Field of the Invention:
The present invention provides novel crystalline polymorph of N-[2-[(lS)-l-(3-emoxy-4-memoxyphenyl)-2-(memylsulfonyl)ethyl]-23-dihydro-l53-dioxo-lH-isoindol-4-yl] acetamide represented by the following structural formula-1 and process for its preparation.

Background of the Invention:
N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-253-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide commonly known as Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast was approved by the USFDA for the treatment of adults with active psoriatic arthritis.
US7427638B2 specifically describes Apremilast, its related compounds and process for their preparation.
US7893101B2 describes seven crystalline polymorphic forms of Apremilast namely form-A, form-B, form-C, form-D, form-E, form-F, form-G and also described process for their preparation.
Since the development of new polymorphic forms of an active pharmaceutical ingredient provides new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.
Furthermore, solid state study of an active pharmaceutical ingredient aims to widen the variety of crystalline forms that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.

After numerous trials and earnest efforts, the present inventors surprisingly found
novel crystalline polymorph of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide having
advantageous properties which is useful and well suitable for the preparation of various pharmaceutical compositions.
Brief description of the invention:
The first aspect of the present invention is to provide novel crystalline polymorph of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1, herein after designated as crystalline form-M.
The second aspect of the present invention is to provide a process for the preparation of novel crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydVo-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1.
Brief Description of the Drawings:
Figure-1: Illustrates the PXRD pattern of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l53-dioxo-lH-isoindol-4-yl]acetamide
compound of formula-1.
Figure-2: Illustrates the PXRD pattern of crystalline form-S of N-[2-[(lS)-l-(3-ethoxy-4-
methoxypheny^^-^ethylsulfony^ethy^^^-dihydro-l^-dioxo-lH-isoindoM-ylJacetamide
compound of formula-1 obtained according to example-8.
Figure-3: Illustrates the DSC thermogram of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-
4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]
acetamide compound of formula-1.
Figure-4: Illustrates the DSC thermogram of crystalline form-S of N-[2-[(lS)-l-(3-ethoxy-4-
methoxypheny^^methylsulfonylJethylj^^-dihydro-l^-dioxo-lH-isoindol^-yl]
acetamide compound of formula-1 obtained according to example-8.

Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane- 1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the aforementioned solvents.
The first aspect of the present invention provides novel crystalline polymorph of N-p-KlS^l-CS-emoxy^-methoxyphenyl^^methylsulfonyOethylJ^^-dihydro-l^-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1, herein after designated as form-M.
The novel crystalline polymorph of compound of formula-1 of the present invention is characterized by its PXRD pattern having peak at 5.4 ± 0.2° of 20.
The novel crystalline polymorph of compound of formula-1 is further characterized by its PXRD pattern having peaks at 8.5, 16.7 and 27.3' ± 0.2° of 26.
In another embodiment, the novel crystalline polymorph is further characterized by its PXRD pattern having peaks at 7.5, 9.9, 14.1, 14.9, 16.9, 17.7, 19.7, 21.6, 22.5, 22.8, 24.0, 25.5 and 28.9 ±0.2° of 26.
In another embodiment of the present invention, the novel crystalline form-M of compound of formula-1 is characterized by its PXRD pattern as shown in figure-1 and DSC thermogram as shown in figure-3.

The novel crystalline form-M of compound of formula-1 of the present invention is stable and non-hygroscopic in nature which is highly advantageous for the formulators.
The crystalline form-M of compound of formula-1 of the present invention was found to be stable under the following conditions;
a) Stress (10 ton pressure, 3 min)
b) UV light (254 nm, 24 hrs)
c) Thermal (60°C, 24 hrs)
d) Hygroscopicity (75% relative humidity, 24 hrs)
After exposing the crystalline form-M of compound of formula-1 to the above mentioned conditions, the sample was analyzed by PXRD to check the stability of the polymorph. From the results obtained, no change in the PXRD pattern of the sample has been observed which proves the crystalline form-M to be a stable polymorph.
The above data shows that crystalline form-M of compound of formula-1 is highly stable and non-hygroscopic in nature which is highly advantageous for the formulation scientist to prepare finished drug product.
The crystalline form-M of compound of formula-1 of the present invention is prepared by the process as illustrated in the present invention and it is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-1 is present in the composition in particular polymorphic form mentioned.
An embodiment of the present invention provides the use of crystalline form-M of compound of formula-1 for the preparation of pharmaceutical formulations.
The other embodiment of the present invention provides pharmaceutical composition comprising crystalline form-M of compound of formula-1 and at least one pharmaceutically acceptable excipient.

