FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
"A NOVEL PROCESS FOR THE PREPARATION OF APREMILAST IN AMORPHOUS FORM"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASH1SH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI -400013, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
FIELD OF THE INVENTION
'The present invention relates to a novel process for the preparation of Apremilast in amorphous form.
BACKGROUND OF THE INVENTION
Apremilast-known as per IUPAC nomenclature as N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl) ethylJ-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide, is a selective inhibitor of phosphodiesterase 4 (PDE4) which in turn results in increased intracellular cyclic adenosine monophosphate or cAMP levels t thus useful in the treatment of severe psoriatic arthritis, plaque psoriasis, and also many other chronic inflammatory diseases such as psoriasis, ankylosing spondylitis, Behcet's disease, and rheumatoid arthritis. It is represented by the following chemical structure:

U.S. Patent No. 6,030,358 discloses substituted phenethylsulfones, including Apremilast, and method
of use thereof for reducing TNFα levels.
European Patent No. EP2420490B1 claims (+) Apremilast wherein it is synthesized from 3-aeetamidophthalie anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in the presence of glacial acetic acid. The present inventors have discovered a process for preparing Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of 3-acetarnidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)- l-(methylsulfonyI)-eth-2-ylamine in a reaction solvent in the absence of glacial acetic acid by treating the crude Apremilast with a purification solvent

comprising acetonitrile, DMF, DMSO or mixtures thereof, and isolating Apremilast in amorphous form by combining with water,
PCT publication WO200912067 teaches seven solid forms of the (+) enantiomer of Apremilast, designated as Forms A to G, including methods of preparation. WO2009120167 also generally mentions an amorphous form of Apremilast, but does not teach a method of preparation of such an amorphous form or its characterization.
PCT publication WO2014072259 discloses Apremilast in amorphous form in a composition arrived at by a melting process. Though this PCT application discloses a composition containing Apremilast in amorphous form, it fails to disclose a process for preparing Apremilast in amorphous form as an active pharmaceutical ingredient itself.
U.S. Patent No. 9,351,957 discloses amorphous solid dispersion of Apremilast and a polymer, wherein the amorphous solid dispersion of Apremilast is prepared by a process comprising grinding a solid-solid mixture of Apremilast and a polymer under controlled humidity. It also teaches a general method of preparing Apremilast in amorphous form by spray drying. Though it discloses a composition consisting Apremilast in amorphous form, it fails to disclose a process for preparing Apremilast in amorphous form as an active pharmaceutical ingredient itself.
PCT publication WO2016135755 teaches a process for preparing Apremilast in amorphous form by dissolving Apremilast in solvents selected from methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, l-pentanol, 2-pentanol, 3-pentanoJ, 2-methyl-l-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, dichloromethane, chloroform, and mixtures thereof, followed by addition of a nonpolar antisolvent selected from a group consisting of an ethereal solvent, a non-polar hydrocarbon solvent, and mixtures thereof It also teaches a process for preparing a premix of Apremilast in amorphous form with a pharmaceutical excipient and also an anisole solvate of Apremilast. The process of the present invention which involves the use of a unique solvent combination comprising acetonitrile and water, DMF and water, DMSO and water or mixtures thereof enable isolation of Apremilast in amorphous form directly from the crude reaction mixture which is not taught by any of the prior arts.
PCT publication WO2015173792 herein referred to as WO'792, discloses a process for Apremilast in amorphous form by at least 3 methods: viz: i.) heating Apremilast to melt under vacuum and cooling,

ii.) dissolving Apremilast (Form J) in solvents or solvent mixtures selected from THF, acetone and DMF: EtOH = 1:3 (vol./vol.) at room temperature followed by spontaneous evaporation and iii.) by dissolving Form 1 of Apremilast in a solvent selected from acetone, THF, MEK and combining with antisolvent selected from water and heptane. Thus WO'792 teaches a method for converting specifically a Form I of Apremilast to amorphous form and would not be suitable for direct conversion of a crude Apremilast unlike the present invention. The present invention provides a direct process for isolating Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-H methylsulfonyl)-eth-2-ylamine, isolated in amorphous form using a solvent-antisolvent mixture comprising acetonitrile-water, DMF-water, DMSO-water or mixtures thereof.
Thus, there is an unmet need to provide an economical, ecofriendly, and simple industrial process for the preparation of Apremilast in amorphous form. The process of the present invention which involves the use of a unique solvent combination comprising acetonitrile and water , DMF and water, DMSO and water or mixtures thereof, enables isolation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l-(methyIsulfonyl)-eth-2-ylamine in a reaction solvent preferably toluene in the absence of glacial acetic acid, is not taught by any of the prior arts. The advantageous property of better solubility, better availability, and purity of the present amorphous polymorph and also ease of removal of residual solvents achieved by the current process distinguishes the present invention from the rest.
SUMMARY OF THE INVENTION
The present invention provides an economical, ecofriendly, and simple industrial process for the preparation of Apremilast in a stable amorphous form with residual solvent content within the ICH prescribed limits.
A main aspect of the present invention is to provide a process for the preparation of Apremilast in amorphous form by treating a crude Apremilast obtained directly from the reaction mixture with a unique solvent - antisolvent combination comprising acetonitrile and water, DMF and water, DMSO and water or mixtures thereof
Thus according to an aspect of the present invention, is provided a process for the preparation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage

condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent optionally in the absence of a
condensing agent such as glacial acetic acid.
Thus according to an important aspect of the present invention, is provided a process for the preparation of amorphous form of Apremilast comprising the steps of:


(b)treating the compound of formula a purification solvent comprising
acetonitrile, dimethylformamide, dimethylsulfoxide or mixtures thereof,
(c) optionally removing the purification solvent comprising acetonitrile, dimethylformamide,
dimethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a
range between zero and 1000 ppm,
(d) combining with water and isolating Apremilast in amorphous form.
Thus according to an important aspect of the present invention, is provided a process for the preparation of amorphous form of Apremilast comprising the steps of:

(a) treating a compound of formula optionally obtained from a feedstock
comprising a reaction solvent with a purification solvent comprising acetonitrile, dimethylforrnamide,
dirnethylsulfoxide or mixtures thereof,
(b)optionally removing the purification solvent comprising acetonitrile, dimethylforrnamide,
dirnethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a
range between zero and 1000 ppm,
(c) combining with water and isolating Apremilast in amorphous form.
A general aspect of the present invention is summarized by the following reaction scheme as in Figure-1:
|Figure - 1 follows on the next page]


