FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of various polymorphs/solid forms of apremifast.
The present invention further relates to a novel crystalline Form-MK of apremilast and the process of preparation thereof.
BACKGROUND OF THE INVENTION
Apremilast is known for the treatment of certain types of psoriasis and psoriatic
arthritis. Apremilast is a phthalimide derivative and is a white to pale yellow, non-
hygroscopic powder that is practically insoluble in water and buffer solutions in a
wide pH range, but is soluble in lipophilic solvents such as acetone, acetonitrile,
butanone, dichloromethane, and tetrahydrofuran. There are several crystal forms
known for apremilast. ^ . -
United States Pat. No. 6,020,358 discloses apremilast and process for the preparation
/ ' •
i
of thereof. In US 7,427,638; stereomerically pure apremilast substantially free of its (-) isomer, metabolites, polymorphs, salts, solvates, hydrates, and clathrates thereof are discussed; Various solid crystalline forms of apremilast are disclosed in US 8,093,283. US'283 discloses seven crystalline forms (A to G) of apremilast and the process of preparation of the same. WO 2016/141503, discloses crystal Form II of apremilast and process of preparation thereof.
WO-2014/072259 discloses amorphous apremilast and a process for the preparation of a composition comprising amorphous apremilast. WO 2016/189486, discloses crystalline i.e. Form M of the apremilast.

PCT application number, WO 2016/135755 discloses process of preparation of amorphous apremilast by dissolving apremilast in solvent followed by cooling and filtering of the precipitates.
v. <
Chinese patent application, CN 105111127 A, discloses process of preparation of
amorphous apremilast by dissolving apremilast in a solvent under heating followed
by removal of solvent by vacuum concentration under pressure.
Although there are several processes available in the literature for preparation of
various solid crystalline and amorphous forms of apremilast. However, there is
always a need to develop a stable polymorph that can be easily formulated without
any degradation. -
Hence, the present • invention is focussed towards the development of a stable polymorph as well as towards the development of an economical process for preparation of the said polymorph of apremilast. The present invention is also focussed towards the new manufacturing processes for preparation of various known polymorphs of apremilast in an economical and environmental.friendly way.
OBJECT OF THE INVENTION
The principal object of the present invention is to develop novel processes for preparation of various solid forms of apremilast.
Another object of the present invention is to prepare a novel crystalline form of apremilast.
Another object of the present invention is to prepare a pharmaceutical composition comprising a novel crystalline form of apremilast.

SUMMARY OF THE INVENTION
The present invention relates to a novel crystalline Form-MK of apremilast and process for preparation thereof.
The present invention further relates to novel process of preparation of various solid forms of apremilast.
The present invention further provides a composition comprising a novel crystalline Form-MK of apremilast.
Accordingly, the present invention provides a novel crystalline Form-MK of apremilast, wherein said polymorphic form is characterised by X-Ray powder diffraction pattern comprising peaks at about 5.86, 8.96, 15.69, 24.79, 30.21, 32.53, 37.57, 38.63±0.2°2e.
furthermore, the present invention provides a process for preparation of novel crystalline Form-MK of apremilast comprising the steps of:
a) dissolving apremilast in an organic solvent to get a reaction solution;
b) heating the reaction solution at a temperature below 60°C;
c) adding organic solvent system comprising one or more organic solvent wherein one solvent is tetrachloromethane; and
d) filtering and isolating to get Form-MK of apremilast.
Further, the present invention provides a novel process of conversion of crystalline Form-MK to other solid form of apremilast, wherein said process comprising the steps of:
a) dissolving apremilast Form-MK in an organic solvent to get a solution;
b) optionally heating the solution at a temperature in the range of 75-90°C;
c) optionally cooling the solution;
d) stirring the solution at a temperature in the range of 15-30°C; and

e) filtering and isolating to get solid form of apremilast.
Further, the present invention provides a novel process of preparation of solid form
of apremilast comprising the steps of: ^
a) subjecting apremilast to heating to get a molten form;
b) optionally dissolving apremilast to a solvent prior to the heating;
c) adding the molten form of apremilast to either dry ice, or to another solvent, or mixture thereof; and
d) cooling and filtering to get solid form of apremilast.
Furthermore, the present invention provides another novel process for the preparation of polymorphic forms of apremilast comprising the steps of:
a) dissolving apremilast in a solvent to get apremilast solution;
b) heating the apremilast solution to get a hot reaction mixture;
c) cooling the hot reaction mixture at a temperature in the range of 0-35°C; and
d) filtering to get polymorph of apremilast.
DESCRIPTION OF THE INVENTION
Brief Description of Drawings
Fig, 1 depicts X-Ray Powder Diffraction (XRPD) of apremilast polymorphic Form-
MK
Fig. 2 depicts Differential Scanning Calorimetry (DSC) of apremilast polymorphic
Form-MK
The present invention will.now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
In one embodiment, the present invention provides a novel crystalline, Form-MK of apremilast, wherein said polymorphic form is characterised by X-Ray powder diffraction pattern comprising peaks at about 5.86, 8.96, 15.69, 24.79, 30.21, 32.53, 37.57, 38!63±0.2°26.
In one another embodiment, the novel crystalline Form-MK of apremilast is characterised by X-Ray powder diffraction pattern comprising peaks at about 5.86, 8.75, 8.96, 9.58,11.75,12.53,13.71,14.89,15.69,16.27,16.95,17.29,17.56,17.99, 18.61, 19.25, 19.50, 19.92, 20.11, 20.56, 21.03, 21.77, 22.84, 23.09, 23.66, 24.02, 24.79, 25.67, 2'5.96, 26.36, 26.67, 27.74, 28.11, 29.11, 30.21, 30.80, 31.27, 31.62, 32.53, 33.04, 34.28, 34.83, 35.15, 35.74, 36.71, 37.57, 38.63±O.2°20.
In yet another embodiment, the novel crystalline Form-MK of apremilast is characterised by Differential Scanning Calorimetry (DSC) plot comprising an endothermic event with an onset temperature of about 88.77°C.
Further, the present invention provides a process for preparation of novel crystalline Form-MK of apremilast comprising the steps of:
a) dissolving apremilast in an organic solvent to get a reaction solution;
b) heating the reaction solution at a temperature below 60°C;

