DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of vortioxetine hydrobromide ß form. More particularly, the present invention relates to a reproducible process for consistently obtaining crystalline vortioxetine hydrobromide ß form.
BACKGROUND OF INVENTION
Vortioxetine is known chemically as 1-[2-(2, 4-dimethyl-phenylsulfanyl)-phenyl]-piperazine of formula I, is an atypical anti-depressant.

Formula I
It exerts serotonin reuptake inhibition activity combined with an activity on the serotonin receptor 1A (5-HT1a) and the serotonin receptor 3 (5-HT3). Vortioxetine has been approved as hydrobromide salt and is present in the market under the trade name trintellix.
Vortioxetine and its pharmaceutically acceptable salts have been first time disclosed in the US patent 7,144,884 (refer as US’884). The patent describes several synthetic routes for preparing vortioxetine. In US’884 patent the preparation of vortioxetine or its pharmaceutically acceptable acid addition salt has been exemplified using different processes which involves use of chromatographic techniques for the purification of final product i.e., vortioxetine. The use of such methods for purification on industrial scale is quite cumbersome and tedious.
A PCT publication WO2007/144005 discloses various crystalline forms of vortioxetine and its salts. In particular, a crystalline form of vortioxetine base, three crystalline forms of vortioxetine hydrobromide (defined as the alpha (a), beta (ß) and gamma (?) crystalline forms), a hemi hydrated crystalline form of vortioxetine hydrobromide, and other crystalline forms of vortioxetine salts (hydrochloride, mesylate, fumarate, maleate, meso-tartrate, L-tartrate, D- tartrate, sulphate, phosphate and nitrate). As per FDA label the marketed polymorphic form is the ß form of vortioxetine hydrobromide.
The process to prepare ß form of vortioxetine hydrobromide as disclosed in said publication comprises of dissolving vortioxetine in ethyl acetate followed by addition of 48% w/w of aqueous hydrobromide solution. This addition forms thick slurry which was stirred overnight at room temperature. Thereafter, the slurry is filtered and dried at 50°C under vacuum overnight to give the desired product as white solid. However, as per some literature studies, it was observed that the process has poor reproducibility. So, it is difficult to obtain ß form in a consistent manner since the production process is critical and sensitive. The single crystalline forms are only obtained in pure form by using the same solvent in a quite narrow range of critical parameters i.e., crystallization temperature, the concentration, and the stirring time.
Another PCT publication WO2010/094285 discloses an isopropanol solvate of vortioxetine hydrobromide as well as a process for the purification of vortioxetine and pharmaceutically acceptable salts thereof. Moreover, it should be noted that the solvent content in the active ingredients must not exceed specific limits as expressly regulated by the ICH Guidelines. As per prior art studies, the isopropanol solvate of vortioxetine hydrobromide is not suitable for use in pharmaceutical formulations as they clearly exceed the permissible solvent amount for class 3 solvent.
One another PCT publication WO2014/044721 also discloses crystalline forms of vortioxetine hydrobromide, such as anhydrous delta form or hydrated form such as monohydrate.
A European patent EP3564224 unveils three different crystalline forms of vortioxetine hydrobromide as ?, ? and s and preparation process thereof.
A Chinese patent CN112125868 discloses a preparation method for vortioxetine hydrobromide ß form comprising the steps of a) adding water into ß form of vortioxetine hydrobromide, b) heating the vortioxetine hydrobromide ß form until it gets completely dissolved, c) thereafter cooling the solution to 45-55 ? followed by stirring, filtering and drying to obtain the product.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
However, the processes for preparation of crystalline ß form of vortioxetine hydrobromide as described in the aforementioned prior arts suffer from several disadvantages such as lack of reproducibility, contamination of the desired ß form with other crystalline forms and solvated forms; require the use of column chromatographic purifications and the use of excess amounts of solvents which generates a large quantity of chemical waste which is difficult to treat.
synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
In the formulation of drug compositions, it is essential for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of subsequent manufacture of pharmaceutical formulation comprising the active compound. The chemical stability, solid state stability and shelf life of the active ingredients are also very important factors. The drug substance and compositions containing it should be capable of being effectively stored over appreciable periods of time without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility). Moreover, it is also important to be able to provide drug in a form which is as pure as possible. Thus, in the manufacture of commercially viable and pharmaceutically acceptable, drug compositions, it is desirable, wherever possible, to provide drug in a stable form.

