DESC:Title: Novel Reference Marker of Vortioxetine, and Method of preparing
beta crystalline form of Vortioxetine hydrobromide.
FIELD OF THE INVENTION
The invention encompasses methods of preparing beta crystalline
5 form of Vortioxetine hydrobromide and also a novel compound as a
reference marker of vortioxetine or its pharmaceutically acceptable salt
thereof.
BACKGROUND OF THE INVENTION
Vortioxetine hydrobromide (I) is indicated for the treatment of major
10 depressive disorder (MDD). It is a serotonin (5-HT) reuptake inhibitor,
which is considered as its mechanism of action for the treatment of MDD.
It is available in the market as trade name of BRINTELLIX, which contains
the beta (ß) polymorph of Vortioxetine hydrobromide.
S
N
N
H .HBr
(I)
15 WO2007144005 disclose process of preparation of beta form of
vortioxetine hydrobromide via reaction vortioxetine base with 48%-wt. HBr
in presence of solvent ethyl acetate. According to patent, beta form of
vortioxetine hydrobromide is most stable crystalline form from all other
crystalline forms of vortioxetine hydrobromide.
20 WO2010094285 disclose process of preparation of beta form of
vortioxetine hydrobromide by dissolving vortioxetine hydrobromide
3
isopropanol solvate in non-solvate forming solvent like water, THF, xylene, benzene, methanol, ethanol, acetone and toluene, and mixtures thereof.
Although, novel processes were disclosed in literature and patents, there is need to develop process which gives consistently beta form of vortioxetine hydrobromide claimed in WO2007144005. Therefore, our 5 main focus of present invention is to develop robust process to get polymorphically pure beta crystalline form.
It is well known in the art that, for human administration, safety considerations require the establishment, by national and international regulatory authorities, of very low limits for identified, but toxicologically 10 uncharacterized impurities, before an active pharmaceutical ingredient (API) product or drug product is commercialized. Typically, these limits are less than about 0.15 percent by weight of each impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically, less than 0.1 percent by weight. Therefore, in the manufacture of 15 APIs and/or drug product, the purity of the products, such as Vortioxetine, is required before commercialization.
Further, in order to secure marketing approval for a pharmaceutical product, a manufacturer must submit detailed evidence to the appropriate regulatory authorities to prove that the product is suitable for release on to 20 the market. It is therefore necessary to satisfy regulatory authorities that the product is acceptable for administration to humans and that the particular pharmaceutical composition, which is to be marketed, is free from impurities at the time of release and that it has acceptable storage stability. 25
Those skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to
4
quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern 5 Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.
SUMMARY OF THE INVENTION
One embodiment of present invention encompasses a method or 10 process of preparing beta form of vortioxetine hydrobromide comprising;
a) providing solution of vortioxetine using hydrocarbon solvent.
b) adding hydrobromic acid into step-a;
c) collecting beta form of vortioxetine hydrobromide.
In another embodiment of present invention encompasses obtaining 15 beta form of vortioxetine hydrobromide from hydrocarbon solvents.
In another embodiment of present invention is to prepare beta crystalline form of vortioxetine hydrobromide using cyclohexane solvent.
In another embodiment of present invention provides novel compound of formula-IV, for use as a reference marker of vortioxetine or 20 its pharmaceutically acceptable salt thereof.
In another embodiment of present invention provides preparation of novel compound of formula-IV.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of present invention encompasses a method of 25 preparing beta form of vortioxetine hydrobromide comprising;
5
a) providing solution of vortioxetine using hydrocarbon solvent.
b) adding hydrobromic acid into step-a;
c) collecting beta form of vortioxetine hydrobromide.
In embodiment of present invention vortioxetine solution can be prepared by dissolving vortioxetine or its pharmaceutical acceptable salts 5 or solvates thereof into hydrocarbon solvent or mixture thereof.
In embodiment of present invention hydrocarbon solvents can be selected from but not limited to cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane, pentane, hexane, heptane, benzene, xylene, toluene, methylcyclohexane, petroleum ether, pentamethylbenzene, 10 octadecene or mixtures thereof.
In embodiment of present invention beta crystalline form of vortioxetine hydrobromide is collected by filtration, distillation or drying process.
In another embodiment of present invention encompasses obtaining 15 beta crystalline form of vortioxetine hydrobromide from hydrocarbon solvents.
A "reference marker" is used in qualitative analysis to identify components of a mixture based upon their position, e.g., in a chromatogram or on a Thin Layer Chromatography (TLC) plate (Strobel 20 pp. 921, 922, 953). For this purpose, the compound does not necessarily have to be added to the mixture if it is present in the mixture. A "reference marker" is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included 25 within the definition of a reference standard.
As used herein, the term "reference standard" refers to a compound that may be used both for quantitative and qualitative analysis of an active
6
pharmaceutical ingredient. For example, the HPLC retention time of the
compound allows a relative retention time to be determined, thus making
qualitative analysis possible. The concentration of the compound in
solution before injection into an HPLC (or GC) column allows the areas
5 under the HPLC (or GC) peaks to be compared, thus making quantitative
analysis possible.
