Crisaborole free crystal form and preparation method and application thereof

Abstract

The invention relates to four free crystal forms of crisaborole and a preparation method thereof. The invention also relates to a pharmaceutical composition containing the crystal form and application thereof. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with the application date of May 9, 2017, application number 201780009362.9, and invention name "Crystalline form of free form of crisaborole and its preparation method and use". Technical Field

[0002] The present invention relates to the technical field of drug crystals, and in particular to a crystal form of free form of crisaborole, a preparation method thereof and a use thereof. Background Art

[0003] Polymorphism or polymorphism is a unique property of certain molecules and molecular combinations. The same molecule may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility, stability, thermal properties, mechanical properties, purification ability, X-ray diffraction spectra, infrared absorption spectra, Raman spectroscopy and solid-state nuclear magnetic resonance, etc. One or more analytical detection methods can be used to distinguish different crystal forms of the same molecule or molecular combination.

[0004] The discovery of new crystalline forms of active pharmaceutical ingredients (including anhydrates, hydrates, solvates, etc.) may produce more processing advantages or provide substances with better physical and chemical properties, such as better bioavailability, storage stability, easy processing, easy purification, or serve as intermediate crystalline forms that promote conversion to other crystalline forms. New crystalline forms of certain pharmaceutically useful compounds can also help improve the performance of drugs. It expands the raw material forms available in pharmaceutical formulations, such as improving dissolution, improving shelf life, and being easier to process.

[0005] Psoriasis and atopic dermatitis are non-infectious inflammatory diseases with chronic and relapsing courses. Although some treatments are currently available to control these diseases, other treatments are still under investigation. Appropriate treatments can help relieve symptoms and prolong the interval between attacks. Crisaborole (also known as Crisaborole, AN-2728) is a topically administered boron-containing anti-inflammatory compound developed by Anacor Pharmaceuticals Inc., which inhibits PDE4 activity and thus inhibits the release of TNFalpha, IL-12, IL-23 and other cytokines. Crisaborole has a good therapeutic effect on skin diseases such as psoriasis and atopic dermatitis, and was approved by the US FDA on December 14, 2016. The chemical name of Crisaborole is: 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, and its chemical structure is shown in the following formula (I):

[0006]

[0007] However, there is no public report on the crystal form of Crisaborole in the prior art. Therefore, it is necessary to conduct a comprehensive and systematic polymorph screening of Crisaborole and select the crystal form with beneficial properties for Crisaborole product development.

[0008] The inventors of the present invention surprisingly discovered four crystal forms of Crisaborole during the research process. The crystal form of Crisaborole provided by the present invention has good stability, low hygroscopicity, uniform particle size distribution, solubility that meets pharmaceutical requirements, can be stably stored, and avoids crystal transformation during the development of drugs, which has great development value. Summary of the invention

[0009] In view of the deficiencies in the prior art, the present invention aims to provide a crystalline form of Crisaborole and a preparation method and use thereof.

[0010] According to the purpose of the present invention, the present invention provides a crystalline form I of free form of crisaborole (hereinafter referred to as "crystalline form I").

[0011] Using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form I has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 26.1°±0.2°, and 14.1°±0.2°.

[0012] In a preferred embodiment of the present invention, the X-ray powder diffraction of the crystalline form I has characteristic peaks at diffraction angles 2θ of 18.1°±0.2°, 24.8°±0.2°, and 16.0°±0.2°.

[0013] In another preferred embodiment, the X-ray powder diffraction of the crystalline form I has characteristic peaks at diffraction angles 2θ of 28.4°±0.2°, 21.4°±0.2°, and 6.0°±0.2°.

[0014] In a further preferred embodiment, the X-ray powder diffraction of the crystalline form I has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 26.1°±0.2°, 14.1°±0.2°, 18.1°±0.2°, 24.8°±0.2°, 16.0°±0.2, 28.4°±0.2°, 21.4°±0.2°, and 6.0°±0.2°.

[0015] In a non-limiting manner, in a specific embodiment of the present invention, the X-ray powder diffraction spectrum of Form I is as follows: Figure 1 shown.

[0016] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form I, the preparation method comprising:

[0017] 1) dissolving the solid of the free form of Crisaborole in a single volatile solvent, volatilizing and crystallizing to obtain a solid of Form I, wherein the single volatile solvent is an alkyl nitrile, an alkyl ether, a halogenated hydrocarbon, or an ester;

[0018] in:

[0019] The alkyl nitrile solvent is acetonitrile,

[0020] The alkyl ether solvent is methyl tert-butyl ether,

[0021] The halogenated hydrocarbon solvent is a chlorinated alkane, preferably, the chlorinated alkane is chloroform, dichloromethane,

[0022] The ester solvent is ethyl acetate,

[0023] The volatilization and crystallization are carried out at room temperature; or

[0024] 2) suspending a solid sample of Crisaborole in free form in a single solvent or a mixed solvent to obtain a suspension, stirring the suspension at a certain temperature, centrifuging, and drying to obtain a crystalline form I solid,

