Pharmaceutically acceptable salt of EGFR inhibitor, crystal form thereof, preparation method therefor and application thereof

Abstract

Provided in the present disclosure are a pharmaceutically acceptable salt of an epidermal growth factor receptor (EGFR) inhibitor, a crystal form thereof, a preparation method therefor and an application thereof. The structural formula of the EGFR inhibitor is as shown in formula I, and the pharmaceutically acceptable salt is a mesylate, p-toluenesulfonate, phosphate, hydrochloride or citrate salt of the EGFR inhibitor. The pharmaceutically acceptable salt of EGFR inhibitor of the present disclosure has a specific crystal form, has a higher solubility and stability than a corresponding free base, is more suitable for preparing drugs for use in treating cancer (especially non-small cell lung cancer), and satisfies the requirements for bioavailability and drug efficacy. ##STR00001##

Claims

1. A crystal form E of a citrate salt of the EGFR inhibitor represented by formula I, ##STR00004## wherein the X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 2 values of 5.40.2, 10.80.2, 12.00.2, 17.50.2, 21.20.2, 24.90.2, and 25.40.2.

2. A crystal form A of a mesylate salt of the EGFR inhibitor represented by formula I, ##STR00005## wherein the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2 values of 6.80.2, 13.50.2, 14.00.2, 15.60.2, 18.10.2, 21.60.2, and 24.00.2.

3. A crystal form B of a p-toluenesulfonate salt of the EGFR inhibitor represented by formula I, ##STR00006## wherein the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2 values of 10.60.2, 15.10.2, 18.10.2, 22.40.2 and 24.80.2.

4. A crystal form C of a phosphate salt of the EGFR inhibitor represented by formula I, ##STR00007## wherein the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2 values of 8.90.2, 14.10.2, 16.00.2, 19.90.2, 22.70.2, and 25.30.2.

5. A crystal form D of a hydrochloride salt of the EGFR inhibitor represented by formula I, ##STR00008## wherein the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2 values of 7.80.2, 9.80.2, 16.20.2, 21.30.2, 26.30.2, and 27.60.2.

6. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form E of the EGFR inhibitor according to claim 1.

7. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form A of the EGFR inhibitor according to claim 2.

8. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form B of the EGFR inhibitor according to claim 3.

9. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form C of the EGFR inhibitor according to claim 4.

10. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form D of the EGFR inhibitor according to claim 5.

11. The crystal form E of the EGFR inhibitor according to claim 1, wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 10.

12. The crystal form A of the EGFR inhibitor according to claim 2, wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

13. The crystal form B of the EGFR inhibitor according to claim 3, wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 3.

14. The crystal form C of the EGFR inhibitor according to claim 4, wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 5.

15. The crystal form D of the EGFR inhibitor according to claim 5, wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 8.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a XRPD pattern of an EGFR inhibitor mesylate salt present in the form of a crystal form A;

(2) FIG. 2 is a DSC plot of the EGFR inhibitor mesylate salt present in the form of the crystal form A;

(3) FIG. 3 is a XRPD pattern of an EGFR inhibitor p-toluenesulfonate salt present in the form of a crystal form B;

(4) FIG. 4 is a DSC plot of the EGFR inhibitor p-toluenesulfonate salt present in the form of the crystal form B;

(5) FIG. 5 is a XRPD pattern of an EGFR inhibitor phosphate salt present in the form of a crystal form C;

(6) FIG. 6 is a DSC plot of the EGFR inhibitor phosphate salt present in the form of the crystal form C;

(7) FIG. 7 is a XRPD pattern of an EGFR inhibitor phosphate salt present in an amorphous form;

(8) FIG. 8 is a XRPD pattern of an EGFR inhibitor hydrochloride salt present in the form of a crystal form D;

(9) FIG. 9 is a DSC plot of the EGFR inhibitor hydrochloride salt present in the form of the crystal form D;

(10) FIG. 10 is a XRPD pattern of an EGFR inhibitor citrate salt present in the form of a crystal form E;

(11) FIG. 11 is a DSC plot of the EGFR inhibitor citrate salt present in the form of the crystal form E;

(12) FIG. 12 is the stability test result of the EGFR inhibitor mesylate salt present in the crystal form A (XRPD comparison graph), wherein the XRPD pattern of the sample determined at the start time and the XRPD pattern of the sample determined after standing for 1 month at 40 C./75% RH are in bottom-to-top order.

(13) FIG. 13 is the stability test result of the EGFR inhibitor p-toluenesulfonate salt present in the form of the crystal form B (XRPD comparison graph), wherein the XRPD pattern of the sample determined at the start time and the XRPD pattern of the sample determined after standing for 1 month at 40 C./75% RH are in bottom-to-top order.

(14) FIG. 14 is the stability test result of the EGFR inhibitor phosphate salt present in the crystal form C (XRPD comparison graph), wherein the XRPD pattern of the sample determined at the start time and the XRPD pattern of the sample determined after standing for 1 month at 40 C./75% RH are in bottom-to-top order.

(15) FIG. 15 is the stability test result of the EGFR inhibitor phosphate salt present in the amorphous form (XRPD comparison graph), wherein the XRPD pattern of the sample determined at the start time and the XRPD pattern of the sample determined after standing for 1 month at 40 C./75% RH are in bottom-to-top order.

