DESC:Field of invention
This invention provides improved processes for preparation of the Form II of apremilast.

Background of invention
Tumor Necrosis Factor alpha (TNFa) is a cytokine produced by monocytes and macrophages. It is found in synovial cells and macrophages in the tissues. It can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons.
Apremilast is a new TNFa inhibitor and approved by the FDA under the name as OTEZLA®. Apremilast is proving useful for treating psoriatic arthritis. It is also used to treat moderate to severe plaque psoriasis in certain patients. The chemical structure of apremilast described in compound 1 as below.

Compound 1
Apremilast is a white to pale yellow powder in appearance. The drug substance is the S - enantiomer of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide.
The US Patent 7,427,638 describes S - enantiomer of apremilast as a product and process for preparation thereof.
The US Patent 7,893,101 describes a Form B of apremilast and process for preparation thereof. This patent also discloses the Form A to G of apremilast.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms, where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Solvent medium and mode of crystallization play very important role in obtaining a new salt or a crystalline form over the other.
The discovery of novel solid forms, including amorphous forms and crystal forms and improved processes for preparation of known forms of pharmaceutically useful compound provide a new opportunity to improve the performance characteristics of a pharmaceutical product.
Hence, there is a need to develop a process for preparing novel polymorph as well as for known polymorph of apremilast, which will be stable, cost effective, eco-friendly and viable at plant scale.

Summary of invention
This invention describes processes for preparation of Form II of apremilast. Particularly, these processes of Form II of apremilast are viable and stable at plant scale.
In an aspect, this invention provides a process for preparation of Form II of apremilast comprising the steps of: a) mixing apremilast in/or presence of an organic solvent, b) heating the same at suitable temperature to get clear solution; c) removing the solvent till amorphous solid and further treated with water at a suitable temperature and d) isolating Form II of apremilast.
In another aspect, the instant invention provides a process for preparing Form II of apremilast, comprising the steps of: a) mixing apremilast in an organic solvent; b) heating the same at suitable temperature to get the clear solution; c) treating the clear solution with water at suitable temperature; d) isolating Form II of apremilast.
In another aspect, the instant invention provides a process for preparing amorphous apremilast, comprising the steps of: a) mixing apremilast in an organic solvent; b) heating the same at suitable temperature to get the clear solution; c) further removing the solvent till amorphous apremilast.

Brief Description of the drawings
Figure 1 depicts P-X Ray Diffraction pattern of Form II of apremilast obtained from the present invention;
Figure 2 depicts DSC thermogram of Form II of apremilast obtained from the present invention;
Figure 3 depicts TG thermogram of Form II of apremilast obtained from the present invention;
Figure 4 depicts P-X Ray Diffraction pattern of amorphous apremilast;
Figure 5 depicts DSC thermogram of amorphous apremilast.

