DESC:F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“PHARMACEUTICAL COMPOSITION OF STABLE AMORPHOUS FORM OF AGOMELATINE”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

The following specification particularly describes the invention and the manner in which is to be performed.

FIELD OF THE INVENTION
The present invention relates to process for preparing stable amorphous form of agomelatine which is stable under accelerated condition and a pharmaceutical composition comprising stable amorphous form of Agomelatine for oral administration and process for preparation of said pharmaceutical composition.

BACKGROUND OF THE INVENTION
Agomelatine, or N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide of formula (I):

and its hydrates, crystalline forms, complexes, co-crystals, and addition salts with a pharmaceutically acceptable acid or base has following pharmacological properties: it is a selective agonist of receptors of the melatoninergic system and, on the other hand, an antagonist of the 5-HT2C receptor. These properties provide it with activity in the central nervous system and, more especially, in the treatment of major depression, seasonal affective disorder, generalized anxiety disorder, obsession compulsive disorder, bipolar disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, appetite disorders and obesity.

Agomelatine tablets (agomelatine tablets) developed by the French company Servier and marketed under the trade name Valdoxan ® / Thymanax ® in the Europe and used for the treatment of major depression in adults. Further as per the EMA (Europe medicine agency) public assessment report agomelatine was rapidly and almost completely absorbed after oral administration, but with a low absolute bioavailability (7 % and 0.2 % in rat and monkey, respectively) caused by a high level of first-pass metabolism.

Agomelatine, its preparation and use in therapy has been disclosed in European patent specification EP0447285B1.

S. Yous et al. in J. Med. Chem. 1992, 35, 1484-1486 discloses a process for the preparation of agomelatine, wherein agomelatine is obtained from a biphasic medium of water and chloroform.

Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910 discloses a full crystallographic investigation of the agomelatine produced by Yous et al. The polymorph form of the product obtained by Yous et al. and analyzed by Tinant and Declercq is designated as the polymorph form I of agomelatine. Tinant and Declercq provide the full crystal data of this polymorph form, and regarding the identification of the polymorph form I of agomelatine.

Different polymorphic form of agomelatine know through US7250531B2 (form II), US7635721B1 (form III), US7645905B2 (form IV), US7358395B2 (form V), US8067639B2 (form VI).

WO2008137461 discloses method of enhancing bioavailability is the use of an amorphous form of a compound of this disclosure optionally formulated with a poloxamer, or block copolymers of ethylene oxide and propylene oxide.

CN 102670514A discloses dispersion comprises agomelatine and carrier (povidone, Poloxamers or the like), and the mass ratio of agomelatine and carrier is 1:0.5-1:5. The prepn. method consists of mixing agomelatine and carrier, melting mixture and preparing dispersion by extrusion at 100-160°C. However, the main drawbacks of melt extrusion technique is not suitable for relatively high heat sensitive molecules and melt extrusion technique comprising high processing temperatures, which can degrade sensitive drugs.

EP1427724A discloses solid orodispersible pharmaceutical composition of agomelatine containing agomelatine and granules consisting of lactose and starch dried by co-atomisation and marketed under the name STARLAC®. This pharmaceutical composition makes it possible to obtain tablets having a very good capacity for disintegrating in the oral cavity and, more specifically, in the sublingual cavity, meeting the criteria for orodispersibility. The orodispersible tablets make it possible to deliver the active ingredient into the oral cavity and, more specifically, into the sublingual cavity in less than three minutes. Dissolution of the active ingredient in the saliva and then absorption via the mucous membranes of the oral cavity and, more specifically, the sublingual mucous membrane, and rapid passage into the blood make it possible to avoid presystemic degradation and the hepatic first-pass effect. Accordingly, bioavailability is very clearly improved with much lower variability and rapid appearance of the active ingredient in the blood.

EP1800669B1 discloses orodispersible formulation having a central core or central layer containing agomelatine and excipients to obtain a formulation orodispersible and Orodispersible coating. However, it quickly became apparent that this formulation had a drawback due to the active ingredient used agomelatine which causes a pronounced sensation of irritation in the mucous membranes of the oral cavity.