(16) FIG. 16 is the stability test result of the EGFR inhibitor hydrochloride salt present in the form of the crystal form D (XRPD comparison graph), wherein the XRPD pattern of the sample determined at the start time and the XRPD pattern of the sample determined after standing for 1 month at 40 C./75% RH are in bottom-to-top order.

(17) FIG. 17 is the stability test result of the EGFR inhibitor citrate salt present in the form of the crystal form E (XRPD comparison graph), wherein the XRPD pattern of the sample determined at the start time and the XRPD pattern of the sample determined after standing for 1 month at 40 C./75% RH are in bottom-to-top order.

(18) FIG. 18 is a .sup.1H-NMR spectrum of the EGFR inhibitor present in a free base form;

(19) FIG. 19 is a mass spectrogram of the EGFR inhibitor present in a free base form;

(20) FIG. 20 is a .sup.1H-NMR spectrum of the EGFR inhibitor mesylate salt present in the form of the crystal form A;

(21) FIG. 21 is a .sup.1H-NMR spectrum of the EGFR inhibitor p-toluenesulfonate salt present in the form of the crystal form B;

(22) FIG. 22 is a .sup.1H-NMR spectrum of the EGFR inhibitor phosphate salt present in the form of the crystal form C;

(23) FIG. 23 is a .sup.1H-NMR spectrum of the EGFR inhibitor hydrochloride salt present in the form of the crystal form D; and

(24) FIG. 24 is a .sup.1H-NMR spectrum of the EGFR inhibitor citrate salt present in the form of the crystal form E.

DETAILED DESCRIPTION

(25) The present disclosure provides a pharmaceutically acceptable salt of EGFR inhibitor, and the structure of the EGFR inhibitor is shown in formula I (chemical name: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide):

(26) ##STR00003##

(27) The pharmaceutically acceptable salt includes mesylate, p-toluenesulfonate, phosphate, hydrochloride or citrate salt.

(28) Unless otherwise stated, the EGFR inhibitor in the present disclosure refers to the above compound.

(29) The present disclosure further provides a crystal form of the pharmaceutically acceptable salt of EGFR inhibitor.

(30) When the pharmaceutically acceptable salt is a mesylate salt, the crystal form is a crystal form A. In one specific embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2 values of 5.80.2, 6.80.2, 11.50.2, 12.00.2, 13.50.2, 14.00.2, 14.80.2, 15.60.2, 17.20.2, 17.50.2, 18.10.2, 18.60.2, 19.00.2, 21.60.2, 22.20.2, 24.00.2, 24.60.2, 27.20.2, and 27.70.2; further, the X-ray powder diffraction pattern of the crystal form A is substantially consistent with FIG. 1; more further, in a specific embodiment of the present disclosure, the differential scanning calorimetry thermogram of the crystal form A is substantially consistent with FIG. 2.

(31) When the pharmaceutically acceptable salt is a p-toluenesulfonate salt, the crystal form is a crystal form B. In one specific embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2 values of 7.80.2, 10.20.2, 10.60.2, 11.20.2, 11.70.2, 12.90.2, 14.20.2, 15.10.2, 16.10.2, 16.50.2, 18.10.2, 18.70.2, 19.70.2, 21.00.2, 21.40.2, 22.40.2, 23.20.2, 23.70.2, 24.30.2, 24.80.2, 26.90.2, 28.00.2, and 29.50.2; further, the X-ray powder diffraction pattern of the crystal form B is substantially consistent with FIG. 3; more further, the differential scanning calorimetry thermogram of the crystal form B is substantially consistent with FIG. 4.

(32) When the pharmaceutically acceptable salt is a phosphate salt, the crystal form is a crystal form C. In one specific embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2 values of 8.90.2, 11.20.2, 11.90.2, 12.60.2, 14.10.2, 16.00.2, 16.80.2, 17.80.2, 19.90.2, 20.50.2, 21.40.2, 22.10.2, 22.70.2, 23.20.2, 23.80.2, 24.50.2, 25.30.2, 26.00.2, and 28.20.2; further, the X-ray powder diffraction pattern of the crystal form C is substantially consistent with FIG. 5; more further, the differential scanning calorimetry thermogram of the crystal form C is substantially consistent with FIG. 6.

(33) When the pharmaceutically acceptable salt is a hydrochloride salt, the crystal form is a crystal form D. In one specific embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 20 values of 7.80.2, 9.80.2, 13.80.2, 14.50.2, 15.50.2, 16.00.2, 16.20.2, 16.70.2, 17.10.2, 18.20.2, 20.50.2, 21.30.2, 21.90.2, 22.50.2, 23.50.2, 24.60.2, 25.80.2, 26.30.2, and 27.60.2; further, the X-ray powder diffraction pattern of the crystal form D is substantially consistent with FIG. 8; more further, the differential scanning calorimetry thermogram of the crystal form D is substantially consistent with FIG. 9.

(34) When the pharmaceutically acceptable salt is a citrate salt, the crystal form is a crystal form E, the X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 2 values of 5.40.2, 9.00.2, 10.80.2, 12.00.2, 12.40.2, 13.30.2, 16.00.2, 17.50.2, 20.40.2, 21.20.2, 24.90.2, and 25.40.2, further, the X-ray powder diffraction pattern of the crystal form E is substantially consistent with FIG. 10; more further, the differential scanning calorimetry thermogram of the crystal form E is substantially consistent with FIG. 11.

