Crystal Forms of Crisaborole In Free Form And Preparation Method And Use Thereof

Abstract

The present invention relates to four crystal forms of crisaborole in free form and the preparation method thereof. The present invention also relates to the pharmaceutical composition containing the crystal forms and the use thereof.

##STR00001##

Claims

1.-3. (canceled)

4. A method of preparing crisaborole crystal form I comprising the steps of dissolving crisaborole in a single volatile solvent and allowing the single volatile solvent to volatilize to provide the crisaborole crystal form I, wherein the single volatile solvent is selected from the group consisting of alkyl nitriles, alkyl ethers, halogenated hydrocarbons and esters.

5. The method according to claim 4 wherein the single volatile solvent is selected from the group consisting of acetonitrile, methyl tert-butyl ether, chloroform, dichloromethane, and ethyl acetate.

6.-8. (canceled)

9. A method of preparing crisaborole crystal form II comprising the steps of suspending crisaborole in a mixed solvent of water and an alcohol, stirring the suspension, subjecting the suspension to centrifugal separation and drying the suspension to provide crisaborole crystal form II, wherein the water to alcohol volume ratio is 1:1.

10.-13. (canceled)

14. A method of preparing crisaborole crystal form III comprising the steps of dissolving crisaborole in a ketone solvent until the resultant mixture is clear, and the resultant mixture is subjected to volatile crystallization, to provide crisaborole crystal form III.

15. The method according to claim 14 wherein the ketone solvent is acetone.

16.-31. (canceled)

32. A method of preparing crisaborole crystal form I comprising the steps of suspending crisaborole in a single solvent to give a suspension wherein the suspension is stirred, subjected to separation, and dried, to provide the crystal form I of crisaborole, wherein the single solvent is selected from the group consisting of water and toluene.

33. A method of preparing crisaborole crystal form I comprising the steps of suspending crisaborole in a mixed solvent to give a suspension wherein the suspension is stirred, subjected to separation, and dried, to provide the crisaborole crystal form I, wherein the mixed solvent is water and a further solvent wherein the further solvent is selected from the group consisting of alcohols, alkyl nitriles, esters, ketones, amides, cyclic ethers and dimethyl sulfoxide, wherein the volume of the water is greater than the volume of the further solvent.

34. The method of claim 33 wherein the further solvent is selected from the group consisting of isopropanol, acetonitrile, isopropyl acetate, acetone, dimethyl formamide, 1,4-dioxane, and dimethyl sulfoxide.

35. A method of preparing crisaborole crystal form I comprising the steps of suspending crisaborole in a mixed solvent to give a suspension wherein the suspension is stirred, subjected to separation, and dried, to provide the crystal form I of crisaborole, wherein the mixed solvent is a hydrocarbon and a further solvent selected from the group consisting of ketones, esters, cyclic ethers, halogenated hydrocarbons and alcohols.

36. The method of claim 35 wherein the hydrocarbon is n-heptane and the further solvent is selected from the group consisting of methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, chloroform, and ethanol, wherein the volume of the n-heptane is less than the volume of the further solvent.

37. A method of preparing crisaborole crystal form I comprising the steps of suspending crisaborole in a mixed solvent to give a suspension wherein the suspension is stirred, subjected to separation, and dried, to provide the crystal form I of crisaborole, wherein the mixed solvent is toluene and a halogenated hydrocarbon.

38. The method of claim 37 wherein the halogenated hydrocarbon is dichloromethane and wherein the volume of the dichloromethane is less than the volume of the toluene.

39.-46. (canceled)

47. A method of preparing crisaborole crystal form II comprising the steps of dissolving crisaborole in a positive solvent, adding a reverse solvent, stirring until crystallization, separation via centrifugal separation, and drying to provide crisaborole crystal form II, wherein the positive solvent is selected from the group consisting of alcohols, ketones, cyclic ethers, amides, and dimethyl sulfoxide, and the reverse solvent is water, wherein the volume of the water is equal to or greater than the volume of the positive solvent.

48. The method according to claim 47 wherein the positive solvent is selected from the group consisting of isopropanol, acetone, 1,4-dioxane, tetrahydrofuran, dimethylformamide, and dimethylsulfoxide.

49.-51. (canceled)

Description

BRIEF DESCRIPTIONS OF THE DRAWINGS

[0067] FIG. 1 is the X-ray powder diffraction pattern of the crystal form I as prepared in Example 1 of the invention.

