Crystal form of ACP-196 salt and preparation method, pharmaceutical composition, and use thereof

Abstract

The present invention relates to novel crystalline forms of ACP-196 (acalabrutinib) salts, compared with the known solid form of ACP-196, the crystalline forms of ACP-196 salts of the present invention have advantages in crystallinity, solubility and hygroscopicity. The present invention also relates to the preparation methods for the preparation of the crystalline forms of ACP-196 salts, pharmaceutical compositions thereof and their uses in the preparation of methods for treating and/or preventing diseases mediated by Bruton tyrosine kinase (BTK), such as autoimmune diseases or disorders, xenoimmune diseases or disorders, cancer, including lymphoma and inflammatory diseases or disorders.

Claims

1. ACP-196 malate Form 1 having the structure shown in the formula (I) below, ##STR00007## wherein, measured using Cu-K radiation, the X-ray powder diffraction pattern of the ACP-196 malate Form 1, expressed as 2 angles, has the following characteristic peaks: 6.20.2, 8.90.2, 12.00.2, 12.40.2, 16.90.2 and 22.90.2.

2. The ACP-196 malate Form 1 according to claim 1, wherein the X-ray powder diffraction pattern of the ACP-196 malate Form 1, expressed as 2 angles, has the following characteristic peaks: 6.20.2, 8.90.2, 12.00.2, 12.40.2, 15.60.2, 16.90.2, 19.60.2 20.30.2, 20.70.2, 22.90.2, 23.80.2 and 27.60.2.

3. The ACP-196 malate Form 1 according to claim 2, wherein the X-ray powder diffraction pattern of the ACP-196 malate Form 1, expressed as 2 angles, has the following characteristic peaks and relative intensity: TABLE-US-00019 Diffraction angel 2 Relative intensity % 6.2 0.2 81.9 8.9 0.2 21.3 12.0 0.2 70.1 12.4 0.2 100.0 12.9 0.2 8.7 15.6 0.2 12.5 16.9 0.2 22.5 17.9 0.2 10.9 18.7 0.2 7.7 19.6 0.2 21.5 20.3 0.2 16.3 20.7 0.2 16.9 21.2 0.2 10.7 22.9 0.2 32.7 23.8 0.2 28.8 24.9 0.2 12.1 26.3 0.2 9.7 27.6 0.2 17.6.

4. A method of preparing the ACP-196 malate Form 1 according to claim 1, comprising any one of the following methods: 1) dissolving ACP-196 and malic acid respectively in a solvent to form solutions, then mixing and stirring for crystallization and precipitation, and then separating and drying to obtain the ACP-196 malate Form 1; wherein: the solvent is an alcohol or a ketone; the weight to volume ratio of ACP-196 to the solvent when the solution is formed is from 30 mg/mL to 100 mg/mL; the molar ratio of ACP-196 to malic acid is from 1:0.8 to 1:1.1; the stirring time is 1 day to 2 days; and the operation is carried out at room temperature; or 2) forming a solution of a mixture of ACP-196 and malic acid in a co-solvent, adding anti-solvent, stirring for crystallization and precipitation, and then separating and drying to obtain the ACP-196 malate Form 1; wherein: the co-solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, and chloroform; the weight to volume ratio of ACP-196 to the co-solvent is from 20 mg/mL to 100 mg/mL; the molar ratio of ACP-196 to malic acid is from 1:0.8 to 1:1.1; the anti-solvent is selected from the group consisting of an ether, an alkane, and toluene; the stirring time is from 1 day to 3 days; and the operation is carried out at room temperature.

5. The method according to claim 4, wherein the solvent is isopropanol and wherein the weight to volume ratio of ACP-196 to the solvent is from 30 mg/mL to 50 mg/mL.

6. The method according to claim 4, wherein the co-solvent is tetrahydrofuran and wherein the weight to volume ratio of ACP-196 to the co-solvent is from 20 mg/mL to 50 mg/mL.

7. The method according to claim 4, wherein the anti-solvent is isopropyl ether.

8. The method according to claim 4, wherein ACP-196 and malic acid use the same solvent to form a solution.

9. A pharmaceutical composition comprising a therapeutically effective amount of the ACP-196 malate Form 1 according to claim 1, and at least one pharmaceutically acceptable carrier or additive.