(35) The preparation method of the crystal form of the pharmaceutically acceptable salt of EGFR inhibitor comprises:

(36) adding the EGFR inhibitor present in a free base form and an acid into an alcoholic solvent or water to form a salt, then adding (preferably dropwise) a ketonic solvent to denitrify and obtain the crystal form of the pharmaceutically acceptable salt of EGFR inhibitor. The EGFR inhibitor present in a free base form and the acid preferably form a salt equimolarly.

(37) Preferably, the alcoholic solvent has a carbon number of 1 to 6; more preferably, the alcoholic solvent is methanol or ethanol.

(38) Preferably, in the preparation method described above, the usage amount ratio of the alcoholic solvent to the EGFR inhibitor is 2 to 5 ml: 1 g, preferably 3 ml: 1 g.

(39) Preferably, in the preparation method described above, the ketonic solvent has a carbon number of 3 to 6; more preferably, the ketonic solvent is acetone.

(40) Preferably, in the preparation method described above, the usage amount ratio of the ketonic solvent to the EGFR inhibitor is 10 to 30 ml: 1 g, preferably 20 ml: 1 g.

(41) The preparation method of the EGFR inhibitor phosphate salt (amorphous) comprises forming a salt by the EGFR inhibitor present in a free base form and phosphoric acid, then adding a ketonic solvent so that the solid precipitates.

(42) The EGFR inhibitor present in a free base form and phosphoric acid preferably form a salt equimolarly. Preferably, in the preparation method described above, the ketonic solvent has a carbon number of 3 to 6; more preferably, the ketonic solvent is acetone.

(43) In a specific embodiment of the present disclosure,

(44) the technical solution of the present disclosure will be further explained below in conjunction with the drawings and specific examples. It is to be understood that the following examples are for illustration and explanation of the present disclosure only, and are not for limitation of the scope of protection of the present disclosure.

(45) The abbreviations referred to in the present disclosure have the following meanings:

(46) XRPD: X-ray powder diffraction;

(47) DSC: differential scanning calorimetry;

(48) .sup.1H-NMR: hydrogen nuclear magnetic resonance spectrum;

(49) LC-MS: liquid chromatography-mass spectrometry.

(50) The EGFR inhibitor used in the following examples is self-made, has a purity of 99.7% and an appearance of a light yellow granular solid. For the preparation method of the EGFR inhibitor, refer to Chinese patent application CN106132957A. The structure confirmation data is as follows:

(51) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.30 (1H, s), 9.67 (1H, s), 9.32 (1H, s), 8.56 to 8.54 (1H, dd), 8.47 to 8.46 (1H, d), 8.25 to 8.24 (1H, d), 8.05 to 8.03 (1H, d), 7.73 (1H, s), 7.32 to 7.29 (1H, dd), 7.08 (1H, s), 6.53 to 6.38 (2H, m), 5.87 to 5.84 (1H, dd), 4.02 (3H, s), 3.93 (3H, s), 2.92 to 2.89 (2H, t), 2.72 (3H, s), 2.30 (2H, s), 2.24 (6H, s) (as shown in FIG. 18);

(52) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+ (as shown in FIG. 19).

Example 1: EGFR Inhibitor Mesylate Salt (Crystal Form A)

(53) At room temperature, the EGFR inhibitor present in a free base form (12.0 g, 24 mmol) was weighed, placed in a 500 mL flask, and 36 mL ethanol was added. Methanesulfonic acid (2.32 g, 24 mmol) was added, and was stirred at 40 to 50 C. to dissolve. Then 240 mL acetone was added dropwise, stirred at 0 to 5 C., and a grey solid precipitated. The mixture was filtered with suction, and the filter cake was rinsed with a small amount of acetone, dried using a vacuum drying oven at 60 C. to obtain a light brown solid (10.1 g, purity: 99.0%, moisture: 0.97%, melting point: 150.5 to 152.8 C.).

(54) The structure confirmation data of the above product was as follows:

(55) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.47 (1H, s), 9.39 (1H, s), 9.30 (1H, s), 9.15 (1H, s), 8.62 (1H, s), 8.56 to 8.55 (1H, d), 8.48 to 8.47 (1H, d), 8.25 to 8.24 (1H, d), 8.06 to 8.04 (1H, d), 7.76 (1H, s), 7.33 to 7.30 (1H, m), 7.06 (1H, s), 6.83 to 6.79 (1H, dd), 6.46 to 6.41 (1H, d), 5.89 to 5.86 (1H, d), 4.00 (3H, s), 3.95 (3H, s), 3.27 (4H, m), 2.84 (6H, s), 2.64 (3H, s), 2.29 (3H, s) (as shown in FIG. 20);

(56) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+.

(57) As tested, the solid obtained in the present example was an EGFR inhibitor mesylate salt, and the crystal form thereof was named as crystal form A. The XRPD data of the crystal form was as shown in Table 1, the XRPD pattern was as shown in FIG. 1, and the DSC plot was as shown in FIG. 2.