EP2556824A1 discloses solid buccal controlled release pharmaceutical composition comprising agomelatine or one of its hydrates, complexes, co-crystals, crystalline forms, addition salts with a pharmaceutically acceptable acid or base, and one or more excipients selected from diluents, binders, flow agents, lubricants, coating agents, plasticizers, flavorings, counter-irritants and sweeteners, wherein the composition is intended for systemic action, and wherein the composition has an absolute bioavailability greater than 25%. However, disadvantages associated with buccal drug delivery are the patient acceptability (mouth feel, taste and irritation) and the non ubiquitous distribution of drug within saliva for local therapy.

CN102824327 discloses agomelatine containing enteric tablet composed of plain tablet containing agomelatine and excipient, enteric coating and isolation layer. However, Agomelatine is used for treatment of major depression in adults which need immediate action so there is no rational behind the preparation of delayed release tablet.

WO2012093402A1 discloses process for preparing agomelatine and further discloses amorphous form of agomelatine by using organic solvent and also use of spray drying, freeze drying, heating followed by rapid cooling, solvent–anti solvent technique and the pharmaceutically acceptable carriers that can be used for the preparation of amorphous agomelatine include, but are not limited to, pharmaceutical hydrophilic carriers such as polyvinylpyrrolidone (homopolymers, also called "povidone," or copolymers of N-vinylpyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cylcodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols. Further discloses pharmaceutical composition comprising amorphous agomelatine prepared by processes described above and at least one pharmaceutically acceptable carrier. However, the said patent application doesn’t disclose the stability data of the amorphous form of agomelatine and more specifically with any cross-linked acrylic acid polymer like Carbomers. Further the said publication did not disclose any examples for tablet prepared by the amorphous form of agomelatine.

WO2012130837A1 discloses non-crystalline agomelatine.Further in the working example discloses process for preparing non–crystalline agomelatine by melt extrusion technique and formulates a tablet of agomelatine without binder. However the main drawbacks of melt extrusion technique is not suitable for relatively high heat sensitive molecules and melt extrusion technique comprising high processing temperatures, which can degrade sensitive drugs.

WO2014040228 and WO2014041015 are disclosed a stabilized amorphous form of agomelatine and process for preparation. Further disclosed a solid dispersion of agomelatine within an organic polymer more especially methacrylic acid polymer or vinyl polymer or cellulosic polymer and prepared by dissolution – evaporation and extrusion techniques. However, the said patent application doesn’t disclose the amorphous form of agomelatine with any cross-linked acrylic acid polymer like Carbomers.

Several attempts have been done in past to solve the issues of stability of agomelatine, low bioavailability, to avoid first pass metabolism of agomelatine in the final formulation by preparing composition like Immediate release tablet comprising crystalline form of agomelatine (Valdoxan/ Thymanax), orodispersible tablet, buccal delivery or by developing amorphous form of agomelatine with melt extrusion technique followed by tableting.

Generally, amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound. The rate of dissolution is also a consideration in formulating tablet, syrups, elixirs and other liquid medicaments.

As discussed above different approaches have been used in past to provide pharmaceutical composition of agomelatine having improved dissolution rate and improved bioavailability by different method having the major drawbacks.

However the prior art discloses amorphous form of agomelatine prepared by the melt extrusion technique. In the melt extrusion technique the agomelatine might be degrade at the high temperature and for melt extrusion technique sophisticated instrument require. Further large scale execution of melt extrusion and reproducibility is difficult task.

Hence, there is unmet need to provide a stable amorphous form of agomelatine and pharmaceutical composition comprising amorphous form of agomelatine having with improved solubility, dissolution, and bioavailability.

The present invention provide a novel process for preparing amorphous form of agomelatine having stability over accelerated condition and preparation of a pharmaceutical composition comprising amorphous agomelatine with at least one cross-linked acrylic acid polymer having improved solubility, dissolution and bioavailability over the marketed agomelatine product and process for preparing pharmaceutical composition of stable amorphous agomelatine.

OBJECT OF THE INVENTION
An object of present invention is to provide a stable amorphous form of agomelatine with cross linked acrylic acid polymer, preferably carbomers.
Another object of the present invention is to provide a novel process for preparing amorphous form of agomelatine having stability over accelerated condition.

Another object of present invention is to provide pharmaceutical composition comprising amorphous agomelatine with at least one binder having improved solubility, dissolution and bioavailability over the marketed agomelatine product, which can applicable to the industrial scale.

DESCRIPTION OF THE DRAWINGS
Fig.1: The XRD data of agomelatine 25 mg tablet (Example 3) at 6 months accelerated condition.

