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Field of the invention:
The present invention provides novel crystalline polymorphs of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide represented by the following structural formula-la and process for their preparation.
N -Mr
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Formula-la Background of the invention:
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide is an atypical antidepressant made by Lundbeck and Takeda. It was approved by USFDA on September 30, 10 2013 and by European Medicines Agency on December 18, 2013 for the treatment of major depressive disorder (MDD) in adults.
1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and its pharmaceutically acceptable salts were first described in US7144884B2 (herein after referred as US'884 15 patent). This patent discloses process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base 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
20 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 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide have been reported in the literature.
2

US8722684B2 discloses various crystalline polymorphic forms of l-[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. 5
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. 10
Still, there is a significant need in the art to develop novel polymorphic forms of the said compound which are having advantageous physical properties such as free flowability, greater stability and greater bioavailability.
15 Brief description of the invention:
The first aspect of the present invention is to provide novel crystalline polymorph of 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein designated as crystalline form-L.
20 The second aspect of the present invention is to provide novel crystalline polymorph
of 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-1 a, herein designated as crystalline form-R.
The third aspect of the present invention is to provide process for the preparation of 25 crystalline form-L of 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
The fourth aspect of the present invention is to provide process for the preparation of crystalline form-R of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
30 The fifth aspect of the present invention is to provide crystalline solid dispersion
comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la and at least one pharmaceutically acceptable excipient.

The sixth aspect of the present invention is to provide a process for the preparation of crystalline solid dispersion comprising 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la and at least one pharmaceutically acceptable excipient. 5
Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline form-L of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. Figure-2: Illustrates the PXRD pattern of- crystalline form-R of l-[2-(2,4-dimethyl-10 phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.
Figiire-3: Illustrates the PXRD pattern of solid dispersion of crystalline form-L of compound of formula-la comprising compound of formula-la and microcrystalline cellulose. Figure-4: Illustrates the PXRD pattern of crystalline solid dispersion comprising compound of formula-la and lactose.
15
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
20 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
25 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, 2-butanol,
iso-butanol, tert-butanol, n-pentanol, ethane- 1,2-diol, propane-1,2-diol, alkyl ethers of
30 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. 5
The first aspect of the present invention provides novel crystalline polymorph of 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. The said novel crystalline polymorph is hereinafter designated as form-L. The crystalline form-L of compound of formula-la of the present invention is characterized by its 10 PXRD pattern having peaks at 4.4, 9.0, 11.8, 15.1, 15.9, 19.8 ± 0.2° of 2-theta. The said crystalline form-L is further characterized by its PXRD pattern as illustrated in figure-1.
The second aspect of the present invention provides novel crystalline polymorph of 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of 15 formula-la. The said novel crystalline polymorph is hereinafter designated as form-R. The crystalline form-R of compound of formula-la of the present invention is characterized by its PXRD pattern having peaks at 3.7, 11.2, 14.5, 15.2, 20.5, 22.6 ± 0.2° of 2-theta values. The said crystalline form-R is further characterized by its PXRD pattern as illustrated in figure-2.
20 The novel crystalline polymorphs of compound of formula-la of the present
invention 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.
25
The third aspect of the present invention provides process for the preparation of crystalline form-L of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. The said process comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide 30 compound of formula-1 a in a suitable first solvent,
b) optionally filtering the solution obtained in step-a),

c) combining the solution with a suitable second solvent,
d) filtering the precipitated solid and drying the material to provide crystalline form-L of compound of formula-la.
5 Wherein, in step-a) the suitable first solvent can be selected from chloro solvents,
alcohol solvents, formic acid, acetic acid, polar-aprotic solvents or their mixtures; and the said dissolution step can be performed at a suitable temperature ranging from 20°C to reflux temperature of the solvent used;
In step-c) the suitable second solvent can be selected from hydrocarbon solvents, 10 ether solvents, ester solvents, ketone solvents, nitrile solvents and the like.
In step-c) of the above process, combining the solution of step-a) or step-b) with a suitable second solvent can be carried out at a suitable temperature ranging from -70°C to 40°C.
15 Tne fourth aspect of the present invention provides process for the preparation of
crystalline form-R of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) • Dissolving the compound of formula-la in a mixture of organic solvent and water,
b) optionally filtering the solution obtained in step-a),
20 c) combining the solution with a suitable second solvent,
d) filtering the precipitated solid and drying the material to provide crystalline form-R of compound of formula-1 a.
Wherein, in step-a) of the above process the suitable organic solvent is same as the 25 first solvent defined in the third aspect of the present invention and the said dissolution step can be performed at a suitable temperature ranging from 20°C to reflux temperature of the solvent used
In step-c) the suitable second solvent is same as defined in the third aspect of the present invention; and combining the solution of step-a) or step-b) with a suitable •second 30 solvent can be carried out at a suitable temperature ranging from -70°C to 40°C.