10. A method of preparing the ACP-196 sulfate Form 1 having the structure shown in the formula (V) below, ##STR00008## wherein, measured using Cu-K radiation, the X-ray powder diffraction pattern of the ACP-196 sulfate Form 1, expressed as 2 angles, has the following characteristic peaks: 8.90.2, 9.70.2, 17.50.2, 19.60.2, 21.90.2, and 23.60.2, the method comprising any one of the following methods: 1) dissolving ACP-196 and sulfuric acid respectively in a solvent to form solutions, then mixing and stirring for crystallization and precipitation, and then separating and drying to obtain the ACP-196 sulfate Form 1; wherein: the solvent is an alcohol or a ketone; the weight to volume ratio of ACP-196 to the solvent when the solution is formed is from 30 mg/mL to 100 mg/mL; the molar ratio of ACP-196 to sulfuric acid is from 1:0.8 to 1:1.1; the stirring time is 1 day to 2 days; and the operation is carried out at room temperature; or 2) forming a solution of ACP-196 in a co-solvent, dropwisely adding sulfuric acid and anti-solvent, stirring for crystallization and precipitation, and then separating and drying to obtain the ACP-196 sulfate Form 1; wherein: the co-solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, and chloroform; the weight to volume ratio of ACP-196 to the co-solvent is from 10 mg/mL to 500 mg/mL; the molar ratio of ACP-196 to sulfuric acid is from 1:0.8 to 1:1.1; the anti-solvent is selected from the group consisting of an ether, an alkane, and toluene; the stirring time is from 1 day to 3 days; and the operation is carried out at room temperature, wherein the solvent is isopropanol and wherein the weight to volume ratio of ACP-196 to the solvent is from 30 mg/mL to 50 mg/mL.

11. The method according to claim 10, wherein the co-solvent is ethyl acetate and wherein the weight to volume ratio of ACP-196 to the co-solvent is from 25 mg/mL to 50 mg/mL.

12. The method according to claim 10, wherein the anti-solvent is n-hexane.

13. The method according to claim 10, wherein the X-ray powder diffraction pattern of the ACP-196 sulfate Form 1, expressed as 2 angles, has the following characteristic peaks: 4.60.2, 7.90.2, 8.90.2, 9.70.2, 14.60.2, 15.00.2, 17.50.2, 19.60.2, 20.00.2, 21.90.2, 23.60.2 and 25.90.2.

14. The method according to claim 13, wherein the X-ray powder diffraction pattern of the ACP-196 sulfate Form 1, expressed as 2 angles, has the following characteristic peaks and relative intensity: TABLE-US-00020 Diffraction angel 2 Relative intensity % 4.6 0.2 21.6 7.9 0.2 14.2 8.9 0.2 41.9 9.7 0.2 70.4 14.6 0.2 21.2 15.0 0.2 20.7 17.5 0.2 100.0 17.8 0.2 47.5 19.6 0.2 50.7 20.0 0.2 31.4 21.9 0.2 59.7 23.6 0.2 53.3 24.3 0.2 31.8 24.8 0.2 18.5 25.6 0.2 27.9 25.9 0.2 33.4 27.1 0.2 16.0 27.5 0.2 13.2 28.0 0.2 8.2 29.2 0.2 26.7 30.2 0.2 11.1 31.6 0.2 13.3.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 is the XPRD pattern of amorphous ACP-196 prepared according to CN103889987A.

(2) FIG. 2 is the TGA thermogram of amorphous ACP-196 prepared according to CN103889987A.

(3) FIG. 3 is the PLM plot of amorphous ACP-196 prepared according to CN103889987A.

(4) FIG. 4 is the isothermal sorption plot of amorphous ACP-196 prepared according to CN103889987A.

(5) FIG. 5 is the XRPD pattern of ACP-196 malate Form 1 prepared by the present invention.

(6) FIG. 6 is the TGA thermogram of ACP-196 malate Form 1 prepared by the present invention.

(7) FIG. 7 is the DSC thermogram of ACP-196 malate Form 1 prepared by the present invention.

(8) FIG. 8 is the PLM plot of ACP-196 malate Form 1 prepared by the present invention.

(9) FIG. 9 is the isothermal sorption plot of ACP-196 malate Form 1 prepared by the present invention.

(10) FIG. 10 is the XRPD pattern of ACP-196 hemifumarate Form 1 prepared by the present invention.

(11) FIG. 11 is the TGA thermogram of ACP-196 hemifumarate Form 1 prepared by the present invention.

(12) FIG. 12 is the DSC thermogram of ACP-196 hemifumarate Form 1 prepared by the present invention.

(13) FIG. 13 is the PLM plot of ACP-196 hemifumarate Form 1 prepared by the present invention.

(14) FIG. 14 is the isothermal sorption plot of ACP-196 hemifumarate Form 1 prepared by the present invention.

(15) FIG. 15 is the XRPD pattern of ACP-196 maleate Form 1 prepared by the present invention.

(16) FIG. 16 is the TGA thermogram of ACP-196 maleate Form 1 prepared by the present invention.