Fig.2: The XRD data of agomelatine 25 mg tablet (Placebo) at 6 months accelerated condition.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable amorphous form of agomelatine with cross-linked acrylic acid polymer, preferably carbomers. The stable amorphous form of agomelatine comprising a ratio of agomelatine to cross-linked acrylic acid polymer is 1:0.5 to 1:6, preferably 1:1.

The present invention thus relates to the stabilized amorphous form of agomelatine. The term "stabilized" is understood that the amorphous form of agomelatine is preserved when it is subjected to storage at conditions of temperature and humidity for six months. The storage conditions of temperature and humidity according to the invention will be, for example 40°C / 75% RH (relative humidity), 30°C / 65% RH, and 25°C / 60% RH.

Unexpectedly, a stable amorphous form of agomelatine which meets the above requirement prepared by the process comprising crystalline form(s) of agomelatine is dissolved in organic solvent and add carbomers to form uniform dispersion and add other optional adjuvant inactive ingredient(s) like TEC (Triethyl citrate), MCC (Microcrystalline cellulose) in dispersion. Further, a suitable anti-solvent, for example water, is added to the previous dispersion to yield stable amorphous agomelatine complex. The complex is dried to yield stable amorphous agomelatine complex in dried form.

Stable amorphous form of agomelatine meeting the general stability requirements is prepared by the process comprising dispersing agomelatine and at least one carbomer in an organic solvent and subjecting the said mixture to heating wherein the dispersed agomelatine and carbomer mixture form a solid complex in the organic solvent environment. The excess solvent is filtered off and the residual solid complex is washed a suitable washing solvent and dried under vacuum.
For the purpose of the present invention, agomelatine is as base or pharmaceutically acceptable salt of agomelatine.

As per the more preferred embodiment, agomelatine used for the purpose of the preparation of amorphous form of agomelatine is agomelatine polymorphic Form 1 was known from the Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910 discloses a full crystallographic investigation of the agomelatine produced by Yous et al. The polymorph form of the product obtained by Yous et al. and analyzed by Tinant and Declercq is designated as the polymorph form I of agomelatine. Tinant and Declercq provide the full crystal data of this polymorph form, and regarding the identification of the polymorph form I of agomelatine. Further crystalline form-1 is input material for preparation of amorphous agomelatine as per the invention.

As per the present invention, polymers used in preparation of amorphous agomelatine are cross linked acryclic acid polymers like carbomers.

Carbomers are synthetic high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol. They contain between 52% and 68% of carboxylic acid groups calculated on the dry basis. The BP 2009 and PhEur 6.4 have a single monograph describing carbomer. The USP 32 – NF 27 contains several monographs describing individual carbomer grades that vary in aqueous viscosity polymer type and polymerization solvent. Various synonyms of carbomers are Acrypol®, Acritamer®, acrylic acid polymer, carbomera, Carbopol®, carboxy polymethylene, polyacrylic acid, carboxyvinyl polymer, Pemulen®, Tego Carbomer®.

Various organic solvents can be employed for the purpose of dissolving agomelatine and to form uniform dispersion with cross-linked acrylic acid polymer and other optional inactive ingredients.

The solvents that can be used for dissolving agomelatine and to form uniform dispersion with cross-linked acrylic acid polymer, include, but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ketonic solvents such as acetone, and methyl ethyl ketone; halogenated solvents such as dichloromethane, ethylene dichloride and chloroform; preferably acetone. As per present invention, anti solvent is water.

As per the more preferred embodiment process comprising crystalline Form-1 of agomelatine is use up to 30% w/w to 70% w/w, carbomer is use up to 20%w/w to 70% w/w, TEC (Triethyl citrate) is use up to 0.5 to 2%, organic solvent and water.

As per the more preferred embodiment, process for preparing agomelatine involves following steps
1. Dissolve weighed quantity of crystalline Agomelatine in Acetone under constant stirring & continue mixing for 10 min or until clear solution is obtained.
2. Add slowly Carbomer in above Step-1 solution under constant stirring to get uniform dispersion.
3. After complete addition of Carbomer, mix the dispersion for further 30 minutes under stirring.
4. Add TEC in above step 3 dispersion under constant stirring & mix for 10 minutes.
5. Slowly add purified water in above step 4 dispersion under constant stirring & continue addition until complex is formed (Milky white gel like mass which gradually gains viscosity).
6. Collect the complex and dried it on tray drier/vacuum dryer @ 60°C for 18 hours.
7. Sift the dried granules /powder through # 40 sieves.
8. If required, mill the over sized granules in turbo sifter cum multimill or sifter cum multimill equipped with 1.0 / 0.5 mm S. S. Screen at medium speed with knives forward.
9. Mix the sifted and milled granules in conta blender for 10 min at 16 rpm.
10. Collect above granule/powder in polybag.

