Field of the Invention:
The present invention provides process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide represented by the following structural formula-la.
Formula-la The present invention also provides amorphous form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Background of the Invention:
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is an atypical antidepressant made by Lundbeck and Takeda. It was approved by USFDA on September 30, 2013 and by European Medicines Agency on December 18, 2013 for the treatment of major depressive disorder (MDD) in adults.
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and its pharmaceutical ly acceptable salts were first described in US7144884B2 (herein after referred as US1884 patent). This patent discloses process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and its analogs.
US7144884B2 discloses the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base using solid phase synthesis. The crude product obtained was purified by preparative LC-MS and subsequently by ion-exchange chromatography. This patent didn't mention any physical characteristics data of l-[2-(2,4-dimethyl-phenylsulfanyl)-pheny 1] -piperazine.
The above mentioned US'884 patent didn't provide any specific method for the preparation of HBr salt of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.

Different polymorphic forms of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide have been reported in the literature.
US8722684B2 discloses various crystalline polymorphic forms of 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and processes for their preparation. Those polymorphs include alpha form, beta form, gamma form, hemihydrate form, mixture of ethyl acetate solvate and alpha form.
US8598348B2 patent discloses crystalline isopropanol solvate form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for its preparation.
WO2014044721A1 discloses delta crystalline form and crystalline hydrate (monoclinic) form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Still, there is a significant need in the art to develop novel polymorphic form of the said compound which is stable and having advantageous physical properties such as free flowability, greater stability and greater bioavailability.
Brief description of the invention:
The first aspect of the present invention is to provide amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and at least one pharmaceutically acceptable excipient.
The second aspect of the present invention is to provide process for the preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and at least one pharmaceutically acceptable excipient.
The third aspect of the present invention is to provide pure amorphous form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for its preparation.
The fourth aspect of the present invention is to provide process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.

Brief description of the Drawings:
Figure-1: Illustrates the PXRD pattern of amorphous solid dispersion comprising l-[2-(2,4-
dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and povidone K29/32 prepared
in accordance with example-13.
Figure-2: Illustrates the PXRD pattern of amorphous solid dispersion comprising l-[2-(2,4-
dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and povidone K30 prepared in
accordance with example-14.
Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising l-[2-(2,4-
dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl cellulose
(HPC) prepared in accordance with example-15.
Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising l-[2-(2,4-
dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl
methylcellulose (HPMC) prepared in accordance with example-16.
Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising l-[2-(2,4-
dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl
methylcellulose acetate succinate (HPMCAS) prepared in accordance with example-17.
*
Detailed description of the Invention:
The "suitable solvent" used in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, ethane-1,2-diol, propane-1,2-diol, alkyl ethers of ethylene

glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether and the like; "polar solvents" such as water; formic acid, acetic acid or mixtures thereof.
The "suitable base" used in the present invention can be selected from but not limited to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or their mixtures.
The "suitable acid" used in the present invention can be selected from but not limited to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic

acid, succinic acid, malic acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid, aceturic acid, phloretinic acid, phthalic acid, methane sulfonic acid, - ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, orotic acid and the like.
The "suitable catalyst" used in the present invention can be selected from but not limited to alkali metal halides such as sodium bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide, lithium iodide, methanesulfonic acid, p-toluenesulfonic acid (PTSA) and the like.
The suitable "phase transfer catalyst" used in the present invention can be selected from but not limited to tetra alkyl/aryl ammonium halide/hydroxide, (alkyl)m(aryl),j.m ammonium halide, (alkyl)m(aryl)4_m ammonium hydroxide, wherein, the alkyl groups can be same or different in tetra alkyl ammonium halide/hydroxide, (alkyl)m(aryl)4_m ammonium halide/hydroxide; the aryl groups can be same or different in tetra aryl ammonium halide/hydroxide, (alkyl)m(aryl)4_m ammonium halide/hydroxide, wherein 'm' is between land 3;
The term "alkyl" used in the present invention refers to Ci-Cs straight chain or branched chain alkyl groups such as methyl ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl and the like; the term "aryl" refers to substituted or unsubstituted Ce-Cio aryl such as phenyl, tolyl and the like; halide represents chloride, bromide or iodide; hexadecyl tributyl phosphonium bromide.
The "suitable leaving group" used in the present invention can be selected from but not limited to halogens such as CI, Br, I; hydroxy, alkyl/arylsulfonyloxy selected from but not limited to methanesulfonyloxy, ethanesulfonyloxy, p-toluenesulfonyloxy and the like.
The first aspect of the present invention provides amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and at least one pharmaceutical^ acceptable excipient.
Wherein, the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol,

polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
The second aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and at least one pharmaceutically acceptable excipient. The said process comprising of the following steps;
a) Dissolving l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la and at least one excipient in a suitable solvent or mixture of solvents at a suitable temperature,
b) removing the solvent from the reaction mixture and drying the material to provide amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and excipient.

Wherein, in step-a) the suitable excipient is same as defined in the first aspect of the present invention;
the suitable solvent can be selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid, alkyl ethers of ethylene glycol or propylene glycol or their mixtures; the suitable temperature ranges from 0°C to reflux temperature of the solvent used;
After dissolving the compound of formula-la and excipient in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution;
The solution obtained above may optionally be filtered to remove any insoluble particles or extraneous matter. The solution may be filtered by passing through paper, glass fiber or other membrane material or a bed of a clarifying agent such as Celite® or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In step-b) suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, decantation, filtration, centrifugation, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any other suitable techniques.
The solvent may be removed optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C or at less than about -80°C.
In the present invention, the ratio of the amount of weight of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la within the solid

dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1:0.05 to about 1:5.
The third aspect of the present invention provides process for the preparation of pure amorphous form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide. The said process comprising of;
a) Dissolving l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la in a suitable solvent or mixture of solvents,
b) optionally filtering the reaction mixture,
c) removing the solvent from the reaction mixture and drying the material to provide amorphous form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Wherein, in step-a) the suitable solvent is same as defined in step-a) of the second aspect of the present invention and the dissolution of compound of formula-la in a suitable solvent or mixture of solvents can be carried out at 25-30°C or by heating the reaction mixture to a temperature ranging from 30°C to reflux temperature of the solvents employed;
in step-c) the solvent can be removed from the reaction mixture by using suitable techniques as described in step-b) of the second aspect of the present invention.
The l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la utilized as starting material in the present invention can be prepared by any of the known processes or it can be synthesized by the process of the present invention.
The fourth aspect of the present invention provides a process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of; a) Reacting the 2,4-dimethylbenzenethiol with compound of general formula-2

in presence of a suitable base in a suitable solvent to provide (2,4-dimethylphenyl)(2-nitrophenyl)sulfane compound of formula-3,
Formula-3 b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide 2-(2,4-dimethylphenylthio)aniline compound of formula-4,
Formula-4 c) cyclization of compound of formula-4 by reacting it with protected compound of general formula-6 or its acid-addition salt
Formula-6 wherein 'X5 represents suitable leaving group and T' represents amine protecting group; in a suitable solvent optionally in presence of a suitable base and/or a suitable catalyst to provide compound of general formula-7 or its salt,
Formula-7 wherein T5 is as defined above; d) deprotecting the compound of general formula-7 with a suitable deprotecting agent in a suitable solvent to provide l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine compound of formula-1,