c) adding organic solvent system comprising one or more organic solvent wherein one solvent is tetrachloromethane; and
d) filtering and isolating to get Form-MK of apremilast.
In other embodiment, the organic solvent in step a) is selected from the group comprising of ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as methylene dichloride, carbon tetrachloride; and mixture thereof.
In another embodiment, the organic solvent used in step c) is selected from carbon tetrachloride (tetrachloromethane), heptane, cyclohexane and mixture thereof.
In another embodiment, the crude apremilast used for preparing the novel crystalline Form-MK can be prepared either by any of the conventional process or by the process of the present invention.
In a preferred embodiment, the organic solvent used in step a) and c) are different except for carbon tetrachloride.
In one another preferred embodiment, the organic solvent system used in step c) comprises of mixture of organic solvent wherein one of the solvent is at least carbon tetrachloride (tetrachloromethane).
In another preferred embodiment, the crystalline Form-MK can be converted to any other solid forms such as Form A, B, C, D, Form II and amorphous form.
Accordingly, in another embodiment, the present invention provides the process of conversion of crystalline Form-MK to other solid forms of apremilast, wherein said process comprising the steps of:
a) dissolving apremilast Form-MK in an organic solvent to get a solution;
b) optionally heating the solution at a temperature in the range of 75-90°C;

c) optionally cooling the solution;
d) stirring the solution at a temperature in the range of 15-30°C; and
e) filtering and isolating to get solid form of apremilast.
\ ■ ■
In another embodiment, the organic solvent is selected from cyclohexane, anisole, methyl tert butyl ether, ethanol, n-propanol, methyl ethyl ketone, heptane, and mixture thereof.
In a preferred embodiment, the process of the present invention results into the preparation of solid forms such as Form A, B, C, D, Form II and amorphous form.
In another embodiment, the present invention provide a novel process of preparation of solid forms of apremilast comprising the steps of:
a) subjecting apremilast to heating to get a molten form;
b) optionally dissolving apremilast to a solvent prior to the heating;
c) adding the molten form of apremilast to either dry ice, or to another solvent, or mixture thereof; and
d) cooling and filtering to get solid form of apremilast.
In one another embodiment, the solvent used in step b) is selected from the group comprising of hydrocarbons such as heptane, cyclohexane, toluene, xylene, 2,2-dimethoxy propane, dimethoxy ethane, nitromethane; pyrrolidinones such as N-methyl pyrrolidinone (NMP); formamides such as Dimethyl formamide (DMF), halogenated solvents such as chloroform, methylene dichloride (MDC), ethylene dichloride (EDC); alcohols such as ethylene glycol, N-propanol, ethanol, methanol, isoamyl alcohol, isobutanol; acetamides such as dimethyl acetamide (DMA); acetates such as ethyl acetate, methyl acetate, isopropyl acetate, propyl acetate, pentyl acetate, butyl acetate; sulfoxides such as dimethyl sulfoxide (DMSO); ketones such as dimethyl ketone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone; ethers such as methyl tert-butyl ether (MTBE), 1,4-dioxane, other polar solvent such as water; amines such as triethyl amine; and mixture thereof.

In one another embodiment, the solvent used in step c) is selected from the group comprising of water; hydrocarbon such as cyclohexane, toluene, heptane, dimethoxypropane, n-pentane; ethers such as isopropyl ether (IPE), methyl tert butyl ether; acetates such as ethyl acetate; ketones such as acetone, methyl ethyl ketone (MEK); alcohols such as ethanol, n-propanol, isopropyl alcohol (IPA); formamide such as dimethyl formamide; and mixture thereof.
In a preferred embodiment, the solvent used in step b) is different from the solvent used in step c).
In another embodiment, the apremilast is optionally dissolved in a solvent in step b) which is then followed by heating to get hot reaction mixture.
In one another embodiment, the heating of apremilast in step a) or, heating of apremilast solution in organic solvent in step b) is performed at a temperature in the rangeof30°Ctol90°C.
In another embodiment, the cooling in step d) is performed at a temperature in the rangeof-50°Cto30°C.
In another preferred embodiment, the molten form of apremilast is optionally added to dry ice and the temperature of reaction mixture is maintained to -50°C or below.
In another embodiment, the crude apremilast used for preparing solid/polymorphic forms is can be prepared by any of the conventional process.
In a preferred embodiment, the process of the present invention results into the preparation of solid forms such as Form A, B, C, D, Form II and amorphous form.