As per an another embodiment, process for preparing agomelatine involving following steps
1. Charge organic solvent into reaction vessel
2. Charge Carbomer
3. Charge Agomelatine form-I
4. Heat the reaction mixture under reflux condition and stir the reaction mixture for 4 hrs
6. Filter the solid
7. Wash with hot cyclohexane
8. Dry the solid under vacuum at 50±3°C

The organic solvent used for dispersing agomelatine and carbomer as per the above process are hexanes, di-isopropyl ether, methyl t-butyl ether and long chain alkanes. The organic solvent preferably used in the above process is hexanes; more preferably cyclohexane. Preferably, agomelatine and carbomer have very limited solubility in the said organic solvent.

As per the preferred embodiment stability study of prepared amorphous agomelatine is carried out at 40°C/75% RH, 30°C/65% RH 25°C/60% RH, and 2-8°C in Transparent glass vial with and without nitrogen purging for Initial 15 days, 1month, 3 months and up to 6 months.

As per the most preferred embodiment amorphous form of agomelatine obtain by present invention is stable for 6 month study carried out at 40°C/75% RH, 30°C/65% RH, 25°C/60% RH, and 2-8°C.

As per the preferred embodiment pharmaceutical composition includes any solid dosage form, preferably such as tablet, capsule, granules or a powder, pellets, beads, microspheres, spheroids, capsule containing pellets/beads/granules/ microspheres, MUPS (Multiple Unit Pellet System) tablets.

As per the more preferred embodiment pharmaceutical composition is table with at least one binder.

The term "tablet" used throughout the text refers to tablet types such as tablet, effervescent tablet, film-coated tablet, enteric-coated tablet, orodispersible tablet, water-soluble tablet, extended release tablet, modified-release tablet and delayed-release tablet.

In a preferred embodiment of the invention, the pharmaceutical formulation of the present invention is in “immediate release tablet “dosage form.
The term “immediate release” means any type of release of the active ingredient, Agomelatine, from the composition of the present invention resulting in in-vitro release over a short period of time, i.e., (less than one hour) sufficient to provide therapeutically effective plasma levels over similarly short time interval and/or to modify other pharmacokinetic properties of the active ingredient.

As per the preferred embodiment of the invention, a pharmaceutical composition comprising stable amorphous form of agomelatine or pharmaceutically acceptable salt thereof comprises water soluble diluent, water soluble/swellable binder, disintegrant,optionally one or more surfactant and/or one or more pharmaceutically acceptable excipients.

From the experiment, it was found that it is advantageous to use water-soluble/swellable excipients to prepare pharmaceutical composition for immediate release tablet of stable amorphous form of agomelatine or pharmaceutically acceptable salt thereof.

As per the most preferred embodiment water swellable diluent is pregelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthum gum, gum arabic or any combination thereof.

As per the preferred embodiment of the invention, water soluble diluent is selected from, but not limited to lactose, mannitol, xylitol, sorbitol, calcium sulfate dihydrate, inositol, dextrin, calcium sulfate anhydrous, fructose, kaolin, sugar compressible, sucrose, lactitol, dextrates, confectioner's sugar, sucrose, sodium chloride, dextrose, cyclodextrin or any combination thereof.
As per the more preferred embodiment of the invention, water soluble/swellable binder is selected from but not limited to polyvinyl pyrrolidone, starch, gelatin, cellulose derivative like Hydroxypropyl methyl cellulose, Hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyl methyl cellulose or mixture of any thereof.

As per the more preferred embodiment of the invention, disintegrant is selected form, but not limited to cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium and low substituted hydroxyl propyl cellulose or mixture thereof.

As per another embodiment of the invention optionally containing one or more surfactant is selected from, but not limited to ionic, nonionic.

For the purpose of the present invention optionally contain ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants.