(17) FIG. 17 is the DSC thermogram of ACP-196 maleate Form 1 prepared by the present invention.

(18) FIG. 18 is the PLM plot of ACP-196 maleate Form 1 prepared by the present invention.

(19) FIG. 19 is the isothermal sorption plot of ACP-196 maleate Form 1 prepared by the present invention.

(20) FIG. 20 is the XRPD pattern of ACP-196 phosphate Form 1 prepared by the present invention.

(21) FIG. 21 is the TGA thermogram of ACP-196 phosphate Form 1 prepared by the present invention.

(22) FIG. 22 is the DSC thermogram of ACP-196 phosphate Form 1 prepared by the present invention.

(23) FIG. 23 is the PLM plot of ACP-196 phosphate Form 1 prepared by the present invention.

(24) FIG. 24 is the isothermal sorption plot of ACP-196 phosphate Form 1 prepared by the present invention.

(25) FIG. 25 is the isothermal sorption plot of ACP-196 sulfate Form 1 prepared by the present invention.

SPECIFIC IMPLEMENTATIONS

(26) The following examples will help to further understand the present invention, but are not intended to limit the contents of the present invention.

(27) Instruments and Characterization Methods:

(28) X-ray powder diffraction (XRPD): performed on Bruker D8 Advance diffractometer. Samples were tested at room temperature. Testing conditions: 20 scan range 3-40, step size 0.02, and speed 0.2 s/step.

(29) Polarized light microscopy (PLM) plots were collected on XP-500E polarized light microscopy. Took a small amount of powder sample on a glass and added some mineral oil, covered with the cover glass, placed it on the stage for observation and took a picture.

(30) Differential thermal analysis data were collected on TA Instruments Q200 DSC. Method: A sample of 1 to 10 mg was placed in an aluminum pan with a pin-holed lid, and the sample was heated from room temperature to 200 C. at a heating rate of 10 C./min under the protection of dry nitrogen purge at 40 mL/min.

(31) Thermogravimetric analysis data were collected on TA Instruments Q500 TGA. Method: A sample of 5 to 15 mg was placed in a platinum pan, using High Resolution, the sample was heated from room temperature to 350 C. at a heating rate of 10 C./min under the protection of dry nitrogen purge at 40 mL/min.

(32) Dynamic vapor sorption data and isothermal sorption data were collected on TA Instruments Q5000 TGA. Method: A sample of 1 to 10 mg was placed in a platinum pan; the weight change of the sample during the change in relative humidity from 0% to 80% to 0% was measured.

(33) 1H Nuclear magnetic resonance spectrum (.sup.1H-NMR) data were collected on Bruker Avance II DMX 500 MHz nuclear magnetic resonance spectrometer. Method: place 1 mg to 10 mg sample and dissolve it into a nuclear magnetic sample tube with 0.5 mL deuterated reagent for detection.

(34) Ion chromatograph (IC) data were collected on Dionex ICS-900. The workstation and analysis software are Chromeleon Console. Ion content was determined by external standard method.

(35) Unless particularly specified, all reagents used in the Examples were commercially available.

(36) Unless particularly specified, all Examples were operated at room temperature.

Preparation Example 1

(37) Prepare ACP-196

(38) The ACP-196 prepared by referencing the methods described in Example 6 of patent document CN103889987A. Data: LCMS(B)Rt: 2.08 min; m/z 466.1 (M+H)+.

(39) Its XRPD pattern is shown in FIG. 1, showing no diffraction peaks.

(40) Its TGA thermogram is shown in FIG. 2, showing more than 10% surface solvent.

(41) Its PLM plot is shown in FIG. 3, showing irregular particles with no polarization.

(42) Its isothermal sorption plot is shown in FIG. 4, showing a weight change of 5.5% in the range of 30% to 80% relative humidity.

(43) The above characterization results indicate that ACP-196 obtained by the method described in Example 6 of patent document CN100352817A is an amorphous substance.

Example 1

(44) Placed 3 g ACP-196 of Preparation Example 1 in 100 mL isopropanol to form a solution, slowly and dropwisely added 50 mL isopropanol solution containing malic acid (1.1 eq), stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 3.3 g ACP-196 malate Form 1; 85% yield. .sup.1H-NMR (d6-DMSO, 500 MHz): 10.84 (s, 1H), 8.50-8.34 (m, 1H), 8.32-8.08 (m, 2H), 7.87 (td, 3H), 7.26-7.04 (m, 2H), 6.22 (s, 2H), 5.73 (dd, 1H), 5.49 (dd, 1H), 4.26 (s, 1H), 3.84 (t, 1H), 3.62 (dtt, 1H), 2.62 (dd, 1H), 2.48-2.18 (m, 3H), 2.15 (dt, 1H), 2.08-1.92 (m, 2H), 1.64 (s, 1H).