Formula-1
e) optionally purifying the compound of formula-1 from a suitable solvent or mixture of solvents,
f) treating the compound of formula-1 with HBr in a suitable solvent to provide l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.
Wherein, in step-a) & step-c) the suitable base can be selected from inorganic bases, organic bases, organosilicon bases, organolithium bases or their mixtures;
in step-b) the suitable reducing agent can be selected from but not limited to Pd, Pt, PtC>2, metals such as Fe, Zn, Sn in presence of a suitable acid/acid source such as HC1, acetic acid, NH4CI; SnCl2, Ni, Raney Ni, sodium borohydride, lithium borohydride, lithium aluminium hydride, sodium aluminium hydride, diborane, hydrazine hydrate, sodiumdithionate, thiourea dioxide, sodium sulfide, ammonium sulfide and the like;
in step-c) the suitable catalyst can be selected from but not limited to alkali metal halides such as sodium bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide, lithium iodide, methanesulfonic acid, p-toluenesulfonic acid (PTSA) and the like; and the reaction can be carried out optionally in presence of a suitable phase transfer catalyst as defined above;
in step-a) to step-f) wherever necessary the suitable solvent can be selected from but not limited to hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, chloro solvents, polar solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alkyl ethers of ethylene glycol or propylene glycol or their mixtures;
In the present invention, the suitable amine protecting group 'P' is selected from but not limited to tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (Fmoc), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), trityl (Tr), alkyl/aryl sulfonyl such as

methanesulfonyl, ethanesulfonyl, benzenesulfonyl, toluenesulfonyl and the like; acyl groups such as acetyl (Ac), trifluoroacetyl (TFA), benzoyl (Bz) group and the like.
The suitable amine protecting agent is selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.
Suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), trityl chloride, acetyl chloride, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, benzoyl halides, benzyl halides, alkyl/arylsulfonic acids/acid halides/anhydrides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic anhydride and the like; alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate; trifluoroacetic acid, trifluoroacetyl chloride and the like.
The suitable deprotecting agent is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid, p-toluenesulfonic acid and the like; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, cesium carbonate/imidazole, ammonia, cerium(IV) ammonium nitrate (CAN); organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-Iiquid ammonia, Raney-Ni, tri(Cj-C6)alkylsilanes, tri(Ci-C6)alkylsilyl halides and the like.
In one embodiment of the present invention, compound of formula-1 or its salt can also be prepared by reacting the compound of formula-4 with compound of general formula-5 or its acid addition salt in a suitable solvent.

The said reaction can be carried out optionally in presence of a suitable base or a suitable catalyst or a suitable phase transfer catalyst or any of their combination.
The protected intermediate compounds of general formula-7 of the present invention can also be prepared by reacting the compound of formula-1 with a suitable amine protecting agent in a suitable solvent and optionally in presence of a suitable acid or a base under suitable conditions. In case of some of the protecting groups such as Boc, the obtained protected compound of general formula-7 can be treated with a suitable acid in a suitable solvent to directly provide acid-addition salt of compound of formula-1.
Various intermediate compounds of the present invention such as for example compound of formula-4 and compound of formula-1 can be purified by using salt formation technique. For example the said compounds can be treated with a suitable acid in a suitable solvent to provide corresponding acid-addition salt followed by neutralization of obtained salt by treating with a suitable base in a suitable solvent to provide pure compounds.
Wherein, the suitable acid, the suitable base and the suitable solvent are same as defined above.
The 2,4-dimethylbenzenethiol, compound of general formula-2, compound of general formula-5 and compound of general formula-6 utilized in the present invention can be procured from various commercial sources or they can be prepared by any of the processes known in the art.
Compound of general formula-6 or its salt utilized in the present invention can also be prepared by reacting corresponding free amine compound of general formula-5 or its salt with a suitable amine protecting agent under suitable conditions.
The pure amorphous form and amorphous solid dispersion of compound of formula-la of the present invention are stable at room temperature and are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-la is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula-la present in the composition in a range