In further embodiment, the present invention provides another novel process of preparation of polymorphic forms of apremilast comprising the steps of:
a) dissolving apremilast in a solvent to get apremilast solution;
b) heating the apremilast solution to get a hot reaction mixture;
c) cooling the hot reaction mix at a temperature in the range of 0-35°C; and
d) filtering to get polymorph of apremilast.
In another embodiment, the solvent is selected from the,group comprising of water, nitromethane; hydrocarbon such as heptane, cyclohexane, xylene, toluene; alkoxy alkanes such as 1,1-dimethoxy ethane, 2,2-dimethoxy propane; acetamides such as dimethyl acetamide,' sulfoxides such as dimethyl sulfoxide, ethers such as 1,4-dioxane, methyl tert butyl ether; formamides such as dimethyl formamide; sulfoxide such as dimethyl sulfoxide, pyrrolidones such as N-methyl pyrrolidinone, alcohol such as iso.butanol, ethanol, n-propanol, iso-amyl alcohol; ketones such as methyl ethyl ketone, methyl isobutyl ketones, acetone; halogenated solvents such as. methylene dichloride; acetates such as pentyl acetate, propyl acetate, methyl acetate, n-butyl acetate, isopropyl acetate, amines such as triethyl amine (TEA); and mixture thereof.
In still another embodiment, the temperature in step b) is in the range of 30°C to 130°C.
In another embodiment, the crude apremilast used for preparing polymorphic forms is prepared either by any of the conventional process or by the process of the present invention.
In a preferred embodiment, the process of the present invention results into the preparation of polymorphic forms such as Form A, B, C, D, Form II and amorphous form.

In further embodiment, the present invention provides a pharmaceutical composition comprising apremilast and at least one pharmaceutically acceptable excipient.
The apremilast used in preparation of pharmaceutical composition is selected from apremilast solvates, hydrates, anhydrous form, crystalline form and amorphous form.
In a preferred embodiment, the present invention provides a composition comprising apremilast Form-MK and at least one pharmaceutically acceptable excipient.
In other embodiment, the crystalline Form-MK of apremilast is isolated with purity of 98% or above and preferably, 99% or above.
In another embodiment, the crystalline Form-MK of apremilast is characterized by particle size distribution wherein, dw is 0.1 (am to 200fim.
In another embodiment, the crystalline Form-MK of apremilast is characterized by particle size distribution wherein, d90 is 2.0 ^im to 150(am.
In another preferred embodiment, the present invention provides a pharmaceutical composition comprising apremilast. and at least one pharmaceutically acceptable excipient wherein said apremilast is selected from polymorphic forms prepared as per the process of the present invention.
Further, the present invention is illustrated in detail by way of the following examples. The examples are given herein for illustration of the invention and are not intended to be limiting thereof.
EXAMPLES
Preparation of Amorphous form of apremilast

Example 1: Added 2:0 g of apremilast in RBF and heated to 170 to 180°C to get a molten form. Cooled the molten form thus obtained to 5 to 10°C and added heptane to the reaction mass. Stirred for l.Ohr and filtered at 5 to 10°C to get 1.60 g of amorphous form of apremilast:
Example 2: Added 2.0 g of apremilast to 6.0 ml of NMP in RBF and heated to 85 to 90°C followed by addition of water (15.0V) to the reaction mass thus obtained. Stirred the reaction mass for 10 to 20min at 85 to 90°C. Cooled the reaction solution thus obtained at 25 to 30°C. Stirred for l.Ohr at 25. to 30°C and filtered to get 1.17 g of amorphous form of apremilast.
Example 3: Added 2.0 g of apremilast to 4.0 ml of DMF in RBF and heated to 50 to 55°C. Distilled out the solvent completely under vacuum and added cyclohexane (15.0V) to the reaction mass. Stirred the reaction mass for 20 to 30min at 25 to 30°C and filtered to get 0.90 g of amorphous form of apremilast.
Example 4: Added 2.0 g of apremilast to 8.0 ml of CHCb (8.0ml) in RBF and heated to 60 to 65°C. Cooled the solution below 25 to 30°C and added cyclohexane: IPE (10.0V:7V) to the reaction mass thus obtained. Stirred the reaction mass for lO.Ohr at 25 to 30°C and filtered at 25 to 30°C to get 1.21 g of amorphous form of apremilast.
Example 5: Added 2.0 gm of apremilast to 10.0 ml of ethylene glycol and heated at 120 to. 125°C. Cooled the reaction mass at 85 to 90°C followed by addition of water (15.0V). Stirred the reaction mass for 20 to 30min at 85 to 90°C. Cooled the solution at 25 to 30°C and stirred for lO.Ohr at 25 to 30°C and filtered to get 1.30 g of, amorphous form of apremilast.
Preparation of Polymorphic Form D
Example 6: Added 2.0 gm of apremilast to 8.0 ml of DMA in RBF and heated to 35 to 40°C. Cooled the solution at 25 to 30°C and added isopropyl ether (15.0V) to the