The second aspect of the present invention provides process for the preparation of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyI)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable first solvent,
b) optionally filtering the reaction mixture,
c) combining the solution with a suitable second solvent,
d) filtering the precipitated solid and drying the material to provide crystalline form-M of compound of formula-1.
Wherein, in step-a) the suitable first solvent is selected from ketone solvents; and the dissolution of compound of formula-1 in a suitable first solvent can be carried out at a suitable temperature ranges between 10°C to reflux temperature of the solvent used.
In step-c) the suitable second solvent is selected from polar solvents; and combining the solution with a suitable second solvent can be done at a suitable temperature ranges from 0°C to reflux temperature of the solvent used.
In the above described process, the first solvent and the second solvent are used in a ratio of 1:5 to 1:15 v/v, preferably in a ratio of 1:5 to 1:10 v/v.
In the above described process, the suitable first solvent is preferably acetone and the suitable second solvent is preferably water.
The compound of formula-1 which is used as input in the above process for the preparation of crystalline form-M can be prepared by any of the known processes. For example, it can be prepared by the process as described in US7427638B2 patent or it can be prepared by the process as described in our pending Indian patent applications IN4513/CHE/2015 and IN6950/CHE/2015 or it can be prepared by the process as described in the present invention.
The crystalline form-M of compound of formula-1 can be utilized as input for the preparation of any of the known polymorphic forms and it can also be used as input for the preparation of novel polymorphs of compound of formula-1.

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in acetone,
b) optionally filtering the reaction mixture,
c) combining the solution with water,
d) filtering the precipitated solid and drying the material to provide crystalline form-M of compound of formula-1.
A more preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in acetone,
b) optionally filtering the reaction mixture,
c) slowly adding the solution to pre-cooled water at 5-10°C,
d) filtering the precipitated solid and drying the material to provide crystalline form-M of compound of formula-1.
A further embodiment of the present invention provides crystalline form-M of N-[2-[(1 S)-l -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-133-dioxo-1H-isoindoI-4-yl]acetamide compound of formula-1 which is obtained by the process as described in the present invention.
The crystalline form-M of compound of formula-1 is useful and well suitable for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-1 is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula-1 present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.

In a further aspect of the invention, a polymorph of compound of formula-1 was obtained on isolation from N,N-dimethylformamide/water solvent system by anti-solvent technique by using N,N-dimethylformamide as solvent and water as anti-solvent. The said polymorph is herein designated as crystalline form-S.
Crystalline form-S of compound of formula-1 is characterized by its PXRD pattern having peaks at 11.2, 13.2 and 13.5 ± 0.2° of 2-theta. The crystalline form-S is further characterized by its PXRD pattern having peaks at 5.3, 7.4, 8.4, 9.8, 14.0, 14.8, 16.7, 17.6, 17.9, 18.8, 19.6, 20.3, 20.9, 21.5, 22.8, 23.9, 25.5, 27.2, 28.9 ± 0.2° of 2-theta. The said polymorph is further characterized by its PXRD pattern as shown in figure-2.
Crystalline form-S of compound of formula-1 is further characterized by its DSC thermogram having three endotherms as descried below;
a) an endotherm at 75-80°C
b) an endotherm at 102-107°C
c) an endotherm at 145-150°C
The crystalline form-S of compound of formula-1 is further characterized by its DSC thermogram as shown in figure-4.
The moisture content in crystalline form-S of compound of formula-1 was found to be 3-3.5%.
An embodiment of the present invention provides crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1 H-isoindol-4-yljacetamide compound of formula-1 having particle size distribution of D90 less than 600 um.
A preferred embodiment of the present invention provides compound of formula-1 having particle size distribution of D90 less than 500 um, preferably less than 400 um, more preferably less than 300 um, most preferably less than 200 um.
Another embodiment of the present invention provides compound of formula-1 having particle size distribution of D% less than 100 um, preferably less than 50 um, more preferably less than 20 um, most preferably less than 10 um.

The PXRD analysis of compound of formula-1 of the present invention was carried out using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406A0 and at a continuous scan speed of 0.03°/min.
The differential scanning calorimetric (DSC) analysis was performed on a Q2000 V24.ll Build 124 calorimeter with aluminium pans. Samples held in a closed pan were analyzed at a heating rate of 10°C/min under nitrogen atmosphere.
Compound of formula-1 produced by the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: Kromasil 100 CI8, 250 x 4.6 mm, 5 urn or equivalent; Column temperature: 30°C; Wave length: 230 nm; Auto sampler temperature: 5°C; Injection volume: 5 uL; Elution: Gradient; Diluent: Acetonitrile : Buffer (70:30 v/v); Buffer: Take 1.0 mL of orthophosphoric acid and 3 gm of 1-octane sulfonic acid anhydrous in 1000 mL of milli-Q-water and filter this solution through 0.22 urn Nylon membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30 v/v).
The crystalline form-M of compound of formula-1 of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples have been provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]
acetamide (Formula-1)
A mixture of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l)3-dioxo-lH-isoindol-4-yl]acetamide (5 gm) and acetone (35 ml) was heated to 50-55°C and stirred the reaction mixture for 10 min at the same temperature. The obtained solution was slowly added to pre-cooled water (500 ml) at 5-10°C and stirred the reaction mixture for 6 hrs at the same temperature. Filtered the precipitated solid, washed with water and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 4.3 gm.
Example-2; Preparation of l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine
3M Methyl magnesium chloride solution in tetrahydrofuran (235.15 Lt) was slowly added to a pre-cooled mixture of 3-ethoxy-4-methoxybenzonitrile (50 Kg), dimethyl sulfone (53.12 Kg) and tetrahydrofuran (500 Lt) at 0-5°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. Sodium borohydride (21.5 Kg) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°*C, acetic acid (129 Lt) was slowly added and stirred for 45 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Water was slowly added to the reaction mixture at 0-5°C and basified the reaction mixture using aqueous sodium carbonate solution. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Distilled off tetrahydrofuran completely from the reaction mixture under

