DESC:FIELD OF INVENTION:
The present invention primarily discloses a new polymorphic form of Vortioxetine Hydrobromide & Novel Processes for its preparation using Spray drier technique. The Polymorphic form will be known as “Form M” hereinafter.

BACKGROUND OF INVENTION
Vortioxetine, sold under the trade names Trintellix among others, is a medication used to treat major depressive disorder. Effectiveness is viewed as similar to that of other antidepressants. It is only recommended for people who have not improved sufficiently on two other antidepressants. It is taken by mouth.

Common side effects include constipation and nausea. Serious side effects may include suicide in those under the age of 25, Serotonin syndrome, bleeding and mania. A withdrawal syndrome may occur if the dose is rapidly decreased. Use during pregnancy and breastfeeding is not generally recommended. It is classified as a serotonin modulator. How it works is not entirely clear but is believed to be related to increasing serotonin levels.

It was approved for medical use in the United States in 2013. A month supply in the United Kingdom costs the NHS about £27.72 as of 2019. In the United States the wholesale cost of this amount is about 368.40 USD. In 2016 it was the 260th most prescribed medication in the United States with more than a million prescriptions.

Vortioxetine is used as a treatment for major depressive disorder. Effectiveness appears to be similar to other antidepressants. It may be used when other treatments have failed.
It increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and by modulating (activating certain receptors while blocking, or antagonizing, others) certain serotonin receptors. This puts it in the class of atypical antidepressants known as serotonin modulators and stimulators. Vortioxetine is a serotonin modulator and stimulator like Vilazodone.

Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and the synthesis of the drug (then called Lu AA21004) in a 2011 paper. In 2007, the compound was in Phase II clinical trials, and Lundbeck and Takeda entered into a partnership in which Takeda paid Lundbeck $40 million upfront, with promises of up to $345 million in milestone payments, and Takeda agreed to pay most of the remaining cost of developing the drug. The companies agreed to co-promote the drug in the US and Japan, and that Lundbeck would receive a royalty on all such sales. The deal included another drug candidate, Tedatioxetine (Lu AA24530), and could be expanded to include two other Lundbeck compounds.

Vortioxetine was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults in September 2013, and it was approved in Europe later that year.

US 7,144,884 first disclosed Vortioxetine and related compounds. The patent also discloses process for preparation of Vortioxetine which involves polystyrene bound amine intermediate and resin bound complex reagents wherein reaction takes place on the resin surface. The patent disclosure is limited by the use of expensive polymer support material, slow rate of reaction and low yield making the process unsuitable for large scale industrial manufacturing.

Vortioxetine is disclosed as Example 1e in WO 2003/029232 A1 and is described as being prepared analogously to Example 1. The process used to prepare Example 1 involves the preparation of 1-(2-((2-(trifluoromethyl)phenyl)thio)phenyl)piperazine on a solid polystyrene support, followed by decomplexation using visible light irradiation, and purification by preparative LC-MS and ion-exchange chromatography. The overall yield for the preparation of Vortioxetine is described as 17%.
Several alternative palladium catalysed processes for the preparation of Vortioxetine are described in Examples 17 to 25 of WO 2007/144005 A1. These processes describe the preparation of Vortioxetine from 2,4-dimethylthiophenol and 2-bromoiodobenzene (or 1,2-dibromobenzene) starting materials via a 1-(2-bromo-phenylsulfanyl)-2,4-dimethyl-benzene intermediate. Each of these processes involves the use of a palladium catalyst and a phosphine ligand.

The preparation of Vortioxetine is also described by Bang-Andersen et al. in J. Med. Chem. (2011), Vol. 54, 3206-3221. Here, in a first step, tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate intermediate is prepared from Boc-piperazine and 2-bromoiodobenzene in a palladium catalyzed coupling reaction. tert-Butyl 4-(2-bromophenyl)piperazine-1-carboxylate is then reacted with 2,4-dimethylthiophenol, again in the presence of palladium catalyst and a phosphine ligand, to provide Boc-protected Vortioxetine. In the final step, Vortioxetine is deprotected using hydrochloric acid to give Vortioxetine hydrochloride.

WO 2013/102573 A1 describes a reaction between 1-halogen-2,4-dimethyl-phenyl, 2-halogen-thiophenol and an optionally protected piperazine in the presence of a base and a palladium catalyst consisting of a palladium source and a phosphine ligand.

