DESC:FIELD OF THE INVENTION
The present invention relates to process for preparation of amorphous form of apremilast (I).

Formula (I)
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however reference to any prior-art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

“Apremilast” is a phosphodiesterase-4 (PDE4) inhibitor. Apremilast is chemically known as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. It's empirical formula is C22H24N2O7S and the molecular weight is 460.5.

Apremilast is approved in the United States for treatment of adult with active psoriatic arthritis. It is also being tested for treating other chronic inflammatory diseases such as psoriasis, Ankylosing Spondylitis, Behcet’s disease, and rheumatoid arthritis. It is available under the trade name of OTEZLA® as an inhibitor of phosphodieasterase 4 (PDE4) and OTEZLA tablets are supplied in 10, 20 and 30 mg strengths for oral administration.

US Patent No. 6,020,358 discloses racemic 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-
methylsulfonylethyl]-4-acetamidoisoindoline-1,3-dione and process for its preparation, which is incorporated herein by reference.

WO 2003/080048 and WO 2003/080049 discloses the use of the (-) and (+) enantiomers of apremilast respectively in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.

US Patent No. 7,427,638 discloses stereomerically pure (+)-2-[1-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition. The stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione is the (+)-isomer of racemic 2-[l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide.

WO 2009/120167 and US Patent No. 7,893,101 disclose various solid forms of apremilast including crystal forms and amorphous forms and their mixture.

WO 2014/072259 discloses pharmaceutical composition of amorphous apremilast with at least one excipients prepared by melt extrusion technique.

WO 2015/173792 and US 9,351,957 disclose the process for preparation of an amorphous form of apremilast.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g. differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g. tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity).

An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing.

There is no enabling disclosure available in the prior art for the preparation of an amorphous form of apremilast which can suffice to meet the emerging need of the large scale preparation at industrial level.

In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of amorphous form of apremilast. The amorphous form provided herein is stable under ordinary stability conditions with respect to purity and storage.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for preparation of amorphous apremilast (I)

Formula (I)
Another object of the present invention is to provide a process for preparation of amorphous apremilast (I), wherein the process includes dissolving apremilast in a suitable solvent or mixture thereof followed by addition of anti-solvent to obtain amorphous apremilast.
Yet another object of the invention is to provide a process for preparation of amorphous apremilast wherein the process includes dissolving apremilast in a solvent selected from alkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol or a mixture thereof followed by addition of anti-solvent such as water to obtain amorphous apremilast.

Yet another object of the invention is to provide a process for preparation of amorphous apremilast wherein the process includes dissolving apremilast in a solvent selected from dimethyl formamide, or mixture of acetone and ethanol followed by addition of anti-solvent such as water to obtain amorphous apremilast.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide a process for preparation of amorphous apremilast (I).

Formula (I)
In an aspect the present invention provides a process to prepare amorphous apremilast wherein apremilast is dissolved in a suitable solvent or mixture of solvent followed by addition of anti-solvent to obtain amorphous apremilast.

Another aspect of the present invention is to provide a process for preparation of amorphous apremilast wherein, the process comprises steps of:
(a) dissolving apremilast in a solvent selected from alkyl formamide, ketone, alkanol or mixture thereof.
(b) adding anti-solvent to the solution obtained in step (a);
(c) isolating amorphous apremilast.

Yet another aspect of the present invention is to provide a process for preparation of amorphous apremilast comprising steps of:
(a) dissolving apremilast in dimethyl formamide
(b) adding the solution obtained in step (a) to water;
(c) isolating amorphous apremilast.

Yet another aspect of the invention is to provide a process for preparation of amorphous apremilast comprising steps of:
(a) dissolving apremilast in a mixture of acetone and ethanol
(b) adding the solution obtained in step (a) to water;
(c) isolating amorphous apremilast.
DETAILED DESCRIPTION OF THE DRAWINGS
Fig.1: Discloses XRPD pattern of amorphous form of apremilast as prepared by Example 1.
Fig.2: Discloses XRPD pattern of amorphous form of apremilast as prepared by Example 2.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide a process for preparation of amorphous apremilast (I).

Formula (I)
In another embodiment, the present invention provides a process wherein apremilast is dissolved in a suitable solvent or mixture thereof to form a solution, followed by combining said solution with a suitable anti-solvent to obtain amorphous apremilast.