reduced pressure. Cooled the reaction mixture to 25-30°C. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with methyl tert.butyl ether under reduced pressure. Methyl tert.butyl ether (100 Lt) and methanol (100 Lt) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 90 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried the material to provide the title compound. Yield: 55.3 Kg; Purity by HPLC: 99.5%.
Imine impurity: Not detected; Benzaldehyde impurity: Not detected; Benzonitrile impurity: Not detected.
Example-3: Preparation of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt
N-acetyl-L-leucine (19 Kg) was added to a mixture of l-(3-ethoxy-4-methoxy phenyl)-2-(methylsulfonyl)ethanamine (50 Kg), methanol (200 Lt) and Dimethyl formamide (200 Lt) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. The obtained solid was added to water (175 Lt) at 25-30°C. Dichloromethane (225 Lt) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Basified the reaction mixture using aqueous sodium carbonate solution at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Dimethylformamide (85 Lt) and methanol (85 Lt) were added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. N-Acetyl-L-leucine (12.7 Kg) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. The obtained solid was added to water (150 Lt) at 25-30°C. Dichloromethane (200 Lt) was added to the reaction mixture at 25-30°C and stirred

for 15 min at the same temperature. Basified the reaction mixture using aqueous sodium carbonate solution at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Dimethylformamide (75 Lt) and methanol (75 Lt) were added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. N-Acetyl-L-leucine (11.1 Kg) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. Methanol (125 Lt) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and dried the material to get the title compound. Yield: 20.6 Kg; Purity by HPLC: 99.98%. Imine impurity; Not detected; Benzonitrile impurity: Not detected; (R)-isomer: 0.05%.
ExampIc-4: Preparation of 3-aminophthalic acid hydrochloride
3-Nitrophthalic acid (25 Kg) was added to a solution of sodium bicarbonate (24.75 Kg) in water (175 Lt) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Iron powder (0.65 Kg) and charcoal (2.5 Kg) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 95-100°C. 80% Hydrazine hydrate solution (14.75 Lt) was slowly added to the reaction mixture at 90-95°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed .with water. Cooled the filtrate to 10-15°C, slowly acidified the reaction mixture using aqueous hydrochloric acid solution and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried the material. Aqueous hydrochloric acid solution was added to the obtained compound at 25-30°C and stirred the reaction mixture for 90 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 90 min at the same temperature. Filtered the solid, washed with isopropyl alcohol and then dried the material to get the title compound. Yield: 16.5 Kg.

Example-5: Preparation of N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide
A mixture of 3-aminophthalic acid hydrochloride (16 Kg) and acetic anhydride (52.18 Kg) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 85-90°C and stirred for 4 hrs at the same temperature. Slowly cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether and then dried the material to get the title compound. Yield: 12.1 Kg.
Example-6: Preparation of compound of formula-1
A mixture of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt (5 Kg), N-(l,3-dioxo-l,3-dihydroisobenzoniran-4-yl)acetamide (2.3 Kg) and dimethylformamide (15 Lt) was stirred for 15 min at 25-30°C. Heated the reaction mixture to 85-90°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and aqueous sodium bicarbonate solution was added to it. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium bicarbonate solution followed by with aqueous hydrochloric acid and then with water. Distilled off the solvent completely from the organic layer and co-distilled with acetone. Cooled the obtained compound to 25-30°C, acetone (25 Lt) was added to it and stirred the reaction mixture for 10 min at the same temperature. Slowly added the obtained solution to pre-cooled water (125 Lt) at 5-10°C and stirred the reaction mixture for 3/2 hrs at the same temperature. Filtered the precipitated solid, washed with chilled water and dried the material to get the title compound. Yield: 4.7 Kg.
Example-7: Preparation of crystalline form-M of compound of formula-1
A mixture of compound of formula-1 (4.5 Kg), methanol (14 Lt) and ethyl acetate (5 Lt) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. The obtained solid was added to acetone (23 Lt) at 25-30°C. Heated the reaction mixture to