[0025] in,

[0026] The single solvent includes but is not limited to water, aromatic hydrocarbons, preferably water, toluene,

[0027] The mixed solvent is a mixed solvent of water and alcohols, alkyl nitriles, esters, ketones, amides, cyclic ethers or dimethyl sulfoxide, wherein the volume ratio of water to other solvents is between 4:3 and 5:1, or

[0028] The mixed solvent is a mixed solvent of saturated aliphatic hydrocarbons and ketones, esters, cyclic ethers, halogenated hydrocarbons or alcohols, wherein the volume ratio of saturated aliphatic hydrocarbons to ketones, esters, cyclic ethers, halogenated hydrocarbons or alcohols is preferably 5:4 to 7:1; or,

[0029] The mixed solvent is a mixed solvent of aromatic hydrocarbons and halogenated hydrocarbons, wherein the volume ratio of the aromatic hydrocarbons to the halogenated hydrocarbons is preferably 5:4.

[0030] Preferably, the mixed solvent is a mixed solvent of water and methanol, acetonitrile, isopropyl acetate, 1,4-dioxane, acetone, dimethylformamide or dimethyl sulfoxide.

[0031] Preferably, the mixed solvent is a mixed solvent of n-heptane and methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, chloroform or ethanol.

[0032] Preferably, the mixed solvent is a mixed solvent of toluene and dichloromethane.

[0033] The certain temperature is preferably from room temperature to 50°C.

[0034] According to the purpose of the present invention, the present invention provides a free form of Crisaborole, Form II (hereinafter referred to as "Form II").

[0035] Using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form II has characteristic peaks at diffraction angles 2θ of 20.8°±0.2°, 16.6°±0.2°, and 22.6°±0.2°.

[0036] In a preferred embodiment of the present invention, the X-ray powder diffraction of the crystalline form II has characteristic peaks at diffraction angles 2θ of 27.9°±0.2°, 21.8°±0.2°, and 17.6°±0.2°.

[0037] In another preferred embodiment, the X-ray powder diffraction of the crystalline form II has characteristic peaks at diffraction angles 2θ of 18.4°±0.2°, 21.4°±0.2°, and 23.1°±0.2°.

[0038] In a further preferred embodiment, the X-ray powder diffraction angle 2θ of the crystalline form II has characteristic peaks at 20.8°±0.2°, 16.6°±0.2°, 22.6°±0.2°, 27.9°±0.2°, 21.8°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 21.4°±0.2°, and 23.1°±0.2°.

[0039] In a non-limiting manner, in a specific embodiment of the present invention, the X-ray powder diffraction spectrum of Form II is as follows: Figure 4 shown.

[0040] According to the purpose of the present invention, the present invention also provides a method for preparing the crystal form II, which comprises:

[0041] 1) suspending a solid sample of Crisaborole free form in a mixed solvent of water and alcohol to obtain a suspension, stirring, centrifuging, and drying to obtain a crystalline form II solid, wherein the volume ratio of water to alcohol is 1:1,

[0042] The alcohol is preferably methanol;

[0043] The stirring and separation steps are both performed at room temperature; or

[0044] 2) dissolving a solid sample of Crisaborole free form in a positive solvent, then adding an anti-solvent thereto, stirring to crystallize, separating, and drying to obtain a solid of Form II, wherein the solid of Crisaborole free form is present in the positive solvent in a manner of being clearly dissolved or completely dissolved, and the anti-solvent is added in an amount until a solid is obtained,

[0045] The positive solvents include but are not limited to alcohols, ketones, cyclic ethers, amides, dimethyl sulfoxide, and the anti-solvent is preferably water, wherein:

[0046] The alcohol solvent is isopropanol,

[0047] The ketone solvent is acetone,

[0048] The cyclic ether solvent is tetrahydrofuran or 1,4-dioxane.

[0049] The amide solvent is dimethylformamide,

[0050] The stirring crystallization and separation steps were both carried out at room temperature.

[0051] According to the purpose of the present invention, the present invention provides a free form of Crisaborole, Form III (hereinafter referred to as "Form III").

[0052] Using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form III has characteristic peaks at diffraction angles 2θ of 20.6°±0.2°, 27.8°±0.2°, and 18.6°±0.2°.

[0053] In a preferred embodiment of the present invention, the X-ray powder diffraction of the crystalline form III has characteristic peaks at diffraction angles 2θ of 13.6±0.2°, 19.5°±0.2°, and 21.7°±0.2°.

[0054] In another preferred embodiment, the X-ray powder diffraction of the crystalline form III has characteristic peaks at diffraction angles 2θ of 21.3°±0.2°, 16.3°±0.2°, and 22.5°±0.2°.

[0055] In a further preferred embodiment of the present invention, the X-ray powder diffraction of the crystalline form III has characteristic peaks at diffraction angles 2θ of 20.6°±0.2°, 27.8°±0.2°, 18.6°±0.2°, 13.6±0.2°, 19.5°±0.2°, 21.7°±0.2°, 21.3°±0.2°, 16.3°±0.2°, and 22.5°±0.2°.