A specific aspect of the present invention is summarized by the following reaction scheme is as in Figure-2A:
|Figure - 2A follows on the next page]


A yet another specific aspect of the present invention is summarized by the following reaction scheme is as in Figure-2B;
[Figure - 2B follows on the next page)


A yet another specific aspect of the present invention is summarized by the following reaction scheme is as in Figurc-2C:
| Figure - 2C follows on the next page]


A yet another specific aspect of the present invention is summarized by the following reaction scheme is as in Figure-2D:
| Figure - 2D follows on the next page]


Iii accordance with the above objective, one aspect thereof, the present invention also provides a one pot process for the preparation of ApremiJast in amorphous form by directly treating the crude Aprernilast obtained from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine in a reaction solvent preferably toluene in the absence of condensing agent such as glacial acetic acid.
The key aspects of the present invention may be summarized as in the following steps:

A. A process for the preparation of amorphous form of Apremilast comprising the steps of:
(a) reacting a compound of formula in a reaction
solvent, optionally in the absence of glacial acetic acid to afford a compound of

(b) treating the compound of formula with a purification solvent comprising acetonitrile, dimethylformamide, dimethy (sulfoxide or mixtures thereof,
(c) optionally removing the purification solvent comprising acetonitrile, dimethylformamide, dimethylsu.lfox.ide or mixtures thereof, or/and controlling the residual reaction solvent content to a range between zero and 1000 ppm,
(d) combining with water and isolating Apremilast in amorphous form.
B. The process according to A above, wherein the residual reaction solvent content is between zero
and 500 ppm.
C. The process according to A above, wherein the residual reaction solvent content is between zero
and 100 ppm.

1), The process according to A above, wherein the reaction solvent comprises toluene, xylene,
mesitylene, benzene, chlorobenzene anil the like, or mixtures thereof.
E. The process according to A above, wherein the process comprises a one pot process.
F. A process for the preparation of amorphous form of Apremilast comprising the steps of:
(a) treating a compound of formula optionally obtained from a feedstock
comprising a reaction solvent with a purification solvent comprising aeetonitrile, dimethylformamide,
dimethylsulfoxide or mixtures thereof,
(b)optionally removing the purification solvent comprising aeetonitrile, dimethylformamide,
dimethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a
range between zero and 1000 ppm,
(e) combining with water and isolating Apremilast in amorphous form,
G. The process according to F above, wherein the residual reaction solvent content is between zero
and 500 ppm.
H. The process according to F above, wherein the residual reaction solvent content is between zero and 100 ppm.
I.The process according to F above, wherein the reaction solvent comprises toluene, xylene, mesitylene, benzene, chlorobenzene and the like, or mixtures thereof.
J. The process according to A&F above, wherein, the amorphous form of Apremilast is stable.

BRIEF DESCRIPTION OF DRAWING FIGURES
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:
F1GURE-1 IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST AS PER THE PRESENT
INVENTION
FIGURE-2A IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
FIGURE-2B IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
FIGURE-2C IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
FIGURE-2D IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC
EMBODIMENT OF THE PRESENT INVENTION
FIGURE-3 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN -WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
FIGURED IS A REPRESENTATIVE IR SPECTRUM OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN -WATER AS PER EXAMPLE-1. OF THE PRESENT INVENTION


APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN -
WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
F1GURE-6 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS (S) (+) APREMILAST BY TREATING APREMILAST FORM B WITH ACN-WATER AS PER EXAMPLE-10
F1GURE-7 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS (S) (+) APREMILAST OBTAINED BY TREATING APREMILAST FORM M WITH ACN-WATER AS PER EXAMPLE-11
F1GURE-8 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS (S) (+) APREMILAST OBTAINED BY A ONE POT PROCESS AS PER EXAMPLE-12
F1GURE-9 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART ACETONE/n-
HEPTANE COMBINATION AS PER REFERENCE EXPERIMENT-!
FIGURE- 10 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM ACETONE/WATER COMBINATION AS PER REFERENCE EXPERIMENT -2
FIGURE-11 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM
• OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART MEK/n-
HEPTANE AS PER REFERENCE EXPERIMENT -3
FIGURE- 12 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART THF/n-
HEPTANE AS PER REFERENCE EXPERIMENT -4
FIGURE-13 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE APREMILAST OBTAINED BY USING A PRIOR ART SOLVENT -MEK FOR AZEOTROPIC

DISTILLATION FOR REMOVAL OF RESIDUAL TOLUENE & EMPLOYING A PRIOR ART SOLVENT- ANTISOLVENT MEK-WATER AS PER REFERENCE EXPERIMENT -5
FIGURE-1.4 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE APREMILAST OBTAINED BY USING A PRIOR ART SOLVENT -ACETONE FOR AZEOTROPIC DISTILLATION FOR THE REMOVAL OF RESIDUAL TOLUENE & EMPLOYING A PRIOR ART SOLVENT- ANTISOLVENT ACETONE-WATER AS PER REFERENCE EXPERIMENT-6
FIGURE-IS IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE APREMILAST OBTAINED BY USING PRIOR ART SOLVENT -THF FOR AZEOTROPIC DISTILLATION FOR THE REMOVAL OF RESIDUAL TOLUENE & EMPLOYING A PRIOR ART
SOLVENT- ANTISOLVENT THF-WATER AS PER REFERENCE EXPERIMENT -7
FIGURE-16 IS A REPRESENTATIVE XRPD PATTERN OF APR-3-TOLUENE SOLVATE OF (S) (+) APREMILAST OBTAINED BY A PROCESS AS IN EXAMPLE-1 -WHICH IS SUBSEQUENTLY CONVERTED TO AMORPHOUS FORM BY ACN-WATER
TREATMENT.
FIGURE-17 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH DMF-WATER AS PER EXAMPLE-13 OF THE PRESENT INVENTION.
F1GURE-18 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH A 1:1 MIXTURE OF DMF-WATER AS PER EXAMPLE-15 OF THE PRESENT INVENTION.
TABLE-1 PROVIDES ILLUSTRATIVE EXAMPLES OF AMORPHOUS APREMLAST OBTAINED FROM APR-3-TOLUENE SOLVATE BY STRIPPING WITH ACN FOR REMOVAL OF RESIDUAL TOLUENE FROM APR-3-TOLUENE SOLVATE BY
AZEOTROPIC DISTILLATION, FOLLOWED BY RECRYSTATUSATION FROM ACN-WATER AS PER THE PRESENT INVENTION

