and heated to 45°C for dissolution. After the solution was clarified, it was cooled to 20°C for crystallization for 50 h, filtered, and the filter cake was washed with methanol. It was dried at 50°C for 11 h to obtain osimertinib-2,3-dihydroxybenzoic acid crystals with a yield of 94.7% and a purity of 99.8%.

[0155] Example 15

[0156] 2.0 g of osimertinib and 0.62 g of 2,3-dihydroxybenzoic acid were dissolved in a mixed solvent of 55 mL of methanol and 80 mL of acetone, heated under reflux to 50°C for dissolution. After the solution was clarified, it was cooled to 25°C for crystallization for 70 h, filtered, and the filter cake was washed with acetone. It was dried at 70°C for 12 h to obtain osimertinib-2,3-dihydroxybenzoic acid crystals with a yield of 92.5% and a purity of 99.7%.

[0157] Example 16

[0158] Dissolve 2.0 g of osimertinib and 1.23 g of 2,3-dihydroxybenzoic acid in 200 mL of ethanol and heat to 40°C for dissolution. After the solution becomes clear, cool to 5°C for crystallization for 45 hours, filter, wash the filter cake with ethanol, and dry at 45°C for 8 hours to obtain osimertinib-2,3-dihydroxybenzoic acid crystals with a yield of 86.4% and a purity of 99.5%.

[0159] Example 17

[0160] 2.0 g of osimertinib and 1.54 mg of 2,3-dihydroxybenzoic acid were dissolved in 200 mL of acetonitrile and heated to 50°C for dissolution. After the solution was clarified, it was cooled to 0°C for crystallization for 65 hours, filtered, and the filter cake was washed with acetonitrile and dried at 55°C for 10 hours to obtain osimertinib-2,3-dihydroxybenzoic acid crystals with a yield of 75.6% and a purity of 99.5%.

[0161] (IV) Preparation of osimertinib-3,5-dihydroxybenzoate

[0162] Example 18

[0163] 1.0 g of osimertinib and 0.34 g of 3,5-dihydroxybenzoic acid were added to 100 mL of methanol and 8 mL of purified water, heated to 60°C and stirred for 10 min, slowly cooled to 15°C, and allowed to stand for crystallization for 62 hours. The mixture was filtered and dried under vacuum at 25°C for 10 hours to obtain osimertinib-3,5-dihydroxybenzoate with a yield of 95.69% and a purity of 99.96%.

[0164] Example 19

[0165] 1.0 g of osimertinib and 0.40 g of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 14 mL of methanol, 70 mL of ethanol, and 5 mL of purified water. The mixture was heated to 65°C and stirred for 10 min. The mixture was slowly cooled to 20°C and allowed to stand for crystallization for 50 hours. The mixture was filtered and dried under vacuum at 28°C for 11 hours to obtain osimertinib-3,5-dihydroxybenzoate with a yield of 93.89% and a purity of 99.94%.

[0166] Example 20

[0167] 1.0 g of osimertinib and 0.46 g of 3,5-dihydroxybenzoic acid were added to 53 mL of methanol and 5 mL of purified water, heated to 55°C with stirring for 10 min, slowly cooled to 10°C, and allowed to stand for crystallization for 48 hours. The mixture was filtered and dried under vacuum at 22°C for 9 hours to obtain osimertinib-3,5-dihydroxybenzoate with a yield of 87.10% and a purity of 99.91%.

[0168] Example 21

[0169] 1.0 g of osimertinib and 0.31 g of 3,5-dihydroxybenzoic acid were added to 67 mL of isopropanol and 5 mL of purified water, heated to 70°C with stirring for 10 min, slowly cooled to 30°C, and allowed to stand for crystallization for 72 hours. The mixture was filtered and dried under vacuum at 30°C for 12 hours to obtain osimertinib-3,5-dihydroxybenzoate with a yield of 94.67% and a purity of 99.93%.

[0170] Example 22

[0171] 1.0 g of osimertinib and 0.62 g of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 5 mL of methanol, 95 mL of acetone, and 10 mL of purified water. The mixture was heated to 50°C and stirred for 10 min. The mixture was slowly cooled to 0°C and allowed to stand for crystallization for 55 hours. The mixture was filtered and dried under vacuum at 20°C for 8 hours to obtain osimertinib-3,5-dihydroxybenzoate with a yield of 76.89% and a purity of 99.88%.

[0172] Verification test

[0173] 1. Solubility test

[0174] A comparative solubility study was conducted on osimertinib-3-hydroxybenzoate prepared according to Example 1 of the present invention, osimertinib-4-hydroxybenzoate prepared according to Example 7, osimertinib-2,3-dihydroxybenzoate prepared according to Example 13, osimertinib-3,5-dihydroxybenzoate prepared according to Example 18, and osimertinib mesylate crystalline form A of the prior art. Method: 10 ml of the medium (water, 0.1 mol / L HCl solution, and pH = 6.8 phosphate buffer) were respectively measured and placed in a vial, an excess amount of the sample to be tested was added, the vial was sealed and placed in a constant temperature water bath at 25°C with stirring for 1 hour, filtered through a 0.45 μm filter membrane, and the filtrate was collected; the absorbance was measured at a wavelength of 210 nm, and its solubility was calculated by testing the absorbance of the standard reference substance.