[0056] In a non-limiting manner, in a specific embodiment of the present invention, the X-ray powder diffraction spectrum of Form III is as follows: Figure 7 shown.

[0057] According to the purpose of the present invention, the present invention also provides a method for preparing the crystal form III, which comprises: dissolving Crisaborole free form solid in a ketone solvent, volatilizing and crystallizing to obtain the crystal form III solid, wherein

[0058] The ketone solvent is preferably acetone,

[0059] The temperature of the volatilization and crystallization is room temperature.

[0060] According to the purpose of the present invention, the present invention provides a free form of crisaborole, Form IV (hereinafter referred to as "Form IV").

[0061] Using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form IV has characteristic peaks at diffraction angles 2θ of 20.0°±0.2°, 18.6°±0.2°, and 26.4°±0.2°.

[0062] In a preferred embodiment of the present invention, the X-ray powder diffraction of the crystalline form IV has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 24.9°±0.2°, and 23.2°±0.2°.

[0063] In another preferred embodiment, the X-ray powder diffraction of the crystalline form IV has characteristic peaks at diffraction angles 2θ of 17.2°±0.2°, 21.4°±0.2°, and 13.0°±0.2°.

[0064] In a further preferred embodiment, the X-ray powder diffraction of the crystalline form IV has characteristic peaks at diffraction angles 2θ of 20.0°±0.2°, 18.6°±0.2°, 26.4°±0.2°, 5.3°±0.2°, 24.9°±0.2°, 23.2°±0.2°, 17.2°±0.2°, 21.4°±0.2°, and 13.0°±0.2°.

[0065] In a non-limiting manner, in a specific embodiment of the present invention, the X-ray powder diffraction spectrum of Form IV is as follows: Fig.10 shown.

[0066] According to the purpose of the present invention, the present invention also provides a method for preparing the crystal form IV, which comprises: heating the free form solid, crystal form I, crystal form II or crystal form III of Crisaborole to 120°C-150°C to obtain the crystal form IV solid, preferably heating to 130°C-145°C.

[0067] According to the purpose of the present invention, the present invention also provides a pharmaceutical composition, which comprises a therapeutically and / or preventively effective amount of one or more of the Crisaborole free form crystalline form I, or Crisaborole free form crystalline form II, or Crisaborole free form crystalline form III, or Crisaborole free form crystalline form IV as described above, or any combination of these crystalline forms, and at least one pharmaceutically acceptable carrier or excipient.

[0068] Use of Crisaborole free form crystal form I, Crisaborole free form crystal form II, Crisaborole free form crystal form III, Crisaborole free form crystal form IV, or any combination of these crystal forms in the production of pharmaceutical preparations for treating psoriasis and allergic dermatitis.

[0069] In the present invention, "room temperature" refers to 15-25°C.

[0070] In the present invention, the meanings of “2θ” and “2theta” are consistent.

[0071] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm, and most preferably 500 rpm.

[0072] The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.

[0073] Unless otherwise specified, the "drying" can be carried out at room temperature or higher. The drying temperature is room temperature to about 60°C, or to 40°C, or to 50°C. The drying time can be 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven, or a vacuum oven.

[0074] In the present invention, "crystal" or "crystalline form" refers to the one confirmed by the X-ray diffraction pattern shown. It will be understood by those skilled in the art that the physicochemical properties discussed here can be characterized, and the experimental errors depend on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will usually change with the conditions of the instrument. It should be noted in particular that the relative intensity of the X-ray diffraction pattern may also change with the change of experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In addition, the diffraction angle 2θ is usually allowed to have an error of ±0.2°. In addition, due to the influence of experimental factors such as sample height, the overall shift of the peak angle will be caused, and a certain shift is usually allowed. Therefore, it will be understood by those skilled in the art that the X-ray diffraction pattern of a crystalline form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the examples referred to here. Any crystalline form having a pattern that is the same or similar to the characteristic peaks in these spectra belongs to the scope of the present invention. Those skilled in the art can compare the spectra listed in the present invention with the spectra of an unknown crystalline form to confirm whether the two sets of spectra reflect the same or different crystalline forms.

[0075] "Crystal form" and "polymorph" and other related terms in the present invention refer to the existence of a solid compound in a specific crystalline state in a crystal structure. The difference in the physicochemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate, etc. In extreme cases, the difference in solubility or dissolution rate can cause drug inefficiency or even toxicity.

[0076] It should be noted that the numerical values ​​and numerical ranges mentioned in the present invention should not be narrowly understood as the numerical values ​​or numerical ranges themselves. Those skilled in the art should understand that they can fluctuate around the specific numerical values ​​based on different specific technical environments without departing from the spirit and principles of the present invention. In the present invention, such floating ranges that can be foreseen by those skilled in the art are mostly expressed by the term "approximately". BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 This is the X-ray powder diffraction pattern of Form I obtained in Example 1 of the present invention.

[0078] Figure 2 This is the DSC graph of Form I obtained in Example 1 of the present invention.