(45) The result showed that ACP-196 and malic acid formed a salt at a molar ratio of about 1:1.

(46) Its XRPD pattern is shown in FIG. 5, showing it was crystalline.

(47) Its TGA thermogram is shown in FIG. 6, showing an anhydrate with a decomposition temperature at about 181 C.

(48) Its DSC thermogram is shown in FIG. 7, showing a melting point at about 177 C.

(49) Its PLM pattern is shown in FIG. 8, showing regular block particles.

(50) Its isothermal sorption plot is shown in FIG. 9, showing a weight change of about 1.5% in the range of 30% to 80% relative humidity.

Example 2

(51) Placed 200 mg ACP-196 of Preparation Example 1 in 4 mL isopropanol to form a solution, slowly and dropwisely added 3 mL isopropanol solution containing malic acid (0.8 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 20 hours to obtain 170 mg ACP-196 malate Form 1; 82% yield.

Example 3

(52) Placed 200 mg ACP-196 of Preparation Example 1 in 2 mL acetone to form a solution, slowly and dropwisely added 1 mL acetone solution containing malic acid (1 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 10 hours to obtain 150 mg ACP-196 malate Form 1; 58% yield.

Example 4

(53) ACP-196 malate Form 1 can also be obtained by replacing the solvents in Example 3 with solvents in the following table.

(54) TABLE-US-00006 Experiment Number Solvent 1 (ACP-196) Solvent 2 (malic acid) Experiment 1 Ethanol Ethanol Experiment 2 n-Propanol n-Propanol Experiment 3 sec-Butanol sec-Butanol Experiment 4 Acetone Methanol Experiment 5 Butanone Acetone Experiment 6 Isopropanol Acetone Experiment 7 n-Propanol Ethanol Experiment 8 Acetone Butanone Experiment 9 Acetone Isopropanol

Example 5

(55) Placed 30 mg ACP-196 of Preparation Example 1 and 6.9 mg malic acid in 1.5 mL tetrahydrofuran to form a solution, added 5 mL isopropyl ether, stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 26 mg ACP-196 malate Form 1; 84% yield.

Example 6

(56) Placed 50 mg ACP-196 of Preparation Example 1 and 15.8 mg malic acid in 1 mL tetrahydrofuran to form a solution, added 4 mL isopropyl ether, stirred for 3 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 48 hours to obtain 53 mg ACP-196 malate Form 1; 82% yield.

Example 7

(57) Placed 40 mg ACP-196 of Preparation Example 1 and 11.5 mg malic acid in 0.4 mL dichloromethane to form a solution, added 2.5 mL n-heptane, stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 30 hours to obtain 37 mg ACP-196 malate Form 1; 72% yield.

Example 8

(58) ACP-196 malate Form 1 can also be obtained by replacing the solvents in Example 7 with the following table.

(59) TABLE-US-00007 Experiment Number Co-solvent Anti-solvent Experiment 1 Ethyl acetate Methylcyclohexane Experiment 2 Isopropyl acetate Toluene Experiment 3 1,4-Dioxane Methyl tert-butyl ether Experiment 4 Acetonitrile Diethyl ether Experiment 5 Chloroform Cyclohexane Experiment 6 Dichloromethane Isopropyl ether Experiment 7 Tetrahydrofuran n-Hexane

(60) .sup.1H-NMR data, XRPD patterns, PLM plots, TGA thermograms, DSC thermograms, isothermal sorption plots (not shown) of the samples prepared in Examples 2 to 8 are the same as or similar to that of the sample prepared in Example 1, indicating the crystalline forms obtained in Examples 2 to 8 are the same as that of Example 1.

Example 9

(61) Placed 3 g ACP-196 of Preparation Example 1 in 75 mL acetone to form a solution, slowly and dropwisely added 60 mL acetone solution containing fumaric acid (1.1 eq), stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 3 g ACP-196 hemifumarate Form 1; 89% yield. .sup.1H-NMR (d6-DMSO, 500 MHz): 10.84 (s, 1H), 8.50-8.34 (m, 1H), 8.32-8.08 (m, 2H), 7.87 (td, 3H), 7.26-7.04 (m, 2H), 6.22 (s, 2H), 5.73 (dd, 1H), 5.49 (dd, 1H), 4.26 (s, 1H), 3.84 (t, 1H), 3.62 (dtt, 1H), 2.62 (dd, 1H), 2.48-2.18 (m, 3H), 2.15 (dt, 1H), 2.08-1.92 (m, 2H), 1.64 (s, 1H).

(62) The results shows that ACP-196 and fumaric acid formed a salt at a molar ratio of about 2:1.

