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 processes for their preparation.
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, 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 pharmaceutically acceptable salts were first described in US7144884B2 (herein after referred as US'884 patent). This patent discloses process for the preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base and its analogs.
US7144884B2 discloses the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenylj-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)-phenyl]-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 1 -[2-(2,4-dimethyl-phenylsulfanyl)-pheny]]-piperazine hydrobromide.
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.
Brief description of the invention:
The first aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein after designated as form-M|.
The second aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfany!)-phenyl]-piperazine hydrobromide compound of formula-la, herein after designated as form-M2.
The third aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethy!-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein after designated as form-M3.

The fourth aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein after designated as form-M}.
The fifth aspect of the present invention is to provide novel crystalline polymorph of 1 -[2-(234-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein after designated as form-Ms.
The sixth aspect of the present invention is to provide crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, characterized by its PXRD pattern as illustrated in figure-7.
Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline form-M| of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-2: Illustrates the PXRD pattern of crystalline form-M2 of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-3: Illustrates the PXRD pattern of crystalline form-M3 of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-4: Illustrates the PXRD pattern of crystalline form-M4 of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-5: Illustrates the PXRD pattern of crystalline form-M5 of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-6: Illustrates the PXRD pattern of crystalline isopropyl alcohol solvate form of l-[2-
(2,4-dimethyl-phenylsuIfanyl)-phenyl]-piperazine hydrobromide.
Figure-7: Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide obtained according to example-7.

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, h-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 (isopropyl alcohol), n-butanol, 2.-butanol, iso-butanol, tert-butanol, n-pentanol, cyclohexanol, 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 first aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. The said polymorph is herein after designated as form-Mi and it is characterized by its PXRD pattern as illustrated in figure-1. The crystalline form-M| of compound of formula-la of the present invention is found to be 2-butanol solvate form.

An embodiment of the present invention provides process for the preparation of novel crystalline form-M| of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-1 a, comprising of;
a) Adding 2-butanol to compound of formula-la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline form- Mi of compound of formula-la.
The second 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 polymorph is herein after designated as forrn-M2 and it is characterized by its PXRD pattern as illustrated in figure-2. The crystalline form-M2 of compound of formula-la of the present invention is found to be cyclohexanol solvate form.
An embodiment of the present invention provides process for the preparation of novel crystalline form-M2 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Adding a mixture of cyclohexanol and methanol to compound of formula-la,
b) heating the reaction mixture to a suitable temperature,
c) combining the obtained solution with methyl tert.butyl ether,
d) filtering the precipitated solid and drying to provide crystalline form-M2 of compound of formula-la.
The third 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 polymorph is herein after designated as form-M3 and it is characterized by its PXRD pattern as illustrated in figure-3.

An embodiment of the present invention provides process for the preparation of novel crystalline form-M3 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-1 a, comprising of;
a) Adding ethyl acetate to compound of formula-1 a,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline form-M3 of compound of formula-1 a.
The fourth aspect of the present invention provides novel crystalline polymorph of 1 -^-^^-dimethyl-phenylsulfany^-phenylj-piperazine hydrobromide compound of formula-la. The said polymorph is herein after designated as form-M4 and it is characterized by its PXRD pattern as illustrated in figure-4.
An embodiment of the present invention provides process for the preparation of novel crystalline form-M4 of l-[2-(2,4-dimethyl-phenylsu!fanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Adding 2-butanol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) adding aqueous HBr solution to the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid and drying to provide crystalline form-M4 of compound of formula-la.
The fifth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. The said polymorph is herein after designated as form-Ms and it is characterized by its PXRD pattern as illustrated in figure-5.

An embodiment of the present invention provides process for the preparation of novel crystalline form-Ms of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Adding isopropyl alcohol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) adding aqueous HBr solution to the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid and drying to provide crystalline form-Ms of compound of formula-la.
One embodiment of the present invention provides isopropyl alcohol solvate form of l-[2-(2,4-dimethyl-phenylsulfanyI)-pheny]]-piperazine hydrobromide compound of formula-la. The said isopropyl alcohol solvate form is characterized by its PXRD pattern as illustrated in figure-6.
The other embodiment of the present invention provides process for the preparation of isopropyl alcohol solvate form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Adding isopropyl alcohol to compound of formula-la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture" to a suitable temperature,
d) filtering the solid and drying to provide crystalline isopropyl alcohol solvate form of compound of formula-1 a.
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 30°C to -70°C.

The sixth aspect of the present invention provides crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. The said crystalline polymorph is characterized by its PXRD pattern having peaks at 7.9. 15.9 and 19.1 ± 0.2° of 20. The said polymorph is further characterized by its PXRD pattern as illustrated in figure-7.
An embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la characterized by its PXRD pattern as illustrated in figure-7, comprising of;
a) Adding 2-butanol to compound of formula-1 a,
b) heating the reaction mixture to a suitable temperature,
c) adding water to the reaction mixture,
d) optionally filtering the reaction mixture,
e) cooling the reaction mixture to a suitable temperature,
f) filtering the solid and drying the material to provide crystalline polymorph of compound of formula-la having PXRD pattern as shown in figure-7.
Wherein, in step-b) the suitable temperature ranges from 35°C to reflux temperature of the solvent used; and
in step-e) the suitable temperature ranges from 30°C to -70°C.
Any polymorphic form of compound of formula-la viz.., crystalline form or amorphous form can be used as input for the preparation of crystalline polymorphs 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 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.
The 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.
An embodiment of the present invention provides use of crystalline polymorphs of compound of formula-la of the present invention for the preparation of pharmaceutical compositions.
The other embodiment of the present invention provides pharmaceutical composition comprising any of the crystalline polymorphs of compound of formula-la of the present invention and at least one pharmaceutically acceptable excipient.
The crystalline polymorphs of compound of formula-la of the present invention can be micronized or milled to achieve the desired particle size distribution in order to make suitable formulation.
P-XRD Method of Analysis:
The PXRD analysis of crystalline solids of the present invention was carried out using BRUKER/D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A0 and at a continuous scan speed of 0.03°/min.
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:
Example-l: Preparation of crystalline form-Mi of l-[2-(2,4-dimethyl-phenylsulfanyl)-
phenyl]-piperazine hydrobromide (Formula-la)
2-Butanol (10 ml) was added to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (0.5 gm) at 25-30°C. Slowly heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 5 min at the same temperature. Filtered the solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 0.6 gm.
Examplc-2: Preparation of crystalline form-M2 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenylj-piperazine hydrobromide (Formula-la)
A mixture of cyclohexanol and methanol (200 ml; 1:1 ratio) was added to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (15 gm) at 25-30°C. Slowly heated the reaction mixture to 70-75°C and stirred for 30 min at the same temperature. Filtered the reaction mixture to make it particle free. Slowly added the obtained solution to pre-cooled methyl tert.butyl ether (300 ml) at -45°C to -50°C and stirred the reaction mixture for 2 hrs at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 15.5 gm.
ExampIe-3: Preparation of crystalline form-M3 of l-[2-(2,4-dimethyI-phenylsulfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (0.5 gm) and ethyl acetate (10 ml) was slowly heated to 50-55°C and stirred the reaction mixture for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C. Filtered the solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 0.4 gm.

Example-4: Preparation of crystalline form-Mi of l-I2-(2,4-dimethyl-phenylsulfanyl)-phenylj-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula-1 (1 gm) and 2-butanol (7 ml) was slowly heated to 70-75°C and stirred the reaction mixture for 30 min at the same temperature. 48% Aqueous HBr solution (0.7 ml) was slowly added to the obtained solution at 70-75°C and stirred the reaction mixture for 1 hr at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-4. Yield: 0.8 gm.
Example-5: Preparation of crystalline form-Ms of H2-(2,4-dimethyl-phenyIsuIfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2]4-dimethyl-phenylsulfanyl)-phenyl]-pipera2ine free base compound of formula-1 (1 gm) and isopropyl alcohol (10 ml) was slowly heated to 70-75°C and stirred the reaction mixture for 1 hr at the same temperature. 48% Aqueous HBr solution (0.7 ml) was slowly added to the obtained solution at 70-75°C and stirred the reaction mixture for 1 hr at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 1.0 gm.
Example-6: Preparation of isopropyl alcohol solvate form of l-|2-(2,4-dimethyl-phenylsulfanyl)-phenyl|-piperazine hydrobromide (Formula-la)
Isopropyl alcohol (10 ml) was added to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (0.5 gm) at 25-30°C. Slowly heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 5 min at the same temperature. Filtered the solid and then dried the material to provide the title compound. The PXRD pattern of obtained compound is shown in figure-6. Yield: 0.7 gm.

Example-7: Preparation of crystalline polymorph of l-I2-(2,4-dimethyl-phenyIsulfanyl)-phenylj-piperazine hydrobromide (Formula-la)
A mixture of phenol (77.96 gm) and 33% HBr in acetic acid (750 ml) was stirred for 1 hr at 25-30°C. Cooled the reaction mixture to 0-5°C and l-(2-(2,4-dimethylphenylthio)phenyl)-4-tosylpiperazine (150 gm) was added to it. Raised the temperature of the reaction mixture to 25-30°C and stirred for 24 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and water was drop wise added to it. Raised the temperature of the reaction mixture to 25-30°C. Methyl tert.butyl ether (300 ml) and cyclohexane (1200 ml) were added to the reaction mixture at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid and washed with cyclohexane. 2-Butanol (450 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 65-70°C, water (30 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 0-5cC and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material. 2-butanol (515 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, water (35 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material. 2-Butanol (450 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, water (40 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with 2-butanol. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material to get the title compound.
The PXRD pattern of the obtained compound is shown in figure-7. Yield: 51.0 gm; Purity by HPLC.