reaction mass. Stirred for l.Ohr at 25-to 30°C, cooled to 10 to 20°C and filtered to get 1.40 g of Form D of apremilast.
Example 7: Added 2.0 gm of apremilast to 4.0 ml of MDC in RBF and heated to 35 to 40°C. Cooled the solution at 25 to 30°C. Added the above solution to cyclohexane (10.0V). Stirred for -6.0hr at 25 to 30°C and filtered to get 0.80 g of Form D of apremilast.
Example 8: Added 2.0 gm of apremilast to 6.0 ml of MDC in RBF and heated to 30
to 35°C. Added ethyl acetate (10.0V) to the reaction mass at 25 to 30°C and cooled
the solution at 5 to 10°C. Stirred for 12.0hr at 5 to 10°C and filtered to get 0.72 g of
Form D of apremilast. ^
Example 9; Added xylene (30.0ml) to apremilast 2.0gm in RBF and heated to 130 to 135°C. Cooled the solution at 25 to 30°C and stirred for 8.0hr at 25 to 30°C and filtered to get 1.35 g of Form D of apremilast.
Example 10; Added apremilast 2.0gm to DMF (4.0ml) in RBF and heated to 70 to
75°C. Added ethyl acetate (10!0V) in material at 70 to 75°C. Copied the solution at
5 to 10°C and stirred for lO.Ohr at 25 to 30°C and filtered to get 0.55 g of FormD of
apremilast. .
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Example 11: Added apremilast 2.0gm to ethyl acetate (20.0ml) in RBF and heated to 70 to 75°C. Added cyclohexane (20.0V) in material at70 to 75°C and cooled the solution at 20 to 25°C. Stirred the solution for lO.Ohr at 20 to 25°C and filtered to get 1.60 g of Form D of apremilast.
Example 12: Added DMSO (6.0ml) to apremilast 2.0gm in RBF and heated to 50 to
- 55°C. Cooled the solution at 25 to 30°C and added the above solution to ethyl acetate
(15.0V). Stirred the solution for 6.0hr at 5 to 10°C and filtered to get 0.90 g of Form

Example 13; Added MEK (20.0ml) to Apremilast 2.0gm in RBF and heated to 70 to 75°C. Added the above hot solution in RBF containing heptane maintained at a temperature at -50°C by using dry ice. Stirred the solution for 30.0min at -50°C. Then stirred for 4.0 hrs at 25 to 30°C and filtered to get 1.35 g of Form D of apremilast.
Example 14: Added 1, 1-Dimethoxy ethane (12.0ml) to apremilast2.0gm in RBF and heated to 80 to 85°C. Cooled the solution at 25 to 30°C and stirred for 2.0hr at 5 to 10°C and filtered to get 0.70g of Form D of apremilast.
Example 15: Added 2,2-Dimethoxy propane (200.0ml) to apremilast 2.0gm in RBF and heated to 80 to 85°C. Cooled the solution at 25 to 30°C and stirred for 2.0hr at 5 to 10°C and filtered to get 0.80 .g of Form D of apremilast.
Example 16: Added apremilast 2.0gm to DMA (6.0ml) in RBF and heated to 80 to 85°C. Added water (20.0V) in solution at 80 to 85°C and stirred for 20 to 30min at 50 to 55°C. Cooled the solution at 25 to 30°C and stirred for 2.0hr at 25 to 30°C and filtered to get 1.40 g of Form D of apremilast.
Example 17: Added apremilast 2.0gm to DMF (4.0ml) and DMSO (4.0ml) in RBF and heated to 70 to 75°C. Added water (30.0V.) in solution at 70 to 75°C. Stirred for 20 to 30min at 70 to 75°C and cooled the solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 0.55g of Form D of apremilast.
Example 18: Added apremilast 2.0gm to NMP (3.0ml) and DMSO (3.0ml) in RBF and heated to 85 to 90°C. Added water (15.0V) in solution at 85 to 90°C. Stirred for 20 to 30min at 85 to 90°C and cooled solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 0.70 g of form D of apremilast.
Example 19: Added apremilast 2.0gm to NMP (3.0ml) and DMF (3.0ml) in RBF
and heated,to 85 to 90°C. Added water (15.0V) to the solution at 85 to 90°C. Stirred
1 &Z-B4-£&i& If • 1©- ■'" -•
14