(63) Its XRPD pattern is shown in FIG. 10, showing as crystalline.

(64) Its TGA thermogram is shown in FIG. 11, showing an anhydrate with a decomposition temperature at about 170 C.

(65) Its DSC thermogram is shown in FIG. 12, showing an melting point at about 153 C.

(66) Its PLM plot is shown in FIG. 13, showing granular fine particles.

(67) Its isothermal sorption plot is shown in FIG. 14, showing a weight change of about 1.2% in the range of 30% to 80% relative humidity.

Example 10

(68) Placed 200 mg ACP-196 of Preparation Example 1 in 2 mL acetone to form a solution, slowly and dropwisely added 3 mL acetone solution containing fumaric acid (0.5 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 10 hours to obtain 183 mg ACP-196 hemifumarate Form 1; 81% yield.

Example 11

(69) Placed 200 mg ACP-196 of Preparation Example 1 in 1 mL methanol to form a solution, slowly and dropwisely added 6 mL methanol solution containing fumaric acid (0.8 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 165 mg ACP-196 hemifumarate Form 1; 73% yield.

Example 12

(70) ACP-196 hemifumarate Form 1 can also be obtained by replacing the solvents in Example 11 with the following table.

(71) TABLE-US-00008 Experiment Number Solvent 1 (ACP-196) Solvent 2 (fumaric acid) Experiment 1 Acetone Isopropanol Experiment 2 Acetone Ethanol Experiment 3 Butanone Methanol Experiment 4 Butanone sec-Butanol Experiment 5 Methanol Acetone Experiment 6 Ethanol Butanone

Example 13

(72) Placed 200 mg ACP-196 of Preparation Example 1 and 24.9 mg fumaric acid in 4 mL 1,4-dioxane to form a solution, added 6 mL isopropyl ether, stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 198 mg ACP-196 hemifumarate Form 1; 88% yield.

Example 14

(73) Placed 300 mg ACP-196 of Preparation Example 1 and 82.3 mg fumaric acid in 3 mL 1,4-dioxane to form a solution, added 5 mL isopropyl ether, stirred for 3 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 48 hours to obtain 287 mg ACP-196 hemifumarate Form 1; 85% yield.

Example 15

(74) Placed 40 mg ACP-196 of Preparation Example 1 and 8.0 mg fumaric acid in 2 mL tetrahydrofuran to form a solution, added 6 mL isopropyl ether, stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 30 hours to obtain 36 mg ACP-196 hemifumarate Form 1; 80% yield.

Example 16

(75) ACP-196 hemifumarate Form 1 can also be obtained by replacing the solvents in Example 15 with the following table.

(76) TABLE-US-00009 Experiment Number Co-solvent Anti-solvent Experiment 1 Ethyl acetate Methyl tert-butyl ether Experiment 2 Isopropyl acetate Diethyl ether Experiment 3 Tetrahydrofuran n-Heptane Experiment 4 1,4-Dioxane n-Hexane Experiment 5 Acetonitrile Toluene Experiment 6 Dichloromethane Toluene Experiment 7 Chloroform Isopropyl ether Experiment 8 Chloroform Methylcyclohexane

(77) .sup.1H-NMR data, XRPD patterns, PLM plots, TGA thermograms, DSC thermograms, isothermal sorption plots (not shown) of the samples prepared in Examples 10 to 16 are the same as or similar to that of the sample prepared in Example 9, indicating the crystalline forms obtained in Examples 10 to 16 are the same as that of Example 1.

Example 17

(78) Placed 3 g ACP-196 of Preparation Example 1 in 100 mL isopropanol to form a solution, slowly added 50 mL isopropanol solution containing maleic acid (1.1 eq), stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 3.15 g ACP-196 maleate Form 1; 84% yield. .sup.1H NMR (d6-DMSO, 500 MHz): 10.88 (d, 1H), 8.42 (d, 1H), 8.22 (dd, 2H), 8.11-7.69 (m, 3H), 7.64-6.88 (m, 3H), 6.16 (s, 2H), 5.77 (dd, 1H), 5.52 (dd, 1H), 3.94-3.54 (m, 3H), 2.45-1.89 (m, 5H), 1.69 (s, 1H), 1.05 (d, 1H). The results shows that ACP-196 and maleic acid formed a salt at a molar ratio of about 1:1.

(79) Its XPRD pattern is shown in FIG. 15, showing it is crystalline.

(80) Its TGA thermogram is shown in FIG. 16, showing an anhydrate with a decomposition temperature at about 125 C.

(81) Its DSC thermogram is shown in FIG. 17, showing an melting point at about 132 C.