[0068] FIG. 2 is the DSC pattern of the crystal form I as prepared in Example 1 of the invention.

[0069] FIG. 3 is the TGA pattern of the crystal form I as prepared in Example 1 of the invention.

[0070] FIG. 4 is the X-ray powder diffraction pattern of the crystal form II as prepared in Example 4 of the invention.

[0071] FIG. 5 is the DSC pattern of the crystal form II as prepared in Example 4 of the invention.

[0072] FIG. 6 is the TGA pattern of the crystal form II as prepared in Example 4 of the invention.

[0073] FIG. 7 is the X-ray powder diffraction pattern of the crystal form III as prepared in Example 6 of the invention.

[0074] FIG. 8 is the DSC pattern of the crystal form III as prepared in Example 6 of the invention.

[0075] FIG. 9 is the TGA pattern of the crystal form III as prepared in Example 6 of the invention.

[0076] FIG. 10 is the X-ray powder diffraction pattern of the crystal form IV as prepared in Example 8 of the invention.

[0077] FIG. 11 is the DSC pattern of the crystal form IV as prepared in Example 9 of the invention.

[0078] FIG. 12 is the TGA pattern of the crystal form IV as prepared in Example 9 of the invention.

[0079] FIG. 13 is the X-ray powder diffraction pattern of the crystal form I as prepared in Example 2 of the invention.

[0080] FIG. 14 is the X-ray powder diffraction pattern of the crystal form I as prepared in Example 3 of the invention.

[0081] FIG. 15 is the X-ray powder diffraction pattern of the crystal form III as prepared in Example 7 of the invention.

[0082] FIG. 16 is the X-ray powder diffraction pattern of the crystal form IV as prepared in Example 9 of the invention.

[0083] FIG. 17 is the DVS pattern of the crystal form I of the invention.

[0084] FIG. 18 is the DVS pattern of the crystal form II of the invention.

[0085] FIG. 19 is the DVS pattern of the crystal form III of the invention.

[0086] FIG. 20 is the DVS pattern of the crystal form IV of the invention.

[0087] FIG. 21 is the diagram for showing the comparison in the XRPD patterns of the crystal form I according to the invention before and after grinding.

[0088] FIG. 22 is the diagram for showing the comparison in the XRPD patterns of the crystal form IV according to the invention before and after grinding.

[0089] FIG. 23 is the diagram for showing the comparison in the XPRD pattern between the longer-term stability and acceleration stability of the crystal form I according to the invention.

[0090] FIG. 24 is the diagram for showing the comparison in the XPRD pattern between the longer-term stability and acceleration stability of the crystal form II according to the invention.

[0091] FIG. 25 is the diagram for showing the comparison in the XPRD pattern between the longer-term stability and acceleration stability of the crystal form III according to the invention.

[0092] FIG. 26 is the PSD pattern of the crystal form I of the invention.

[0093] FIG. 27 is the PSD pattern of the crystal form II of the invention.

[0094] FIG. 28 is the PSD pattern of the crystal form IV of the invention.

[0095] FIG. 29 is the PLM pattern of the crystal form I of the invention.

[0096] FIG. 30 is the PLM pattern of the crystal form II of the invention.

[0097] FIG. 31 is the PLM pattern of the crystal form IV of the invention.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0098] The invention is defined by further referring to the following examples. The examples describe in detail a method of preparing the crystal forms according to the invention and a method of using the same. It is obvious for a person skilled in the art that variations to the material and methods can be made in the case of no deviation from the scope of the invention.

[0099] Apparatus and Methods as Used for Collecting Data:

[0100] The abbreviations as used in the invention are explained as follows: [0101] XRPD: X-ray powder diffraction, [0102] DSC: Differential scanning calorimetric analysis, [0103] TGA: Thermogravimetric analysis, [0104] DVS: Dynamic vapor sorption, [0105] PSD: Particle size distribution, [0106] PLM: Polarizing microscope [0107] HPLC: High performance Liquid Chromatography

[0108] The X-ray powder diffraction pattern as described in the invention was collected on a Panalytical Empyrean X-ray powder diffraction meter. The X-ray powder diffraction method has the following parameters: [0109] X-ray reflection parameters: Cu, Kα, [0110] Kα1(Å): 1.540598; Kα2(Å): 1.544426, [0111] Kα2/Kα1 intensity ratio: 0.50, [0112] Voltage: 45 kilovolt (kV), [0113] Current: 40 milliampere (mA), [0114] Scanning scope: from 3.0° to 40.0°.