TABLE-2 SUMMARISES THE EFFECT OF PRIOR ART SOLVENTS -ACETONE, THF, MEK-AS STRIPPING SOLVENT FOR REMOVAL OF RESIDUAL TOLUENE FROM, APR-3-TOLUENE SOLVATE BY AZEOTROPIC DISTILLATION AND THE TYPE OF POLYMORPH OBTAINED.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended steps.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended steps, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the
present application. Nothing herein is to be construed as an admission that the present invention is not
entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different: from the actual publication dates which may need to be independently co nil rined.
It should be noted that acronyms or symbols for reagents have the following definition: ACN-acelonitrile, DMF-N, N-dimethylforraamide, DMSO-dimethylsulfoxide.
A main aspect of the present invention is to provide a process for the preparation of Apremilast in amorphous form by treating a crude Apremilast obtained directly from the reaction mixture with a unique solvent - antisolvent combination comprising acetonitrile and water, DMF and water, DM SO and water or mixtures thereof,
Thus according to an aspect of the present invention, is provided a process for the preparation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2- (3-ethoxy-4-methoxyplienyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent optionally in the absence of a
condensing agent such as glacial acetic acid.
In accordance with the above objective, one aspect thereof, the present invention provides a one pot process for the preparation of Apremilast in amorphous form by directly treating the crude Apremilast obtained from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)~2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent preferably toluene in the absence of a condensing agent such as glacial acetic acid.
Thus according to an important aspect of the present invention, is provided a process for the preparation of amorphous form of Apremilast comprising the steps of

(a) reacting a compound of formula j„ a reaction
solvent, optionally in the absence of glacial acetic acid to afford a comnound of

(b) treating the compound of formula with a purification solvent comprising aeetonitrile, dimethylformamide, dimethylsulfoxide or mixtures thereof*
(c) optionally removing the purification solvent comprising aeetonitrile, dimethylformamide, dimethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a range between zero and 1000 ppm,
(d) combining with water and isolating Apremilast in amorphous form.
Thus according to an important aspect of the present invention, is provided a process for the preparation of amorphous form of Apremilast comprising the steps of;

(a)treating a compound of formula optionally obtained from a feedstock
comprising a reaction solvent with a purification solvent comprising acetonitrile, dimetliylformamide,
dimethylsulfoxide or mixtures thereof,
(b)optionally removing the purification solvent comprising acetonitrile, dimethylformamide,
dimethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a
range between zero and 1000 ppm,
(c) combining with water and isolating Apremilast in amorphous form.
The condensation reaction may be carried out optionally in the presence of suitable condensing agents like glacial acetic acid as described in the prior art. An embodiment of the present invention describes the reaction of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine with 3-acetamidopthalic anhydride, in the absence of glacial acetic acid in Toluene.
Suitable reaction solvents for condensation reaction are generally ketonie solvents, nitriles, alcohols, such as methanol, ethanol, isopropanol, hydrocarbons such as toluene, xylene, mesitylene, benzene, chlorobenzene , esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethers such as tetrahydrofuran, and dioxane, polar solvents like DMF, DMSO, chlorinated solvents such as methylene chloride, or mixtures of these solvents preferably hydrocarbon or mixtures thereof, even more preferably toluene, xylene, mesitylene, benzene, ehlorobenzene or mixtures thereof. In a preferred embodiment of the present invention, toluene is the preferred reaction solvent.
Suitable purifications solvents are generally ketonie solvents, nitriles such as acetonitrile, alcohols, such as methanol, ethanol, isopropanol, esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethers such as tetrahydrofuran, and dioxane, polar solvents like DMF, DMSO, chlorinated solvents such as methylene chloride, or mixtures of these solvents preferably hydrocarbon or mixtures thereof, even more preferably acetonitrile, DMF, DMSO or mixtures thereof.

The removal of solvent may be achieved by any suitable method known to a person skilled in the art such as filtration, distillation,
The residual reaction solvent content in the reaction mixture or the feedstock is controlled to a range between zero and 1000 ppm, preferably between zero and 500 pprn and more preferably between zero and 100 ppm.
The reaction may generally be carried out at reflux temperature of the solvent for about 8 hours. The completion of the reaction is monitored by any suitable technique known in the art such as by HPLC or TLC indicating the absence of starting materials.
The compound of formula which is converted to amorphous form may be the
crude obtained directly from the condensation step, or optionally obtained from a feedstock comprising a reaction solvent employed in the condensation step or a crystalline polymorph or a
solvate thereof.
In a preferred embodiment, the compound of formula is a crude toluene
solvate obtained directly from the condensation step. Figure-16 provides a representative XRPD pattern of APR~3(toluene solvate of Apremilast) obtained by condensation of a 3-acetamidophthalic anhydride and a N-acetyl Leucine salt of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-
2-ylamine in toluene in the absence of a condensing agent such as glacial acetic acid.
A preferred embodiment as in Example-1, provides a process of the present invention for the preparation of amorphous (S) (+) Apremilast wherein N-acetyl Leucine salt of (S)-2- (3-ethoxy-4-methoxyphenyl)-I-(methylsullbnyI)-eth-2-ylamine, 3- aeetamidopthalic anhydride, and toluene were refluxed under N2 atmosphere in a 4-necked RBF fitted with a Dean stark apparatus , condenser for

about 8 hours until HPLC showed absence of starting material. The reaction mixture was cooled to
room temperature, filtered and the wet cake washed with sodium bicarbonate solution, water and
filtered to afford crude (S) (+) Apremilast. This was dissolved in acetonitrile, treated with activated Carbon, and filtered through Hyflo®, washed with further acetonitrile, followed by atmospheric distillation. The in-process residual toluene content was checked each time, to ensure if it's content is less than about 100 ppm. When the in-process residual toluene content had reached to about 100 ppm, the stripping was stopped, the reaction mass was fine filtered through Whatman® filter paper, cooled to around 50°C and then poured into water, and the precipitated solid filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S (+) Apremilast as an amorphous solid.
In preferred embodiments, the purification solvents comprised Acetonitrile, DMF, DMSO or mixtures thereof. The dissolution may be carried out at a suitable temperature ranging from room temperature to about reflux temperature of the solvent. The amount of purification solvent employed may range to an amount sufficient to bring about dissolution and apparent to a person skilled in the art. In some embodiments, wherein the purification solvent is acetonitrile, the amount of acetonitrile added initially for stripping ranged from about 36 - 40 volume with respect to the weight of the crude Apremilast. In a preferred embodiment, the distillation carried out preferably at atmospheric pressure was done until about 4 volume solvent remained. In some other embodiments, the distillation was carried to about dryness, followed by a fresh addition of purification solvent in a quantity ranging from about 4 volume to about 8 volume with respect to the weight of the crude Apremilast. Each time after stripping, the in-process residual reaction solvent content was checked. The in process residual reaction solvent content was controlled to a range between zero and 1000 ppm, preferably between zero and 500 ppm or even more preferably between zero and 100 ppm. In some embodiments, wherein the reaction solvent is toluene, when the in-process residual toluene content had reached to about 100 ppm, the stripping was stopped, the reaction mass was fine filtered through Whatman® filter paper, cooled to around 50°C and then poured into water, and the precipitated solid filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S (+) Apremilast as an amorphous solid. The amount of antisolvent--water employed was preferably in the range of about 20 to about 40 volume with respect to the final volume of the purification solvent used in the final recrystallization step.
In certain embodiments performed on a small scale with about 10 gm starting material, a reaction flask of 1 litre capacity and a diameter of about 130 mm, mass height of about 70 mm and impellar length of about 80mm, an optimum RPM of about 180-200 resulted in amorphous form.