(58) TABLE-US-00001 TABLE 1 XRPD data of the EGFR inhibitor mesylate salt (crystal form A) Serial no. 2 d-spacing Intensity (%) 1 5.76 15.35 21.32 2 6.77 13.06 41.28 3 9.08 9.74 3.12 4 11.48 7.71 21.17 5 11.99 7.38 20.19 6 13.48 6.57 32.28 7 14.02 6.32 100.00 8 14.79 5.99 10.65 9 15.57 5.69 31.58 10 16.35 5.42 2.04 11 17.20 5.15 13.31 12 17.54 5.06 16.54 13 18.13 4.89 26.78 14 18.58 4.78 17.72 15 19.03 4.66 11.76 16 20.17 4.40 6.89 17 21.63 4.11 75.68 18 22.19 4.01 19.69 19 22.94 3.88 3.76 20 24.02 3.71 27.52 21 24.59 3.62 20.40 22 25.32 3.52 8.30 23 25.79 3.45 5.31 24 26.19 3.40 4.74 25 27.16 3.28 14.90 26 27.70 3.22 12.32 27 28.74 3.11 3.84 28 29.39 3.04 4.29 29 30.45 2.94 6.77 30 30.92 2.89 5.34 31 32.12 2.79 1.63 32 32.72 2.74 1.54 33 33.80 2.65 1.45 34 34.26 2.62 2.36 35 35.29 2.54 2.03 36 36.26 2.48 0.70 37 37.73 2.38 0.65 38 38.56 2.34 0.85 39 39.69 2.27 0.15 40 40.54 2.23 0.72 41 41.24 2.19 0.79 42 42.11 2.15 1.54 43 43.27 2.09 0.89 44 44.19 2.05 0.57

Example 2: EGFR Inhibitor p-Toluenesulfonate Salt (Crystal Form B)

(59) At room temperature, the EGFR inhibitor present in a free base form (9.0 g, 18 mmol) was weighed, placed in a 500 mL flask, and 27 mL ethanol was added. P-toluenesulfonic acid monohydrate (4.56 g, 18 mmol) was added, and was stirred at 40 to 50 C. to dissolve. Then 240 mL acetone was added dropwise, and a grey solid precipitated. The mixture was filtered with suction, and the filter cake was rinsed with a small amount of acetone, oven-dried to obtain a light tan solid (10.1 g, purity: 98.7%, moisture: 0.57%, melting point: 240.1 to 243.2 C.).

(60) The structure confirmation data of the above product was as follows:

(61) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 9.47 (1H, s), 9.37 (1H, s), 9.24 (1H, s), 9.14 (1H, s), 8.56 to 8.55 (1H, d), 8.48 to 8.47 (1H, d), 8.24 to 8.23 (1H, d), 8.07 to 8.05 (1H, d), 7.77 (1H, s), 7.50 to 7.49 (2H, d), 7.30 to 7.29 (1H, m), 7.06 (1H, s), 6.80 to 6.76 (1H, dd), 6.45 to 6.41 (1H, d), 5.88 to 5.86 (1H, d), 4.00 (3H, s), 3.95 (3H, s), 3.27 (4H, m), 2.84 (3H, s), 2.64 (3H, s), 2.29 (3H, s) (as shown in FIG. 21);

(62) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+.

(63) As tested, the solid obtained in the present example was an EGFR inhibitor p-toluenesulfonate salt, and the crystal form thereof was named as crystal form B. The XRPD data of the crystal form was as shown in Table 2, the XRPD pattern was as shown in FIG. 3, and the DSC plot was as shown in FIG. 4.

(64) TABLE-US-00002 TABLE 2 XRPD data of the EGFR inhibitor p-toluenesulfonate salt (crystal form B) Serial no. 2 d-spacing Intensity (%) 1 5.79 15.26 1.23 2 7.80 11.34 24.21 3 10.20 8.68 29.56 4 10.59 8.35 43.44 5 11.16 7.93 19.76 6 11.66 7.59 17.11 7 12.86 6.88 22.47 8 14.19 6.24 14.12 9 15.05 5.89 59.89 10 16.13 5.50 15.58 11 16.53 5.36 15.01 12 18.07 4.91 76.97 13 18.72 4.74 28.20 14 19.74 4.50 13.66 15 20.22 4.39 9.47 16 20.98 4.23 21.78 17 21.38 4.16 24.22 18 22.39 3.97 100.00 19 23.20 3.83 16.51 20 23.73 3.75 21.26 21 24.30 3.66 12.83 22 24.76 3.60 49.28 23 25.64 3.47 5.03 24 26.33 3.39 9.07 25 26.87 3.32 19.40 26 28.03 3.18 11.96 27 28.76 3.10 9.22 28 29.51 3.03 10.65 29 30.11 2.97 1.72 30 30.58 2.92 7.22 31 31.21 2.87 3.99 32 31.64 2.83 3.60 33 32.14 2.78 3.96 34 32.39 2.76 4.83 35 34.12 2.63 3.44 36 35.48 2.53 2.19 37 35.87 2.50 1.47 38 36.39 2.47 3.38 39 37.27 2.41 2.06 40 38.38 2.35 0.67 41 38.77 2.32 1.04 42 39.68 2.27 2.75 43 40.59 2.22 1.15 44 41.17 2.19 2.07 45 42.07 2.15 2.01 46 43.01 2.10 1.40

Example 3: EGFR Inhibitor Phosphate Salt (Crystal Form C)

(65) At room temperature, the EGFR inhibitor present in a free base form (3.0 g, 6 mmol) was weighed, placed in a 250 mL flask, and 9 mL ethanol was added. An 85 wt % aqueous phosphoric acid solution (0.69 g, 6 mmol in terms of phosphoric acid) was added, and was stirred for 2 hours to dissolve. Then 60 mL acetone was added dropwise, and a grey solid precipitated. The mixture was filtered with suction, and the filter cake was rinsed with a small amount of acetone, oven-dried to obtain a tan solid (3.5 g, purity: 97.9%, moisture: 1.07%, melting point: 182.5 to 184.8 C.).