[0115] The differential scanning calorimetric (DSC) pattern as described in the invention was collected on a TA Q2000. The differential scanning calorimetric (DSC) method has the following parameters: [0116] Scanning speed: 10° C./min, [0117] Protective gas: nitrogen gas.

[0118] The thermogravimetric analysis (TGA) pattern as described in the invention was collected on a TA Q500. The thermogravimetric analysis (TGA) method has the following parameters: [0119] Scanning speed: 10° C./min, [0120] Protective gas: nitrogen gas.

[0121] The dynamic vapor sorption (DVS) pattern as described in the invention was collected on an intrinsic dynamic vapor sorption meter as produced by Surface Measurement Systems Ltd. The dynamic vapor sorption method has the following parameters: [0122] Temperature: 25° C., [0123] Loading gas, flowing speed: N.sub.2, 200 ml/min, [0124] Variation in mass per time: 0.002%/minute, [0125] Relative humidity range: 0% RH-95% RH.

[0126] The particle size distribution (PSD) results as described in the invention were collected on a S3500-type laser particle size analytic meter as produced by Microtrac Company. The Microtrac S3500 is equipped with a SDC (Sample Delivery Controller) feeding system. The test was conducted via a wet process, and the dispersion medium as used in the test was Isopar G. The laser particle size analytic meter has the following parameters:

TABLE-US-00001 Particle size distribution: Collection time: 10 seconds volume distribution Dispersion medium: Isopar G Particle size coordination: standard Collection frequency: 3 times Refractive index of dispersion medium: 1.42 Transparency: transparent Residual: on Particle refractive index: 1.5 Flowing rate: 60* Particle shape: irregular Filtration: on *the flowing rate 60% is meant to 60% of the flowing rate 65 ml/second.

[0127] The high performance liquid chromatography (HPLC) data were collected in an Agilent 1260, and the used detector was a diode array detector (DAD). The HPLC method as described in the invention has the following parameters: [0128] 1. Chromatographic column: Waters Xbridge 018 150×4.6 mm, 5 μm [0129] 2. Flowing phase: A: 0.1% trifluoro acetic acid aqueous solution [0130] B: 0.1% trifluoro acetic acid solution in acetonitrile

[0131] The eluting gradient is shown in the following table:

TABLE-US-00002 Time (minute) % flowing phase B 0.0 10 3.0 10 20.0 90 25.0 90 25.1 10 30.0 10 [0132] 3. flowing rate: 1.0 mL/min [0133] 4. Injection volume: 5 μL [0134] 5. Detection wavelength: 254 nm [0135] 6. Column temperature: 40° C. [0136] 7. Diluent: 50% acetonitrile.

[0137] In the following examples, unless specifically stated, the term “room temperature” refers to the temperature range from 15 to 25° C.

[0138] The solids of crisaborole in free form used in the following examples can be commercially available.

Example 1

[0139] 202.5 mg of solids of crisaborole in free form were added to 6 mL of a mixed solvent system (methanol:water, with the volume ratio 1:5), and the resultant mixture was stirred at 50° C. for 5 days. The reaction mixture was subjected to centrifugal separation and vacuum dried at room temperature, to produce white solid crystals.

[0140] It was found that the resultant solid crystals were the crystal form I as described in the invention by detection. The X-ray powder diffraction pattern of the crystal form is shown in FIG. 1, and the corresponding X-ray powder diffraction data are shown in Table 1.

[0141] Upon conducting the differential scanning calorimetric analysis, the crystal form I, when being heated to a temperature in the vicinity of 123° C., involved heat absorption peaks, and its DSC is shown in FIG. 2. Upon conducting the thermogravimetric analysis, the crystal form I, when being heated to 120° C., had a mass lose gradient of about 4.2%, and its TGA is shown in FIG. 3. The crystal form I according to the invention is a hydrate.

TABLE-US-00003 TABLE 1 2theta d-spacing Intensity % 5.98 14.79 21.09 11.98 7.39 2.61 14.07 6.29 53.95 15.31 5.79 100.00 15.96 5.55 33.66 17.56 5.05 6.53 18.14 4.89 42.95 21.34 4.16 26.11 24.86 3.58 39.83 26.09 3.42 65.72 28.40 3.14 31.42 31.33 2.85 7.91 31.68 2.82 5.53 39.24 2.30 2.84

Example 2

[0142] 51.4 mg of solids of crisaborole in free form were added to 1 mL of acetonitrile solvent. After the solids were dissolved in the solvent, the solvent volatilized at room temperature when exposed to air until it completely volatilized, to produce white solid crystals.