of Apremilast. in an embodiment of the present invention, the number of revolutions per minute (RPM) of the stirrer was adjusted to about 100-200, preferably to about 180-200 resulted in amorphous form, whereas at RPM's less than about 50 resulted in a sticky mass. In still another embodiment, higher RPM's at about 300 and above, resulted in a crystalline polymorph.
'The amorphous solid obtained may initially be dried at a temperature ranging from about 30-35'C for about 3hours, the temperature gradually raised to about 40-45 °C for about 4 hours and finally at 50-60 °C for about 30-36 hours , all drying done under vacuum NLT 730 mm Hg. This resulted in a stable amorphous form of Apremilast of pharmaceulically acceptable grade, stability and having residual toluene, acetonitrile, DMF and DMSO content well within the ICH prescribed limit.
In a series of embodiments incorporated herein as in Exanmples-1 to 9 of the present invention, wherein the reaction solvent is toluene, the present inventors conducted experiments with a purification solvent-antisolvent combination of ACN-Water and studied the maximum amount of in-process residual toluene content that would afford Apremilast in a stable amorphous form and having a residual toluene content below the ICH prescribed limit of 890 ppm.
In still other embodiments, as in Table-1, provide experiments as in Examples 1 to 9 - wherein the reaction solvent is toluene, of a study conducted by the present inventors to understand the maximum and the minimum limit of the in-process residual toluene content of the solvate which needs to be stripped by azeotropic distillation with purification solvents such as acetonitrile so as to afford Apremilast in a stable amorphous form with pharmaceutically acceptable levels of residual solvent content.
in still other embodiments, incorporated herein as in Examples 10 and 11, provide the use of ACN-Water for transforming other crystalline forms of Apremilast such as a polymorphic Form B or a polymorphic Form M to amorphous form. Thus an embodiment provides a process wherein a Form B of Apremilast was dissolved in acetonitrile, then combined with Water to afford amorphous form. Yet, another embodiment provides a process wherein a Form M of Apremilast was dissolved in acetonitrile, and then combined with water to afford amorphous form. The polymorph B employed herein may be obtained by a process as disclosed in a prior art such as in US7893101.The polymorphic Form M employed herein may be obtained by a process as disclosed in WO2016189486

In a specific embodiment, incorporated herein as Example 12, provides a one pot process for the preparation of Apremilast in amorphous form, wherein N-acetyl Leucine salt of (S)-2- (3-ethoxy-4-
methoxyphenyl)-]-(raethylsulfonyl)-eth-2-ylamine, 3- acetatnidopthalic anhydride, and toluene were
refluxed under N2 atmosphere in a 4-necked RBF fitted with a Dean stark apparatus, condenser for about 15 hours until HPLC showed absence of starting material, This was followed by distillation to remove toluene. This was followed by a stripping process that includes the steps of dissolution in a purification solvent such as acetonitrile, treatment with activated carbon, and filtration through Hyflo®, washings with further acetonitrile, followed by atmospheric distillation. The in-process residual toluene content was checked after each stripping with a purification solvent such as acetonitrile and after its removal by atmospheric distillation. When the in-process residual toluene content had reached to about 100 ppm, the stripping was stopped, the reaction mass was fine filtered through Whatman® filter paper, cooled to around 50 °C and then poured into water, and the precipitated solid filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S (+) Apremilast as an amorphous solid.
In an embodiment, incorporated herein as Example 13, a crude Apremilast toluene solvate was added to DMF, and stirred at 25°C-30°C for 30 min until clear solution was obtained. The reaction mixture was filtered through Hyflo®, washed with DMF and then heated to about 150 °C to 155°C.This was followed by distillation until about 3 volume DMF wrt weight of the crude remained. This was followed by addition of DMF and stripping by distillation until about 3 volume remained. The stripping with further DMF & distillation until 3 volume remained was done and each time, the in-process residual toluene content checked to ensure if it's content is less than about 100 ppm. When the in-process residual toluene content had reached to about 100 ppm, the reaction mass was cooled to about 50-55°C, & then poured into water at about 8-12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes. The precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NET 730 mm Fig for about 30 hours at about 50°C to 55°C to afford Apremilast as an amorphous solid.
In an embodiment, incorporated herein as Example 14, crude Apremilast toluene solvate was added to DMSO, and stirred at 25°C-30°C for 30 min until clear solution was obtained. The reaction mixture was filtered through Hyflo®, washed with DMSO and then heated to about 185 °C to 192°C.This was followed by distillation until about 3 volume DMSO wrt weight of the crude remained. This was followed by addition of DMSO and stripping by distillation until about 3 volume remained. The stripping with further DMSO & distillation until 3 volume remained was done and each time, the in-

