FIELD OF THE INVENTION
The present invention relates to a method for the preparation of crisaborole (1) and its' (1:1) mixture of crisaborole (1) with propylene glycol solution.
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-( 1 -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.
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).
The following patents and applications disclose different solid forms 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 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 solutions of Crisaborole (1).
Another objective of the invention is to provide a solution of Crisaborole (1), more specifically propylene glycol solution of Crisaborole (1).
Another further objective of the invention is to provide process for the preparation of mixture of propylene glycol and Crisaborole (1) in 1:1 ratio.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides solutions of Crisaborole (1).
Another aspect of the invention is to provide solution of Crisaborole (1) which may specifically include propylene glycol solution of Crisaborole (1).
In another aspect, the present invention provides process for the preparation of mixture of propylene glycol with Crisaborole (1), comprising:
a) Providing a solution of Crisaborole (1) or its suitable form in a suitable solvent at 25-30 °C;
b) heating the reaction mass at a suitable temperature;
c) stirring the reaction mass at a suitable temperature;
d) cooling the reaction mass at a suitable temperature; and
e) isolating propylene glycol solution of Crisaborole (1).
In another aspect, the Crisaborole used may be selected from a group comprising of salts, solvates, hemi-solvates, hydrates, hemi-hydrates of Crisaborole (1) or the like.

In another aspect, n-butanol content in the propylene glycol solution of Crisaborole (1) may be controlled within the ICH limits by using a suitable technique.
In In another aspect, the present invention Crisaborole (1) used herein may be having purity greater than 99.5% by High-performance liquid chromatography (HPLC).
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention provides solutions of Crisaborole (1).
In another embodiment, the present invention provides process for the preparation of mixture of propylene glycol with Crisaborole (1), comprising:
a) Providing a solution of Crisaborole (1) or its salts or solvates in a suitable solvent at 25-30 °C;
b) heating the reaction mass at a suitable temperature;
c) stirring the reaction mass at a suitable temperature;
d) cooling the reaction mass at a suitable temperature; and
e) isolating propylene glycol solution of Crisaborole (1).
In one embodiment, Crisaborole was dissolved in a suitable protic solvent at 25-30 °C. The reaction mass may be heated to 70-120 °C, preferably 90-95 °C and stirred for lhr to form a clear solution. The reaction mass was cooled to 0-35°C, preferably 25-30 °C.
In another embodiment, the solvents used in the present invention may be selected from organic or inorganic solvents. Preferably, organic solvents comprising of protic or aprotic solvent may be used. More preferably, protic solvents may be selected from a group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, propylene glycol, water or the like. Preferably, propylene glycol may be used in the present invention.
In another embodiment, the Crisaborole (1) used may be selected from a group comprising of salts, solvates, hemi-solvates, hydrates, hemi-hydrates of Crisaborole (1) or the like. The solvates used herein may be selected from a group comprising

of polyethylene glycol, polypropylene glycol, methanol, ethanol, propanol, isopropanol or butanol solvates or hemi-solvates, preferably ethanol hemi-solvate, and n-butanol hemi-solvate were used in the present invention.
In another embodiment, the present invention provides process for the preparation of mixture of propylene glycol with Crisaborole (1), comprising:
a) Providing a solution of Crisaborole (1) butanol solvate in a suitable solvent at 25-30 °C;
b) heating the reaction mass at a suitable temperature;
c) stirring the reaction mass at a suitable temperature;
d) cooling the reaction mass at a suitable temperature; and
e) isolating propylene glycol solution of Crisaborole (1).
In some embodiment, n-butanol content in the propylene glycol solution of Crisaborole (1) may be controlled within the ICH limits by using a suitable technique, preferably evaporation was used during the development of the final formulation.
In another embodiment, the present invention provides process for the preparation of mixture of propylene glycol with Crisaborole (1), comprising:
a) Providing a solution of Crisaborole (1) ethanol solvate in a suitable solvent at 25-30 °C;
b) heating the reaction mass at a suitable temperature;
c) stirring the reaction mass at a suitable temperature;
d) cooling the reaction mass at a suitable temperature; and
e) isolating propylene glycol solution of Crisaborole (1).
In some embodiment, ethanol content in the propylene glycol solution of Crisaborole (1) may be controlled within the ICH limits by using a suitable technique, preferably evaporation was used during the development of the final formulation.