Nevertheless, besides the existing routes for the preparation of crystalline form of vortioxetine hydrobromide, to overcome the aforementioned drawbacks associated to the known crystalline form of vortioxetine hydrobromide in the prior art such as toxicity issues of solvates, stability issues due to water uptake, bioavailability issues due to limited solubility and preparation issues due to similar crystallization processes, there is a continuing need in the art to optimize the preparation process of ß form of vortioxetine hydrobromide which shows high solubility, good stability and is obtained in polymorphically pure form in an easy and reliable manner.

OBJECT OF THE INVENTION
The principal object of the present invention is to provide a stable, consistently reproducible process for the preparation of vortioxetine hydrobromide ß form.

Another object of the present invention is to provide an effective method of consistently obtaining vortioxetine hydrobromide ß form by using a suitable solvent system.
One another object of the present invention is to provide a process for the preparation of vortioxetine hydrobromide ß form by selective crystallization, which enables effective removal of impurities formed, resulting in a product with a better level of purity.
Yet another object of the present invention is to provide a process for the preparation of vortioxetine hydrobromide ß form, which is simple, efficient, cost-effective and industrially feasible.

SUMMARY OF INVENTION
Accordingly, the present invention provides an improved process for the preparation vortioxetine hydrobromide ß form in a substantially pure form, which is without any detectable impurities/ contamination of any other previously known crystalline forms of vortioxetine hydrobromide.
In one embodiment, the present invention provides an efficient process for the preparation of vortioxetine hydrobromide ß form, which comprises the steps of,
i. adding vortioxetine hydrobromide in any form in a first solvent,
ii. heating the reaction mass obtained in step (i) at reflux temperature of the first solvent,
iii. adding second solvent to the solution obtained in step (ii),
iv. cooling the reaction mass at 0 to 10 °C, and
v. isolating pure ß form of vortioxetine hydrobromide.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1- represents PXRD pattern of vortioxetine hydrobromide ß form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous process for consistently obtaining pure ß form of vortioxetine hydrobromide wherein said form is stable and substantially free from contamination of other crystalline forms of vortioxetine hydrobromide.
As used herein, the term “ambient temperature” represents a temperature 25? ± 5?.
The term “substantially free” herein means vortioxetine hydrobromide having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC. In particular, less than about 0.10% by area percentage of HPLC. More particular, less than about 0.05% by area percentage of HPLC. Most particularly, in the range of about 0.01% to about 0.05% by area percentage of HPLC.
The term “substantially free from other crystalline form” herein means vortioxetine hydrobromide as polymorphically pure ß form which is substantially free of any other crystalline forms.
The term "stable" as used herein refers to chemical stability of ß form of vortioxetine hydrobromide wherein there is no significant change in assay values and impurity profile, when the drug substance is kept at 40°C/75% RH for 6 months.
The term “pure” herein refers to a substance free of impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
The purity of vortioxetine hydrobromide, which is substantially free from one or more impurities and having purity of greater than 99% or more of about 99.5% or more, particularly of about 99.9% or more by area percentage of HPLC.
In one general aspect there is provided vortioxetine hydrobromide ß form having purity of about 99.9% or more by area percentage of HPLC.
In another general aspect, there is provided vortioxetine hydrobromide having total impurities less than or equal to 0.15% relative to vortioxetine hydrobromide as measured by area percentage of HPLC. Preferably, total impurities less than or equal to 0.10% relative to vortioxetine hydrobromide as measured by area percentage of HPLC.
Impurities related to other polymorphic forms in vortioxetine hydrobromide ß form are undesirable and may be harmful to a patient being treated with a dosage form of the active pharmaceutical ingredient.
As per regulatory guidance for a drug manufacturer requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. The basic idea of the invention is to specifically develop an improved process for the preparation of vortioxetine hydrobromide ß form which is substantially free from contamination of other polymorphic forms of vortioxetine hydrobromide.
In one embodiment the present invention provides an improved process for the preparation of vortioxetine hydrobromide ß form. The process comprises of dissolving vortioxetine hydrobromide in the first solvent. The vortioxetine hydrobromide used herein can be prepared by the methods reported in literature or by the process as given in the present specification.