for 20 to 30min at 85 to 90°C. Cooled the solution at 25 to 30°C, stirred for 2.0hr at 25 to 30°C and filtered to get 0.82 g of Form D of apremilast.
Example 20; Added apremilast 2.0gm to 1, 4-Dioxane (3.0ml) and DMF (3.0ml) in RBF and heated to 75 to 80°C. Added water (15.0V) in solution at 75 to 80°C. Stirred for 20 to'30min at 75 to 80°C. Cooled the solution at 25 to 30°C, stirred for 2.0hr at 25 to 30°C and filtered to get 1.10 g of Form D of apremilast.
Example 21: Added nitromethane (12.0ml) to the apremilast 2,0gm in RBF and v heated to 90 to 95°C. Cooled the solution at 5 to 10°C and stirred for 2.0hr at 5 to 10°C. Filtered the precipitates so obtained to get 1.1 Og of Form D of apremilast.
Example 22; Added MIBK: DMSO: Ethanol (6.0 ml: 2.0ml: 40.0ml) and DMF ; (3.0ml) in RBF and stirred for 24hrs. Charged apremilast 2.0gm to the above solution and heated to 95 to 100°C. Stirred for 20 to 30min at 95 to 100°C. Cooled the solution at 5 to 10°C and stirred for 2.0hr at 5 to 10°C and filtered to get 0.88g of Form D of apremilast.
Example 23; Added DMA (3.0ml) to apremilast 3.0gm in RBF and heated to 120 to 130°C. Cooled the clear solution at 5 to 10°C and stirred for 2.0 days at 5 to 10°C and filtered to get 1.70 g of Form D of apremilast.
Example 24; Added NMP (4.5ml) to the apremilast 3.0gm in RBF and heated to 125 to 130°C. Cooled the clear solution at 5 to<10°C and stirred for 2.0 days at 5 to 10°C and filtered to get 1.50 g of Form D of apremilast.
Example 25; Added isobutanol (30.0ml) to apremilast 2.0gm in RBF and heated to 100 to 105°C for 30.0 minute. Cooled the solution at 25 to 30°C and stirred for 2.0hr at 25 to 30°C. Filtered the precipitates to get 1.55 g of Form D of apremilast.
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Mi. a^-d^-ZSi:^'. x~S - ±-,.u>-. ■-...,.
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Example 26; Added propyl acetate (24.0ml) to apremilast 2.0gm in RBF and heated to 100 to 110°C. Cooled the clear solution so obtained at 5 to 10°C and stirred for 2.0 days at 5 to 10°C and filtered to get 1.40 g of Form D of apremilast,
Example 27; Added MIBK (6.0ml) to the apremilast 2.0gm in RBF and heated to 110 to 115°C. Added the above hot solution in RBF containing (15.0V) n-pentane maintained at a temperature of -50°C by using dry ice. Stirred the solution for 30.0min at -50°C and then for 4.0 hrs at 25 to 30°C and filtered to get 1.25g of Form D of apremilast.
Example 28; Added apremilast 2.0gm to the DMSO (6.0ml) in RBF and heated to 70 to 75°C. Added slowly MEK: water (5V: 15.0V) in solution at 70 to 75°C. Stirred for 20 to 30min at 70 to 75°C. Cooled the solution at-25 to 30°C. Stirred the solution for 1 .Ohr at 25 to 30°C and filtered to get 0.90 g of Form D of apremilast.
Example 29: Added apremilast 2.0gm to MDC (60.0ml) in RBF and heated to 35 to 40°C. Added MTBE (100.0V) in material at 35 to 40°C. Cooled the solution at 5 to 10°C. Stirred the solution for 3.Ohr at 5 to 10°C and filtered to get 1.44 g of Form D of apremilast.
Example 30; Added.pentyl acetate (14.0ml) to the apremilast 2.0gm in RBF and heated to 75 to 80°C. Cooled the solution at 5 to 10°C. Stirred for 4.0hr at 5 to 10°C and filtered to get 1.31 g of Form D of apremilast.
Example 31: Added apremilast 2.0gm to DMF (6.0ml) in RBF and heated to 70 to 75°C. Added slowly MEK: water (5V:15.0V) to the solution at 70 to 75°C. Stirred the solution for 20 to 30min at 70 to 75°C. Cooled the solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 1.05 g of form D of apremilast.
Example 32: Added apremilast 2.0gm to NMP (6.0ml) in RBF and heated to 55 to
60°C. Added slowly the above solution in acetone: water (5V: 15.0V) at 10 to 15°C.
2 ' &2:'B4-2P:il' -1-.?■'.:•'1.8-
16

Stirred the solution for 20 to 30min at 10 to 15°C and for 2.0hr at 10 to 15°C and filtered to get 0.95 g of Form D of apremilast.
Preparation of Form C of Apremilast
Example 33; Added MIBK (6.0ml) to apremilast 2.0gm in RBF and heated to 110 to 115°C. Cooled the solution at 85 to 90°C and added toluene (15.0V) in material. Stirred for l.Ohr at 85 to 90°C and cooled to 25 to 30°C. Filtered the precipitates at 25 to 30°C to get 1.32 g of Form C of apremilast.
Example 34; Added DMF (4.0ml) to the apremilast 4.0gm in RBF and heated to 130 to 135°C. Cooled the clear solution at 5 to 10°C and stirred for 2.0 days at 5 to 10°C and filtered to get 1.60 g of Form C of apremilast.
Example 35; Added DMSO (4.0ml) to apremilast 4.0gm in RBF and heated to 100 to 110°C. Cooled the clear solution at 5 to 10°C and stirred for 2.0 days at 5 to 10°C and filtered to get 1.05 g of Form C of apremilast.
Example 36; Added apremilast 2.0gm to DMF (4.0ml) in RBF and heated to 75 to 80°C. Added the above solution in RBF containing (1.0V) DMF at -50°C. Stirred for 30.0min at -50°C. Added (15.0V) water to the reaction mass and stirred for 4.0 hrs at 25 to 30°C and filtered to get 1.43 g of Form C of apremilast.
Example 37; Added MEK (6.0ml) to apremilast 2.0gm in RBF and heated to 70, to 75°C. Added the above solution in water (12.0V) at 25 to 30. Stirred for l.Ohr at 25 to 30°C and filtered at 25 to 30°C to get 1.63 g of Form C of apremilast.
Example 38; Added apremilast 2.0gm to DMSO (4.0ml) in RBF and heated to 90 to 95°C. Added toluene (10.0V) to the solution at 90 to 95°C. Cooled the solution at 25 to 30°C and stirred for 6.0hr at 25 to 30°C and filtered to get 1.08 g of Form C of apremilast.
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' 17

