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.

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 pharmaceutically acceptable salts were first described in US7144884B2 (herein after referred as US'884 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)-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 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.

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 novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, which is herein designated as form-E.

The second aspect of the present invention is to provide process for the preparation of novel crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.

The third aspect of the present invention is to provide novel crystalline form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein designated as form-E

The fourth aspect of the present invention is to provide process for the preparation of crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.

The fifth aspect of the present invention is to provide novel crystalline form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, herein designated as form-G.

The sixth aspect of the present invention is to provide process for the preparation of crystalline form-G 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 crystalline form-E of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.

Figure-2: Illustrates the PXRD pattern of crystalline form-F of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la.

Figure-3: Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la obtained
according to example-3.

Figure-4: Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la obtained
according to example-4.

Figure-5: Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la obtained
according to example-5.

Figure-6: Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la obtained
according to example-6.

Figure-7: Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la obtained by
drying the compound obtained according to example-6 for 10 hrs at 60°C.

Figure-8: Illustrates the DSC thermogram of crystalline form-G of l-[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la obtained by
drying the compound obtained according to example-6 for 10 hrs at 60°C.

Figure-9: Illustrates the PXRD pattern of crystalline l-[2-(2,4-dimethyl-phenylsulfanyl)-phenylj-piperazine hydrobromide compound of formula-la obtained by drying the compound obtained according to example-6 for 15 hrs at 100°C.

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, dimethoxy ethane, 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, 2-butanol, iso-butanol, tert-butanol, n-pentanol (n-amyl alcohol), ethane-1,2-diol (ethylene glycol), propane-1,2-diol (propylene glycol), 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 novel crystalline polymorph is hereinafter designated as form-E. The crystalline form-E of compound of formula-la of the present invention is characterized by its PXRD pattern as illustrated in figure-1.

The second aspect of the present invention provides process for the preparation of novel crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la in ethylene glycol at a suitable temperature,
b) combining the solution with water at a suitable temperature,
c) filtering the precipitated solid and drying to provide crystalline form-E of compound of formula-la.
Wherein, in step-a) and step-b) the suitable temperature ranges from -30°C to 30°C.
The third 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 novel crystalline polymorph is hereinafter designated as form-F. The crystalline form-F of compound of formula-la of the present invention is characterized by its PXRD pattern as illustrated in figure-2.

The fourth aspect of the present invention provides process for the preparation of novel crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of;
a) Combining the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la with n-pentanol at a suitable temperature,
b) stirring the reaction mixture,
c) filtering the solid and drying to provide crystalline form-F of compound of formula-la.
Wherein, in step-a) the suitable temperature ranges from -30°C to 30°C; In step-b) stirring of the reaction mixture can be carried out for a suitable time ranges from 0.5-10 hrs.

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-3, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la in propylene glycol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula-la.
Wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
Another 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-4, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la in ethanol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula-la.
Wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
The fifth aspect of the present invention provides novel crystalline form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la. The said novel crystalline polymorph is herein designated as crystalline form-G. The crystalline form-G of compound of formula-la of the present invention is characterized by its PXRD pattern as illustrated in figure-5 or figure-6.

The sixth aspect of the present invention provides a process for the preparation of crystalline form-G 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 suitable alcohol solvent selected from propylene glycol or ethanol at a suitable temperature,
b) combining the solution with aqueous methanol at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline form-G of compound of formula-la.
Wherein, in step-a) the suitable temperature ranges from 20°C to reflux temperature of the solvent used;
In step-b) the suitable temperature ranges from -40°C to 40°C.

Any polymorphic form of compound of formula-la viz.., crystalline forms 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 and well suitable 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 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 pharmaceutically inactive agents.

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 PXRD analysis of compounds of the present invention was carried out using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed on a Q2000 V24.ll Build 124 calorimeter with aluminium pans. Samples held in a closed pan were analyzed at a heating rate of 10°C/min.

The compound of formula-la of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.