Vortioxetine hydrobromide, used as starting material, can be in any form, either crystalline or non-crystalline. Crystalline forms of a substance include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. A hydrated form is a crystalline form that includes water in the crystalline lattice. Hydrated forms can be stoichiometric hydrates, where the water is present in the lattice in a certain water/molecule ratio such as for hemihydrates, monohydrates, dihydrates, etc. The term “anhydrous” herein means that the crystalline form of the compound contains essentially no bound water in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

The dissolution of vortioxetine hydrobromide in the first solvent can be achieved by heating the mixture to reflux temperature of the first solvent. Subsequently, after dissolution of vortioxetine hydrobromide in the first solvent, the second solvent is added to the solution. Thereafter, the reaction mass can be allowed to attain ambient temperature, and cooled the reaction mass at 0 to 10 °C. Preferably, the reaction mass can be cooled at 0 to 8°C.
The first solvent used herein can be selected from water and any suitable organic solvent. Preferably, the solvent can be water. The reflux temperature for water can be at 95±5°C.
The second solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene or mixture thereof and other protic solvents like propylene carbonate and sulfolane.
After cooling the obtained reaction mass can be subsequently stirred and then filtration step may be applied. The filtration can be performed, amongst other methods, by passing the solution, dispersion, or slurry through a filter paper, sintered glass filter or other membrane material, by centrifugation, or using Buchner style filter, Rosenmund filter or plates, or frame press. Preferably, in-line filtration or safety filtration may be advantageously intercalated in the process disclosed above, to increase the polymorphic purity of the resulting crystalline form.
Afterwards, the reaction mass can be stirred for 1-3 hours. Preferably, reaction mass can be stirred for 1-2 hours. Further, the solid can be dried at 50-60? to obtain the desired pure ß form of vortioxetine hydrobromide. The preferable drying temperature can be 45- 55 °C and preferably, the solid can be dried for 12-18 hours, and more preferably for 16-18 hours.
Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.
According to the invention it is also unexpectedly found that a good reproducibility of process in consistently obtaining vortioxetine hydrobromide ß form can be obtained by using a preferable solvent-antisolvent technique.
The present invention also results in the surprising discovery that utilizing a preferred solvent and antisolvent technique can result in consistently getting vortioxetine hydrobromide ß form in terms of purity.
The present invention further provides an efficient process for the preparation of crystalline ß form which is free from contamination of any other polymorphic form of vortioxetine hydrobromide. The pure vortioxetine hydrobromide ß form prepared by using process of present invention have purity of greater than 99.75%, preferably 99.85% and more preferably greater than 99.90% and all impurities have been reduced to less than 0.10% w/w by HPLC. Vortioxetine hydrobromide is crystalline in nature. Preferably, the crystalline form is vortioxetine hydrobromide ß form and has XRD pattern as depicted in Figure-1.
The starting compound vortioxetine hydrobromide can be prepared by the methods reported in the literature or by the process as given in the present specification. The 2,4-dimethylthiophenol can be condensed with 1,2-dibromo-benzene in presence of palladium catalyst and phosphine ligand to get 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene intermediate which can be treated with N-butyloxycarbonylamino piperazine in presence of palladium catalyst and phosphine ligand to get BOC protected vortioxetine which can be subjected for deprotection to obtain vortioxetine.
The conversion of vortioxetine to or its pharmaceutically acceptable salt i.e., vortioxetine hydrobromide salt can be achieved by treating it with hydrobromide source. The hydrobromide source can be selected from hydrobromic acid or its aqueous solution. The hydrobromic acid solution can be added to the resulting reaction mixture and stirred for 19-25 hours, preferably for 22-24 hours. Thereafter, the resulting reaction mixture can be cooled at a temperature less than or equal to 10°C and can be maintained at the same temperature for a further 1-2 hours. Preferably, the reaction mixture can be cooled to temperature of less than or equal 5?. The reaction mass can be filtered and washed with a suitable solvent to obtain vortioxetine hydrobromide. The solvent used for washing herein can be selected from the group consisting of 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene or mixture thereof.