Each of the above processes has disadvantages. The process described in WO 2003/029232 is low yielding and unsuitable for the large scale production of Vortioxetine, whereas the processes described in WO 2007/144005 A1 , WO 2013/102573 A1 and by Bang-Andersen et al.. require the use of expensive starting materials, palladium catalyst and phosphine ligand. In addition, the toxicity of palladium is well known, Liu et al. Toxicity of Palladium, Toxicology Letters, 4 (1979) 469-473, and the European Medicines Agency' s Guideline on the Specification for Residues of Metal Catalysts sets clear limits on the permitted daily exposure to palladium arising from palladium residue within drug substances, www.ema.europa.eu. Thus it would be desirable to avoid the use of a palladium catalyst in the synthesis of Vortioxetine and the subsequent purification steps required to remove palladium residue from the final pharmaceutical product.
US 20140256943 Al discloses the process for preparation of Vortioxetine as shown in Scheme I which involves reacting compound (x), (y) and (z) in presence of a solvent, base, palladium catalyst and phosphine ligands.

Scheme I
WO 2013102573 Al discloses the process for preparation of Vortioxetine Hydrobromide (I) as shown in Scheme II which involves reacting compound (d), (e) and (f) in presence of a solvent, base, palladium catalyst and phosphine ligands.

Scheme II
The process of US '943 and US '573 applications result in a side reaction and an overreaction due to multiple reaction sites available which produces many impurities.
WO2014191548 discloses a process for preparation of Vortioxetine Hydrobromide which uses sulfone or sulfoxide intermediates which is reduced to get Vortioxetine as shown in Scheme-III.

Scheme III
EP3141543 provides a new intermediate II and a method for synthesizing the same. The method comprises: (a) firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain an intermediate II; and (b) reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V. The intermediate II can be used for synthesizing Vortioxetine.

Chinese Patent CN02819025 discloses Vortioxetine ferrocene piperazine complex with the resin protection o-dichlorobenzene, and then 2,4-dimethylbenzene thiol reaction by light irradiation and then complexed with a solution. The method steps are long, need to use ferrocene and other dangerous toxic agents, and the yield is very low; The last step of the reaction yield is only 14%;which is not suitable for mass production.
Morepen’s own patent application IN 202011009866 discloses various new polymorphs of Vortioxetine Hydrobromide (Form V-1, V-2 & V-3) & a novel purification process which can be used at commercial scale for production of Vortioxetine Hydrobromide in plant.
In continuation of search of various new polymorphs of Vortioxetine HBr, spray drying technique is used and is disclosed herein.

SUMMARY OF INVENTION:
The present invention primarily describes a novel process for preparation of Crystalline Form M of Vortioxetine HBr using spray drying technique in a suitable solvent.
To start with, feed stock solution of Vortioxetine HBr is conveniently prepared by dissolving Vortioxetine HBr in solvent that may include but is not limited to a mixture of one or more of alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, t- butyl alcohol with halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof, The second step involves isolation of Crystalline Form M of Vortioxetine HBr from the fine filtered feed solution. The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
In current invention, there is provided spray drying a solution of Vortioxetine HBr that involves the spray drying of feed stock, wherein any crystalline form of Vortioxetine HBr may be used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under the specific parameters which elaborated in further part of the current invention.
In another preferred feature, the spray drying of Vortioxetine HBr may be performed on JISL Mini Spray-drier LSD-48 by maintaining the following parameters a) maintaining the feed rate of the feed stock preferably between 20-25 ml/hr; b) maintaining the inlet temperature in the range of 55°C-65°C; c) maintaining the aspirator rate between 30-40 rpm; d) maintaining the outlet temperature in the range of 25°C to 30° C; e) maintaining air flow at 2-4 kg/cm, preferably 2 kg/cm; f) maintaining vacuum at 60-80 mm of Hg.
In the present invention feedstock of Vortioxetine HBr in solvent system is spray-dried. Thus obtained spray-dried compound is in Crystalline form M, this fact is again confirmed by the X-ray powder diffractogram of spray-dried Vortioxetine HBr. The parameters of obtaining the XRD diffractogram are mentioned below:
a) Scan Axis - Gonio
b) Start Position [°2?] - 4.00
c) End Position [°2?] - 50.00
d) Step Size [°2?] - 0.0170
e) Scan Step Time [s] - 40.0050
f) Scan Type - Continuous
g) PSD Mode - Scanning
h) PSD Length [°2?] - 2.12
i) Offset [°2?] - 0.0000
j) Divergence Slit Type - Fixed
k) Divergence Slit Size [°] - 0.4354
l) Specimen Length [mm] - 10.00
m) Measurement Temperature [°C] - 25.00
n) Anode Material - Cu
o) K-Alpha1 [Å] - 1.54060
p) K-Alpha2 [Å] - 1.54443
q) K-Beta [Å] - 1.39225
r) K-A2 / K-A1 Ratio - 0.50000
s) Generator Settings - 40 mA, 45 kV
t) Diffractometer Type - 0000000011023505
u) Diffractometer Number - 0
v) Goniometer Radius [mm] - 240.00
w) Dist. Focus-Diverg. Slit [mm] - 100.00
x) Incident Beam Monochromator - No
y) Spinning- Yes