For the purpose of the present invention optionally contain anionic surfactant is selected from, but not limited to one or more of sodium lauryl sulphate, sodium dodecyl sulphate, ammonium lauryl sulphate, alkyl benzene sulfonate, perfluorooctanoate, perfluorooctanesulfonate etc.; cationic surfactants may be selected from benzalkonium chloride, benzethonium chloride, polyethoxylated tallow amine, cetylpyridinium chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl ammonium bromide and other alkyltrimethyl ammonium salts etc.; or amphoteric surfactants may be selected from dodecyl betaine, cocamidopropyl betaine, cocoampho glycinate etc. The ionic surfactants may also include alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides, and the like.

For the purpose of the present invention optionally contain cationic surfactants is selected from, but not limited to one or more of quaternary ammonium compounds, such as benzalkonium chloride, cetyl trimethyl ammonium bromide and dodecyl dimethyl ammonium bromide, hexadecyl (cetyl) trimethylammonium bromide, dodecyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, dodecylamine hydrochloride, and the like.

For the purpose of the present invention optionally contain zwitterionic surfactants is selected from, but not limited to one or more of alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates and acyl glutamates wherein the alkyl and acyl groups have from 8 to 18 carbon atoms such as cocamidopropyl betaine, sodium cocoamphoacetate, cocamidopropyl hydroxysultaine, and sodium cocamphopropionate, and the like.

For the purpose of the present invention optionally contain non-ionic surfactant is selected from, but not limited to one or more of ethyleneoxide/propyleneoxide copolymers referred to hereinbelow as poloxamers, such as poloxamer 124 sold under the brand name Synperonic.RTM. PE/L44; poloxamer 188 sold under the brand name Pluronic.RTM. F68 or Synperonic.RTM. PE/F68; poloxamer 237 sold under the brand name Pluronic.RTM. F87 or Synperonic.RTM. PE/F87; poloxamer 338 sold under the brand name Synperonic.RTM. PE/F108 or poloxamer 407 sold under the brand name Pluronic.RTM. F127, Synperonic.RTM. PE/F127 or Lutrol.RTM. F127. polyethoxylated castor oils such as those sold under the brand name Cremophor.RTM. RH40. ethoxylated polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 sold respectively under the brand names Tween.RTM. 20, Tween.RTM. 40, Tween.RTM. 60 and Tween.RTM. 80. or alternatively polyethylene hydroxystearates such as polyethylene hydroxystearate 660 sold under the brand name Solutol.RTM. HS15.

As per another embodiment of the invention, one or more pharmaceutically acceptable excipient are selected from, but not limited to lubricant, glidant, sweeteners, flavoring agent, coloring agent, antiadherents and mixture thereof, Other excipients known in the field of pharmaceutical composition may be also used.

As per another embodiment of the invention solid dosage form further coated film coatings contemplated by the present invention include, but are not limited to, those that include hydroxypropyl methyl cellulose and particularly Opadry™. However, any film-former known in the art may be used.

As per the another aspect of the invention is to provide a process for preparation of Immediate release tablet of stable amorphous form of agomelatine or pharmaceutical acceptable salt thereof having improved bioavailability or is bioequivalent to marketed product.

As per preferred embodiment of the present invention provides immediate release solid dosage forms comprising agomelatine that provide for the in vitro dissolution of more than about 80% of the agomelatine within the first 60 minutes. The preferred method of evaluating the dissolution rate is the USP Type II (Paddle) method at 50 RPM in 900 ml 0.1N HCl, at 37°C.

It has been found that the inventive process of the invention offer advantage compared to prior art process to use agomelatine or pharmaceutically acceptable salt thereof in stable amorphous form and without any limitation or of specific particle size as input material for preparation of pharmaceutical composition.

As per the another aspect of the invention may be manufactured by conventional processes known to those of ordinary skill in the art, including , but not limited to, direct compression, wet granulation or dry granulation such as slugging or compaction of the composition into tablet. All these methods are well known in the art, and are described in detail, for example, Lachman et al., "The theory and Practice of Industrial Pharmacy"
As per another embodiment of the invention solid dosage form further coated film coatings contemplated by the present invention include, but are not limited to, those that include hydroxypropylmethyl cellulose and particularly Opadry™. However, any film-former known in the art for immediate release tablet and process for coating the immediate release tablet as described in detail, for example, Lachman et al., "The theory and Practice of Industrial Pharmacy”

As per the another embodiment, in vitro dissolution study of immediate release tablet as per the present invention and marketed tablet of agomelatine is performed in the USP Type II (Paddle) method at 50 RPM in 900 ml 0.1N HCl, at 37° C.

