FIELD OF THE INVENTION
The present invention relates to a process for preparing novel crystalline forms of Crisaborole (1). More specifically, it provides process for preparing hemi-solvated crystalline forms of Crisaborole (1) which may include ethanol and n-butanol hemi-solvated crystalline forms with purity greater than 99.0%.
BACKGROUND OF INVENTION
Crisaborole is a phosphodiesterase-4 inhibitor, mainly acting on phosphodiesterase 4B (PDE4B), which causes inflammation and used for the treatment of mild to moderate atopic dermatitis (eczema). Chemically it is 4-(l-hydroxy-1,3-dihydrobenzo[c] [1,2] oxaborol-5-yloxy) benzonitrile (1). It was approved by U.S. Food and Drug Administration on Dec 14, 2016.
The following patents and applications disclose different solid forms of Crisaborole (1).
US8039451 patent discloses Crisaborole (1) and the process for the preparation thereof. Process disclosed in this involves column chromatography for the purification of Crisaborole (1), which is cumbersome and not feasible on commercial scale. There is no discussion about the polymorphic form of the compound obtained by the process described therein. So, there is a significant need to develop improved purification and stable forms of Crisaborole (1). Hence, the present inventors hereby disclose a process for the preparation of different solvates of Crisaborole (1).
US8168614 patent discloses the pharmaceutical formulation of Crisaborole (1) which includes a simple solution prepared using polyethylene glycol, polypropylene glycol, methanol, ethanol, propanol, isopropanol or butanol. But does not teach about any solvate of Crisaborole (1).

US2017152273 application relates to different crystalline form 1,2 and 3 of Crisaborole (1), but no solvate forms are discussed.
US2017305936 application claims crystalline form I and form II of Crisaborole (1).
WO2017203514 application discloses process for preparing form A, B, C, D, E, F, specifically crystalline forms with residual solvents like ethyl acetate, acetone, methanol and ethanol.
OBJECTIVE OF THE INVENTION
The primary objective of the invention is to provide process for the preparation of novel crystalline forms of Crisaborole (1).
Another objective of the invention is to provide crystalline solvated forms of Crisaborole (1), more specifically hemi-solvated crystalline forms of Crisaborole (1) which may include ethanol and n-butanol solvates.
Another further objective of the invention is to provide process for the preparing ethanol hemi-solvated form Bl and ethanol hemi-solvated form B2.
Yet another objective of the invention is to provide process for preparing n-butanol hemi-solvated form B3 of Crisaborole (1).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of crystalline solvates of Crisaborole (1).
Another embodiment of the invention is to provide hemi solvated forms of Crisaborole (1) which may include ethanol hemi-solvated form Bl, ethanol hemi-solvated form B2 and n-butanol hemi-solvated form B3 of Crisaborole (1).

In another embodiment, the present invention provides process for the preparation of solvated forms of Crisaborole (1) which comprise of the following steps:
a) Dissolving Crisaborole (1) in a suitable solvent;
b) heating the reaction mass at a suitable temperature;
c) removing the solvent using a suitable technique; and
d) isolating solvated crystalline form of Crisaborole (1).
Alternatively, in another embodiment, the present invention provides process for the preparation of solvates of Crisaborole (1) which comprise of the following steps:
i. Dissolving Crisaborole (1) in a suitable solvent;
ii. heating the reaction mixture at a suitable temperature;
iii. stirring the reaction mass and filtering;
iv. adding step iii) filtrate to a suitable solvent;
v. cooling the solution to a suitable temperature and
vi. isolating solvated crystalline form of Crisaborole (1).
In another embodiment, the present invention Crisaborole (1) used herein may be having purity greater than 99.0%.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: X-Ray powder diffraction pattern of ethanol hemi-solvated form Bl of Crisaborole (1) as prepared in example 1
Figure 2: X-Ray powder diffraction pattern of ethanol hemi-solvated form B2 of Crisaborole (1) as prepared in example 2
Figure 3: X-Ray powder diffraction pattern of n-butanol hemi-solvated form B3 of Crisaborole (1) as prepared in example-3
Figure 4: illustrates the differential scanning calorimetry (DSC) of n-butanol hemi-solvated form B3 of Crisaborole (1).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides solvated crystalline forms of Crisaborole (1).
In another embodiment, the present invention provides process for the preparation of hemi- solvates of Crisaborole (1) which comprise of the following steps:
a) Dissolving Crisaborole (1) in a suitable solvent;
b) heating the reaction mass at a suitable temperature; and
c) isolating suitable solvate of Crisaborole (1).
Crisaborole (1) may be dissolved in a suitable protic solvent at 25-30 °C. The reaction mass may be heated to 50-100 °C, preferably 55-60 °C and stirred for 15-30 min to form a clear solution and filtered. The filtrate may be removed by distillation and dried under vacuum below 60 °C to yield the hemi- solvates of Crisaborole (1).
Alternatively, in another embodiment, the present invention provides process for the preparation of hemi- solvates of Crisaborole (1) which comprise of the following steps: i. Dissolving Crisaborole (1) in a suitable solvent; ii. heating the reaction mixture at a suitable temperature; iii. stirring the reaction mass and filtering; iv. adding step iii) filtrate to a suitable solvent; v. cooling the reaction mixture to a suitable temperature; and vi. isolating suitable solvate of Crisaborole (1).
In another embodiment Crisaborole (1) may be dissolved in a suitable solvent at 25-30 °C. The reaction mass may be heated to 50-100 °C, preferably 55-60 °C in some instances and 60-65 °C in other instances and stirred to form a clear solution. Optionally, the clear filtrate so obtained may be added to another suitable solvent at -60 to 0 °C, preferably - 40 to -50 °C for at least lhr to 5hrs with the formation of suitable solvates of Crisaborole (1).