[0143] It was found that the resultant solid crystals were the crystal form I as described in the invention by detection, and the X-ray powder diffraction data are shown in FIG. 13 and Table 2.

TABLE-US-00004 TABLE 2 2theta d-spacing Intensity % 5.99 14.76 5.42 12.02 7.36 1.01 14.06 6.30 14.60 15.33 5.78 100.00 15.99 5.54 4.06 17.56 5.05 3.30 18.12 4.90 6.76 20.73 4.28 2.27 21.40 4.15 38.10 21.85 4.07 1.80 23.00 3.87 1.32 24.85 3.58 24.19 26.09 3.41 33.54 26.35 3.38 7.30 28.39 3.14 9.99 29.05 3.07 3.25 30.94 2.89 6.24 31.35 2.85 3.33 31.68 2.82 2.59 32.66 2.74 4.91 33.69 2.66 2.40

[0144] The data in Table 3 were obtained by using the same method as described in Example 2. A certain mass quantity of solids of crisaborole in free form were added to a certain volume of solvent. After the solids were dissolved in the solvent, the solvent volatilized at room temperature when exposed to air until the solvent completely volatilized, to produce white solid crystals. The solids were checked by XRPD to be the crystal form I.

TABLE-US-00005 TABLE 3 Solvent Resultant Mass of raw volume crystal No. material (mg) Solvent (mL) form 1 13.1 Ethyl acetate 1.0 Crystal form I 2 13.0 Methyl(t- 1.0 Crystal form I butyl)ether 3 13.5 Chloroform 1.0 Crystal form I 4 13.4 dichloromethane 1.0 Crystal form I

Example 3

[0145] 30.7 mg of solids of crisaborole in free form were added to 1.5 mL of water solvent, and the resultant mixture was magnetically stirred at room temperature for two days. The reaction mixture was subjected to centrifugal separation and vacuum dried at room temperature, to produce white solid crystals.

[0146] It was found that the resultant solid crystals were the crystal form I as described in the invention by detection, and the X-ray powder diffraction data of the crystal form are shown in FIG. 14 and Table 4.

TABLE-US-00006 TABLE 4 2theta d-spacing Intensity % 5.95 14.86 27.13 14.03 6.31 48.74 15.28 5.80 100.00 15.93 5.56 34.94 18.12 4.90 41.14 21.33 4.16 24.57 24.83 3.59 34.19 26.06 3.42 62.24 28.34 3.15 27.26 31.32 2.86 5.69 33.63 2.67 4.16

[0147] The data in Table 5 were obtained by using the same method as described in Example 3. A certain mass quantity of solids of crisaborole in free form were added to a certain volume of solvent, and the resultant mixture was magnetically stirred at room temperature. The reaction mixture was subjected to centrifugal separation and vacuum dried at room temperature, to produce white solid crystals. The resultant solids were determined by the XRPD to be the crystal form I.

TABLE-US-00007 TABLE 5 Mass of starting Solvent Resultant material volume crystal No. (mg) Solvent (mL) form 1 30.2 toluene 1.0 Crystal form I 2 31.6 Acetonitrile/water 0.6/0.8 Crystal form I 3 30.8 Isopropyl acetate/water 0.2/0.8 Crystal form I 4 29.6 1,4-dioxane/water 0.4/0.8 Crystal form I 5 30.5 Acetone/water 0.4/0.8 Crystal form I 6 29.9 Dimethyl formamide/water 0.6/0.8 Crystal form I 7 29.8 Dimethyl sulfoxide/water 0.6/0.8 Crystal form I 8 29.1 methylisobutylketone/n-heptane 0.6/0.5 Crystal form I 9 30.3 Ethyl acetate/n-heptane 0.6/0.5 Crystal form I 10 29.0 2-methyltetrahydrofuran/n-heptane 0.4/0.5 Crystal form I 11 30.3 Chloroform/n-heptane 0.4/0.5 Crystal form I 12 31.4 ethanol/n-heptane 0.2/1.3 Crystal form I 13 30.2 dichloromethane/toluene 0.4/0.5 Crystal form I 14 29.7 isopropanol/water 0.6/0.8 Crystal form I

Example 4

[0148] 34.5 mg of solids of crisaborole in free form were added to 1.6 mL of a mixed solvent system (methanol:water, with the volume ratio 1:1). The resultant mixture was magnetically stirred at room temperature, and then it was subjected to centrifugal separation and vacuum dried at room temperature, to produce white solid crystals.