(82) Its PLM plot is shown in FIG. 18, showing granular fine particles.

(83) Its isothermal sorption plot is shown in FIG. 19, showing a weight change of about 0.4% in the range of 30% to 80% relative humidity.

Example 18

(84) Placed 100 mg ACP-196 of Preparation Example 1 in 2 mL isopropanol to form a solution, slowly and dropwisely added 2 mL isopropanol solution containing maleic acid (0.8 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 18 hours to obtain 79 mg ACP-196 maleate Form 1; 79% yield.

Example 19

(85) Placed 100 mg ACP-196 of Preparation Example 1 in 1 mL acetone to form a solution, slowly and dropwisely added 1 mL acetone solution containing maleic acid (1.0 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 48 hours to obtain 95 mg ACP-196 maleate Form 1; 76% yield.

Example 20

(86) ACP-196 maleate Form 1 can also be obtained by replacing the solvents in Example 19 with the following table.

(87) TABLE-US-00010 Experiment Number Solvent 1 (ACP-196) Solvent 2 (maleic acid) Experiment 1 Isopropanol Ethanol Experiment 2 sec-Butanol sec-Butanol Experiment 3 Ethanol Acetone Experiment 4 Acetone Butanone Experiment 5 Butanone Methanol Experiment 6 Acetone Ethanol

Example 21

(88) Placed 30 mg ACP-196 of Preparation Example 1 and 6.0 mg maleic acid in 1.5 mL tetrahydrofuran to form a solution, added 6 mL n-heptane, stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 25 mg ACP-196 malate Form 1; 83% yield.

Example 22

(89) Placed 50 mg ACP-196 of Preparation Example 1 and 13.7 mg maleic acid in 1 mL tetrahydrofuran to form a solution, added 5 mL n-heptane, stirred for 3 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 48 hours to obtain 49 mg ACP-196 malate Form 1; 78% yield.

Example 23

(90) Placed 100 mg ACP-196 of Preparation Example 1 and 24.9 mg maleic acid in 1 mL dichloromethane to form a solution, added 5 mL n-heptane, stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 30 hours to obtain 96 mg ACP-196 malate Form 1; 77% yield.

Example 24

(91) ACP-196 malate Form 1 can also be obtained by replacing the solvents in Example 23 with the following table.

(92) TABLE-US-00011 Experiment Number Co-solvent Anti-solvent Experiment 1 Chloroform Isopropyl ether Experiment 2 Dichloromethane Methyl tert-butyl ether Experiment 3 Acetonitrile Diethyl ether Experiment 4 1,4-Dioxane Diethyl ether Experiment 5 Tetrahydrofuran n-Hexane Experiment 6 Isopropyl acetate Methylcyclohexane Experiment 7 Ethyl acetate Toluene Experiment 8 Ethyl acetate n-Heptane

(93) .sup.1H-NMR data, XRPD patterns, PLM plots, TGA thermograms, DSC thermograms, isothermal sorption plots (not shown) of the samples prepared in Examples 18 to 24 are the same as or similar to that of the sample prepared in Example 17, indicating the crystalline forms obtained in Examples 18 to 24 are the same as that of Example 17.

Example 25

(94) Placed 3 g ACP-196 of Preparation Example 1 in 100 mL isopropanol to form a solution, slowly added 20 mL isopropanol solution containing phosphoric acid (1.1 eq), stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 285 mg ACP-196 phosphate Form 1; 75% yield.

(95) The IC analysis shows that the PO43-content in ACP-196 phosphate Form 1 is 20.1%, the theoretical PO43-content in monophosphate is 16.9%, and the theoretical PO43-content in diphosphate is 28.7%. Therefore, the molar ratio of ACP-196 to phosphoric acid is about 1:1.

(96) Its XRPD pattern is shown in FIG. 20, showing it is crystalline.

(97) Its TGA thermogram is shown in FIG. 21, combined with a 4.3% stepwise weight loss shown as a sesquihydrate, and a decomposition temperature at about 198 C.

(98) Its DSC thermogram is shown in FIG. 22, showing an melting point at about 170 C.

(99) Its PLM plot is shown in FIG. 23, showing granular block particles.

(100) Its isothermal sorption plot is shown in FIG. 24, showing a weight change of about 4.2% in the range of 30% to 80% relative humidity.

Example 26

(101) Placed 100 mg ACP-196 of Preparation Example 1 in 2 mL isopropanol to form a solution, slowly and dropwisely added 1 mL isopropanol solution containing phosphoric acid (0.8 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 40 hours to obtain 70 mg ACP-196 phosphate Form 1; 69% yield.