[0175] Table 9 Solubility of osimertinib polymorphs in different media (mg / ml)

[0176]

[0177] From the above test data, it can be seen that the solubility of the crystalline forms of osimertinib-3-hydroxybenzoate, osimertinib-4-hydroxybenzoate, osimertinib-2,3-dihydroxybenzoate and osimertinib-3,5-dihydroxybenzoate prepared by the present invention is significantly improved in three different media compared with the osimertinib mesylate crystalline form A, indicating that the crystalline forms prepared by the present invention have good solubility and are beneficial for human absorption when made into pharmaceutical preparations.

[0178] 2. Moisture absorption test

[0179] A comparative study of the hygroscopicity of osimertinib 3-hydroxybenzoate prepared according to Example 1 of the present invention, osimertinib 4-hydroxybenzoate prepared according to Example 7, osimertinib 2,3-dihydroxybenzoate prepared according to Example 13, osimertinib 3,5-dihydroxybenzoate prepared according to Example 18, and osimertinib mesylate form A was performed in accordance with the method 9103 of Appendix 4 of the 2015 edition of the Chinese Pharmacopoeia.

[0180] Table 10 Hygroscopicity results of osimertinib polymorphs

[0181]

[0182] From the above experimental data, it can be seen that the crystalline forms of osimertinib-3-hydroxybenzoate, osimertinib-4-hydroxybenzoate, osimertinib-2,3-dihydroxybenzoate and osimertinib-3,5-dihydroxybenzoate prepared in the present invention have significantly improved hygroscopicity compared with osimertinib mesylate form A, indicating that the crystalline forms prepared in the present invention have good stability and are more suitable for drug development.

[0183] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 Edition, Part IV, Appendix 9103, Guiding Principles for Hygroscopicity Experiments of Drugs, experimental conditions: 25°C ± 1°C, relative humidity 80% ± 2%)

[0184] Deliquescent: Absorbs sufficient water to form a liquid.

[0185] Highly hygroscopic: weight gain upon moisture absorption is not less than 15%.

[0186] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.

[0187] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0188] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0189] After testing, the crystal forms prepared in Examples 2 to 6 of the present invention all achieved hygroscopicity and solubility effects similar to those of the crystal form prepared in Example 1, the crystal forms prepared in Examples 8 to 12 of the present invention all achieved hygroscopicity and solubility effects similar to those of the crystal form prepared in Example 7, and the crystal forms prepared in Examples 19 to 22 of the present invention all achieved hygroscopicity and solubility effects similar to those of the crystal form prepared in Example 18. Therefore, the hygroscopicity and solubility of osimertinib-3-hydroxybenzoate, osimertinib-4-hydroxybenzoate, osimertinib-2,3-dihydroxybenzoate, and osimertinib-3,5-dihydroxybenzoate provided by the present invention are significantly improved compared to the prior art and are more suitable for preparation into drugs.

Claims

1. A pharmaceutically acceptable salt of osimertinib, characterized in that: The pharmaceutically acceptable salt of osimertinib is osimertinib-3-hydroxybenzoate, osimertinib-4-hydroxybenzoate, osimertinib-2,3-dihydroxybenzoate or osimertinib-3,5-dihydroxybenzoate. The osimertinib-3-hydroxybenzoate has a Cu-Kα radiation-based X-ray diffraction spectrum expressed in 2θ with characteristic peaks at 5.78±0.2°, 12.05±0.2°, 13.72±0.2°, 16.27±0.2°, 16.51±0.2°, 20.09±0.2°, 21.44±0.2° and 23.83±0.2°. The osimertinib-4-hydroxybenzoate has a Cu-Kα radiation-based X-ray diffraction spectrum expressed in 2θ with characteristic peaks at 6.05±0.2°, 9. .60±0 .2°, 12 .05±0 .2°, 14.00±0 .2°, 20 .29±0 .2°, and 23 .99±0 .2°. The X-ray diffraction spectrum of osimertinib-2,3-dihydroxybenzoate, using Cu-Kα radiation, expressed in 2θ, has characteristic peaks at 4 .46±0 .2°, 12 .03±0 .2°, 13 .36±0 .2°, 17 .26±0 .2°, 20 .07±0 .2°, and 25 .00±0 .2°. The X-ray diffraction spectrum of osimertinib-3,5-dihydroxybenzoate, using Cu-Kα radiation, expressed in 2θ, has characteristic peaks at 4 .00±0 .2°, 5 .65±0.2°, 11 There are characteristic peaks at 0.05°, 11.93±0.2°, 16.79±0.2°, 19.38±0.2°, 20.04±0.2° and 21.79±0.2°.

2. The method for preparing the pharmaceutical salt of osimertinib according to claim 1, wherein The method comprises the following steps: adding osimertinib and hydroxybenzoic acid or dihydroxybenzoic acid into a solvent, heating or ultrasonically dissolving the osimertinib, and cooling to crystallize the osimertinib.

3. A pharmaceutical composition comprising the pharmaceutically acceptable salt of osimertinib according to claim 1, and other active ingredients and / or pharmaceutically acceptable excipient components that can be used in combination.

4. Use of the pharmaceutically acceptable salt of osimertinib according to claim 1 as an active ingredient in the preparation of drugs for treating lung cancer.

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