process residual toluene content checked to ensure if it's content is less than about 100 ppm. When the
in-process residual toluene content had reached to about 100 ppm, the reaction mass was cooled to
about 50-55°C, & then poured into Water at about 8 -12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes. The precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to55°C to afford amorphous solid,
In an embodiment, incorporated herein as Example 15, crude Apremilast toluene solvate was added to a 1:1 solvent mixture comprising ACN-DMF, and stirred at 25°C-30°C for 30 min until clear solution was obtained. The reaction mixture was filtered through Hyflo®, washed with ACN:DMF mixture and then heated to about 70 °C to IKFC.This was followed by distillation until about 4 volume of ACN:DMF wrt weight of the crude remained. This was followed by addition of 1:1 mixture of ACN-DMF and stripping by distillation continued until about 4 volume remained, each time, the in-process residual toluene content checked to ensure if its content is less than about 100 pprn. When the in-process residual toluene content had reached to about 100 pprn, the reaction mass was cooled to about S0-55°C, & then poured into Water at about 8 -12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes. The precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to55°C to afford amorphous solid.
In some experiments, incorporated herein as Reference Experiments -1 to 4, the present inventors tried to convert a toluene solvate of Apremilast obtained directly from the crude reaction mixture comprising N-acetyl Leucine salt of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine, 3- acetamidopthalic anhydride using prior art solvents Acetone-n-Heptane, Acetone-Water, MEK-n-Heptane, THF-n-Heptane as per the teachings of the PCT application WO2015173792 and discovered that they afforded Apremilast in crystalline form, and not amorphous as desired. The present inventors discovered that the process of the present invention and the novel purification solvent-antisolvent combinations comprising Acetonitrile-Water, DMF-Water, DMSO-Water, ACN:DMF-Water or mixtures thereof was unique as they could convert a crude Apremilast or its solvates or polymorphs thereof,obtained directly from the reaction mixture or a feedstock comprising
the final stage condensation of a 3-acetamidophthalic anhydride and a N-acetyl Leucine salt of (S)-2-(3-ethoxy-4-metlioxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine into stable amorphous form of Apremilast, whereas the prior art solvent-antisolvent combinations such as Acetone-n-Heptane, Acetone-Water, MEK-n-Heptane, THF-n-Heptane felled.

In a series of experiments incorporated herein as Reference Experiments-5, 6 and 7, APR-3(toluene solvate of Apremilast) was dissolved successively in prior art sol vents-Acetone, MEK, and THF, These solutions were then distilled at room temperature and each time after stripping, the in-process toluene content was checked. The present inventors discovered that the residual toluene content in the toluene solvate of Apremilast -APR-3 could not be restricted to a range between zero to 1000 ppm, preferably about zero to 500 ppm, or even more preferably about zero to 100 ppm by distillation using prior art solvents such as Acetone, MEK, or THF (which are known to not form an azeotrope with toluene). Consequently, since the reaction solvent toluene was not: effectively removed by the solvent distillation, the polymorph after quenching in prior art anti-solvents - n-Heptane or Water resulted in a crystalline form and not the amorphous form as desired. Thus amorphous form was not obtained using prior art solvent-antisolvent combinations despite following the present invention's technique comprising distillation by stripping with prior art purification solvents such as Acetone, MEK, THF and combining the resultant solution with anti-solvents selected from n~Heptane, or Water because the in -process residual reaction solvent content could not be brought below to a level sufficient enough such as between zero to 1000 ppm , preferably about zero to 500 ppm , or even more preferably about zero to 100 ppm, which is achieved by the present invention's process.
In yet another reference experiment, the present inventors used a prior art solvent acetone as the stripping solvent for distillation to remove residual toluene at atmospheric pressure, the in-process initial toluene content was 2165.2 ppm, after 1st stripping was 1248 ppm , after 2nd stripping was 1097 ppm ,after 3rd stripping was 894 ppm, after 4th stripping was 782 ppm and after 5th stripping was 588.2 ppm and after 6th stripping was 458.3ppm.Thus , the prior art solvent acetone was found to be incapable of removing residual toluene from a toluene solvate of Apremilast and , since the presence of residual toluene has been shown to provide crystalline Apremilast, consequently the prior art combinations of acetone-water or acetone-n-heptane could not transform a crude Apremilast or a solvate or a toluene solvate obtained directly from the reaction mixture into amorphous form as desired, but rather provided a crystalline form. Similar was the outcome with other prior art solvents-MEK, THF. In each case, the residual toluene remained and a crystalline form was obtained. The results of experiments with acetone, MEK, THF as stripping solvents for removal of residual toluene in a toluene solvate of Apremilast and the in process residual toluene content after each stripping are provided in Table-2. In all cases, which employed prior art solvents such as Acetone, MEK and THF, distillation followed by anti-solvent precipitation, provided a crystalline form instead of the desired amorphous form.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Examples:
Although the invention lias been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the stepped invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood thai the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
EXAMPLE-1
PREPARATION OF APREMILAST IN AMORPHOUS FORM from 3-acetamidophthalic anhydride and N-acetyl Leucine salt of (S)2- (3-ethoxv-4-methoxyphenyl)-l-(methvlsulfonyl)-
eth-2-ylamine
(S)- N-Acetyl Leucine salt of 2- (3-ethoxy-4-metlioxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine
(529g, 1.183 moles) , 3- acetamidopthalic anhydride(256 g, 1.246 moles) and toluene (9051g) were refiuxed under N2 atmosphere in a 20 L 4-necked RBF fitted with a Dean stark apparatus , condenser for 8 hours until HPLC shows absence of starting material. The reaction mixture was cooled to room temperature, and filtered. The wet cake was washed with sodium bicarbonate solution, water and filtered to afford 470 gm of crude APR-3-Toluene solvate of (S) (+) Apremilast. The crude solid was dissolved in 16920 ml acetonitrile(36 volume wrt crude wt of Apremilast) at RT, treated with 25 gm Activated Carbon, and filtered through Hyflo®, washed with 1880 ml acetonitrile(4 volume wrt crude wt of Apremilast) , followed by atmospheric distillation to about 4 volume. The in process residual toluene content was checked for each stripping by atmospheric distillation .When the in process residual toluene content had reached to around 100 ppm, the stripping was stopped. The reaction mass was fine filtered through Whatman® filter paper, cooled to around 50 "C and then poured into 37600 ml water(20 volume wrt 1880 ml ACN) , the precipitated solid was filtered, washed with water and then dried under vaeuum-NLT 730 mm Hg to afford S(+) Apremilast as an amorphous solid.