[0149] It was found that the resultant solid crystals were the crystal form II as described in the invention by detection. The X-ray powder diffraction pattern of the crystal form is shown in FIG. 4, and the corresponding X-ray powder diffraction data are shown in Table 6.

[0150] Upon conducting the differential scanning calorimetric analysis, the crystal form II, when being heated to a temperature in the vicinity of 134° C., involved heat absorption peaks, and its DSC is shown in FIG. 5. Upon conducting the thermogravimetric analysis, the crystal form II, when being heated to 115° C., had a mass lose gradient of about 4.2%, and its TGA is shown in FIG. 6. The crystal form II according to the invention is a hydrate.

TABLE-US-00008 TABLE 6 2theta d-spacing Intensity % 7.01 12.61 2.38 12.17 7.27 3.50 14.21 6.23 4.68 14.77 6.00 1.50 16.55 5.36 37.69 17.60 5.04 9.92 18.32 4.84 8.97 20.76 4.28 100.00 21.35 4.16 11.45 21.75 4.09 11.77 22.55 3.94 19.21 23.08 3.85 6.09 23.43 3.80 4.61 25.97 3.43 4.66 27.00 3.30 2.75 27.89 3.20 24.06 28.65 3.12 3.74 30.03 2.98 3.15 31.44 2.85 4.29 37.29 2.41 2.50

Example 5

[0151] 30.3 mg of solids of crisaborole in free form were added to 0.4 mL of isopropanol solvent, and 0.6 mL of the reverse solvent water were dropwise added thereto while being magnetically stirred at room temperature. The resultant mixture crystallized while being stirred for 5 days, and then it was subjected to centrifugal separation and vacuum dried at room temperature, to produce white solid crystals.

[0152] It was found that the resultant solid crystals were the crystal form II as described in the invention by detection, and the X-ray powder diffraction data of the crystal form are shown in Table 7.

TABLE-US-00009 TABLE 7 2theta d-spacing Intensity % 12.24 7.23 7.02 14.30 6.19 7.68 15.55 5.70 4.38 16.62 5.33 65.89 17.64 5.03 11.91 18.39 4.82 12.60 19.96 4.45 2.68 20.80 4.27 100.00 21.42 4.15 11.19 21.76 4.08 12.83 22.58 3.94 39.24 23.08 3.85 10.59 23.51 3.78 7.85 24.13 3.69 3.90 24.86 3.58 9.95 26.03 3.42 6.30 27.03 3.30 4.79 27.90 3.20 26.46 28.69 3.11 4.04 31.46 2.84 6.90

[0153] The data in Table 8 were obtained by using the same method as described in the example. A certain mass quantity of solids of crisaborole in free form were added to a certain volume of a positive solvent, and a certain volume of a reverse solvent was dropwise added thereto at room temperature while being magnetically stirred. The resultant mixture crystallized while being stirred, and then it was subjected to centrifugal separation and vacuum dried, to produce white solid crystals. The solids were determined by XRPD to be the crystal form II.

TABLE-US-00010 TABLE 8 Mass of Volume of Volume of Whether or starting positive reverse not solids Resultant material Positive solvent Reverse solvent are crystal No. (mg) solvent (mL) solvent (mL) precipitated form 1 32.4 acetone 0.2 water 0.2 Yes Crystal form II 2 29.6 1,4-dioxane 0.2 water 0.2 Yes Crystal form II 3 29.5 tetrahydrofuran 0.2 water 0.4 Yes Crystal form II 4 28.8 dimethylformamide 0.2 water 0.4 Yes Crystal form II 5 28.5 Dimethyl 0.2 water 0.4 Yes Crystal sulfoxide form II

Example 6

[0154] 200.5 mg of solids of crisaborole in free form were charged into a 20 mL glass bottle loaded with 5 mL of solvent acetone, and dissolved until the resultant mixture was clear. The opening of the bottle was sealed with a sealing membrane, and the membrane was pinked with a needle to form several small holes. The bottle was placed at room temperature to allow the solvent to slowly volatize, thereby to produce white solid crystals.

[0155] It was found that the resultant solid crystals were the crystal form III as described in the invention by detection. The X-ray powder diffraction pattern of the crystal form is shown in FIG. 7, and the corresponding X-ray powder diffraction data are shown in Table 9.