(66) The structure confirmation data of the above product was as follows:

(67) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.11 (1H, s), 9.60 (1H, s), 9.27 (1H, s), 8.56 to 8.54 (1H, d), 8.47 to 8.46 (1H, d), 8.24 to 8.23 (1H, d), 8.05 to 8.03 (1H, d), 7.73 (1H, s), 7.32 to 7.29 (1H, in), 7.06 (1H, s), 6.69 to 6.64 (1H, dd), 6.42 to 6.38 (1H, d), 5.85 to 5.82 (1H, dd), 4.02 (3H, s), 3.94 (3H, s), 3.04 to 3.01 (2H, m), 2.69 (3H, s), 2.64 (2H, s), 2.42 (6H, s) (as shown in FIG. 22);

(68) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+.

(69) As tested, the solid obtained in the present example was an EGFR inhibitor phosphate salt, and the crystal form thereof was named as crystal form C. The XRPD data of the crystal form was as shown in Table 3, the XRPD pattern was as shown in FIG. 5, and the DSC plot was as shown in FIG. 6.

(70) TABLE-US-00003 TABLE 3 XRPD data of the EGFR inhibitor phosphate salt (crystal form C) Serial no. 2 d-spacing Intensity (%) 1 5.56 15.90 1.87 2 8.88 9.96 46.45 3 10.64 8.31 6.40 4 11.16 7.93 14.38 5 11.88 7.45 11.42 6 12.60 7.02 18.73 7 14.13 6.27 98.91 8 14.75 6.01 9.15 9 14.94 5.93 8.01 10 15.96 5.55 86.78 11 16.78 5.28 25.83 12 17.78 4.99 28.73 13 19.88 4.47 41.71 14 20.52 4.33 16.18 15 21.41 4.15 15.77 16 22.06 4.03 21.45 17 22.66 3.92 45.13 18 23.17 3.84 24.48 19 23.77 3.74 22.80 20 24.53 3.63 15.12 21 25.30 3.52 100.00 22 25.96 3.43 16.62 23 27.50 3.24 8.75 24 28.21 3.16 26.42 25 28.71 3.11 6.55 26 30.02 2.98 6.52 27 31.28 2.86 5.93 28 32.55 2.75 4.17 29 33.00 2.71 3.15 30 34.27 2.62 1.76 31 36.01 2.49 2.08 32 38.07 2.36 2.15 33 38.46 2.34 2.86 34 39.30 2.29 1.38 35 39.88 2.26 2.36 36 41.29 2.19 1.79 37 42.37 2.13 1.49 38 43.55 2.08 2.49

Example 4: EGFR Inhibitor Phosphate Salt (Amorphous)

(71) At room temperature, the EGFR inhibitor present in a free base form (9.0 g, 18 mmol) was weighed, and placed in a 500 mL flask. An 85 wt % aqueous phosphoric acid solution (2.08 g, 18 mmol in terms of phosphoric acid) was added, and was stirred at 40 to 50 C. to dissolve. Then 180 mL acetone was added dropwise, and a grey solid precipitated. The mixture was filtered with suction, and the filter cake was rinsed with a small amount of acetone, oven-dried to obtain a light grey solid (11.0 g, purity: 98.5%).

(72) The structure confirmation data of the above product was as follows:

(73) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+.

(74) As tested, the solid obtained in the present example was amorphous powder of an EGFR inhibitor phosphate salt, and the XRPD pattern thereof was as shown in FIG. 7.

Example 5: EGFR Inhibitor Hydrochloride Salt (Crystal Form D)

(75) At room temperature, the EGFR inhibitor present in a free base form (15.0 g, 30 mmol) was weighed, and placed in a 500 mL flask. An ethanol (45 mL) solution of concentrated hydrochloric acid (2.5 mL, 30 mmol in terms of hydrogen chloride) was added, and was stirred at 40 to 50 C. to dissolve. Then 360 mL acetone was added dropwise, and a grey solid precipitated. The mixture was filtered with suction, and the filter cake was rinsed with a small amount of acetone, oven-dried to obtain a tan solid (15 g, purity: 99.2%, moisture: 0.77%, melting point: 250.5 C. to 152.8 C.).

(76) The structure confirmation data of the above product was as follows:

(77) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 10.55 (1H, s), 9.76 (1H, s), 9.46 (1H, s), 9.17 (1H, s), 8.56 to 8.55 (1H, d), 8.47 to 8.46 (1H, d), 8.23 (1H, s), 8.06 (1H, s), 7.77 (1H, s), 7.35 to 7.28 (2H, d), 7.01 (1H, s), 6.62 to 6.38 (1H, dd), 5.82 to 5.79 (1H, d), 4.00 (3H, s), 3.95 (3H, s), 3.28 (4H, s), 2.76 to 2.75 (6H, s), 2.61 (3H, s) (as shown in FIG. 23);

(78) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+.