[0079] Figure 3 This is the TGA chart of Form I obtained in Example 1 of the present invention.

[0080] Figure 4 This is the X-ray powder diffraction pattern of Form II obtained in Example 4 of the present invention.

[0081] Figure 5This is the DSC graph of Form II obtained in Example 4 of the present invention.

[0082] Figure 6 This is the TGA chart of Form II obtained in Example 4 of the present invention.

[0083] Figure 7 This is the X-ray powder diffraction pattern of Form III obtained in Example 6 of the present invention.

[0084] Figure 8 This is the DSC graph of Form III obtained in Example 6 of the present invention.

[0085] Fig. 9 This is the TGA chart of Form III obtained in Example 6 of the present invention.

[0086] Fig.10 This is the X-ray powder diffraction pattern of Form IV obtained in Example 8 of the present invention.

[0087] Fig.11 This is the DSC graph of Form IV obtained in Example 9 of the present invention.

[0088] Fig.12 This is the TGA chart of Form IV obtained in Example 9 of the present invention.

[0089] Fig.13 This is the X-ray powder diffraction pattern of Form I obtained in Example 2 of the present invention.

[0090] Fig.14 This is the X-ray powder diffraction pattern of Form I obtained in Example 3 of the present invention.

[0091] Fig.15 This is the X-ray powder diffraction pattern of Form III obtained in Example 7 of the present invention.

[0092] Fig.16 This is the X-ray powder diffraction pattern of Form IV obtained in Example 9 of the present invention.

[0093] Fig.17 This is the DVS diagram of Form I of the present invention.

[0094] Fig.18 This is the DVS diagram of Form II of the present invention.

[0095] Fig.19 This is the DVS diagram of Form III of the present invention.

[0096] Fig. 20 This is the DVS diagram of Form IV of the present invention.

[0097] Fig.21 This is a comparison chart of XRPD before and after grinding of Form I of the present invention.

[0098] Fig. 22 This is a comparison diagram of XRPD of Form IV of the present invention before and after grinding.

[0099] Fig.23 This is a comparison chart of the long-term and accelerated stability XRPD of Form I of the present invention.

[0100] Fig.24 This is a comparison chart of the long-term and accelerated stability XRPD of Form II of the present invention.

[0101] Fig.25 This is a comparison chart of the long-term and accelerated stability XRPD of Form III of the present invention.

[0102] Fig.26 This is the PSD diagram of Form I of the present invention.

[0103] Fig. 27 This is the PSD diagram of Form II of the present invention.

[0104] Fig.28 This is the PSD diagram of Form IV of the present invention.

[0105] Fig.29 This is a PLM diagram of Form I of the present invention.

[0106] Fig.30 This is a PLM diagram of Form II of the present invention.

[0107] Fig.31 This is the PLM diagram of Form IV of the present invention. DETAILED DESCRIPTION

[0108] The present invention is further defined with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods may be implemented without departing from the scope of the present invention.

[0109] Instruments and methods used to collect data:

[0110] The abbreviations used in the present invention are explained as follows:

[0111] XRPD: X-ray powder diffraction

[0112] DSC: Differential Scanning Calorimetry

[0113] TGA: Thermogravimetric analysis

[0114] DVS: Dynamic Water Sorption

[0115] PSD: Particle Size Distribution

[0116] PLM: Polarized Light Microscopy

[0117] HPLC: High Performance Liquid Chromatography

[0118] The X-ray powder diffraction pattern of the present invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0119] X-ray reflection parameters: Cu, Kα

[0120] Kα1 1.540598; Kα2 1.544426

[0121] Kα2 / Kα1 intensity ratio: 0.50

[0122] Voltage: 45 kV

[0123] Current: 40 milliamperes (mA)

[0124] Scanning range: from 3.0 to 40.0 degrees

[0125] The differential scanning calorimetry (DSC) diagram of the present invention is collected on TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0126] Scan rate: 10℃ / min

[0127] Protective gas: Nitrogen

[0128] The thermogravimetric analysis (TGA) graph of the present invention was collected on TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0129] Scan rate: 10℃ / min

[0130] Protective gas: Nitrogen

[0131] The dynamic moisture sorption (DVS) graph of the present invention is collected on an Intrinsic dynamic moisture sorption instrument produced by SMS (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture sorption instrument are as follows:

[0132] Temperature: 25℃

[0133] Carrier gas, flow rate: N2, 200 ml / min

[0134] Mass change per unit time: 0.002% / minute

[0135] Relative humidity range: 0%RH-95%RH

[0136] The particle size distribution (PSD) results described in the present invention are collected on a Microtrac S3500 laser particle size analyzer. Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) sampling system. This test uses a wet method, and the test dispersion medium is Isopar G. The method parameters of the laser particle size analyzer are as follows:

[0137]

[0138] *: Flow rate 60% is 60% of 65 ml / sec.

[0139] High performance liquid chromatography (HPLC) data were collected on an Agilent 1260 using a diode array detector (DAD).