FlGURE-3 IS A REPRESENTATIVE XRFD PATTERN OF AMORPHOUS S (+) APREM1LAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN -
WATER AS PER EXAMPLE-! OF THE PRESENT INVENTION.
F1GURE-4 IS A REPRESENTATIVE IR SPECTRUM OF AMORPHOUS S (+) APREM1LAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN -
WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION
FIGURE-5 IS A REPRESENTATIVE DSC THERMOGRAM OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN -WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
TABLE-1-below provides ILLUSTRATIVE EXAMPLES OF AMORPHOUS APREMLAST OBTAINED FROM APR-3-TOLUENE SOLVATE BY STRIPPING WITH ACN FOR REMOVAL OF RESIDUAL TOLUENE FROM APR-3-TOLUENE SOLVATE BY
AZEOTROPIC DISTILLATION, FOLLOWED BY RECRYSTALLISATION FROM, ACN-WATER AS PER THE PRESENT INVENTION
|Table -1 follows on the next page|

TABLE-1-
ILLUSTRATIVE EXAMPLES OF AMORPHOUS APREMLAST OBTAINED FROM APR-3-
TOLUENE SOLVATE BY STRIPPING WITH ACN FOR REM.OVAL OF IN PROCESS
RESIDUAL TOLUENE FROM APR-3-TOLUENE SOLVATE BY AZEOTROPIC
DISTILLATION, FOLLOWED BY RECRYSTALLISATION FROM ACN-WATER AS PER
THE PRESENT INVENTION
E BRIEF PROCESS RESIDUAL XRPD
v\ PROCESS SOLVENT PATTERN
A RESIDUAL CONTENT OF RESULTS
M TOLUENE APREM1LAST IN
P CONTENT AMORPHOUS
L
E In ppm FORM

TOLUENE ACN

i3 content
(NMT; 890 ppm) content
(NMT:
410
ppm)
1. AS IN EXAMPLE-1 ABOVE.
1.Dissolve toluene solvate of Apremilasl (APR-3) (10 gin) in 40 volume (400 ml) acetonitrile
2. Atmospheric Distillation to about
4.0 volume at temperature 81°C and
the in-process toluene content
checked.
3. Addition of ACN mass(40 ml) in 20
fold water (800 ml) at 10±2 °C in 60
min. 507 1588.4 69.6 Amorphous
1. Dissolve toluene solvate of
Apremilasl (APR-3) (10 gm) in 40
volume (400 ml) acetonitrile
2. Atmospheric Distillation to about
4.0 volume, then distilled under 52 3 136.8
(After 20 hrs drying) 56.7 Amorphous

vacuum completely at temperature 80-85"C followed by addition of 4.0
volume ACN and the in-process
toluene content checked. 3.Addition of ACN mass(40ml) in 20 fold water (800 ml) at 10±2 "C in 60 min.
4. 1. Dissolve toluene solvate of
Apremilast (APR-3) (10 gm) in 40
volume (400 ml) acetonitrile
2. Atmospheric Distillation to about
4.0 volume then distilled under
vacuum completely at temperature 80-
85"C followed by addition of 4.0
volume ACN and the in-process
toluene content checked.
3. Addition of ACN mass(40ml) in 20
fold water (800 ml) at 10±2 °C in 60 48.2 ppm 137.4 78 2 Amorphous
min. Amorphous
5. 1. Dissolve toluene solvate of 84.5 ppm 221.0 50.7

Apremilast (APR-3) (10 gm) in 40 volume (400 ml) acetonitrile
2. Atmospheric Distillation to about
oily mass then addition of 4.0 volume.
ACN and the in-process toluene
content cheeked.
3. Addition of ACN mass (40ml) in 20
fold water (800 ml) at 10±2 °C in 60
min.
6. 1. Dissolve toluene solvate of
Apremilast (APR-3) (20 gm) in 20
volume (400 ml) acetonitrile
2. Atmospheric Distillation to about 8
Volume and sample taken out for 151.0 667.4 81.5 Amorphous

Toluene content. 4 volume
Acetonitrile was again added and distilled atmospherically to about 4
Volume and the in-process toluene
content checked.
3. Addition of ACN mass (80ml) in 20
fold water (1600 ml) at 10±2 "C in 60
min.
4.RPM-180-200
7. Reprocess of Batch containing 30.3 44.9 65.3 Amorphous.

Toluene content 2643 ppm in

product.

1. Dissolve toluene solvate of
Apremilast (APR-3) (10 gm) in 40
volume (400 ml) acetonitrile
2. Atmospheric Distillation to about
oily mass was done, followed by
addition of 4.0 volume ACN and in-
process toluene content checked,
followed by addition of 8.0 volume
Acetonitrile and then atmospheric
distillation to about 4.0 volume,
followed by in-process toluene content
checked.
3,Addition of ACN mass in 20 fold water (800 ml) at 10±2 °C in 60 min.
8. 1.Dissolution of APR-3(1() gm) in 40 volume acetonitrile
2. Atmospheric Distillation to about
oily mass vacuum applied and
degased for 30 min. 4 volume
Acetonitrile was added and the in-
process toluene content checked.
3. Addition of ACN mass in 20 fold 65.1 ppm 36.1 2.7 Amorphous product obtained at RPM=180-
200. At RPM
above 300 Crystalline

water at 10±2C in 60 min. product was
RPM 315-345 observed
9. 1.Dissolution of APR-3(10gm) in 40 volume acetonitrile
2. Atmospheric Distillation to about
oily mass. 4 volume ACN for stripping
was added. ACN distilled out at
atmospheric pressure to about oily
mass. 4 volume ACN again was added,
the in-process toluene content
cheeked.
3. Addition of ACN mass in 20 fold
water at 1 ()±2 C in 60 minutes. 41.0 ppm 41.5 4.1 At moderate RPM (180-
200),
Amorphous
Polymorph
is stable.
HPLC RESULTS of APREMILAST All impurities less than 0.1% and complies as per
IN AMORPHOUS FORM IN specification
EXAMPLES 1 to 9
EXAMPLE-10-CONVERSION OF APREMILAST FORM B TO AMORPHOUS (S) (+)
APREMILAST USING ACN-WATER.
8 gm (0.01739 moles)of Apremilast Form B was added to 32 ml Acetonitrile , stirred at 25°C-30°C for 10 min and the reaction mixture heated at 45 °C to 50°C until clear solution was obtained. The reaction mixture filtered through filter paper at 40°C-45°.Then it was added into Water (640 ml) at 20°C-25C° and stirred for 30 minutes. The reaction mixture filtered, washed with 16 ml water and dried for 18 Hrs. 50°C to 55° C. Dry wt: 6.1 gm
• Conclusion: XRPD PATTERN of Dry material results in Amorphous polymorph-confirmed by XRPD PATTERN as in Figure-6
EXAMPLE-11-CONVERSION OF APREMILAST FORM M TO AMORPHOUS (S) (+) APREMILAST USING ACN-WATER
8 gm (0.01739moles) of Apremilast Form M was added to 32 ml Acetonitrile , stirred at 25°C-30°C for 10 min and the reaction mixture heated at 45 °C to 50°C until clear solution obtained. The reaction mixture filtered through filter paper at 40°C-45°.Then it was added into Water (640 ml) at 20°C-