(79) As tested, the solid obtained in the present example was an EGFR inhibitor hydrochloride salt, and the crystal form thereof was named as crystal form D. The XRPD data of the crystal form was as shown in Table 4, the XRPD pattern was as shown in FIG. 8, and the DSC plot was as shown in FIG. 9.

(80) TABLE-US-00004 TABLE 4 XRPD data of the EGFR inhibitor hydrochloride salt (crystal form D) Serial no. 2 d-spacing Intensity (%) 1 5.28 16.74 2.54 2 7.82 11.31 50.15 3 8.82 10.04 7.91 4 9.77 9.06 48.34 5 10.60 8.34 8.18 6 12.18 7.27 3.59 7 12.79 6.92 4.27 8 13.77 6.43 16.69 9 14.52 6.10 11.75 10 15.51 5.71 14.41 11 15.99 5.54 30.49 12 16.21 5.47 44.59 13 16.73 5.30 17.41 14 17.13 5.18 21.36 15 18.18 4.88 27.33 16 18.81 4.72 6.89 17 19.62 4.53 4.40 18 20.51 4.33 11.17 19 21.34 4.16 100.00 20 21.90 4.06 25.67 21 22.52 3.95 22.26 22 23.50 3.79 11.64 23 24.56 3.62 34.56 24 25.85 3.45 23.64 25 26.34 3.38 56.68 26 27.57 3.26 51.23 27 29.23 3.06 5.97 28 29.79 3.00 7.48 29 30.27 2.95 5.95 30 31.58 2.83 5.36 31 32.61 2.75 4.80 32 33.25 2.69 2.64 33 35.45 2.53 1.26 34 36.17 2.48 2.18 35 37.65 2.39 1.90 36 38.46 2.34 3.29 37 40.80 2.21 0.91 38 42.95 2.11 2.38 39 43.73 2.07 2.18 40 44.59 2.03 1.45

Example 6: EGFR Inhibitor Citrate Salt (Crystal Form E)

(81) At room temperature, the EGFR inhibitor present in a free base form (10.0 g, 20 mmol) was weighed, placed in a 500 mL flask, and 30 mL ethanol was added. Citric acid monohydrate (4.2 g, 20 mmol) was added, and was stirred at 40 to 50 C. to dissolve. Then 200 mL acetone was added dropwise, and a grey solid precipitated. The mixture was filtered with suction, and the filter cake was rinsed with a small amount of acetone, oven-dried to obtain a light grey solid (11.3 g, purity: 98.9%, moisture: 0.97%, melting point: 193.1 to 195.6 C.).

(82) The structure confirmation data of the above product was as follows:

(83) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 11.5 to 10.5 (4H, s), 9.68 (1H, s), 9.54 (1H, s), 9.20 (1H, s), 8.56 to 8.55 (1H, d), 8.48 to 8.47 (1H, d), 8.24 to 8.23 (1H, d), 7.75 (1H, s), 7.32 to 7.30 (1H, d), 7.07 (1H, s), 6.69 to 6.67 (1H, dd), 6.44 to 6.40 (1H, d), 5.89 to 5.86 (1H, d), 4.01 (3H, s), 3.95 (3H, s), 3.13 (3H, m), 2.95 (2H, s), 2.64 to 2.59 (10H, s), 2.57 (2H, s) (as shown in FIG. 24);

(84) ESI-MS: m/z 501.2 [M+H].sup.+, 251.2 [M+2H].sup.2+.

(85) As tested, the solid obtained in the present example was an EGFR inhibitor citrate salt, and the crystal form thereof was named as crystal form E. The XRPD data of the crystal form was as shown in Table 5, the XRPD pattern was as shown in FIG. 10, and the DSC plot was as shown in FIG. 11.

(86) TABLE-US-00005 TABLE 5 XRPD data of the EGFR inhibitor citrate salt (crystal form E) Serial no. 2 d-spacing Intensity (%) 1 5.40 16.37 100.00 2 7.69 11.50 2.04 3 9.00 9.82 16.27 4 10.80 8.19 21.34 5 11.99 7.38 61.71 6 12.39 7.14 16.17 7 13.35 6.63 15.06 8 14.71 6.02 0.71 9 15.95 5.56 14.40 10 16.58 5.35 9.23 11 17.47 5.08 24.39 12 18.19 4.88 6.90 13 19.28 4.60 6.08 14 20.37 4.36 10.15 15 21.21 4.19 29.45 16 23.44 3.80 4.91 17 24.88 3.58 28.55 18 25.36 3.51 21.74 19 26.75 3.33 4.98 20 27.77 3.21 3.24 21 28.92 3.09 6.73 22 31.27 2.86 3.23 23 33.88 2.65 2.55 24 35.98 2.50 0.30 25 39.51 2.28 0.63 26 41.62 2.17 1.39 27 43.59 2.08 0.69

Example 7: Hygroscopicity Study of Crystal Forms

(87) Hygroscopicity comparison study was carried out for various pharmaceutically acceptable salts of EGFR inhibitor present in the form of crystal in Examples 1 to 3 and 5 to 6, the amorphous EGFR inhibitor phosphate salt in Example 4, and the EGFR inhibitor present in a free base form. Tests were conducted according to the method in the Pharmacopoeia of the People's Republic of China, 2015 edition, part 4, appendix 9103 (temperature: 25 C.1 C., relative humidity: 80%2%), and the results were as shown in Table 6.