[0140] The HPLC method parameters of the present invention are as follows:

[0141] 1. Chromatographic column: Waters Xbridge C18150×4.6mm, 5μm

[0142] 2. Mobile phase: A: 0.1% trifluoroacetic acid aqueous solution

[0143] B: 0.1% trifluoroacetic acid in acetonitrile

[0144] The elution gradient is as follows:

[0145] Time (minutes) % Mobile phase B 0.0 10 3.0 10 20.0 90 25.0 90 25.1 10 30.0 10

[0146] 3. Flow rate: 1.0mL / min

[0147] 4. Injection volume: 5μL

[0148] 5. Detection wavelength: 254nm

[0149] 6. Column temperature: 40℃

[0150] 7. Diluent: 50% acetonitrile

[0151] In the following examples, unless otherwise specified, "room temperature" refers to 15-25°C.

[0152] Crisaborole free form solid used in the following examples is commercially available.

[0153] Example 1

[0154] 202.5 mg of Crisaborole free form solid was added to 6 mL of a mixed solvent system (methanol: water, volume ratio of 1:5), stirred at 50° C. for 5 days, centrifuged, and dried in vacuo at room temperature to obtain white solid crystals.

[0155] After testing, the obtained solid crystal is the crystal form I of the present invention, and its X-ray powder diffraction spectrum is as follows: Figure 1 The X-ray powder diffraction data are shown in Table 1.

[0156] When differential scanning calorimetry analysis was performed, an endothermic peak began to appear when Form I was heated to around 123°C. Figure 2 When thermogravimetric analysis was performed, Form I had a mass loss gradient of about 4.2% when heated to 120°C. Its TGA is shown in the attached Figure 3 The crystalline form I of the present invention is a hydrate.

[0157] Table 1

[0158] 2theta d interval strength% 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

[0159] Example 2

[0160] 51.4 mg of Crisaborole free form solid was added to 1 mL of acetonitrile solvent, dissolved and then left to evaporate open at room temperature until the solvent evaporated completely to obtain white solid crystals.

[0161] After testing, the obtained solid crystal is the crystal form I described in the present invention. Its X-ray powder diffraction data is as follows Fig.13 , as shown in Table 2.

[0162] Table 2

[0163]

[0164]

[0165] Table 3 Using the same method as Example 2, a certain mass of Crisaborole free form solid was added to a certain volume of solvent, dissolved, and then left to evaporate open at room temperature until the solvent evaporated completely to obtain white solid crystals. The obtained solid was tested by XRPD to be Form I.

[0166] Table 3

[0167]

[0168] Example 3

[0169] 30.7 mg of Crisaborole free form solid was added to 1.5 mL of solvent water, stirred magnetically at room temperature for two days, centrifuged, and dried in vacuum at room temperature to obtain white solid crystals.

[0170] After testing, the obtained solid crystal is the crystal form I described in the present invention, and its X-ray powder diffraction data is as follows: Fig.14 , as shown in Table 4.

[0171] Table 4

[0172]

[0173]

[0174] Table 5 The same method as in Example 3 was used to add a certain mass of Crisaborole free form solid to a certain volume of solvent. The mixture was stirred magnetically at room temperature, centrifuged, and dried under vacuum at room temperature to obtain white solid crystals. The obtained solid was found to be Form I by XRPD test.

[0175] Table 5

[0176]

[0177] Example 4

[0178] 34.5 mg of Crisaborole free form solid was added to 1.6 mL of a mixed solvent system (methanol: water, volume ratio of 1:1), magnetically stirred at room temperature, centrifuged, and vacuum dried at room temperature to obtain white solid crystals.

[0179] After testing, the obtained solid crystal is the crystal form II of the present invention, and its X-ray powder diffraction spectrum is as follows: Figure 4 , and its X-ray powder diffraction data are shown in Table 6.

[0180] When differential scanning calorimetry analysis was performed, an endothermic peak began to appear when Form II was heated to around 134°C. Figure 5 When thermogravimetric analysis was performed, Form II had a mass loss gradient of about 4.2% when heated to 115°C. Its TGA is shown in the attached Figure 6 The crystal form II of the present invention is a hydrate.

[0181] Table 6

[0182]

[0183]

[0184] Example 5

[0185] 30.3 mg of Crisaborole free form solid was added to 0.4 mL of isopropanol solvent, and 0.6 mL of anti-solvent water was slowly added dropwise at room temperature under magnetic stirring. The mixture was stirred for crystallization for 5 days, centrifuged, and vacuum dried at room temperature to obtain white solid crystals.

[0186] After testing, the obtained solid crystal is the crystal form II described in the present invention, and its X-ray powder diffraction data is shown in Table 7.

[0187] Table 7

[0188]

[0189]

[0190] Table 8 The same preparation method as in this example is used to add a certain mass of Crisaborole free form solid to a certain volume of positive solvent, slowly dropwise add a certain volume of anti-solvent under room temperature and magnetic stirring, stir to crystallize, centrifuge, and vacuum dry at room temperature to obtain white solid crystals. The obtained solid is tested by XRPD to be Form II.