The fifth aspect of the present invention provides crystalline solid dispersion comprising l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la and at least one pharmaceutically acceptable excipient.
Wherein, the excipient is selected from but not limited to polyvinylpyrrolidone 5 (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
10 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
15 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, raffmose, fructose, maltodextrin, anhydrous lactose, lactose
20 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, rumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid,
25 succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
An embodiment of the present invention provides solid dispersion of crystalline form-L of compound of formula-la, comprising compound of formula-la and microcrystalline 30 cellulose which is characterized by its PXRD pattern as illustrated in figure-3.

Another embodiment of the present invention provides crystalline solid dispersion comprising compound of formula-la and lactose which is characterized by its PXRD pattern as illustrated in figure-4.
5 The sixth aspect of the present invention provides a process for the preparation of
crystalline solid dispersion comprising 1 -[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 first
10 solvent at a suitable temperature,
b) removing the solvent from the reaction mixture and drying the material to provide
crystalline solid dispersion comprising compound of formula-la and corresponding
excipient.
15 Wherein, in step-a) the suitable excipient is same as defined in the fifth aspect of the
present invention;
The suitable first solvent is selected from chloro solvents, alcohol solvents, formic acid, acetic acid, polar-aprotic solvents or their mixtures; and the said dissolution step can be performed at a suitable temperature ranging from 20°C to reflux temperature of the solvent 20 used;
In step-b) suitable techniques which may be used for the removal of the 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
25 rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, combining the solution of step-a) with suitable second solvent as 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
30 other suitable techniques.

The suitable second solvent in the above described process is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, ketone solvents, nitrile solvents and the like; and combining the solution of step-a) with a suitable second solvent can be carried out at a suitable temperature ranging from -70°C to 40°C. 5
In the above process, the solvent may be removed from the reaction mixture 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. 10
An embodiment of the present invention provides a process for the preparation of solid dispersion of crystalline form-L of compound of formula-la, comprising compound of formula-la and microcrystalline cellulose. The said process comprising of; a) Dissolving the compound of formula-1 a in a suitable first solvent, 15 b) optionally filtering the reaction mixture,
c) combining the solution with a mixture of suitable second solvent and microcrystalline cellulose,
d) filtering the precipitated solid and drying the material to provide solid dispersion of crystalline form-L of compound of formula-la.
20
Another embodiment of the present invention provides crystalline solid dispersion comprising compound of. formula-la and lactose characterized by its PXRD pattern as illustrated in figure-4, comprising of;
a) Dissolving the compound of formula-1 a in a suitable first solvent, 25 b) optionally filtering the reaction mixture,
c) combining the solution with a mixture of suitable second solvent and lactose,
d) filtering the precipitated solid and drying the material to provide crystalline solid dispersion comprising compound of formula-la and lactose.

Wherein, in the above processes for the preparation of crystalline solid dispersions of
compound of formula-la, the suitable first solvent used in step-a) is selected from chloro
solvents, alcohol solvents, formic acid, acetic acid, polar-aprotic solvents or their mixtures;
and the said dissolution step can be performed at a suitable temperature ranging from 20°C to
5 reflux temperature of the solvent used;
In step-c) the suitable second solvent is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, ketone solvents, nitrile solvents and the like; and combining the solution of step-a) with a suitable second solvent can be carried out at a suitable temperature ranging from -70°C to 40°C. 10
In the above processes, after dissolving the compound of formula-la or 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
15 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.
20 A preferred embodiment of the present invention provides a process for the
preparation of solid dispersion of crystalline form-L of compound of formula-la, comprising compound of formula-1 a and microcrystalline cellulose, comprising of;
a) Dissolving the compound of formula-1 a in dichloromethane,
b) optionally filtering the solution,
25 c) combining the solution with a mixture of n-heptane and microcrystalline cellulose,
d) filtering the precipitated solid and drying the material to provide solid dispersion of crystalline form-L of compound of formula-la.