(88) TABLE-US-00006 TABLE 6 Hygroscopicity study of various pharmaceutically acceptable salts of EGFR inhibitor Weight gain Weight gain over 6 over 24 Type hours (%) hours (%) Hygroscopicity free base 1.7 2.2 hygroscopic mesylate salt 6.86 10.64 hygroscopic p-toluenesulfonate 0.04 0.04 almost salt non-hygroscopic phosphate salt 9.15 11.98 hygroscopic (crystal form C) phosphate salt 1.2 1.5 slightly hygroscopic (amorphous) hydrochloride salt 0.72 1.29 slightly hygroscopic citrate salt 2.23 2.48 hygroscopic
As demonstrated by the results, under the condition of 25 C./RH 80%, among the six crystal forms of the pharmaceutically acceptable salts of EGFR inhibitor of the present disclosure, the p-toluenesulfonate salt crystal form B, hydrochloride salt crystal form D and amorphous phosphate salt all had a lower hygroscopicity, and the citrate salt crystal form E had a comparable hygroscopicity, while the mesylate salt crystal form A and phosphate salt crystal form C had a higher hygroscopicity, as compared with that of the EGFR inhibitor present in a free base form.

(89) With regard to the description of hygroscopic properties and definition of hygroscopic weight gain, refer to the Pharmacopoeia of the People's Republic of China, 2015 edition, part 4, appendix 9103, experimental guideline of drug hygroscopicity, herein descried by way of example as follows.

(90) Deliquescence: absorb enough water to form a liquid.

(91) Very hygroscopic: hygroscopic weight gain less than 15%.

(92) Hygroscopic: hygroscopic weight gain less than 15% but not less than 2%.

(93) Slightly hygroscopic: hygroscopic weight gain less than 2% but not less than 0.2%.

(94) Non- or almost non-hygroscopic: hygroscopic weight gain less than 0.2%.

Example 8: Solubility Study of Crystal Forms

(95) Various pharmaceutically acceptable salts of EGFR inhibitor present in form of crystal in Examples 1 to 3 and 5 to 6 were classified with reference to the relevant requirements of the Pharmacopoeia of the People's Republic of China and the Bio-pharmaceutics Classification System (BCS).

(96) (a) Relevant Requirements of Solubility in the Pharmacopoeia of the People's Republic of China, 2015 Edition, General Notices:

(97) TABLE-US-00007 TABLE 7 Relevant requirements of solubility in general notices of the Pharmacopoeia of the People's Republic of China The amount of solvent Solubility required to dissolve range Definition 1 g solute (ml) (mg/ml) Very soluble (vs) <1 1000 Freely soluble (fs) 1 to less than 10 100 to 1000 Soluble (s) 10 to less than 30 33 to 100 Sparingly soluble (sps) 30 to less than 100 10 to 33 Slightly soluble (ss) 100 to less than 1000 1 to 10 Very slightly soluble (vss) 1000 to less than 10000 0.1 to 1 Practically insoluble or 10000 <0.1 insoluble (pi)

(98) (b) Relevant Requirements of Solubility in BCS:
Do=(Mo/Vo)/Cs;

(99) wherein Do: dose index; Mo: highest single dose of the drug (with reference to the relevant dose of osimertinib, tentatively set to 80 mg); Vo: the volume of body fluid required for dissolving the drug (about 250 ml); Cs: saturated solubility of the drug;

(100) if Do1, solubility is high; and if Do>1, solubility is low.

(101) (c) Experimental Process and Results:

(102) Using an EGFR inhibitor free base as a control, linear regression was carried out by plotting peak area versus concentration, and the corresponding linear equation was obtained in the range of 0.025 to 1.5 mg/ml: A=19775.0411c+2.4256, r=1.0000.

(103) Water was used as solvent. An appropriate amount of the EGFR inhibitor mesylate salt, p-toluenesulfonate salt, phosphate salt, hydrochloride salt and citrate salt prepared in Examples 1 to 3 and 5 to 6 was weighed, and prepared into saturated solutions. Samples were taken after standing for 1 hour, 4 hours, and 24 hours, respectively, and the concentration of each sample in saturation state was calculated according to the linear equation. The results were as shown in Table 8.

(104) TABLE-US-00008 TABLE 8 Solubility classification results of various pharmaceutically acceptable salts of EGFR inhibitor in water Pharmacopoeia of the People's 1 h 4 h 24 h Republic of China BCS level Type (mg/ml) (mg/ml) (mg/ml) Solubility level (Do) mesylate salt 223.02 224.00 255.75 freely soluble 0.0013 < 1 p-toluenesulfonate 1.82 1.78 1.56 slightly soluble 0.2057 < 1 salt phosphate salt 107.15 133.32 137.13 freely soluble 0.0023 < 1 (crystal form C) phosphate salt 88.32 92.14 94.56 freely soluble 0.0034 < 1 (amorphous) hydrochloride salt 13.43 11.09 10.59 sparingly soluble 0.0302 < 1 citrate salt 143.59 137.34 133.57 freely soluble 0.0024 < 1 free base <0.025 <0.025 <0.025 practically 606.30 > 1 insoluble or insoluble

(105) Artificial gastric fluid was used as solvent. An appropriate amount of the EGFR inhibitor mesylate salt (crystal form A), p-toluenesulfonate salt (crystal form B), phosphate salt (crystal form C), phosphate salt (amorphous), hydrochloride salt (crystal form C), and citrate salt (crystal form E) prepared in Examples 1 to 6 was weighed, and prepared into saturated solutions. Samples were taken after standing for 1 hour, 4 hours, and 24 hours, respectively, and the concentration of each sample in saturation state was calculated according to the linear equation. The results were as shown in Table 9.