[0191] Table 8

[0192]

[0193] Example 6

[0194] Add 200.5 mg of Crisaborole free form solid to a 20 mL glass bottle filled with 5 mL of acetone solvent, dissolve it, seal the bottle mouth with a sealing film, poke a few small holes with a needle, and leave it at room temperature to evaporate slowly to obtain white solid crystals.

[0195] After testing, the obtained solid crystal is the crystal form III of the present invention, and its X-ray powder diffraction spectrum is as follows: Figure 7 Its X-ray powder diffraction data are shown in Table 9.

[0196] When differential scanning calorimetry analysis was performed, an endothermic peak began to appear when Form III was heated to around 136°C. Figure 8 When subjected to thermogravimetric analysis, Form III has a mass loss gradient of about 2.5% when heated to 145°C. Its TGA is shown in the attached Fig. 9 The crystal form III of the present invention is a hydrate.

[0197] Table 9

[0198]

[0199]

[0200] Example 7

[0201] 11.5 mg of Crisaborole free form solid was added to 0.2 mL of acetone solvent and evaporated at room temperature until the solvent was completely evaporated to obtain white solid crystals.

[0202] After testing, the obtained solid crystal is the crystal form III of the present invention. Its X-ray powder diffraction data is as follows: Fig.15 , as shown in Table 10.

[0203] Table 10

[0204] 2theta d interval strength% 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

[0205] Example 8

[0206] Add about 5 mg Crisaborole free form solid to the DSC (Q2000) small plate at room temperature, set the heating program as follows: heat to 90°C, 10°C / min; heat to 130°C, 5°C / min; balance for 5 minutes to obtain solid crystals.

[0207] After testing, the obtained solid crystal is the crystal form IV of the present invention, and its X-ray powder diffraction data is as follows: Fig.10 , as shown in Table 11.

[0208] Table 11

[0209]

[0210]

[0211] Example 9

[0212] Weigh 11.5 mg of Crisaborole free form solid, add it to a glass bottle containing 0.2 mL of acetone solvent, and evaporate it at room temperature without opening until the solvent evaporates completely. Place the precipitated solid in a DSC (Q2000) small dish and heat it at room temperature. The heating program is set as follows: heat to 90°C, 10°C / min; heat to 145°C, 5°C / min; balance for 5 minutes to obtain solid crystals.

[0213] After testing, the obtained solid crystal is the crystal form IV of the present invention. Its X-ray powder diffraction spectrum is as follows Fig.16 Its X-ray powder diffraction data are shown in Table 12.

[0214] When differential scanning calorimetry analysis was performed, an endothermic peak began to appear when Form IV was heated to around 172°C. Fig.11 When thermogravimetric analysis was performed, Form IV had a mass loss gradient of about 1.4% when heated to 150°C. Its TGA is shown in the attached Fig.12The crystalline form IV of the present invention is an anhydrate.

[0215] Table 12

[0216]

[0217]

[0218] Experimental Section

[0219] Experimental Example 1: Study on Moisture Absorption

[0220] About 10 mg of the crystal form I, crystal form II, crystal form III, and crystal form IV of the present invention were taken for dynamic moisture sorption (DVS) test. The results are shown in Table 13.

[0221] Table 13

[0222]

[0223] The DVS diagrams of Form I, Form II, Form III, and Form IV are shown in Fig.17 , Fig.18 , Fig.19 and Fig. 20 .

[0224] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for hygroscopicity test of drugs in the appendix of the 2015 edition of the Chinese Pharmacopoeia, experimental conditions: 25℃±1℃, 80% relative humidity):

[0225] Deliquescent: Absorbs enough water to form a liquid

[0226] Highly hygroscopic: weight gain due to moisture absorption is not less than 15.0%

[0227] Hygroscopic: Weight gain due to moisture absorption is less than 15.0% but not less than 2.0%

[0228] Slightly hygroscopic: weight gain due to moisture absorption is less than 2.0% but not less than 0.2%

[0229] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%

[0230] The results show that according to the standards of the 2015 edition of the Chinese Pharmacopoeia, the crystal form I, crystal form II, and crystal form III of the present invention are almost non-hygroscopic, and the crystal form IV is slightly hygroscopic, and is not easily affected by high humidity and deliquesced. In particular, even under conditions of relative humidity as high as 95%, the weight gain due to moisture absorption of the crystal form I, crystal form II, and crystal form III of the present invention is still very low, and has more excellent deliquesce resistance.

[0231] Experimental Example 2 Mechanical Stability Study

[0232] The crystal form I and the crystal form IV of the present invention were placed in a mortar, ground manually for 5 minutes, and tested by solid XRPD. The results are shown in Table 14.

[0233] Table 14

[0234] Starting crystal form Final crystal form Crystalline Form I Crystalline Form I Form IV Form IV

[0235] The results show that under the action of certain mechanical stress, the crystal form I and crystal form IV of the present invention do not change and can still maintain stable physical and chemical properties. The XRPD comparison diagrams of crystal form I and crystal form IV before and after grinding are shown in Figure 21 to Figure 22 (The upper picture is the XRPD picture before grinding, and the lower picture is the XRPD picture after grinding for 5 minutes).

[0236] Experimental Example 3 Dynamic Solubility Study

[0237] The samples of the crystal form I, crystal form II, crystal form III and crystal form IV of the present invention were respectively prepared into saturated solutions with artificial intestinal fluid (FaSSIF) at pH 6.5 in the fasting state, artificial intestinal fluid (FeSSIF) at pH 5.0 in the fed state, simulated artificial gastric fluid (SGF) at pH 1.8 and water, and the content of the drug in the solution was determined by high performance liquid chromatography (HPLC) at 1h, 4h and 24h. The results are shown in Table 15.

[0238] Table 15

[0239]

[0240] ND: Not Detected

[0241] The solubility of the crystal form I, crystal form II, crystal form III and crystal form IV of the present invention all meet the requirements for pharmaceutical use.

[0242] Experimental Example 4: Long-term and accelerated stability studies

[0243] Samples of the crystal form I, crystal form II and crystal form III of the present invention were placed at 25° C., 60% relative humidity and 40° C., 75% relative humidity, respectively. The results of the crystal form changes are shown in Table 16.

[0244] Table 16

[0245]

[0246] The results show that the crystal form I, crystal form II, and crystal form III of the present invention can remain stable for 3 months under two humidity conditions. The long-term and accelerated stability XRPD comparison diagrams of crystal form I, crystal form II, and crystal form III are shown in Fig.23 , Fig.24 and Fig.25(In each figure, the upper figure is the XRPD figure before placement, the middle figure is the XRPD figure after placement for 3 months under the storage conditions of 25°C and 60% humidity, and the lower figure is the XRPD figure after placement for 3 months under the storage conditions of 40°C and 75% humidity).

[0247] Experimental Example 5 Particle Size Distribution Study

[0248] Particle size comparison test:

[0249] Samples of Form I, Form II, Form III and Form IV of the present invention were taken for particle size distribution test.

[0250] The particle size distribution results are shown in Table 17.

[0251] Table 17

[0252] 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 Form IV 52.95 13.43 33.68 99.36

[0253] Note:

[0254] MV: mean particle size by volume

[0255] D10: represents the particle size corresponding to 10% of the particle size distribution (volume distribution).

[0256] D50: indicates the particle size corresponding to 50% of the particle size distribution (volume distribution), also known as the median diameter

[0257] D90: indicates the particle size corresponding to 90% of the particle size distribution (volume distribution)

[0258] The PSD diagrams of Form I, Form II and Form IV are shown in Fig.26 , Fig. 27 and Fig.28 As can be seen from the figure, the particle size distributions of Form I, Form II and Form IV are relatively uniform.

[0259] In addition, the PLM diagrams of Form I, Form II and Form IV are respectively shown in Fig.29 , Fig.30 and Fig.31 It can also be seen from the figure that the particle sizes of Form I, Form II and Form IV are relatively uniform.

[0260] Uniform particle size helps to simplify post-processing in the formulation process and improve quality control.

[0261] Those skilled in the art will appreciate that, based on the teachings of this specification, some modifications or changes may be made to the present invention, and these modifications and changes should also be within the scope defined by the claims of the present invention.

Claims

1. Crisaborole free form Form I with the structural formula shown below, It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 26.1°±0.2°, and 14.1°±0.2°.

2. The crystalline form I of Crisaborole free form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at diffraction angles 2θ of 18.1°±0.2°, 24.8°±0.2°, and 16.0°±0.2°.

3. The crystalline form I of Crisaborole free form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at diffraction angles 2θ of 28.4°±0.2°, 21.4°±0.2°, and 6.0°±0.2°.

4. The method for preparing the crystalline form I of the free form of Crisaborole according to any one of claims 1 to 3, characterized in that: The preparation methods include the following: 1) dissolving the Crisaborole free form solid in a single volatile solvent, volatilizing and crystallizing to obtain a Form I solid, wherein the single volatile solvent is an alkyl nitrile, an alkyl ether, a halogenated hydrocarbon, or an ester; or 2) suspending the Crisaborole free form solid in a single solvent or a mixed solvent to obtain a suspension, stirring, separating, and drying to obtain a crystalline form I solid, wherein the single solvent is water or an aromatic hydrocarbon; the mixed solvent is a mixed solvent of water and alcohols, alkyl nitriles, esters, ketones, amides, cyclic ethers or dimethyl sulfoxide, wherein the volume ratio of water to other solvents is between 4:3 and 5:1, or the mixed solvent is a mixed solvent of saturated aliphatic hydrocarbons and ketones, esters, cyclic ethers, halogenated hydrocarbons or alcohols, or the mixed solvent is a mixed solvent of aromatic hydrocarbons and halogenated hydrocarbons.

5. The method for preparing the free form of Crisaborole Form I according to claim 4, wherein the single volatile solvent is acetonitrile, methyl tert-butyl ether, chloroform, dichloromethane, or ethyl acetate; the mixed solvent is a mixed solvent of water and methanol, acetonitrile, isopropyl acetate, 1,4-dioxane, acetone, dimethylformamide, or dimethyl sulfoxide, or the mixed solvent is a mixed solvent of n-heptane and methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, chloroform, or ethanol, or the mixed solvent is a mixed solvent of toluene and dichloromethane.

6. Crisaborole free form Form II with the structural formula shown below, It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form II has characteristic peaks at diffraction angles 2θ of 20.8°±0.2°, 16.6°±0.2°, and 22.6°±0.2°.

7. The crystalline form II of the free form of Crisaborole according to claim 6, characterized in that The X-ray powder diffraction pattern of the crystalline form II also has characteristic peaks at diffraction angles 2θ of 27.9°±0.2°, 21.8°±0.2°, and 17.6°±0.2°.

8. The crystalline form II of the free form of Crisaborole according to claim 6, characterized in that The X-ray powder diffraction pattern of the crystalline form II also has characteristic peaks at diffraction angles 2θ of 18.4°±0.2°, 21.4°±0.2°, and 23.1°±0.2°.

9. The method for preparing the crystal form II of the free form of Crisaborole according to any one of claims 6 to 8, characterized in that: The preparation methods include the following: 1) suspending a solid sample of Crisaborole free form in a mixed solvent of water and alcohol to obtain a suspension, stirring for reaction, centrifuging, and drying to obtain a suspension, wherein the volume ratio of water to alcohol is 1:1; or 2) Dissolving the Crisaborole free form solid in a positive solvent, then adding an anti-solvent thereto, stirring for crystallization, separating, and drying to obtain a Form II solid, wherein the positive solvent is an alcohol, a ketone, a cyclic ether, an amide, or dimethyl sulfoxide, and the anti-solvent is water.

10. The preparation method according to claim 9, characterized in that: The positive solvent is selected from one of isopropanol, acetone, 1,4-dioxane, tetrahydrofuran and dimethylformamide.

11. Form III of the free form of Crisaborole, whose structural formula is shown below, It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form III has characteristic peaks at diffraction angles 2θ of 20.6°±0.2°, 27.8°±0.2°, and 18.6°±0.2°.

12. The crystalline form III of Crisaborole free form according to claim 11, characterized in that The X-ray powder diffraction pattern of the crystalline form III also has characteristic peaks at diffraction angles 2θ of 13.6±0.2°, 19.5°±0.2°, and 21.7°±0.2°.

13. The crystalline form III of Crisaborole free form according to claim 11, characterized in that The X-ray powder diffraction pattern of the crystalline form III also has characteristic peaks at diffraction angles 2θ of 21.3°±0.2°, 16.3°±0.2°, and 22.5°±0.2°.

14. A method for preparing the free form III of Crisaborole according to any one of claims 11 to 13, characterized in that: The preparation method comprises: dissolving Crisaborole free form solid in a ketone solvent, volatilizing and crystallizing to obtain a crystal form III solid.

15. The preparation method according to claim 14, characterized in that: The ketone is acetone.

16. Crisaborole free form Form IV having the structural formula shown below, It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at diffraction angles 2θ of 20.0°±0.2°, 18.6°±0.2°, and 26.4°±0.2°.

17. The crystalline form IV of free form of Crisaborole according to claim 16, characterized in that The X-ray powder diffraction pattern of the crystalline form IV also has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 24.9°±0.2°, and 23.2°±0.2°.

18. The crystalline form IV of Crisaborole free form according to claim 16, characterized in that The X-ray powder diffraction pattern of the crystalline form IV also has characteristic peaks at diffraction angles 2θ of 17.2°±0.2°, 21.4°±0.2°, and 13.0°±0.2°.

19. A method for preparing the free form of Crisaborole Form IV according to any one of claims 16 to 18, characterized in that: The preparation method comprises: heating the free form solid of Crisaborole, the crystalline form I described in any one of claims 1 to 3, the crystalline form II described in any one of claims 6 to 8, or the crystalline form III described in any one of claims 11 to 13 to 130° C.-145° C. to obtain the crystalline form IV solid.

20. A pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of one or more of the crystalline form I of the free form of Crisaborole according to any one of claims 1 to 3, or the crystalline form II of the free form of Crisaborole according to any one of claims 6 to 8, or the crystalline form III of the free form of Crisaborole according to any one of claims 11 to 13, or the crystalline form IV of the free form of Crisaborole according to any one of claims 16 to 18, or any combination of these crystalline forms, and at least one pharmaceutically acceptable carrier or excipient.

21. Use of the crystalline form I of the free form of Crisaborole according to any one of claims 1 to 3, or the crystalline form II of the free form of Crisaborole according to any one of claims 6 to 8, or the crystalline form III of the free form of Crisaborole according to any one of claims 11 to 13, or the crystalline form IV of the free form of Crisaborole according to any one of claims 16 to 18, or any combination of these crystalline forms in the manufacture of a pharmaceutical preparation for treating psoriasis and allergic dermatitis.

Images