The process of the present invention provides highly pure crystalline ß form of vortioxetine hydrobromide wherein the level of individual specified and unspecified impurities is controlled at a level of equal to or less 0.05% respectively and total impurities at a level of less than 0.10 % as per regulatory guidelines.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES:
Example 1: Preparation of vortioxetine hydrobromide ß form
Vortioxetine hydrobromide (5 g) was taken in water (40 ml) and heated at 95±5°C to get a clear solution. To the resulting solution propylene carbonate (4 ml) was added and thereafter the reaction mass was allowed to attain ambient temperature. The resulting material was then cooled at 5±5°C. Afterwards, the reaction mass was stirred for 1.5 hours and then filtered to obtain a wet cake. The wet cake was dried at 50±5°C for 8-12 hours to get the highly pure crystalline vortioxetine hydrobromide ß form (4.2 g) having HPLC purity [w/w] = 99.97%.
Example 2: Preparation of vortioxetine hydrobromide ß form
Vortioxetine hydrobromide (5 g) was taken in water (40 ml) and heated at 95±5°C to get a clear solution. In the resulting solution isopropyl alcohol (4 ml) was added and then the reaction mass was allowed to attain ambient temperature. The resulting material was cooled at 5±5°C. Afterwards, the reaction mass was stirred for 1.5 hours and filtered to obtain a wet cake. The wet cake was then dried at 50±5°C for 8-12 hours to get highly pure crystalline vortioxetine hydrobromide ß form (4.4 g) having HPLC purity [w/w] = 99.92%.
Example 3: Preparation of vortioxetine hydrobromide ß form
Vortioxetine hydrobromide (5 g) was taken in water (40 ml) and heated at 95±5°C to get a clear solution. To the solution n-heptane (4 ml) was added and thereafter the reaction mass was allowed to attain ambient temperature. The resulting material was cooled at 5±5°C. Afterwards, the reaction mass was stirred for 1.5 hours and filtered to obtain wet cake. The wet cake was then dried at 50±5°C for 8-12 hours to get highly pure vortioxetine hydrobromide ß form (4.6 g) having HPLC purity [w/w] = 99.97%.
Example 4: Preparation of vortioxetine hydrobromide ß form
Vortioxetine hydrobromide (5 g) was taken in water (40 ml) and heated at 95±5°C to get a clear solution. Thereafter n-heptane (40 ml) was added to the resulting solution and then the reaction mass was allowed to attain ambient temperature. After that the resulting material was cooled at 5±5°C. Further, the reaction mass was stirred for 1.5 hours and filtered to obtain wet cake. The wet cake was then dried at 50±5°C for 8-12 hours to get crystalline vortioxetine hydrobromide ß form (4.0 g) having HPLC purity [w/w] = 99.95%.
Example 5: Preparation of vortioxetine hydrobromide ß form
Vortioxetine hydrobromide (5 g) was taken in water (40 ml) and heated at 95±5°C to get a clear solution. Thereafter sulfolane (4 ml) was added to the solution and then the reaction mass was allowed to attain ambient temperature. The resulting material was cooled at 5±5°C. Afterwards, the reaction mass was stirred for 1.5 hours and filtered to obtain wet cake. The wet cake was then dried at 50±5°C for 8-12 hours to get crystalline vortioxetine hydrobromide ß form (4.6 g) having HPLC purity [w/w] = 99.97%.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We Claim
1. A process for the preparation of vortioxetine hydrobromide ß form, which comprises the steps of,
i. adding vortioxetine hydrobromide in any form in a first solvent,
ii. heating the reaction mass obtained in step (i) at reflux temperature of the first solvent,
iii. adding second solvent to the solution obtained in step (ii),
iv. cooling the reaction mass at 0 to 10 °C, and
v. isolating pure ß form of vortioxetine hydrobromide.
2. The process as claimed in claim 1, wherein in step (i) said first solvent is selected from water and any organic solvent thereof.
3. The process as claimed in claim 1, wherein in step (i) said first solvent is preferably water.
4. The process as claimed in claim 1, wherein in step (iii) said second solvent is selected from the group consisting of C1-C8 alcohols; hydrocarbons and other protic solvents.
5. The process as claimed in claim 1, wherein in step (iii) said second solvent is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene or mixture thereof and other protic solvents like propylene carbonate and sulfolane.
6. The process as claimed in claim 1, wherein in step (iii) said reaction mass is allowed to attain ambient temperature.
7. The process as claimed in claim 1, wherein in step (v) pure ß form of vortioxetine hydrobromide is having purity of greater than 99.90% and all impurities are reduced to less than 0.10% w/w, determined by HPLC.
8. The process as claimed in claim 1, wherein in step (v) pure ß form of vortioxetine hydrobromide shows XRD as presented in Figure 1.

Dated this 26th day of December, 2023