The following examples represent specific embodiments of the present invention and are intended to be illustrative and non-limiting.

Example 1
a) Amorphous form for Agomelatine (1:2)

Name of Ingredient % w/w
Agomelatine 32.68
Carbomer 65.36
TEC 1.96
Acetone q.s.
Water q.s.

b) Amorphous form for Agomelatine (1:1)

Name of Ingredient % w/w
Agomelatine 49.02
Carbomer 49.02
TEC 1.96
Acetone q.s.
Water q.s.

Procedure:
1. Dissolve weighed quantity of Agomelatine in Acetone under constant stirring & continue mixing for 10 min or until clear solution is obtained.
2. Add slowly Carbomer in above Agomelatine solution under constant stirring to get uniform dispersion.
3. After complete addition of Carbomer, mix the dispersion for further 30 minutes under stirring.
4. Add TEC in above step 3 dispersion under constant stirring & mix for 10 minutes.
5. Slowly add purified water in above step 4 dispersion under constant stirring & continue addition until complex is formed (Milky white gel like mass which gradually gains viscosity).
6. Collect the complex and dry it on tray drier/vacuum dryer @ 60°C for 18 hours.
7. Sift the dried granules/powder through # 40 sieves.
8. If required, mill the over sized granules in turbo sifter cum multimill or sifter cum multimill equipped with 1.0 / 0.5 mm S. S. Screen at medium speed with knives forward.
9. Mix the sifted and milled granules in conta blender for 10 min at 16 rpm.
10. Collect above granule/powder in polybag.

Example 2
a) Amorphous form for Agomelatine (1:2)

Name of Ingredient % w/w
Agomelatine 33.33
Carbomer 66.67
Cyclohexane q.s.

b) Amorphous form for Agomelatine (1:1)

Name of Ingredient % w/w
Agomelatine 50.00
Carbomer 50.00
Cyclohexane q.s.
Procedure:
1. Charge cyclohexane into reaction vessel
2. Charge Carbopol
3. Charge Agomelatine form-I
4. Heat the mixture under reflux condition at 82±3oC and stir the reaction mixture for 4 hrs
6. Filter the solid
7. Wash with hot cyclohexane
8. Dry the solid under vacuum at 50±3°C

Stress Study of Example 2b
The amorphous form of agomelatine is stable at following stress condition
S.No Stress Condition Initial PXRD Results
PXRD Remarks
1 80±3°C for 3 hrs Amorphous Amorphous Stable
2 60±3°C95 RH for 2 days Amorphous Amorphous Stable
3 Open Petri dish 27±3°C, 45 RH for 3 days Amorphous Amorphous Stable

Example 3
Agomelatine Tablets Composition
Sr no. Name of the Ingredients Quantity/ Tablet (mg/tab) % w/w Quantity/ Tablet (mg/tab) % w/w
Unit Qty. / Unit Qty. / Unit
Stage –I : Amorphous API
1. Agomelatine API mg 25 18.66 25 18.66
2. Carbomer (Carbopol 974 P) mg 50 37.31 25 18.66
3. Triethyl citrate ml 1.5 1.11 1.5 1.11
4. Acetone ml q.s q.s q.s q.s
5. Purified Water ml q.s q.s q.s q.s
Stage –II :Blending
6. Microcrystalline cellulose (Avicel PH 200 LM) mg 31 23.13 59.5 44.40
7. Hydroxy propyl cellulose (Klucel EXF) mg 4 2.99 4 2.98
8. Low substituted Hydroxypropyl cellulose (L-HPC-LH-11) mg 7.5 5.60 4 2.98
9. Croscarmellose Sodium (Ac-Di-Sol) mg 7.5 5.60 7.5 5.60
Stage -III : Lubrication
10. Colloidal silica (Aerosil 200) mg 2 1.50 2 1.50
11. Sodium Stearyl Fumarate mg 1.5 1.12 1.5 1.11
Stage –IV : Coating
12. Opadry yellow (03G520025) mg 4.0 2.99 4.0 2.98
13. Purified Water ml q.s q.s q.s q.s
Total weight 134.0 100 134.0 100