45-50°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-
30°C and filtered it through hyflow bed to make it particle free. Slowly added the filtrate to
pre-cooled water (135 Lt) at 5-10°C and stirred the reaction mixture for Vh hrs at the same
temperature. Filtered the precipitated solid, washed with water and dried the material to get
the title compound.
The PXRD pattern of the obtained compound is similar to figure-1.
Yield: 3.2 Kg; Purity by HPLC: 99.96%.
Particle size distribution:
Before micronization: D(0.1) is 3.34 urn; D(0.5) is 17.70 urn; D(0.9) is 150.0 urn.
After micronization: D(0.1) is 2.50 urn; D(0.5) is 6.63 urn; D(0.9) is 19:8 urn.
Examplc-8: Preparation of crystalline form-S of compound of formula-1
A mixture of compound of formula-1 (10 gm) and N,N-dimethylformamide (10 ml) was heated to 80°C and stirred the reaction mixture for 10 min at the same temperature. Cooled the reaction mixture to 25-30°C and water (500 ml) was slowly added dropwise to it. The slurry was stirred overnight at 25°C. Filtered the solid under vacuum and dried the material under vacuum for 15 to 20 hrs at 45°C to get the title compound. The PXRD and DSC data of the obtained compound are shown in figure-2 and figure-4 respectively. Yield: 7.5 gm; Moisture content: 3.06%.
ExampIe-9: Preparation of crystalline form-M of compound of formula-1
A mixture of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide (250 gm) and acetone (1250 ml) was heated to 40-45°C and stirred the reaction mixture for 20 min at the same temperature. Distilled off the solvent completely from the reaction, mixture and co-distilled with acetone (250 ml). 1250 ml of Acetone was added to the obtained compound, heated the reaction mixture to 45-50°C and Stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and filtered it through hyflow bed. Slowly added the obtained filtrate to pre-cooled water (7.5 Lt) at 5-10°C and stirred the reaction mixture for 2{A hrs at the same

temperature. Filtered the precipitated solid, washed with water and dried the material at 50°C
for 2 hrs to get the title compound.
Yield: 240 gm;
The obtained compound was further dried at 70°C.
Moisture content: about 2.0%.
The PXRD pattern of the obtained compound is similar to figure-1.
Particle size distribution:
Before micronization: D(0.1) is 5.00 urn; D(0.5) is 27.89 urn; D(0.9) is 221.32 urn.
After micronization: D(0.1) is 1.73 urn; D(0.5) is 3.86 urn; D(0.9) is 14.58 urn.

We Claim:
1. Crystalline form-M of N-[2-[( 1S)-1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)
ethyl-dihydro-l-dioxo-lH-isoindoM-ylJacetamide, characterized by;
i) its PXRD pattern having peaks at 5.4, 8.5, 16.7 and 27.3 ± 0.2° of 2-theta, ii) its PXRD pattern as illustrated in figure-1.
2. A process for the preparation of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-
melhoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]
acetamide according to claim 1, comprising of;
a) Dissolving the compound of formula-1 in a suitable first solvent,
b) optionally filtering the reaction mixture,
c) combining the solution with a suitable second solvent,
d) filtering the precipitated solid and drying the material to provide crystalline form-M of compound of formula-1.
3. The process according to claim 2, wherein,
in step-a) the suitable first solvent is selected from ketone solvents; and the dissolution of compound of formula-1 in a suitable first solvent can be carried out at a suitable temperature ranges between 10°C to reflux temperature of the solvent used;
in step-c) the suitable second solvent is selected from polar solvents; and combining the solution with a suitable second solvent can be done at a suitable temperature ranges from 0°C to reflux temperature of the solvent used.
4. The process according to claim 3, wherein the suitable first solvent is preferably acetone and the suitable second solvent is preferably water.
5. The process according to claims 3 and 4, wherein the first solvent and the second solvent are used in a ratio of 1:5 to 1:15 v/v.
6. A process for the preparation of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1 H-isoindol-4-yl] acetamide, comprising of;

a) Dissolving the compound of formula-1 in acetone,
b) optionally filtering the reaction mixture,
c) combining the solution with water,
d) filtering the precipitated solid and drying the material to provide crystalline form-M of compound of formula-1.

7. Crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide obtained by the process as described in any of the preceding claims.
8. A pharmaceutical composition comprising crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl] acetamide according to claim 1 and at least one pharmaceutically acceptable excipient.
9. Use of crystalline form-M of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide according to claim 1 for the preparation of pharmaceutical formulations.
10. Crystalline form-M of N-[2-[(lS)-l-(3-ethoxyl-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide having particle size distribution of D90 less than 600 um.