Another preferred embodiment of the present invention provides a process for the preparation of crystalline solid dispersion comprising compound of formula-la and lactose characterized by its PXRD pattern as illustrated in figure-4, comprising of; a) Dissolving the compound of formula-1 a in dichloromethane, 5 b) optionally filtering the solution,
c) combining the solution with a mixture of n-heptane and lactose,
d) filtering the precipitated solid and drying the material to provide crystalline solid dispersion comprising compound of formula-la and lactose.
10 In all of the above described processes for the preparation of various polymorphic
forms of compound of formula-la, heating of the reaction mixture to a suitable temperature ranges from 35°C to reflux temperature of the solvent used and cooling the reaction mixture to a suitable temperature ranges from 25°C to -70°C.
Any physical form of compound of formula-la viz.., crystalline forms or amorphous
15 form can be used as input for the preparation of various crystalline polymorphs of compound of formula-la of the present invention.
In one embodiment, the said input compound can be prepared by any of the known processes.
In another embodiment, the said compound can be prepared by the process as 20 described in our co-pending Indian patent application IN5018/CHE/2015.
The crystalline polymorphs of compound of formula-la of the present invention are useful as input for the preparation of other polymorphic forms of compound of formula-la viz.., crystalline polymorphs as well as amorphous form of compound of formula-la.

of the pharmaceutical composition comprising additional substances such as excipients diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents perfuming agents, surface stabilizing agents, suspending agents and other conventional 5 pharmaceutically inactive agents.
The novel crystalline polymorphs of compound of formula-la of the presenl
invention can be micronized or milled to achieve the desired particle size distribution in order
to make suitable formulation.
10
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 0.037min.

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.
5 Examples:
Example-1: Preparation of crystalline form-L of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenylj-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (10 gm) and dichloromethane (240 ml) was slowly heated to 10 40-45°C and stirred for 15 min at the same temperature. Filtered the reaction mixture, added the filtrate to pre-cooled n-heptane (240 ml) at -65°C to -70°C and stirred for 10 hrs at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-1. 15 Yield: 4.3 gm.
Example-2: Preparation of crystalline form-L of l-[2-(2,4-dimethyl-phenylsuIfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide 20 compound of formula-la (10 gm) and dichloromethane (240 ml) was slowly heated to 40-45°C and stirred for 15 min at the same temperature. Filtered the reaction mixture, added the filtrate to pre-cooled n-heptane (240 ml) at -15°C to -20°C and stirred for 10 hrs at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound.
25 The PXRD pattern of the obtained compound is shown in figure-1. Yield: 4.5 gm.
Example-3: Preparation of crystalline form-R of l-[2-(2,4-dimethyl-phenylsuIfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
30 A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide
compound of formula-la (20 gm), dichloromethane (480 ml) and water (0.5 ml) was slowly

heated to 40-45°C and stirred for 15 min at the same temperature. Filtered the reaction mixture, added the filtrate to pre-cooled n-heptane (1600 ml) at -60°C to -70°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. 5 The PXRD pattern of the obtained compound is shown in figure-2. Yield: 3.8 gm.
Example-4: Preparation of solid dispersion of crystalline form-L of compound of formula-la comprising compound of formula-la and microcrystalline cellulose
10 A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide
compound of formula-la (3 gm) and dichloromethane (85 ml) was slowly heated to 40-45°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the reaction mixture to make it particle free. The obtained filtrate was slowly added to a pre-cooled mixture of n-heptane (85 ml) and microcrystalline cellulose (1.2 gm) at -15°C to -20°C and
15 stirred the reaction mixture for 10 hrs at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 3.3 gm.
20 Example-5: Preparation of crystalline solid dispersion comprising compound of formula-la and lactose
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (3 gm) and dichloromethane (85 ml) was slowly heated to 40-45°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the reaction
25 mixture to make it particle free. The obtained filtrate was slowly added to a pre-cooled mixture of n-heptane (85 ml) and lactose (1.2 gm) at -15°C to -20°C and stirred the reaction mixture for 10 hrs at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-4.
30 Yield: 3.4 gm.