Example 27

(102) Placed 100 mg ACP-196 of Preparation Example 1 in 1 mL acetone to form a solution, slowly added 1 mL acetone solution containing phosphoric acid (1.0 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 36 hours to obtain 80 mg ACP-196 phosphate Form 1; 63% yield.

Example 28

(103) ACP-196 phosphate Form 1 can also be obtained by replacing the solvents in Example 27 with the following table.

(104) TABLE-US-00012 Experiment Number Solvent 1 (ACP-196) Solvent 2 (malic acid) Experiment 1 Methanol Ethanol Experiment 2 n-Propanol Methanol Experiment 3 sec-Butanol sec-Butanol Experiment 4 n-Butanol Butanone Experiment 5 Butanone Butanone Experiment 6 Acetone Isopropanol

Example 29

(105) Placed 100 mg ACP-196 of Preparation Example 1 in 2 mL dichloroform to form a solution, dropwisely added 19.8 mg 85% phosphoric acid, then added 5 mL methylcyclohexane, stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 87 mg ACP-196 phosphate Form 1; 86% yield.

Example 30

(106) Placed 100 mg ACP-196 of Preparation Example 1 in 1 mL dichloroform to form a solution, added 27.2 mg 85% phosphoric acid, then added 2.5 mL methylcyclohexane, stirred for 3 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 30 hours to obtain 105 mg ACP-196 phosphate Form 1; 83% yield.

Example 31

(107) Placed 300 mg ACP-196 of Preparation Example 1 in 2 mL chloroform to form a solution, dropwisely added 66.9 mg 85% phosphoric acid, then added 6 mL n-heptane, stirred for 3 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 36 hours to obtain 276 mg ACP-196 phosphate Form 1; 81% yield.

Example 32

(108) ACP-196 phosphate Form 1 can also be obtained by replacing the solvents in Example 31 with the following table.

(109) TABLE-US-00013 Experiment Number Co-solvent Anti-solvent Experiment 1 Ethyl acetate Isopropyl ether Experiment 2 Isopropyl acetate n-Heptane Experiment 3 Tetrahydrofuran Methyl tert-butyl ether Experiment 4 1,4-Dioxane Diethyl ether Experiment 5 Acetonitrile Methylcyclohexane Experiment 6 Dichloromethane n-Hexane Experiment 7 Chloroform Diethyl ether Experiment 8 Tetrahydrofuran Toluene

(110) IC data, XRPD patterns, PLM plots, TGA thermograms, DSC thermograms, isothermal sorption plots (not shown) of the samples prepared in Examples 26 to 32 are the same as or similar to that of the sample prepared in Example 25, indicating the crystalline forms obtained in Examples 26 to 32 are the same as that of Example 25.

Example 33

(111) Placed 3 g ACP-196 of Preparation Example 1 in 100 mL isopropanol to form a solution, slowly added 20 mL isopropanol solution containing sulfuric acid (1.1 eq), stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 16 hours to obtain 2.8 g ACP-196 sulfate Form 1; 77% yield.

(112) The IC analysis shows that the SO42-content in ACP-196 sulfate Form 1 is 18.2%, the theoretical SO42-content in monosulfate is 17.0%, and the theoretical SO42-content in disulfate is 29.0%. Therefore, the molar ratio of ACP-196 to phosphoric acid is about 1:1.

(113) Its XRPD pattern is shown in FIG. 25.

Example 34

(114) Placed 300 mg ACP-196 of Preparation Example 1 in 6 mL isopropanol to form a solution, slowly and dropwisely added 2 mL acetone solution containing sulfuric acid (0.8 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 20 hours to obtain 220 mg ACP-196 sulfate Form 1; 76% yield.

Example 35

(115) Placed 300 mg ACP-196 of Preparation Example 1 in 3 mL acetone to form a solution, slowly added 1 mL acetone solution containing sulfuric acid (1.0 eq), stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 20 hours to obtain 250 mg ACP-196 sulfate Form 1; 69% yield.

Example 36

(116) ACP-196 sulfate Form 1 can also be obtained by replacing the solvents in Example 35 with the following table.

(117) TABLE-US-00014 Experiment Number Solvent 1 (ACP-196) Solvent 2 (sulfuric acid) Experiment 1 Methanol Methanol Experiment 2 Ethanol Acetone Experiment 3 sec-Butanol Ethanol Experiment 4 n-Butanol Isopropanol Experiment 5 Butanone Butanone Experiment 6 Acetone n-Propanol

Example 37

(118) Placed 50 mg ACP-196 of Preparation Example 1 in 2 mL ethyl acetate to form a solution, dropwisely added 8.6 mg concentrated sulfuric acid, then added 3 mL n-hexane, stirred for 1 day for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 24 hours to obtain 40 mg ACP-196 sulfate Form 1; 81% yield.