Example 4
Agomelatine Tablets Composition
Sr no. Name of the Ingredients Quantity per Tablet (mg/tab) % w/w Quantity per Tablet (mg/tab) %
w/w
Unit Qty. / Unit Qty. / Unit
Stage –I : Amorphous API
1. Agomelatine API mg 25 18.66 25 18.66
2. Carbomer (Carbopol 974 P) mg 50 37.31 25 18.66
3. Cyclohexane ml q.s. q.s. q.s. q.s.
Stage –II :Blending
4. Microcrystalline cellulose (Avicel PH 200 LM) mg 32.5 24.25 61 45.52
5. Hydroxy propyl cellulose (Klucel EXF) mg 4 2.99 4 2.98
6. Low substituted Hydroxypropyl cellulose (L-HPC-LH-11) mg 7.5 5.60 4 2.98
7. Croscarmellose Sodium (Ac-Di-Sol) mg 7.5 5.60 7.5 5.60
Stage -III : Lubrication
8. Colloidal silica (Aerosil 200) mg 2 1.50 2 1.50
9. Sodium Stearyl Fumarate mg 1.5 1.12 1.5 1.11
Stage –IV : Coating
10. Opadry yellow (03G520025) mg 4.0 2.99 4.0 2.98
11. Purified Water ml q.s q.s q.s q.s
Total weight 134.0 100 134.0 100

Process for preparing Agomelatine tablets:

1. Dispense the granules amorphous form of agomelatine prepared by the above mentioned method (Examples 1 and 2)
2. Avicel PH 200 LM, Klucel EXF and L-HPC-LH-11 are mixed and sifted through 40# and collected in Polybag.
3. Granules of amorphous form of agomelatine is added to the above mixture of Avicel PH 200 LM, Klucel EXF and L-HPC-LH-11 and passed through 40# and collected in polybag.
4. Colloidal silicon dioxide is passed through sieve 40# and Sodium stearyl fumarate (SSF) through 60# and collected separately in polybag.
5. To the mixture blend of step no.3 colloidal silicon dioxide is added and mixed in contablender for 10 min
6. To the above blend of step no.5, sodium stearyl fumarate is added and blending is done for 5 min.
7. The above lubricated blend is collected in polybag.
8. Compressed lubricated blend into Tablets of 130 mg.
9. Coat the compressed tablets using aqueous Opadry yellow solution to ~3% weight gain.

Stability Study of Example 3
The tablet composition of agomelatine is stable at accelerated condition as mentioned below table;
Agomelatine Tablets 25 mg Condition Months XRD(Amorphous form)
Initial, RT 0 Stable
40°C/75% RH 1 Stable
40°C/75% RH 2 Stable
40°C/75% RH 3 Stable
40°C/75% RH 6 Stable

The XRD data of agomelatine 25 mg tablet (Example 3) and placebo at 6 months accelerates condition are shown in figure 1 and 2, respectively. ,CLAIMS:CLAIM

We Claim,

1. A stable amorphous form of agomelatine comprising agomelatine and cross linked acrylic acid polymer.

2. The stable amorphous form of agomelatine according to claim 1, wherein the ratio of agomelatine to cross linked acrylic acid polymer is 1:0.5 to 1:6.

3. The stable amorphous form of agomelatine according to claim 1, wherein the ratio of agomelatine to cross linked acrylic acid polymer is 1:1.

4. The stable amorphous form of agomelatine according to claim 1, wherein cross linked acrylic acid polymer is carbomer.

5. The stable amorphous form of agomelatine according to claim 1, wherein acrylic acid polymer is cross linked with either allyl sucrose or allyl ethers of pentaerythritol.

6. A process for preparing stable amorphous agomelatine according to claim 1 comprises the step of

a) dissolving crystalline agomelatine in organic solvent,
b) adding carbomer in step a) to form uniform dispersion,
c) optionally, adding triethyl citrate or microcrystalline cellulose in above step under constant stirring,
d) adding purified water in above step b) or c) until complex is formed and
e) drying the amorphous complex of step d).

7. The process for preparing stable amorphous agomelatine according to claim 1 comprising heating the mixture of cyclohexane, carbomer and agomelatine under reflux condition.

8. A pharmaceutical composition comprising a stable amorphous form of agomelatine according to claim 1 and at least binder.