of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as conventional pharmaceutical excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutical^ inactive agents.
In a further aspect, the pure amorphous form and amorphous solid dispersion of compound of formula-la of the present invention can be micronized to achieve the better particle size distribution in order to make suitable formulation.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The present invention is schematically represented as follows;
Wherein, CX' represents a suitable leaving group and 'P' represents amine protecting group.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:
Exam pie-1: Preparation of (2,4-dimethylphenyl)(2-nitrophenyI)suIfane (Formula-3)
l-Chloro-2-nitro benzene compound of formula-2b (100 gm) was slowly added to a mixture of potassium carbonate (105.3 gm) and dimethylformamide (400 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 10 min at the same temperature. 2,4-Dimethylbenzenethiol (92.1 gm) was slowly added to the reaction mixture at 25-30°C and stirred for 4 hrs at the same temperature. Water was slowly added to the reaction mixture and stirred for 1 hr. Filtered the precipitated solid, washed with water and dried. Isopropyl alcohol (400 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried the material to get the title compound. Yield: 150.0 gm. ExampIe-2: Preparation of (2,4-dimethyIphenyl)(2-nitrophenyl)sulfane (Formula-3)
2,4-Dimethylbenzenethiol (25 gm) was slowly added to a mixture of potassium carbonate (26.6 gm) and dimethylformamide (107.5 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 10 min at the same temperature. l-Fluoro-2-nitro benzene compound of formula-2a (25 gm) was slowly added to the reaction mixture at 25-30°C and stirred for 45 min at the same temperature. Water was slowly added to the reaction mixture and stirred for 1 hr. Filtered the precipitated solid, washed with water and dried. Isopropyl alcohol (100 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried the material to get the title compound. Yield: 39.0 gm. Example-3: Preparation of 2-(2,4-dimethylphenyIthio)aniline (Formula-4)
(2,4-dimethylphenyl)(2-nitrophenyl)sulfane compound of formula-3 (150 gm) and Iron powder (160 gm) were added to a mixture of ammonium chloride (170 gm) and water (1050 ml) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Heated the reaction mixture to 85-90°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 5-10°C. Filtered the reaction mixture, ethyl acetate was added to the filtrate and the reaction mixture was stirred for 10 min. Both the organic and aqueous layers

were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 120.0 gm.
ExampIe-4: Preparation of l-[2-(2,4-dimethyI-pheny!suIfanyI)-phenyI]-piperazine hydrochloride (Formula-lb)
A mixture of 2-(2,4-dimethylphenylthio)aniline compound of formula-4 (120 gm), bis(2-chloroethyl)amine hydrochloride compound of formula-5a (93.5 gm) and diethyleneglycol monoethyl ether (240 ml) was heated to 130-135°C and stirred for 35 hrs at the same temperature under nitrogen atmosphere. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the reaction mixture to 40-45°C and acetone was added. The temperature of the reaction mixture was further reduced to 25-30°C and stirred for 90 min at the same temperature. Filtered the precipitated solid and washed with acetone. To the obtained compound, acetone (360 ml) was added. Heated the reaction mixture to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with acetone and then dried the material. Yield: 65.0 gm. Example-5: Preparation of l-[2-(2,4-dimethyI-phenylsulfanyl)-phenyl]-piperazine
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride compound of formula-lb (65 gm) and dichloromethane (720 ml) was cooled to Q-5°C. The obtained reaction mixture was basified using 5% sodium carbonate solution and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer to get the title compound. Yield: 55.0 gm. Example-6: Preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr
A mixture of l-[2-(2?4-dimethyl-phenylsulfanyl)-phenyl]-piperazine compound of formula-1 (65 gm) and isopropyl acetate (2275 ml) was stirred for 30 min at 25-30°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with isopropyl acetate. 48% HBr solution (26.5 ml) was added to the filtrate at 25-30°C and stirred for 1 hr

at the same temperature. Filtered the precipitated solid, washed with isopropyl acetate and
dried the material to get the title compound.
Yield: 65.0 gm.
Example-7: Purification of l-[2-(2,4-dimethyl-phenylsulfanyI)-phenyl]-piperazine HBr
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (65 gm) and ethanol (975 ml) was heated to 85-90°C and stirred the reaction mixture for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with ethanol and dried to get the title compound. Yield: 50.0 gm.
Example-8: Preparation of tert-butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate (Formual-7a)
Bis(2-chloroethylamine) hydrochloride compound of formula-5a (6.2 gm) and p-toluenesulfonic acid (0.18 gm) were added to a mixture of 2-(2,4-dimethylphenylthio)aniline compound of formula-4 (8 gm) and xylene (24 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 135-140°C and stirred for 35 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Triethylamine (808 gm) followed by di-tert-butyl dicarbonate (9.2 gm) were added to the reaction mixture at 25-30°C and stirred for 1 hr at the same temperature. Water and methyl tert.butyl ether were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 10.0 gm.
ExampIe-9: Preparation of tert-butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate (Formual-7a)
Bis(2-chloroethylamine) hydrochloride compound of formula-5a (6.2 gm), tetra butyl ammonium bromide (0.6 gm) and potassium iodide (0.6 gm) were added to a mixture of 2-(2,4-dimethylphenylthio)aniline compound of formula-4 (8 gm) and diethyleneglycol monoethyl ether (40 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 135-140°C and stirred for 35 hrs at the same temperature. Cooled the reaction mixture to