(106) TABLE-US-00009 TABLE 9 Solubility classification results of various pharmaceutically acceptable salts of EGFR inhibitor in artificial gastric fluid Pharmacopoeia of the People's 1 h 4 h 24 h Republic of China BCS level Type (mg/ml) (mg/ml) (mg/ml) Solubility level (Do) mesylate salt 248.77 370.37 379.12 freely soluble 0.0008 < 1 p-toluenesulfonate 46.21 46.75 47.03 soluble 0.0068 < 1 salt phosphate salt 156.70 159.14 147.08 freely soluble 0.0022 < 1 (crystal form C) phosphate salt 123.56 136.76 138.91 freely soluble 0.0023 < 1 (amorphous) hydrochloride salt 83.79 79.18 70.03 soluble 0.0046 < 1 citrate salt 168.51 196.47 176.88 freely soluble 0.0018 < 1 free base 0.84 0.86 0.71 very slightly 0.4515 < 1 soluble

(107) (d) Result:

(108) The six pharmaceutically acceptable salts, i.e., the EGFR inhibitor mesylate salt, p-toluenesulfonate salt, phosphate salt (crystal form C), phosphate salt (amorphous), hydrochloride salt and citrate salt prepared in the present disclosure and the EGFR inhibitor free base had higher solubility in artificial gastric fluid than in water, and no significant degradation occurred. In addition, whether in water or in artificial gastric fluid, the solubility of the pharmaceutically acceptable salts prepared in the present disclosure was much higher than that of the free base, and salt formation might improve the low solubility of free base. According to the BCS solubility standard, five pharmaceutically acceptable salts had a Do value less than 1 in water and artificial gastric fluid. The solubility of the EGFR inhibitor mesylate salt, phosphate salt (crystal form C), phosphate salt (amorphous) and citrate salt in water and artificial gastric fluid was high, with reference to solubility classification in the Pharmacopoeia of the People's Republic of China, 2015 edition, general notices.

Example 11: Stability Study of Crystal Forms

(109) The six pharmaceutically acceptable salts of EGFR inhibitor in Examples 1 to 6 were placed in a condition of 40 C./75% RH, and a one month accelerated stability study was carried out. Samples were taken at the end of 0 and 1 month respectively, and emphasis was placed upon the shape, purity and crystal form stability (XRPD pattern) of the samples. The results were as shown in Table 10. The stability result of the mesylate salt crystal form A was as shown in FIG. 12, the stability result of the p-toluenesulfonate salt crystal form B was as shown in FIG. 13, the stability result of the phosphate salt crystal form C was as shown in FIG. 14, the stability result of the phosphate amorphous powder was as shown in FIG. 15, the stability result of the hydrochloride salt crystal form D was as shown in FIG. 16, and the stability result of the citrate salt crystal form E was as shown in FIG. 17.

(110) TABLE-US-00010 TABLE 10 Results of stability of the various pharmaceutically acceptable salts of EGFR inhibitor Purity XRPD Sample name and batch no. Appearance (%) pattern mesylate salt 0 month light brown solid 99.0 consistent (crystal form A) 1 month light brown solid 99.2 p-toluenesulfonate 0 month light tan solid 98.7 consistent salt (crystal form B) 1 month light tan solid 98.7 phosphate salt 0 month tan solid 98.5 consistent (crystal form C) 1 month tan solid 98.5 phosphate salt 0 month light grey solid 98.9 consistent (amorphous) 1 month light grey solid 98.7 hydrochloride salt 0 month tan solid 99.2 consistent (crystal form D) 1 month tan solid 99.3 citrate salt 0 month light grey solid 98.9 consistent (crystal form E) 1 month light grey solid 99.1

(111) According to the experiment results, after standing for 1 month under the experiment condition, the six pharmaceutically acceptable salts of EGFR inhibitor of the present disclosure were all stable, without any change, demonstrating good stability. Stable refers to no occurrence of degradation and no detection of transformation to other crystal forms by analytical means such as chromatography and XRPD.

(112) Based on the above hygroscopicity, solubility and stability study results, the pharmaceutically acceptable salts of EGFR inhibitor of the present disclosure and specific crystal forms thereof have excellent physicochemical properties, more suitable for development into drugs, and satisfy requirements for bioavailability and drug efficacy.

(113) The above examples are merely preferred examples of the present disclosure and are not intended to limit the present disclosure. Although the present disclosure has been described in detail with reference to the foregoing examples, those skilled in the art can still modify the technical solutions described in the foregoing examples, or substitute some of the technical features with equivalents thereof. Any modification, equivalent substitution, improvement, etc. made within the spirit and scope of the present disclosure is intended to be included within the scope of protection of the present disclosure.