[0156] Upon conducting the differential scanning calorimetric analysis, the crystal form when being heated to a temperature in the vicinity of 136° C., involved heat absorption peaks, and its DSC is shown in FIG. 8. Upon conducting the thermogravimetric analysis, the crystal form III, when being heated to 145° C., had a mass lose gradient of about 2.5%, and its TGA is shown in FIG. 9. The crystal form III according to the invention is a hydrate.

TABLE-US-00011 TABLE 9 2theta d-spacing Intensity % 10.20 8.67 1.03 13.63 6.49 1.19 16.21 5.47 7.54 17.55 5.05 3.06 18.24 4.86 2.64 18.62 4.77 8.91 19.58 4.53 3.64 20.59 4.31 100.00 20.72 4.29 91.97 21.30 4.17 12.98 21.69 4.10 7.34 22.49 3.95 2.14 23.70 3.75 2.18 23.95 3.72 1.80 26.29 3.39 2.04 26.50 3.36 2.82 26.93 3.31 2.79 27.41 3.25 2.88 27.86 3.20 22.34 31.38 2.85 5.26 37.17 2.42 1.12

Example 7

[0157] 11.5 mg of solids of crisaborole in free form were added to 0.2 mL of acetone solvent, and the solvent volatilized at room temperature until it completely volatilized, to produce white solid crystals.

[0158] It was found that the resultant solid crystals were the crystal form III as described in the invention by detection. The X-ray powder diffraction data of the crystal form are shown in FIG. 15 and Table 10.

TABLE-US-00012 TABLE 10 2theta d-spacing Intensity % 13.66 6.48 16.96 15.63 5.67 3.67 16.43 5.40 13.85 18.22 4.87 8.94 18.62 4.76 27.66 19.54 4.54 14.45 20.58 4.32 100.00 21.26 4.18 5.22 21.70 4.10 10.34 22.54 3.94 6.87 23.74 3.75 19.42 26.01 3.43 2.08 27.67 3.22 67.83 28.51 3.13 3.66 31.19 2.87 3.78 37.12 2.42 3.30

Example 8

[0159] About 5 mg of crisaborole in free form were placed in a DSC(Q2000) tray, and the heating program was set as follows: the solids were heated to the temperature of 90° C., in a rate of 10° C./min; the solids were heated to the temperature of 130° C., in a rate of 5° C./min. The solids were balanced for 5 minutes, to produce white solid crystals.

[0160] It was found that the resultant solid crystals were the crystal form IV as described in the invention by detection. The X-ray powder diffraction data of the crystal form are shown in FIG. 10 and Table 11.

TABLE-US-00013 TABLE 11 2theta d-spacing Intensity % 5.34 16.54 44.99 12.42 7.13 16.46 13.01 6.80 34.31 15.12 5.86 9.66 15.72 5.64 9.34 16.20 5.47 16.87 17.19 5.16 52.62 17.47 5.08 44.48 18.56 4.78 92.02 19.29 4.60 6.44 19.98 4.44 100.00 20.50 4.33 6.81 20.90 4.25 2.46 21.36 4.16 33.74 21.67 4.10 12.74 22.39 3.97 5.76 23.14 3.84 41.01 23.73 3.75 16.09 24.88 3.58 70.56 25.62 3.48 6.62 26.33 3.39 90.16 27.56 3.24 7.25 29.11 3.07 2.09 30.24 2.96 10.28 31.03 2.88 6.06 33.02 2.71 1.14 36.13 2.49 1.37

Example 9

[0161] About 11.5 mg of crisaborole in free form were weighted and charged into a glass bottle loaded with 0.2 mL of acetone solvent, and the resultant mixture volatilized at room temperature when exposed to air until the solvent completely volatilized. The precipitated solids were placed in a DSC(Q2000) tray, and the heating program was set as follows: the solids were heated to the temperature of 90° C., in a rate of 10° C./min; the solids were heated to the temperature of 145° C., in a rate of 5° C./min. The solids were balanced for 5 minutes, to produce white solid crystals.

[0162] It was found that the resultant solid crystals were the crystal form IV as described in the invention. The X-ray powder diffraction pattern of the crystal form is shown in FIG. 16 and the X-ray powder diffraction data of the crystal form are shown Table 12.

[0163] Upon conducting the differential scanning calorimetric analysis, the crystal form IV, when being heated to a temperature in the vicinity of 172° C., involved heat absorption peaks, and its DSC is shown in FIG. 11. Upon conducting the thermogravimetric analysis, the crystal form IV, when being heated to 150° C., had a mass lose gradient of about 1.4%, and its TGA is shown in FIG. 12. The crystal form IV according to the invention is an anhydrate.