25-30°C. Triethylamine (8.8 gm) followed by di-tert-butyl dicarbonate (9.2 gm) were added
to the reaction mixture at 25-30°C and stirred for 1 hr at the same temperature. Water and
methyl tert.butyl ether were added to the reaction mixture at 25-30°C and stirred for 10 min
at the same temperature. Both the organic and aqueous layers were separated and distilled off
the solvent completely from the organic layer under reduced pressure.
Yield: 10.0 gm.
Example-10: Preparation of l-[2-(2,4-dimethyl-phenylsuIfanyl)-phenyl]-piperazine HBr
A mixture of tert-butyl 4-(2-((2?4-dimethylphenyl)thio)phenyl)piperazine-l-carboxylate compound of formual-7a (10 gm) and isopropyl acetate (100 ml) was stirred for 30 min at 25-30°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with isopropyl acetate. 48% HBr solution (9 ml) was added to the filtrate at 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with isopropyl acetate and then dried the material to get the title compound. Yield: 5.0 gm.
Example-11: Preparation of N,N-bis(2-chloroethyl)«4-methylbenzenesulfonamide (Formula-6b)
p-Toluenesulfonyl chloride (8.9 gm) and triethylamine (16 ml) were added to a pre-cooled mixture of bis(2-chloroethylamine) hydrochloride compound of formula-5a (10 gm) and dichloromethane (70 ml) at 0-5°C under nitrogen atmosphere. Heated the reaction mixture to 40-45°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and water was added. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer to get the title compound. Yield: 12.0 gm.
Example-12: Preparation of l-(2-(2,4-dimethylpheny!thio)phenyl)-4-tosylpiperazine (Formula-7b)
A mixture of 2-(2,4-dimethylphenylthio)aniline compound of formula-4 (2 gm), N,N-bis(2-chloroethyl)-4-methylbenzene-sulfonamide compound of formula-6b (2.6 gm), sodium carbonate (2.2 gm), sodium iodide (2.6 gm) and n-butanol (10 ml) was heated to 135-140°C and stirred for 24 hrs at the same temperature under nitrogen atmosphere. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the reaction

mixture to 20-25°C and dichloromethane was added. Filtered the reaction mixture, water was added to the filtrate and stirred the reaction mixture for 10 min. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer. Ethanol (20 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with ethanol and dried to get the title compound. Yield: 2.0 gm.
Example-13: Preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and povidone K29/32
a) By using 0.05% w/w of povidone K29/32:
A mixture of l-[2-(254-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (500 mg), povidone K29/32 (25 mg) and dichloromethane (25 ml) was stirred for 15 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material obtained to get the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 460.0 mg.
b) By using 0.1% w/w of povidone K29/32:
A mixture of l-[2-(2?4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (500 mg), povidone K29/32 (50 mg) and dichloromethane (25 ml) was stirred for 15 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 460.0 mg.
c) By using 0.25% w/w of povidone K29/32:
A mixture of l-[2-(2?4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (500 mg), povidone K29/32 (125 mg) and dichloromethane (25 ml) was stirred for 30 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 580.0 mg.
d) By using 0-5% w/w of povidone K29/32:

A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (500 mg)s povidone K29/32 (250 mg) and dichloromethane (25 ml) was stirred for 20 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 670.0 mg.
Example-14: Preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and povidone K30
A mixture of l-[2«(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (250 mg), povidone K30 (250 mg) and methanol (25 ml) was stirred for 15 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 280.0 mg.
Example-15: Preparation of amorphous solid dispersion comprising l-|2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl cellulose (HPC)
a) By using 0.05% w/w of hydroxypropyl cellulose:
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (500 mg), hydroxypropyl cellulose (25 mg) and dichloromethane (30 ml) was stirred for 20 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 460.0 mg.
b) By using 0,25% w/w of hydroxypropyl cellulose:
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (500 mg), hydroxypropyl cellulose (125 mg) and dichloromethane (30 ml) was stirred for 10 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 510.0 mg.

c) By using 1:1% w/w of hydroxypropyl cellulose:
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr (250 mg), hydroxypropyl cellulose (250 mg) and methanol (50 ml) was stirred for 10 min at 25-30°C to get clear solution. Distilled off solvent completely from the reaction mixture under reduced pressure and dried the material to get the title compound. PXRD pattern of compound is shown in figure-3. Yield: 280.0 mg.
Example-16: Preparation of amorphous solid dispersion comprising l-[2~(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl methylcellulose (HPMC or hypromellose)
A mixture of l-[2-(234-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr (250 mg), hydroxypropyl methylcellulose (250 mg) and methanol (50 ml) was stirred for 15 min at 25-30°C to get a clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-4. Yield: 300.0 mg.
Example-17: Preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyI-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl methylcellulose acetate succinate (HPMC-AS)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr (250 mg), hydroxypropyl methylcellulose acetate succinate (250 mg) and methanol (50 ml) was stirred for 15 min at 25-30°C to get a clear solution. Filtered the reaction mixture, distilled off the solvent completely from the filtrate under reduced pressure and dried the material obtained to get the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 250.0 mg. Example-18: Preparation of pure amorphous form of compound of formula-la
A mixture of l-[2-(254-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr (1 gm) and dichloromethane (100 ml) was stirred for 15 min at 25-30°C to get a clear solution. Filtered the reaction mixture, distilled off the solvent completely from the filtrate under reduced pressure and then dried the obtained material to get the title compound. Yield: 680.0 mg.

We Claim:
1. Amorphous solid dispersion comprising 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and at least one pharmaceutically acceptable excipient.
2. Amorphous solid dispersion according to claim 1, wherein the excipient is selected from polyvinylpyrrolidone (povidone or PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
3. A process for the preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la and at least one pharmaceutically acceptable excipient, comprising of;

a) Dissolving the compound of formula-la and at least one excipient in a suitable solvent or mixture of solvents,
b) removing the solvent from the reaction mixture and drying the material to provide amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and excipient.
4. The process according to claim 3, wherein the suitable solvent is selected from chloro
solvents, alcohol solvents.
.5. The process according to claim 4, wherein the suitable solvent is selected from
dichloromethane, methanol.
*
6. The process according to claim 3, wherein the removal of solvent from the reaction
mixture is carried out by using one or more techniques such as evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, decantation, filtration, centrifugation, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying.
7. Amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-
piperazine hydrobromide and hydroxypropyl cellulose.

8. Process for the preparation of amorphous solid dispersion comprising l-[2~(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine. hydrobromide compound of formula-la and
hydroxypropyl cellulose, comprising of;
a) Dissolving the compound of formula-la and hydroxypropyl cellulose in dichloromethane,
b) distilling off the solvent from the reaction mixture to provide amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl cellulose.
9. Process for the preparation of amorphous solid dispersion comprising l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-1 a and
hydroxypropyl cellulose, comprising of;
a) Dissolving the compound of formula-la and hydroxypropyl cellulose in methanol,
b) distilling off the solvent from the reaction mixture to provide amorphous solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and hydroxypropyl cellulose.
10. A process for the preparation of amorphous form of l-[2-(2,4-dimethyI-phenylsulfanyl)-
phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Dissolving the compound of formula-la in dichloromethane,
b) distilling off the solvent from the reaction mixture to provide amorphous form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.