In another embodiment, the solvents used in the present invention may be selected from protic solvents which may be selected from a group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, water or the like. Preferably ethanol and n-butanol may be used in the present invention.
In a specific embodiment of the present invention, the solvates of Crisaborole (1) may be isolated using a method selected from a group comprising of drying, evaporation, distillation, air try drying (ATD), freeze drying or spray drying, filtration and precipitation. Preferably, distillation and air try drying (ATD) was used in the present invention.
In another embodiment, the crystalline ethanol hemi-solvated form Bl and B2 may contain 5.0 % to 10.0 % of ethanol as measured by GC (Gas Chromatography).
In another embodiment the crystalline n-butanol solvated form B3 may contain 10.0% to 15.0% of n-butanol by GC (Gas Chromatography).
In another aspect, the ethanol hemi-solvated form Bl of Crisaborole (1) can be characterized by X-ray diffraction (XRD) pattern as illustrated in figure 1 and table-1 below:

In another aspect of the invention ethanol hemi-solvate B2 of Crisaborole (1) may have the characteristic X-Ray powder diffraction is as shown in figure 2, with 2(0) values (+0.2) as tabulated in table 2 below:

In another embodiment, figure 3 illustrates the endothermic peak of differential scanning calorimetry (DSC) at 68.05 °C for n-butanol hemi-solvate form B3 of Crisaborole (1).
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLES
EXAMPLE -1: Preparation of ethanol hemi-solvate form Bl of Crisaborole (1)
50g of pure Crisaborole (1) was added to 250 mL of ethanol at 25-35 °C and heated to 55-60 °C. The reaction mass was stirred for 15-30 mins to form a clear solution and filtered. The filtrate was distilled off completely and the solid obtained was dried under vacuum below 60 °C to obtain ethanol hemi-solvated form Bl of Crisaborole (1). Yield: 91.6 %; XRD: Figure 1.
EXAMPLE -2: Process for the preparation of ethanol hemi-solvated form B2 of Crisaborole (1)
50g of pure Crisaborole (1) was added to 250mL of ethanol at 25-35 °C and heated to 55-60 °C. The reaction mass was stirred for 15-30 mins to form a clear solution and filtered. The clear filtrate was added to 500mL of chilled ethanol and cooled at - 40 to -50 °C and stirred for 1-2 hr. The solid formed was dried in air try dryer (ATD) at 30-35 °C to yield ethanol hemi-solvate form B2 of Crisaborole (1). Yield: 87.0 %; XRD: Figure 2.
EXAMPLE -3: Preparation of n-butanol hemi-solvated form B3 of Crisaborole (1)
50g of pure Crisaborole (1) was added to 200mL of n-butanol at 25-35 °C and heated to 60-65 °C. The reaction mass was stirred for 15-30 mins to form a clear solution. The clear filtrate was cooled at - 40 to -50 °C and stirred for l-2hr.The solid formed was filtered and dried in air try dryer (ATD) at 30-35 °C to yield n-butanol hemi-solvate form B3 of Crisaborole (1). Yield:84.5%; XRD: Figure 3, Figure 4.

We Claim:
1. A process for the preparation of hemi- solvated crystalline form of Crisaborole (1).
comprising:
a) Dissolving Crisaborole (1) in a suitable solvent at 25-30 °C;
b) heating the reaction mass at a suitable temperature; and
c) isolating crystalline form of Crisaborole (1).

2. The process as claimed in claim 1, wherein the crystalline form obtained is n-butanol solvated form B3 Crisaborole (1) having X-ray diffraction (XRD) pattern as illustrated in figure 3 and with 2(0) values (± 0.2) as tabulated in table 3.
3. The process as claimed in claim 1, wherein the crystalline n-butanol solvated form B3 contains less than 15.0% of n-butanol.
4. A process for the preparation of hemi- solvated crystalline form of Crisaborole (1) comprising:

a) dissolving Crisaborole (1) in a suitable solvent;
b) heating the reaction mixture at a suitable temperature;
c) stirring the reaction mass and filtering;
d) adding step iii) filtrate to a suitable solvent;
e) cooling the reaction mixture to a suitable temperature; and
f) isolating crystalline form of Crisaborole (1).
5. The process as claimed in, claim 1 and claim 2, wherein the solvents used in
the present invention may be selected from a group comprising of methanol,

ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, water or mixtures thereof.
6. The process as claimed in, claim 1 and claim 2, wherein the crystalline forms of Crisaborole (1) may be isolated using a method selected from a group comprising of drying, evaporation, distillation, air try drying (ATD), freeze drying or spray drying, filtration and precipitation.
7. The process as claimed in, claim 1 and claim 2, wherein the crystalline form obtained may be hemi-solvated ethanol form Bl and hemi solvated ethanol form B2.
8. The process as claimed in claim 1 and claim 2, wherein the hemi solvated ethanol crystalline form Bl and B2 of Crisaborole (1) contains less than 10.0 % of ethanol.
9. The process as claimed in claim 1 and claim 2, wherein the crystalline ethanol hemi-solvated form Bl of Crisaborole (1) is having X-Ray powder diffraction is as shown in figure 1, with 2(0) values (± 0.2) as tabulated in table 1.
10. The process as claimed in claim 1 and claim 2, wherein the crystalline ethanol hemi-solvated form B2 of Crisaborole (1) is having X-Ray powder diffraction is as shown in figure 2 , with 2(0) values (± 0.2) as tabulated in table 2.