25C° and stirred for 30 minutes. The reaction mixture filtered, wash with 16 ml water and dried for 18 Mrs. 50°C to55° C, Dry wt: 6.0 gm
• Conclusion; XRPD PATTERN of Dry material results in Amorphous polymorph -confirmed by
XRPD PATTERN as in Figure-7
EXAMPLE-12-ONE POT PROCESS FOR THE PREPARATION OF APREMILAST IN AMORPHOUS FORM,
(S)- N-Aceryl Leucine salt of 2- (3-ethoxy-4-methoxyphenyl)-l-(methylsuIfonyl)-eth-2-ylamine (ISg,
0.033 moles), 3- acetamidopthalic anhydride(7.23g, 0.0352 moles) and toluene (225ml) were retluxed under N2 atmosphere in a 500 niL 4-necked RBF fitted with a Dean stark apparatus , condenser for 15 hours until HPLC shows absence of starting material. This was followed by distillation to remove toluene completely, Then treated with 600 ml acetonitrile followed by atmospheric distillation to about around 4 volume or until around 60 ml solvent remained in the flask. The in process toluene content was checked for each stripping. When the in process toluene content had reached to around 100 ppm, the stripping was stopped. The reaction mass was fine filtered through Whatman® filter paper, cooled to around 50 "C and then poured into 1200 ml water, the precipitated solid was filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S(+) Apremilast as an amorphous solid.
• Conclusion: XRPD PATTERN of Dry material results in Amorphous polymorph -confirmed by XRPD PATTERN as in Figure-8
EXAMPLE-13-CONVERSION OF APREM.ILAST-TOLUENE SOLVATE TO AMORPHOUS (S) (+) APREMILAST USING DMF-WATER
25 gm (0.054 moles) of Apremilast toluene solvate was added to 500 ml DMF, stirred at 25°C-30°C for 30 min until clear solution was obtained. The reaction mixture was filtered under hyflo bed, washed with DMF (2x 50 ml) and then heated to about 150 °C to l55°C.This was followed by distillation until about 3 volume (75 ml) remained. This was followed by addition of 50 ml DMF and stripping by distillation until about 3 volume remained. The stripping with further 50 ml DMF & distillation until 3 volume remained was done and each time, the in-process residual toluene content checked to ensure if it's content is less than about 100 ppm. The reaction mass was cooled to about 50-55°C, & then poured into 2000 ml Water at about 8 -12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes. The precipitated solid was filtered, washed with about 100 ml water

and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to 55°C to afford 20 gin of the amorphous solid
• Conclusion: XRPD PATTERN of Dry material results in Amorphous polymorph -confirmed by
XRPD PATTERN as in Figure-17
EXAMPLE-14-CONVERSION OF APREMILAST-TOLUENE SOLVATE TO AMORPHOUS
(S) (+) APREMILAST USING DMSO-WATER
25 gm (0.054 moles) of Apremilast toluene solvate was added to 400 ml DMSO, stirred at 25°C-30°C for 30 min until clear solution was obtained. The reaction mixture was filtered under hyfio bed, washed with DMSO (2x 50 ml) and then heated to about 185 °C to 192°C.This was followed by distillation until about 3 volume (75 ml) remained. This was followed by addition of 50 ml DMSO and stripping by distillation until about 3 volume remained. The stripping with further 50 ml DMSO & distillation until 3 volume remained was done and each time, the in-process residual toluene content cheeked to ensure if it's content is less than about 100 ppm. The reaction mass was cooled to about 50-55°C, & then poured into 2000 ml Water at about 8 -12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes. The precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to55°C to afford 14.2 gm of the amorphous solid
• Conclusion: XRPD PATTERN of Dry material results in Amorphous polymorph -confirmed by
XRPDPATTERN.
EXAMPLE-15-CONVERSION OF APREMILAST-TOLUENE SOLVATE TO AMORPHOUS (S) (+) APREMILAST USING D1METHYLFORMAMIDE-ACN (1:1) MIXTURE
15 gm (0.032 moles) of Apremilast toluene solvate was added to about 20 volume of a 1:1 mixture of 150 ml DMF and 150 ml ACN, stirred at 25-30°C for 30 min until clear solution was obtained. The reaction mixture was filtered through hyfio bed, then heated to about 70 °C to 110 °C and distilled out under vacuum. This was followed by distillation until about 4 volume (60 ml) remained. The stripping with 1:1 mixture of DMF (30 ml): ACN (30ml) & distillation until 4 volume remained was done thrice and each time, the in-process residual toluene content was checked to ensure that it is less than about 100 ppm. The reaction mass was cooled to about 50-55°C, & then poured into 1200 ml Water at about 8-12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes. The precipitated solid was filtered, washed with about 2 x 30 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to55°C to afford 12.1 gm of the amorphous solid


Dry material results in Amorphous polymorph "Confirmed by

COMPARATIVE EXPERIMENTS USING PRIOR ART SOLVENTS-ACETONE, MEK, THF
and ANTISOLVENTS -WATER/ n-HEPTANE as per WO2015173792
REFERENCE EXPERIMENT-1: ACETONE-n-HEPTANE AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREM1LAST.
4 gm (0.0086 moles) of APR-3(toluene solvate of Apremilast) was added to 88 ml acetone & stirred at 25°C-30°C for 10 minutes. The reaction mixture was filtered through a Celite® bed and added into n-heptane (880ml) at 25°C-30°C, then stirred at 25°C-30°C, Dried for 24 hours and Filtered Conclusion: XRPD PATTERN -Not Amorphous, but crystalline product obtained-confirmed by XRPD PATTERN as in Figure-9
REFERENCE EXPERIMENTS: ACETONE-WATER AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREMILAST.
10 gm (0.0217moles) of APR-3(toluene solvate of Apremilast) was added to 220ml acetone & stirred at 25°C-3Q°C for 20 min. The reaction mixture was filtered through a Celite® bed and added into Water (2400ml) at 25°C-30°C, then stirred at 25°C-30°C for about 3 hours, vacuum dried for about 16 hours and Filtered to afford 6 gms of Crystalline solid
Conclusion: XRPD PATTERN -Not Amorphous, but crystalline product obtained -confirmed by XRPD PATTERN as in Figure-10
REFERENCE EXPERIMENT-3 MEK-n-HEPTANE AS SOLVENT-ANTISOLVENT
COMBINATION AFFORDED CRYSTALLINE APREMILAST.
4 gm (0.0086 moles) of APR-3(toluene solvate of Apremilast) was added to 60 ml MEK and stirred at 50°C-60°C for 30 minutes. The reaction mixture was filtered through a Celite® bed and added into N-heptane (600rnl) at 25°C-30°C, then stirred at 25°C-30°C for 6 hours, dried and filtered, Conclusion: XRPD PATTERN - Not Amorphous, but crystalline product obtained-confirmed by XRPD PATTERN as in Figure-11
REFERENCE EXPERIMENT-4: THF-n-HEPTANE AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREMILAST.