The complete process details are disclosed in next section.
DETAILED DESCRIPTION OF THE INVENTION:
According to the current embodiment of the present invention, a novel Crystalline Form M of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed which comprises:
i. Dissolving any crystalline form of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide in a suitable solvent mixture of an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol with halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
ii. stirring the reaction mass at25-35°C for 30 minutes to ensure complete dissolution followed by fine filtration and used as feed stock / solution in spray drier.
iii. the spray drying of Vortioxetine Hydrobromide is to be performed on JISL Mini Spray-drier LSD-48 by a) maintaining the feed rate of the feed stock preferably between 20-25 ml/hr; b) maintaining the inlet temperature in the range of 55°C-65°C; c) maintaining the aspirator rate between 30-40 rpm; d) maintaining the outlet temperature in the range of 25°C to 30° C; e) maintaining air flow at 2-4 kg/cm, preferably 2 kg/cm; f) maintaining the vacuum at 60-80 mm of Hg.
iv. Isolating the pure Crystalline Form M of Vortioxetine Hydrobromide from cyclone flask in almost powdered form which is further dried at 45-60°C for 8-12 hours, having XRD as given in Figure 1 and Figure 2, & Characteristic peaks at 2-Theta values 11.8, 16.0, 17.1, 18.2, 18.7, 23.5 & 25.3 ± 0.2.
According to another aspect of the current invention, solvent system used for dissolution is in ratio 1:2, of an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof with a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof. The feed stock rate is preferably between 20-25 ml/hr, aspirator rate in the range of 32-38 rpm with outlet temperature 28-30°C.
The current invention is supported by following non limiting examples.
Example 1:
20g of Vortioxetine Hydrobromide was dissolved in Methanol (60 ml) & Methylene Chloride (120 ml). The reaction mass was stirred for 30min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.
S.No. Parameter Conditions
a) Feed Pump Rate 22 rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 28-30°C
d) Aspiration Rate 34 rpm
e) Vacuum 70 mm of Hg
f) Hot Air Supply 2 kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hrs at 45-55°C. The obtained solid (9.70 g) was Crystalline Form M of Vortioxetine Hydrobromide as shown by X-Ray Diffraction pattern Fig 1.
Example 2:
25g of Vortioxetine Hydrobromide was dissolved in Methanol (75 ml) & Methylene Chloride (150 ml). The reaction mass was stirred for 30min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.
S.No. Parameter Conditions
a) Feed Pump Rate 24 rpm
b) Inlet Temperature 62°C
c) Outlet Temperature 26-28°C
d) Aspiration Rate 32 rpm
e) Vacuum 70 mm of Hg
f) Hot Air Supply 2 kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hrs at 45-55°C. The obtained solid (11.20 g) was Crystalline Form M of Vortioxetine Hydrobromide as shown by X-Ray Diffraction pattern Fig 2.

CLAIMS:WE CLAIM:
1. A novel process for preparation of Crystalline Form M of 1-[2-[(2,4-Dimethylphenyl) this] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide which comprises:
I. dissolving any crystalline form of 1-[2-[(2,4-Dimethylphenyl) this] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide in suitable solvent mixture of an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol or diethylene glycol with halogenated hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
II. stirring the reaction mass at 25-35°C for 30 minutes and used it as feed stock / solution in JISL Mini Spray-drier LSD-48;
III. maintaining the feed rate of the feed stock preferably 20-25 ml/hr;
IV. maintaining the inlet temperature in the range of 55°C-65°C;
V. maintaining the aspirator rate between 30-40 rpm;
VI. maintaining the outlet temperature in the range of 25°C to 30° C;
VII. maintaining air flow at 2-4 kg/cm, preferably 2 kg/cm;
VIII. maintaining the vacuum at 60-80 mm of Hg;
IX. isolating the pure Crystalline Form M of Vortioxetine Hydrobromide from cyclone flask in powdered form;
X. further drying the powder at 50-60°C for 8-12 hours to get final crystalline form M, having XRD as given in figure 1 and 2 & Characteristic peaks at 2-Theta values 11.8, 16.0, 17.1, 18.2, 18.7, 23.5 & 25.3 ± 0.2;

2. A novel process for preparation of Crystalline Form M of 1-[2-[(2,4-Dimethylphenyl) this] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide as claimed in claim 1 wherein the solvent system used for dissolution is in ratio 1:2, and consists of an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol or diethylene glycol with halogenated hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride.