Crystal forms of crisaborole in free form and preparation method and use thereof

1. 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.

2. The method according to claim 1 wherein the single volatile solvent is selected from the group consisting of acetonitrile, methyl tert-butyl ether, chloroform, dichloromethane, and ethyl acetate.

3. 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.

4. 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.

5. The method according to claim 4 wherein the ketone solvent is acetone.

6. 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.

7. 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.

8. The method of claim 7 wherein the further solvent is selected from the group consisting of isopropanol, acetonitrile, isopropyl acetate, acetone, dimethyl formamide, 1,4-dioxane, and dimethyl sulfoxide.

9. 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.

10. The method of claim 9 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.

11. 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.

12. The method of claim 11 wherein the halogenated hydrocarbon is dichloromethane and wherein the volume of the dichloromethane is less than the volume of the toluene.

13. 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.

14. The method according to claim 13 wherein the positive solvent is selected from the group consisting of isopropanol, acetone, 1,4-dioxane, tetrahydrofuran, dimethylformamide, and dimethylsulfoxide.