A
Example 39: Added methyl acetate (10.0ml) to the apremilast 2,0gm in RBF and heated to 55 to 60°C. Cooled the solution at 5 to 10°C and stirred for 4.0hr at 5 to -10°C. Filtered the precipitates to get 1.32 g of Form C of apremilast.
Example 40; Added acetone (16.0ml) to the apremilast 2.0gm in RBF and heated to 50 to 55°C. Charged the above hot solution in RBF containing dry ice at -50°C. Stirred the reaction mass for 30.0min at -50°C till precipitation occurred. Stirred further for 1.0 hr at 5 to 10°C and filtered to get 0.75 g of Form C of apremilast
Example 41; Added ethyl acetate (24.0ml) to apremilast 2.0gm in RBF and heated to 70 to 75°C. Added the above hot solution in RBF containing dry ice below -50°C. Stirred the reaction mass thus obtained for 30.0min below -50°C till precipitation. Stirred further for 1.0 hr at 5 to 10"°C and filtered to get 1.67 g of Form C of apremilast.
Preparation of Form B of Apremilast
Example 42; Added ethanol (80.0ml) to apremilast 2.0gm in RBF and heated to 80 to 85°C. Added water (80.6ml) in material and stirred for lO.Ohr at 25 to 30°C and filtered to get 1.80 g of Form B of apremilast.
Example 43; Added isopropyl acetate (40.0ml) to apremilast 2.0gm in RBF and heated to 85 to 90°C. Cooled the solution at 5 to 10°C. Stirred for 2.0hr at 5 to 10°C and filtered to get 1.52 g of Form B of apremilast.
Example 44: Added triethylamine (20.0ml) to apremilast 2.0gm in RBF and heated to 80 to 85°C for 60.0 minutes. Cooled the solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 1.75 g of Form B of apremilast.
18

Example 45: Added apremilast 2.0gm, MEK (20.0ml) in RBF and heated to 50 to 55°C. Added 2, 2-dimethoxy propane (10.0V) in solution at 50 to 55°C. Stirred for 20 to 30min at 50 to 55°C and cooled the solution at 25 to 30°C. Stirred for 6.0hr at 25 to 30°C and filtered to get 0.96 g of Form B of apremilast.
Example 46: Added cyclohexane (20.0ml) to apremilast 2.0gm in RBF and heated to 80 to 85°C. Cooled the solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 1.75 g of Form B of apremilast.
Example 47: Added propanol (20.0ml) to apremilast 2.0gm in RBF and heated to 90 to 95°C. Cooled the solution at 25 to 30°C and stirred for 2.0hr at 25 to 30°C. Filtered the precipitates to get 1.27 g of Form B of apremilast.
Example 48: Added apremilast 2.0gm to DMSO (4.0ml) in RBF and heated to 75 to 80°C. Added water (12.0V): n-propanol (6.0V) to the solution at 75 to 80°C. Stirred the solution for 20 to 30min at 75 to 80°C and then cooled the solution at 25 to 30°C. Stirred for l.Ohr at 25 to 30°C and filtered to get 0.98 g of Form B of apremilast.
Example 49: Added apremilast 2.0gm, n-propanol (20.0ml) in RBF and heated to 80 to 85°C. Added heptane (15.0V) to the solution at 80 to 85°C. Stirred for 20 to 30min at 80 to 85°C. Cooled the solution at 25 to 30°C. Stirred for 5.0hr at 25 to 30°G and filtered to get 1.26 g of Form B of apremilast.
< Example 50: Added acetone (10.0ml) to apremilast 2.0gm in RBF and heated to 40
to 45°C. Cooled the solution at 25 to 30°C and added heptane (20.0Y) to the said
solution. Stirred for 2.0hr at 25 to 30°C and filtered to get 1.05 g of Form B of
apremilast.
Example 51: Added butyl acetate (20.0ml) to the apremilast 2.0gm in RBF and heated to 125 to 130°C. Cooled the solution at 25 to 30°C. Stirred the solution for 6.0hr at 25 to 30°C and filtered to get 1.65 g of Form B of apremilast.
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19

Example 52: Added acetone (10.0ml) to apremilast 2.0gm in RBF and heated to 40 to 45°C. Cooled the solution at 25 to 30°C and added IPE (20.0V). Stirred the solution for 8.0hr at 5 to 10°C and filtered to get 1.44g of Form B of apremilast.
Example 53: Added apremilast 2.0gm to DMSO (4.0ml) in RBF and heated to 70 to 75°C. Added ethanol (10.0V) to the solution at 70 to 75°C. Cooled the solution at 25 to 30°C. Stirred for 6.Qhr at 2'5 to 30°C and filtered to get 0.80g of Form B of
apremilast.
Preparation of Form A of Apremilast
Example 54: Added apremilast 2.0gm to DMSO (4.0ml) in RBF and heated to 50 to 55°C. Cooled the solution at 25 to 30°C. Added the above solution in ethanol (10.0V) containing new form (seeding) material at 25 to 30°C. Stirred for 6.0hr at 25 to 30°C and filtered to get 0.76 g of Form A of apremilast.
Example 55: Added DMF (6.0ml) to apremilast 2.0gm in RBF and heated to 50 to 55°C. Cooled the solution at 25 to 30°C. Added the above solution in RBF containing (15.0V) MTBE maintained at -50°C. Stirred the solution for 30.0min at -50°C. Stirred the solution further for 6.0 hrs at 25 to 30°C and filtered to get 0.97 g of Form A of apremilast.
Example 56: Added isoamyl alcohol (10.0ml) to apremilast 2.0gm in RBF and heated to 120 to 125°C. Cooled solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 0.66 g of Form A of apremilast.
Example 57: Added acetone (20.0ml) to apremilast 2.0gm in RBF and heated to 50
to 55°C. Added the above hot solution to chilled 15.0V heptane. Stirred the solution
v
for3.0hr at 5 to 10°C and filtered to get 1.08 g of Form A of apremilast.
20