Detailed description
The present invention provides improved processes for preparation of Form II of apremilast.
The instant invention provides an improved processes for Form II of apremilast, wherein, apremilast can be treated with a water miscible or water immiscible solvents selected from ketone, ester, hydrocarbons, amide, halocarbons, alcohol and ether solvents at a particular temperature. The resulting solid is filtered, washed and dried at higher temperature. The solvent/s have treated can be selected from water, acetone, diethylketone, methylisobutylketone, N-methylpyrrolidone, ethyl acetate, n-hexane, n-heptane, toluene, xylene, cyclohexane, N,N’-dimethylformamide, N,N’-dimethylacetamide, chloroform, dichloromethane, methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol, diethyl ether, isopropyl ether, dioxane, tetrahydrofuran and acetonitrile in a single solvent or mixture of solvents said herein. The temperature used in the process of present invention may be -5 °C to 100°C.
The resultant solid analyzed by different techniques such as, thermogravimetric analysis, differential scanning calorimetry, moisture content, powder x-ray diffraction and other available analytical techniques well-known in the literature with the available procedures.
The present invention provides a process for preparation of Form II of apremilast comprising steps:
a) mixing apremilast in an organic solvent;
b) heating the same at suitable temperature to get the clear solution;
c) treating the clear solution with water at suitable temperature;
d) isolating the solid i.e. Form II of apremilast.
In another aspect, the instant invention provides a process for preparing amorphous apremilast, comprising the steps of:
a) mixing apremilast in an organic solvent;
b) heating the same at suitable temperature to get the clear solution;
c) further removing the solvent till to get amorphous apremilast.
Wherein, the apremilast can be treated with water miscible or water immiscible solvents or organic solvents selected from ketone, ester, hydrocarbons, amide, halocarbons, alcohol and ether solvents at a particular temperature. The resulting solid is washed and dried at higher temperature. The temperature used in the process of present invention may be -5 to 100°C.
The amorphous apremilast can be obtained by removal of solvents with the available known techniques such as distillation, spray drying, Agitated Thin Film Dryer (ATFD), or lyophilization.
The resultant solid analyzed by different techniques such as, thermogravimetric analysis, differential scanning calorimetry, moisture content, powder x-ray diffraction and other available analytical techniques well known in the literature with the available procedures.
Analytical Methods
(1) Powder X-ray Diffraction
Using a PANalytical X’Pert powder diffraction meter, the powder x-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45 kV 40 mA) as the x-ray source. Data collection was done in 2theta values continuous scan mode in the range of 3.5° to 40°.
(2) Thermogravimetric analysis
Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 25 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.
(3) Differential Scanning Calorimetry
Differential Scanning Calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument. 2-3 mg samples were placed in crimped aluminum pans and heated from 30 °C to 250 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute.
The described invention of apremilast may be used as a pharmaceutical composition with the particular dosage forms for treating the psoriasis or psoriasis related disorders.
The apremilast used as a starting material can be obtained by the processes known in the art.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention in any way.
Example 1: Process for preparation of amorphous apremilast:
In a 1L round bottom flask, 200 gm of apremilast was added followed by 1000 ml of acetone. The reaction temperature was raised to 50°C and was stirred till clear solution was obtained. The reaction mass was stirred for 30 minutes at 45 to 50°C. The reaction mass was filtered through 0.45micron filter paper. The resultant filtrate was distilled off and dried under vacuum to get solid amorphous product. Yield: 185 gm. The P-X Ray diffraction pattern, DSC thermogram obtained is identical with Fig. 4 and 5 respectively.
Example 2: Process for preparation of Form II of apremilast from amorphous apremilast:
In a 5L round bottom flask, 2500 ml of water was charged followed by 100 gm. of amorphous apremilast. Reaction mass was heated to 45 °C to 50°C for 30minutes and flushed the solid with 500ml water. The reaction mass was heated and stirred for 15 to 20 hrs. at 45 °C to 50°C. The solid was filtered and dried under vacuum to obtain Form II of apremilast. Yield: 94.8gm. The P-X Ray diffraction pattern, TG thermogram, DSC thermogram obtained is identical with Fig. 1, 2, and 3 respectively.
Example 3: Process for preparation of Form II of apremilast from crystalline apremilast:
In a 250 mL round bottom flask, 50 ml of tetrahydrofuran was added followed by 10 gm of crystalline apremilast. This reaction solution was heated for 15 to 20minutes to 80°C. The tetrahydrofuran solution was filtered under vacuum to make sure that there were no undissolved particles. Then tetrahydrofuran extract was added dropwise to 500 ml deionized water and it was stirred for 48 hours. The white precipitate was filtered under vacuum and dried overnight at 45°C to 50°C. Yield: 9.1gm. The P-X Ray diffraction pattern, TG thermogram, DSC thermogram obtained is identical with Fig. 1, 2, and 3 respectively.

Example 4: Process for preparation of Form II of apremilast from amorphous apremilast:
In a 1L round bottom flask, 20g amorphous apremilast was dissolved in 60ml N,N’-dimethylformamide followed by addition of 60 ml water. The resultant slurry was stirred for 20 to 24 hrs. and filtered and dried to obtain Form II of apremilast. Yield: 16gm.

Example 5: Process for preparation of Form II of apremilast from crystalline apremilast:
In a 1L round bottom flask, 400ml water was taken and it was heated to 45°C. In another 100ml round bottom flask, 50ml acetone was taken and heated to 45°C followed by addition of 10g of crystalline apremilast to form a solution. This apremilast solution was added to 400ml water and the resultant slurry was stirred at 45°C for 20 to 24 hrs. The slurry was filtered and solid was dried under vacuum to obtain Form II of apremilast.Yield:5.6gm.
,CLAIMS:1. An improved process for preparing Form II of apremilast comprising the steps of: a) mixing apremilast in/or presence of an organic solvent; b) heating the same at suitable temperature to get the clear solution; c) further removing the solvent till to get amorphous solid and this solid treating with water at a suitable temperature; d) isolating Form II of apremilast.
2. The process described in claim 1, wherein organic solvent is selected from ketone, ester, hydrocarbons, amide, halocarbons, alcohol and ether solvents.
3. The process described in claim 2, wherein suitable solvents are N,N’-dimethylformamide and N,N’-dimethylacetamide.
4. The process described in claim 3, wherein suitable temperature is 20 to 100°C.
5. A process for preparing Form II of apremilast, comprising the steps of: a) mixing apremilast in an organic solvent; b) heating the same at suitable temperature to get the clear solution; c) treating the clear solution with water at suitable temperature; d) isolating Form II of apremilast.
6. The process described in claim 5, wherein organic solvent is selected from ketone, ester, hydrocarbons, amide, halocarbons, alcohol and ether solvents.
7. The process described in claim 6, wherein suitable solvents are acetone and tetrahydrofuran.
8. The process described in claim 7, wherein suitable temperature is 20 to 100°C.
9. A process for preparing amorphous apremilast, comprising the steps of: a) mixing apremilast in an organic solvent; b) heating at suitable temperature to get the clear solution; c) further removing the solvent till to get amorphous apremilast.
10. The process described in claim 9, wherein suitable organic solvent is acetone.
11. The process described in claim 10, wherein suitable temperature is 20 to 50°C.