In yet another embodiment, the form of Crisaborole (1) so obtained may be mixed with suitable excipients to form the final formulation.
In another embodiment, propylene glycol used in the present invention is excipient grade with high purity.
In another embodiment, the mixture of crisaborole and propylene glycol is in the 1:1 to 1:10 ratio, more preferably the ratio was selected as 1:1 ratio.
In another embodiment, crisaborole solution of propylene glycol obtained in the present invention is having purity greater than 99.5% and total impurities less than 0.5% (w/w) by HPLC.
In In another embodiment, the present invention Crisaborole (1) used herein may be having purity greater than 99.5% by HPLC.
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES EXAMPLE 1 Process for the preparation of propylene glycol solution of Crisaborole (1)
5.0g of pure Crisaborole (1) was added to 5mL of propylene glycol at 25-35 °C and heated to 90-95 °C. The reaction mass was stirred for lhr to form a clear solution. The reaction mass was then cooled to 25-35 °C to obtain propylene glycol solution of Crisaborole (1). Yield: 85.0 %.
EXAMPLE 2
Process for the preparation of propylene glycol solution of Crisaborole (1)
5.0g of pure Crisaborole ethanol hemi-solvate was added to 5mL of propylene glycol at 25-35 °C and heated to 90-95 °C. The reaction mass was stirred for lhr to form a clear solution. The reaction mass was then cooled to 25-35 °C to obtain propylene glycol solution of Crisaborole (1). Yield: 91.0 %.

EXAMPLE 3
Process for the preparation of propylene glycol solution of Crisaborole (1)
5.0g of pure Crisaborole ethanol solvate was added to 5mL of propylene glycol at 25-35 °C and heated to 90-95 °C. The reaction mass was stirred for lhr to form a clear solution. The reaction mass was then cooled to 25-35 °C to obtain propylene glycol solution of Crisaborole (1). Yield: 92.0 %.
EXAMPLE 4
Process for the preparation of propylene glycol solution of Crisaborole (1)
5.0g of pure Crisaborole n-butanol hemi-solvate was added to 5mL of propylene glycol at 25-35 °C and heated to 90-95 °C. The reaction mass was stirred for lhr to form a clear solution. The reaction mass was then cooled to 25-35 °C to obtain propylene glycol solution of Crisaborole (1). Yield: 90.0 %.
EXAMPLE 5
Process for the preparation of propylene glycol solution of Crisaborole (1)
5.0g of pure Crisaborole n-butanol solvate was added to 5mL of propylene glycol at 25-35 °C and heated to 90-95 °C. The reaction mass was stirred for lhr to form a clear solution. The reaction mass was then cooled to 25-35 °C to obtain propylene glycol solution of Crisaborole (1). Yield: 93.0 %.

We claim:
1. A process for the preparation of pharmaceutical solution of Crisaborole (1),
comprising:
a) providing a solution of Crisaborole (1) or its suitable form in propylene glycol at 25-30 °C;
b) heating the reaction mass at a suitable temperature;
c) stirring the reaction mass at a suitable temperature;
d) cooling stirring the reaction mass at a suitable temperature; and
e) isolating propylene glycol solution of Crisaborole (1).

2. The process according to claim 1, wherein the mixture of crisaborole and propylene glycol is in the ration of 1:10
3. The process according to claim 1, wherein the crisaborole can be selected from the group comprising of salts, solvates, hemi-solvates, hydrates, hemi-hydrates of Crisaborole.
4. A process for the preparation of propylene glycol solution of Crisaborole comprising:
a. providing a solution of Crisaborole (1) butanol solvate in a suitable
solvent at 25-30 °C;
b. heating the reaction mass at a suitable temperature;
c. stirring the reaction mass at a suitable temperature;
d. cooling the reaction mass at a suitable temperature; and
e. isolating propylene glycol solution of Crisaborole (1).
5. A process for the preparation of propylene glycol solution of Crisaborole
comprising:
i. providing a solution of Crisaborole (1) ethanol solvate in a suitable solvent at 25-30 °C;
ii. heating the reaction mass at a suitable temperature; iii. stirring the reaction mass at a suitable temperature; iv. cooling the reaction mass at a suitable temperature; and
v. isolating propylene glycol solution of Crisaborole (1).

6. The process according to claim 1, 4 and 5, wherein the reaction mass is heated to 90-95 °C