In an embodiment the process of present invention provides amorphous apremilast by
(a) dissolving apremilast in a solvent or mixture thereof;
(b) adding solution obtained in step (a) to anti-solvent or
(c) adding anti-solvent to solution obtained in step (a);
(d) isolating amorphous apremilast.

The solvent used in step (a) can be selected from dialkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol, methanol or a mixture of solvent can be used for the purpose of present invention.
The anti-solvent used in step (b) can be water or any solvent in which apremilast is less soluble.

In one embodiment, the apremilast solution obtained in step (a) is added to anti-solvent such as water or as an alternate; anti-solvent can be added to the apremilast solution.

The process can be carried out at a suitable temperature ranging from room temperature to the temperature suitable for dissolving apremilast in the selected solvent or mixture of solvents.

Amorphous apremilast precipitated after addition of anti-solvent can be isolated by filtration or any other similar technique. The product may be further dried under vacuum at a temperature of about 25°C.
In general, amorphous apremilast is prepared by solvent-anti-solvent precipitation technique.

The starting material i.e. apremilast used in present invention may be prepared in accordance with any method known in the art, including for example, the methods described in WO 2009/120167, WO 2003/080049, WO 2003/080049 and US 6,020,538. The contents of each of which are hereby incorporated by reference in their entirety.

Apremilast can also be prepared by process disclosed by following scheme;

Step 1 of the above scheme relates to reaction of 3-nitrophthalic acid (II) with 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (III) to obtain compound of formula IV i.e. (S)-2-(1-(3-ethoxy-4-methoxyphenyl)2-(methylsulfonyl)ethyl-4-nitro isoindoline-1,3-dione. Nitro compound of formula IV is subjected to reduction to obtain amino compound of formula V. Reduction can be carried out in presence of Pd/C and solvents selected from alkanol such as methanol, ethanol, propanol, isopropanol, butanol alkyl acetate such as ethyl acetate, isopropyl acetate or any other suitable solvent. Reaction of amino compound of formula V with acetic anhydride provides apremilast (I), the reaction can be carried out in presence of solvent selected from halogenated solvents like dichloromethane or alcohols such as methanol, ethanol isopropanol or mixture thereof. Apremilast thus prepared can be further purified from any suitable solvent or mixture of solvent. Solvent for purification/ recrystallization of apremilast can be affected in presence of alkanol like methanol, ethanol isopropanol, butanol, nitrile such as acetonitrile or any other suitable solvent.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
EXAMPLES
Example-1: Preparation of amorphous apremilast
N,N-dimethylformamide (30 ml) was taken in a 2 litre round bottom flask, to this 10 g of apremilast was added, the resultant mixture was stirred at 25-30°C to obtain clear solution. This solution was added to 400 ml of pre-cooled water at 0-5°C. The product thus precipitated was isolated by filtration. The solid was dried under vacuum at 55-60°C to obtain 8.5 g of title product.

Example-2: Preparation of amorphous apremilast
Acetone (6 ml) and ethanol (6 ml) were taken in a 2 litre round bottom flask, to this 10 g of apremilast was added, the resultant mixture was stirred at 50-55°C to obtain clear solution. This solution was added to 360 ml of pre-cooled water at 0-5°C. The product thus precipitated was isolated by filtration. The solid was dried under vacuum at 55-60°C to obtain 8.5 g of title product. ,CLAIMS:We Claim:

1. A process for preparation of amorphous form of apremilast comprising steps of:
a) dissolving apremilast in a solvent selected from dimethyl formamide, ketone, alkanol and mixture thereof;
b) combining the solution obtained in step (a) with an antisolvent selected from water and n-heptane.

2. The process according to claim 1, which comprises adding an antisolvent to the apremilast solution.

3. The process according to claim 1, which comprises adding apremilast solution to antisolvent.

4. The process according to claim 1, which comprises use of dimethylformamide and water as solvent-antisolvent mixture.

5. The process according to claim 1, which comprises use of acetone, ethanol and water as solvent-antisolvent mixture.

6. A process for preparation of amorphous apremilast comprising the steps of :
a) dissolving apremilast in dimethyl formamide
b) combining the solution obtained in step (a), to water.

7. A process for preparation of amorphous apremilast comprising the steps of :
a) dissolving apremilast in a mixture of acetone and ethanol
b) combining the solution obtained in step (a), with water.

8. Amorphous apremilast prepared by process according to claim 1, 6 or 7.

9. Amorphous apremilast characterized by X-ray diffraction (XRD) profile substantially as shown in figure 1 or 2.