Example 58; Added acetone (20.0ml) to apremilast 2.0gm in RBF and heated to 50 to 55°C. Added the above hot solution in RBF containing heptane maintained at temperature at -50°C. Added IPE to above reaction mass and stirred for 30.0min at -,50°C then for 4.0 Hrs at 25 to 30°C and filtered to get 0.85 g of Form A of apremilast.
Example 59: Added apremilast 2.0gm to DMSO (4.0ml) in RBF and heated to 60 to 65°C. Added the above solution (RT) in RBF contains (15.0V) ethanol maintained at temperature at -50°C. Stirred the solution for 30.0min at -50°C and then for 4.0 hrs at 25 to 30°C and filtered to get 0.65 g of Form A of premilast
Example 60: Added MEK (10.0ml) to apremilast 2.0gm in RBF and heated to 70 to 75°C. Cooled the solution below 45 to 50°C and added the above solution to cyclohexane (15.0V) containing new form material (seeding) 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 1,10 g of Form A of apremilast.
Example 61: Added apremilast 2.0gm to NMP (6.0ml) in RBF and heated to 55 to 60°C. Added slowly the above cooled solution in IPA: water (5V:25.0V) at 10 to 15°C. Stirred for 20 to 30min at 10 to 15°C then for 2.0hr at 10 to 15°C and filtered to get 1.15 g of Form A of apremilast.
Example 62: Added ethanol (80.0ml) to apremilast 2.0gm in RBF and heated to 70 to 75°C. Added the above hot solution in RBF containing dry ice at -50°C. Stirred the reaction mass for 30.0min at -50°C up till precipitation. Stirred for 1.0 hrs at 5 to 10°C and filtered to get 0.82 g of Form A of apremilast.
Example 63: Added n-propanol (10.0ml) to apremilast 2.0gm in RBF and heated to 90 to 95°C. Added the above hot solution in RBF containing dry ice at -50°C. Stirred the reaction mass for 30.0min at -50°C up till precipitation. Stirred for 2.0 hrs at 25 to 30°C and filtered to get 1.0 g of Form A of apremilast.
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Example 64; Added ethanol (80.0ml) to apremilast 2.0gm in RBF and heated to 75 to 80°C for 30.0 minute. Cooled the solution at 55 to 60°C. Added new form (seeding) material in the above reaction mass at 55 to 60°C. Stirred for 2.0hr at 5 to 10°C and filtered to get 0.98 g of Form A of apremilast. ,
Example 65: Added apremilast 2.0gm to MEK (10.0ml) in RBF and heated to 70 to 75°C. Added heptane (15.0V) to the solution at 70 to 75°C. Stirred for 20 to 30min at 70 to 75°C and cooled the solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 0.78 g of Form A of apremilast.
Preparation of Form II of Apremilast
Example 66; Added apremilast 2.0gm to DMF (6.0ml) in RBF and heated to 50 to 55°C. Added hot solution in ice (15.0V). Stirred for 4.0hr at 25 to 30°C and filtered to get 0.70 g of Form II of apremilast.
Example 67; Added apremilast 2.0gm to DMF (6.0ml) in RBF and heated to 55 to 60°C. Added slowly acetone: water (5V: 15.0V) to the solution at 55 to 60°C. Stirred for 20 to 30min at 55 to 60°C. Cooled the solution at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 1.05 g of Form II of apremilast.
Preparation of novel Form MK of Apremilast
Example 68; Added acetone (20.0ml) to Apremilast 2.0gm in RBF and heated to 45 to 50°C: Cooled the solution at 25 to 30°C and added the above solution to - cyclohexane: CC14 (15V:15.0V) at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C and filtered to get 1.35 g of new Form MK of apremilast.
Example 69; Added acetone (14.0ml) to apremilast 2.0gm in RBF and heated to 35 , to 40°C. Cooled the solution at 25 to 30°C and added the above solution in CCU
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(15.0V) containing new form material (seeding) below l6°C. Stirred for 6.0hr at 25 to 30°C and filtered to get 1.55 g of Form MK of apremilast.
Example 70: Added MEK (10.0ml) to apremilast 2.0gm in RBF and heated to 35 to 40°C. Cooled the solution below 25 to 30°C and added the above solution to CCU (15.0V) below 10°C. Stirred for 2.0hr at 5 to 10°C and filtered to get 1.44 g of Form MK of apremilast.
Example 71: Added acetone (20.0ml) to apremilast 2.0gm in RBF and heated to 45 to 50°C. Cooled the solution at 25 to 30°C and added the above solution in heptane: CCU (15V:15.0V) at 25 to 30°C. Stirred for 2.0hr at 25 to 30°C arid filtered to get 1.30 g of Form MK of apremilast.
Example 72; Added carbon tetrachloride (160.0ml) to apremilast 2.0gm in RBF and heated to 80 to 85°C. Cooled the solution at 5 to 10°C. Stirred for 2,0hr at 5 to 10°C and filtered to get 1.76 g of Form MK of apremilast.
Example 73: Added MDC (6.0ml) to Apremilast 2.0gm in RBF and heated to 35 to 40°C, Cooled solution below 30 to 35°C and added CCU (30.0ml) in material. Stirred for 4.0hr at 20 to 25°C and filtered to get 1.05 g of Form MK of apremilast.
Example 74: Added apremilast 2.0gm to MDC (10.0ml) in RBF and heated to 35 to 40°C. Added CCU (10.0V) to the solution at 35 to 40°C. Distilled out the solvent completely without vacuum at 60 to 65°C. Added CCU (10.0V) to the solution. Stirred for 3 hrs at 25 to 30°C and filtered to get 1.60 g of Form MK of apremilast.
Example 75: Added MEK (10.0ml) to apremilast 2.0gm in RBF and heated to 35 to 40°C. Cooled the solution below 25 to 30°C and added the above solution in CCU (15.0V) below 10°C. Stirred for 2.0hr at 5 to 10°C and filtered to get 1.15 g of Form MK of apremilast.