Example 38

(119) Placed 200 mg ACP-196 of Preparation Example 1 in 4 mL ethyl acetate to form a solution, added 47.3 mg concentrated sulfuric acid, then added 6 mL n-hexane, stirred for 3 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 48 hours to obtain 192 mg ACP-196 sulfate Form 1; 79% yield.

Example 39

(120) Placed 300 mg ACP-196 of Preparation Example 1 in 30 mL tetrahydrofuran to form a solution, dropwisely added 58.0 mg concentrated sulfuric acid, then added 30 mL diethyl ether, stirred for 2 days for crystallization and precipitation, filtrated, and then vacuum dried at room temperature for 20 hours to obtain 210 mg ACP-196 sulfate Form 1; 63% yield.

Example 40

(121) ACP-196 sulfate Form 1 can also be obtained by replacing the solvents in Example 39 with the following table.

(122) TABLE-US-00015 Experiment Number Co-solvent Anti-solvent Experiment 1 Tetrahydrofuran Toluene Experiment 2 1,4-Dioxane Isopropyl ether Experiment 3 Acetonitrile Diethyl ether Experiment 4 Ethyl acetate Methyl tert-butyl ether Experiment 5 Isopropyl acetate n-Heptane Experiment 6 Dichloromethane Methylcyclohexane Experiment 7 Chloroform n-Hexane Experiment 8 Chloroform Methyl tert-butyl ether

(123) IC data, XRPD patterns (not shown) of the samples prepared in Examples 34 to 40 are the same as or similar to that of the sample prepared in Example 33, indicating the crystalline forms obtained in Examples 34 to 40 are the same as that of Example 33.

Example 41

(124) TABLE-US-00016 Component (active ingredient basis) Dosage (mg) ACP-196 malate Form 1/ACP-196 hemifumarate 50 Form 1/ACP-196 maleate Form 1/ACP-19 phosphate Form 1/ACP-196 sulfate Form 1 Compressible starch 110 Cross-linked providone 5 Microcrystalline cellulose 80 Silica 5 Total 250

(125) Mixed ACP-196 malate Form 1 or ACP-196 hemifumarate Form 1 or ACP-196 maleate Form 1 or ACP-196 phosphate Form 1 or ACP-196 sulfate Form 1, compressible starch, microcrystalline cellulose and crosslinked polyvinyl ketone, then use silica as lubricant, and then finally compressed as tablets.

Example 42

(126) TABLE-US-00017 Component (active ingredient basis) Dosage (mg) ACP-196 malate Form 1/ACP-196 hemifumarate 100 Form 1/ACP-196 maleate Form 1/ACP-196 phosphate Form 1/ACP-196 sulfate Form 1 Ethyl cellulose 100 Hydroxypropylmethylcellulose 10 Lactose 110 Microcrystalline cellulose 80 Magnesium stearate 5 Talc 5 Total 410

(127) Mixed ACP-196 malate Form 1 or ACP-196 hemifumarate Form 1 or ACP-196 maleate Form 1 or ACP-196 phosphate Form 1 or ACP-196 sulfate Form 1, ethyl cellulose, hydroxypropyl methyl cellulose, lactose and microcrystalline cellulose, granulated with 75% ethanol, dried, crushed, shifted through 80 mesh sieve, then added magnesium stearate and talc to mix evenly and filled into the capsule.

Comparative Example 1

(128) Solubility test: took 20 mg ACP-196 of Preparation Example 1, 20 mg ACP-196 malate Form 1 of the invention, 20 mg ACP-196 hemifumarate Form 1 of the invention, 20 mg ACP-196 maleate Form 1 of the invention, 20 mg ACP-196 phosphate Form 1 of the invention and 20 mg ACP-196 sulfate Form 1 of the invention, then placed in the beaker respectively added 1.0 mL water, stirred for 1 to 2 minutes under the condition of 25 C. water bath, observed and if not totally dissolved, added water (not more than 200 mL in total) until it's completely dissolved. The test results are shown in the table below.

(129) TABLE-US-00018 Sample Test results ACP-196 Less than 0.1 mg/mL ACP-196 malate Form 1 1.43 mg/mL ACP-196 hemifumarate Form 1 0.91 mg/mL ACP-196 maleate Form 1 1.33 mg/mL ACP-196 phosphate Form 1 4.0 mg/mL ACP-196 sulfate Form 1 1.5 mg/mL

(130) The results showed that the solubility of ACP-196 malate Form 1, ACP-196 hemifumarate Form 1, ACP-196 maleate Form 1, ACP-196 phosphate Form 1 and ACP-196 sulfate Form 1 of the present invention in water are higher than that of ACP-196 of Preparation Example 1.