TABLE-US-00014 TABLE 12 2theta d-spacing Intensity % 5.35 16.53 59.32 11.50 7.69 8.63 12.47 7.10 13.07 13.01 6.80 25.27 15.75 5.63 12.05 17.22 5.15 33.73 18.58 4.78 80.18 20.03 4.43 100.00 21.39 4.15 28.17 23.21 3.83 34.72 23.74 3.75 17.17 24.91 3.57 53.77 26.39 3.38 86.10 27.62 3.23 9.18

[0164] Test Part

Experimental Example 1 Study of Moisture Absorption

[0165] About 10 mg of the crystal form I, crystal form II, crystal form Ill and crystal form IV according to the invention were taken respectively to perform the dynamic vapor sorption (DVS) test. The obtained results were shown in Table 13:

TABLE-US-00015 TABLE 13 Relative humidity Weight increase of 80% Weight increase of 95% Weight increase (%) relative humidity relative humidity Crystal form I 0.14% 0.32% Crystal form II 0.13% 0.32% Crystal form III 0.09% 0.15% Crystal form IV 1.53% 4.90%

[0166] The DVS patterns of the crystal form I, crystal form II, crystal form III and crystal form IV are respectively shown in FIG. 17, FIG. 18, FIG. 19 and FIG. 20.

[0167] With regard to the descriptions for the moisture absorption characteristic and the definition for the increased weight of moisture absorption (Guidelines for the Moisture Absorption Tests of Drugs in the Appendix of Chinese Pharmacopoeia (2015), Experimental conditions: 25° C.±1° C., 80% relative humidity): [0168] Deliquescence: enough moisture is absorbed to form a liquid [0169] High moisture absorption: the increased weight as caused by absorbing moisture is not less than 15.0% [0170] Moisture absorption: the increased weight as caused by absorbing moisture is less than 15.0% but not less than 2.0% [0171] Slight moisture absorption: the increased weight as caused by absorbing moisture is less than 2.0% but not less than 0.2% [0172] No or almost no moisture absorption: the increased weight as caused by absorbing moisture is less than 0.2%.

[0173] The results show that according to the standards in Chinese Pharmacopoeia (2015), the crystal form I, crystal form II, and crystal form III of the invention almost have no moisture absorption, and the crystal IV has slight moisture absorption. Thus, each of the above crystal forms will not be ready to be influenced by high moisture so as to take the deliquescence. Particularly, even under the condition that the relative humidity was up to 95%, the crystal form I, crystal form II, and crystal form III of the invention still each have a low increased weight as caused by absorbing moisture, and thus they have more excellent deliquescence resistance.

Experimental Example 2 Study of Mechanical Stability

[0174] The crystal form I and crystal form IV of the invention were respectively placed in a mortar, and they were ground for 5 minutes by hand. The XRPD of the ground solids was tested, and the results were shown in Table 14:

TABLE-US-00016 TABLE 14 Starting crystal form Final crystal form Crystal form I Crystal form I Crystal form IV Crystal form IV

[0175] The results show that under the action of certain mechanical stress, the crystal form I and crystal form IV of the invention are not changed, and they still can maintain stable physical and chemical properties. The diagrams for showing the comparison of the XRPD patterns before and after grinding of the crystal form I and the crystal form IV are respectively shown in FIG. 21 and FIG. 22 (the upper figure is the XRPD pattern before grinding, and the lower figure is the XRPD pattern after grinding for 5 minutes.

Experimental Example 3 Study of Dynamic Solubility

[0176] Samples of the crystal form I, crystal form II, crystal form III and crystal form IV of the invention were respectively formulated into a saturated solution with a fasting stimulated intestinal fluid (FaSSIF) with a pH of 6.5, a feeding state stimulated intestinal fluid (FeSSIF) with a pH of 5.0, a stimulated gastric fluid (SGF) with a pH of 1.8, and water, and the high performance liquid chromatography (HPLC) was used to respectively measure the amounts of compounds in the solutions at 1 h, 4 h and 24 h. The results are shown in Table 15.