Preparation of other forms of Apremilast by using Form-MK as starting material
Example 76; (Amorphous form):
Added cyclohexane (20.0ml) to apremilast form MK (2.0gm) in RBF and heated to 80 to 85°C for 30.0 minutes. Cooled the solution at 25 to 30°C. Stirred the solution for 2.0hr at 25 to 30°C and filtered to get 1.75 g of amorphous form of apremilast.
Example 77; (Form D):
Added MTBE (30.0ml) to apremilast form MK (2.0gm) in RBF and stirred the slurry mass for 3.0hrat 25 to 30°C and filtered to get 1.65 g of form D of apremilast.
Example 78; (Form C):
Added anisole (10.0ml) to apremilast form MK (2.0gm) in RBF and stirred the slurry mass for 3.0hr at 25 to 30°C and filtered to get 1.05 g of Form C.
Example 79; (Form A):
Added ethanol (40.0ml) to apremilast form MK (2.0gm) in RBF and stirred the slurry mass for 3.0hr at 25 to 30°C and filtered to get 1.32 g of Form A.
Example 80; (Form A);
Added n-propanol (20.0ml) to apremilast form MK (2.0gm) in RBF and stirred the slurry mass for 3.0hr at 25 to 30°C and filtered to get 1.20 g of Form A.
Example 81; (Form A):
Added MEK: heptane (10:0ml: 18.0ml) to apremilast form MK (2.0gm) in RBF and stirred the slurry mass for 3.0hr at 25 to 30°C and filtered to get 0.95 g of Form A.
The present invention provides a pharmaceutical composition comprising apremilast and at least one pharmaceutical^ acceptable excipient as represented in Table 1 below:

Table-1: Table 1 represents the oral dosage form comprising Apremilast;

WE CLAIM
1. A crystalline Form-MK of apremilast characterised by X-Ray powder diffraction pattern comprising peaks at 5.86, 8.96, 15.69, 24.79, 30.21, 32.53, 37.57, 38.63±0.2°29.
2. The crystalline Form-MK as claimed in claim 1, wherein said' form is characterised by Differential Scanning Calorimetry (DSC) plot comprising an endothermic event with an onset temperature of about 88.77°C.
3. A process for preparation of crystalline Form-MK of apremilast comprising the steps of:
. a) dissolving apremilast in an organic solvent to get a reaction solution;
b) heating the reaction solution at a temperature below 60°C;
c) adding organic solvent system comprising one or more organic solvent wherein one solvent is tetrachloromethane; and
d) filtering and isolating to get Form-MK of apremilast.

4. The process as claimed in claim 3, wherein said organic solvent used in step a) is selected from ketones, halogenated hydrocarbons, and mixture thereof; and wherein said organic solvent used in step c) is selected from carbon tetrachloride, heptane, cyclohexane and mixture thereof
5. The process as claimed in claim 3, wherein said process optionally comprising conversion of crystalline Form-MK to other solid form of apremilast, wherein said process comprising the steps .of:

a) dissolving apremilast Fprm-MK in an organic solvent to get a solution;
b) optionally heating the solution at a temperature in the range of 75-90°C;
c) optionally cooling the solution;
d) stirring the solution at a temperature in the range of 15-30°C; and
e) filtering and isolating to get solid form of apremilast.

The process as claimed in claim 5, wherein said organic solvent used in step a) is selected from cyclohexane, anisole, methyl tert-butyl ether, ethanol, n-propanol, methyl ethyl ketone, heptane, and mixture thereof.
A process of preparation of solid form of apremilast comprising the steps of:
a) subjecting apremilast to heating to get a molten form;
b) optionally dissolving apremilast to a solvent prior to the heating;
c) adding the molten form of apremilast to either dry ice, or to another solvent, or mixture thereof; and ,
d) cooling anci filtering to get a solid form of apremilast.
The process as claimed in claim 7, wherein said solvent used in step b) is selected from the group comprising of heptane, cyclohexane, toluene, xylene, 2,2-dimethoxy propane, dimethoxy ethane, nitromethane; N-methyl pyrrolidinone (NMP); Dimethyl formamide (DMF), chloroform, methylene dichloride (MDC), ethylene dichloride (EDC); ethylene glycol, N-propanol, ethanol, methanol, isoamyl alcohol, isobutanol; dimethyl acetamide (DMA); ethyl acetate, methyl acetate, isopropyl acetate, propyl acetate, pentyl acetate, butyl acetate; dimethyl sulfoxide (DMSO); dimethyl*ketone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone; methyl tert-butyl ether (MTBE), 1,4-dioxane, water, triethyl amine; and mixture thereof; and
wherein solvent used in step c) is selected from water, cyclohexane, toluene, heptane, dimethoxypropane, n-pentane, isopropyl ether (IPE), methyl tert butyl ether, ethyl acetate, acetone, methyl ethyl ketone (MEK), ethanol, n-propanol, isopropyl alcohol (IPA), dimethyl formamide, and mixture thereof.
The process as claimed in claim 8, wherein the solvent used in step b) is different from the solvent used in step c).

10. The process as claimed in claim 5 and 7, wherein said solid form obtained in
>
step d) is either a crystalline or an amorphous form, and wherein said crystalline form is selected from Forms A, B, C, D and Form II of apremilast.