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-1: Preparation of crystalline form-E of compound of formula-la

l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (5.0 gm) was added to pre-cooled ethylene glycol (100 ml) at 0-5°C and stirred the reaction mixture for 15 hrs at the same temperature. Water (100 ml) was added to the obtained solution at 0-5°C and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the precipitated solid and suck dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 3.2 gm.

Example-2: Preparation of crystalline form-F of compound of formula-la

l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (5.0 gm) was added to n-pentanol (100 ml) at 0-5°C and stirred the reaction mixture for 5 hrs at the same temperature. Filtered the solid and suck dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 3.8 gm.

Example-3: Preparation of crystalline polymorph 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 (1 gm) and propylene glycol (10 ml) was heated to 70-75°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the obtained solution to make it particle free. The obtained solution was added to pre-cooled water (50 ml) at 0-5°C and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 0.6 gm.

Example-4: Preparation of crystalline polymorph 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 (1 gm) and ethanol (10 ml) was heated to 70-75°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the obtained solution to make it particle free. The obtained solution was added to pre-cooled water (50 ml) at 0-5°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound.
The PXRD pattern of the obtained compound shown in figure-4. Yield: 0.6 gm.

Example-5: Preparation of crystalline form-G of compound of formula-la
A mixture of compound of formula-la (2 gm) and propylene glycol (40 ml) was slowly heated to 60-65°C and stirred the reaction mixture for 30 min at the same temperature. The obtained solution was added to a pre-cooled mixture of methanol (20 ml) and water (80 ml) at -5°C to -10°C and stirred the reaction mixture for 3 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-5. Yield: 1.8 gm.

Example-6: Preparation of crystalline form-G of compound of formula-la
A mixture of compound of formula-la (2 gm) and ethanol (40 ml) was slowly heated to 60-65°C and stirred the reaction mixture for 30 min at the same temperature. The obtained solution was added to a pre-cooled mixture of methanol (20 ml) and water (80 ml) at -5°C to -10°C and stirred the reaction mixture for 3 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-6. Yield: 1.6 gm.

We Claim:

1. Crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, characterized by its PXRD pattern as illustrated in figure-1.
2. A process for the preparation of crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenylj-piperazine hydrobromide compound of formula-la of claim 1, comprising of;

a) Dissolving the compound of formula-1 a in ethylene glycol at a suitable temperature,
b) combining the solution with water at a suitable temperature,
c) filtering the precipitated solid and drying to provide crystalline form-E of compound of formula-la.

3. The process according to claim 2, wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 30°C.
4. Crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, characterized by its PXRD pattern as illustrated in figure-2.
5. A process for the preparation of crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenylj-piperazine hydrobromide compound of formula-la of claim 4, comprising of;

a) Combining the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la with n-pentanol at a suitable temperature,
b) stirring the reaction mixture,
c) filtering the solid and drying to provide crystalline form-F of compound of formula-la,
wherein in step-a) the suitable temperature ranges from -30°C to 30°C.

6. 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-3, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la in propylene glycol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline compound of formula-la.
7. A process for the preparation of crystalline polymorph of 1 -[2-(2,4-dimethyl-
phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la characterized
by its PXRD pattern as illustrated in figure-4, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la in ethanol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula-la.

8. The processes according to claims 6 and 7, wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
9. Crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, characterized by its PXRD pattern as illustrated in figure-5 or figure-6.
10. A process for the preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la of claim 9, comprising of;
a) Dissolving the compound of formula-la in a suitable alcohol solvent selected from propylene glycol or ethanol at a suitable temperature,

b) combining the solution with aqueous methanol at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline form-G of compound of formula-la,
wherein, in step-a) the suitable temperature ranges from 20°C to reflux temperature of the solvent used; and
in step-b) the suitable temperature ranges from -40°C to 40°C.

ABSTRACT
The present invention relates to novel crystalline polymorphs of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide represented by the following structural formula-la and process for preparation thereof.