TABLE-US-00017 TABLE 15 FaSSIF (pH = 6.5) FeSSIF (pH = 5.0) Time Crystal Crystal Crystal Crystal Crystal Crystal Crystal Crystal (h) form I form II form III form IV form I form II form III form IV Solubility 1 0.006 0.011 0.008 0.009 0.044 0.018 0.025 0.062 (mg /ml) 4 0.007 0.005 0.010 0.017 0.059 0.049 0.067 0.061 24 0.012 0.008 0.012 0.013 0.059 0.055 0.074 0.056 SGF (pH = 1.8) H.sub.2O Time Crystal Crystal Crystal Crystal Crystal Crystal Crystal Crystal (h) form I form II form III form IV form I form II form III form IV Solubility 1 0.011 0.010 0.033 0.031 0.004 0.003 0.005 ND (mg /ml) 4 0.037 0.026 0.034 0.027 0.005 0.001 0.004 0.006 24 0.038 0.015 0.040 0.026 0.006 0.006 0.006 0.004 ND: un-detected.

[0177] The crystal form I, crystal form II, crystal form III and crystal form IV of the invention each have a solubility that is in line with medicinal requirements.

[0178] Experimental Example 4 Study of long-term and acceleration stabilities Samples of the crystal form I, crystal form II, and crystal form III of the invention were respectively placed under the conditions of 25° C. and a 60% relative humidity, and under the conditions of 40° C. and a 75% relative humidity, and the results of the changes in the crystal form are shown in Table 16:

TABLE-US-00018 TABLE 16 Starting crystal Storage form Storage condition time Changes of crystal form Crystal form I 25° C., 60% 3 months Crystal form I remained relative humidity unchanged Crystal form I 40° C., 75% 3 months Crystal form I remained relative humidity unchanged Crystal form II 25° C., 60% 3 months Crystal form II remained relative humidity unchanged Crystal form II 40° C., 75% 3 months Crystal form II remained relative humidity unchanged Crystal form III 25° C., 60% 3 months Crystal form III remained relative humidity unchanged Crystal form III 40° C., 75% 3 months Crystal form III remained relative humidity unchanged

[0179] The results show that the crystal form I, crystal form II and crystal form Ill of the invention can still maintain their stability placed in the two kinds of humidity for 3 months. The XRPD diagrams for showing the comparisons in the long-term and acceleration stabilities of the crystal form I, crystal form II, and crystal form Ill of the invention are respectively shown in FIG. 23, FIG. 24 and FIG. 25 (in each figure, the upper pattern shows the XRPD pattern of the crystal forms before the storage, the middle pattern shows the XRPD pattern of the crystal forms after 3 months by being placed under the storage conditions of 25° C. and a 60% relative humidity, and the lower pattern shows the XRPD pattern of the crystal forms after 3 months by being placed under the conditions of 40° C. and a 75% relative humidity).

Experimental Example 5 Study of Particle Size Distribution

[0180] Particle Size Comparative Test

[0181] Samples of the crystal form I, crystal form II, crystal form III, and crystal form IV of the invention were taken to carry out the particle size distribution test.

[0182] The results of the particle size distribution are shown in Table 17:

TABLE-US-00019 TABLE 17 Crystal form MV (μm) D10 (μm) D50 (μm) D90 (μm) Crystal form I 9.62 1.69 5.52 20.35 Crystal form II 23.13 8.24 20.46 40.42 Crystal form III 289.0 21.68 163.0 903.1 Crystal form IV 52.95 13.43 33.68 99.36 Note: MV represents average particle size as calculated in terms of the volume D10 represents the particle size corresponding to 10% of the particle size distribution (volume distribution) D50 represents the particle size corresponding to 50% of the particle size distribution (volume distribution), also called as median size D90 represents the particle size corresponding to 90% of the particle size distribution (volume distribution).

[0183] The PSD patterns of the crystal form I, the crystal form II and the crystal form IV are respectively shown in FIG. 26, FIG. 27 and FIG. 28, and from these figures, it can be seen that the particle size distributions of the crystal form I, the crystal form II and the crystal form IV are homogeneous.

[0184] In addition, the PLM patterns of the crystal form I, the crystal form II and the crystal form IV are respectively shown in FIG. 29, FIG. 30 and FIG. 31, and from these figures, it can be seen that the particle sizes of the particles of the crystal form I, the crystal form II and the crystal form IV are homogeneous.

[0185] The homogenous particle size can help to simplify the post-treatment processes of the formulation, and to increase quantity controls.

[0186] A person skilled in the art could understand that under the teachings of the description, some variations or changes to the invention are allowable. These variations and changes also should be in the scope as defined by the claims in the invention.