10 gm (0.0217moles) of APR-3(toluene solvate of Apremilast) was added to 80 ml THF and stirred
at 25°C-30°C for 30 minutes. The reaction mixture was filtered through a Celite® bed and added into N-heptane (800ml) at 25°C-30°C. The reaction mixture stirred at 25°C-30°C for 6 hours, filtered and
dried to afford crystalline solid.
Conclusion; Not Amorphous, but crystalline product obtained-confirmed by XRPD PATTERN as in
Figure-12
COMPARATIVE EXPERIMENTS USING PRIOR ART SOLVENTS-ACETONE, MEK,THF as STRIPPINGSOLVENTS FOR AZEOTROJPIC DISTILLATION FOR REMOVAL OF
RESIDUAL TOLUENE FROM A TOLUENE SOLVATE OF APREMILAST
REFERENCE EXPERIMENT -5- PRIOR ART SOLVENT-MEK -WATER
To 10 gm (0.0217moles) of APR-3(toluene solvate of Apremilast) was added 800ml MEK (RBF is
initially marked with 40 ml of volume). 0.5gm activated carbon was added and stirred. The reaction
mixture was filtered through a Celite© bed and washed with MEK (lxl0ml). The solvent was
removed by distillation at atmospheric pressure up to the mark. Fresh MEK was added and the process
repeated 5 times .The reaction mixture was added to Water within 30-60 minutes at 25°C -30 °C,
stirred for 30 minutes, filtered and dried at 50°C-55°C under vacuum
Conclusion: Not Amorphous, but crystalline product obtained-confirmed by XRPD PATTERN as in
Figure-1.3
REFERENCE EXPERIMENT -6- PRIOR ART SOLVENT-ACETONE-WATER To 20 gm (0.043 moles) of APR-3(toluene solvate of Apremilast) was added 400 ml acetone (RBF is initially marked with 80 ml of volume). 1.0 gm activated carbon was added and stirred. The reaction mixture was filtered through a Celite® bed and washed with acetone (2x20ml).The solvent was removed by distillation at atmospheric pressure up to the mark. Added fresh 80 ml acetone and distilled at atmospheric pressure up to the mark .The process repeated 5 times .The Reaction mixture was added to Water (1600ml) within 30-60 minutes at 25°C -30°C, stirred for 30 minutes, filtered and dried at 50°C-55°C under vacuum to afford 16.5 gm of crystalline solid
• Conclusion: Not Amorphous, but crystalline product obtained-confirmed by XRPD PATTERN as in Figure-14,

REFERENCE EXPERIMENT -7- PRIOR ART SOLVENT-THF-WATER
To 10 gm (0.02l7moles) of APR-3 (toluene solvate of Apremilast) was added 200ml THF (RBF is initially marked with 80 ml of volume). 1.0 gm activated carbon was added and stirred. The reaction mixture was filtered through a Celite® bed and washed with THF (2x!0ml).The solvent was removed by distillation at atmospheric pressure up to the mark. Added fresh THF and distilled at atmospheric pressure up to the mark .The process repeated 5 times .The Reaction mixture was added to Water (800ml) within 30-60 minutes at 20°C -25°C, stirred for 30 minutes, filtered and dried at 50°C-55°C under vacuum to afford 14 gm of crystalline solid
• Conclusion: Not Amorphous, but crystalline product obtained-eonfirmed by XRPD PATTERN as
in Figure-15
(Table -2 follows on the next page]

POLYMORPH OBTAINED NOT NOT NOT
AMORPHOUS AMORPHOUS AMORP
YIELDED YIELDED HOIJS
CRYSTALLINE CRYSTALLINE YIELDE
FORM FORM CRYSTA LLINE
FORM
The amorphous form of Apremilast described herein, exhibits physical and chemical stability for a long term. The table below presents stability data on amorphous form of Apremilast prepared by processes of the present invention. The amorphous form of Apremilast described herein is stable since it shows no significant degradation or change in PXRD pattern when stored at 2-8°C and at 25 °C /60% relative humidity (RH).

Condition Amorphous Apremilast

PXRD
at 25°C/60%RH
Initial Amorphous
1 month Amorphous
2 month Amorphous
3 month Amorphous
6 month Amorphous
12 month Amorphous
at 2 to 8°C
Initial Amorphous
3 month Amorphous
6 month Amorphous
12 month Amorphous

1. A process for the preparation of amorphous form of Apremilast comprising the steps of:
(a) reacting a compound of formula in a reaction
solvent, optionally in the absence of glacial acetic acid to afford a compound of
formula
(b)treating the compound of formula with a purification solvent comprising
acetonitrile, dimethylformamide, dimethylsulfoxide or mixtures thereof,
(c) optionally removing the purification solvent comprising acetonitrile, dimethylformamide,
dimethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a
range between zero and 1000 ppm,
(d) combining with water and isolating Apremilast in amorphous form.
2. The process according to claim 1 wherein the residual reaction solvent content is between zero and 500 ppm.
3. The process according to claim 1 wherein the residual reaction solvent content is between zero and 100 ppm.

4. The process according to claim 1, wherein the reaction solvent comprises tollll flyfene mesitylene, benzene, chlorobenzene and the like, or mixtures thereof.
5. The process according to claim 1, wherein the process comprises a one pot process.
6. A process for the preparation of amorphous form of Apremilast comprising the steps of;
(a) treating a compound of formula optionally obtained from a feedstock
comprising a reaction solvent with a purification solvent comprising acetonitrile, dimethylformarnide,
dimethylsulfoxide or mixtures thereof,
(b)optionally removing the purification solvent comprising acetonitrile, dimethylformarnide,
dimethylsulfoxide or mixtures thereof, or/and controlling the residual reaction solvent content to a
range between zero and 1000 pprn,
(e) combining with water and isolating Apremilast in amorphous form.
7. The process according to claim 6 wherein the residual reaction solvent content is between zero and 500 pprn.
8. The process according to claim 6 wherein the residual reaction solvent content is between zero and 100 pprn.
9. The process according to claim 6, wherein the reaction solvent comprises toluene, xylene, mesitylene, benzene, chlorobenzene and the like, or mixtures thereof.
lO.The process according to claims 1 & 6, wherein, the amorphous form of Apremilast is stable.