Reference standards are described in general terms above.
However, as will be understood by those skilled in the art, a detector
response can be, for example, the peak heights or integrated peak areas
10 of a chromatogram obtained, e.g., by UV or refractive index detection,
from the eluent of an HPLC system or, e.g., flame ionization detection
(FID) or thermal conductivity detection, from the eluent of a gas
chromatograph, or other detector response, e.g., the UV absorbance of
spots on a fluorescent TLC plate. The position of the reference standard
15 may be used to calculate the relative retention time for Vortioxetine and
impurities of Vortioxetine.
In one embodiment the present invention provides a novel
compound of formula-IV
N
S
N
OH
O
HO
O
20 Formula-IV
The compound of formula-IV can form during the synthesis of drug
product, or during the stability of the drug product.
7
In an embodiment, the compound of formula-IV is detected and resolved by HPLC at RRT 1.1 formed during the stability of drug product of vortioxetine.
In an embodiment, the compound of formula-IV is isolated from the drug product of vortioxetine HBr, identified and characterized by analytical 5 techniques.
In an embodiment, the present invention relates to the use compound of formula-IV as a reference marker in a qualitative analysis of Vortioxetine or its pharmaceutically acceptable salt thereof, salts such as Vortioxetine HBr. 10
In an embodiment, the present invention relates to the use compound of formula-IV as a reference standard to analytically quantify the purity of Vortioxetine or its pharmaceutically acceptable salt thereof, salts such as Vortioxetine HBr.
In an embodiment, the present invention provides compound of 15 formula-IV according to the invention is in an isolated form. Most preferably, the isolated form is in substantially pure form, preferably having a purity of greater than about 90%, preferably greater than about 95%, preferably greater than about 98%, most preferably greater than about 99%, preferably as measured by HPLC 20
In an embodiment, the present invention provides a method of preparation of compound of formula-IV comprising steps of reacting vortioxetine base with fumaric acid in a suitable solvent under suitable reaction conditions such as suitable temperature and time, followed by isolation to afford the compound of formula-IV. 25
The suitable solvent in the present invention is selected from dialkylsulfoxides such as but not limited to dimethyl sulfoxide (DMSO) and the like; lower alcohols such as methanol, ethanol, propanol and butanol;
8
polyalcohols such as ethyleneglycol and glycerin, ketones such as acetone, methylethyl ketone, diethyl ketone and cyclohexanone; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol and 1,2-dimethoxyethane; nitriles such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, isopropyl 5 acetate, butyl acetate and diethyl phthalate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene and tetrachloroethylene; aromatic compounds such as benzene, toluene, xylene, monochlorbenzene, nitrobenzene, indene, pyridine, quinoline, collidine and phenol; 10 hydrocarbons such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine and petroleum ether, amines such as ethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine and toluidine, amides such as formamide, N-methylpyrrolidone, N,N-15 dimethylimidazolone, N,N-dimethylacetamide and N,N-dimethylformamide, phosphoric/phosphorous amides such as hexamethylphosphosphoric triamide and hexamethylphosphorous triamide; and water, as well as other commonly used solvents, either alone or in mixtures of two or more, with no particular restrictions on the solvent ratio. 20
The suitable reaction conditions, refers to maintaining a reaction a suitable temperature and time to achieve the desired results.
The suitable temperature may range from about 0°C to about the reflux temperature of the solvent used in the reaction.
In a specific embodiment, the invention provides preparation of 25 compound of formula-IV comprising reacting Vortioxetine Base with Fumaric acid in DMSO at 120oC for 24 hrs, and isolating using the known techniques.
9
In a specific embodiment, the invention provides preparation of
compound of formula-IV as shown in below scheme.
N
S
N
OH
O
HO
O
N
S
N
H
OH
O
HO
O
+ Aza-Michael reaction
In a further embodiment, the invention provides a pharmaceutical
5 composition comprising vortioxetine HBr, a compound of formula-IV along
with other excipients.
In an embodiment, the invention provides a pharmaceutical
composition comprising vortioxetine HBr, a compound of formula-IV along
with other excipients; wherein the compound of formula-IV is less than
10 about 0.15 percent by weight.
In an embodiment, the invention provides a pharmaceutical
composition comprising vortioxetine HBr, a compound of formula-IV along
with other excipients; wherein the compound of formula-IV is less than 0.1
percent by weight.
15 In an embodiment the invention provides a pharmaceutical
composition comprising Vortioxetine or pharmaceutically acceptable salts,
for example vortioxetine HBr, which is substantially free of compound of
formula-IV.
Vortioxetine HBr is “substantially free” of a compound of formula-IV,
20 if it comprises less than about 5% of that compound, preferably less than
about 3%, preferably less than about 2%, preferably less than about 1%,
preferably less than about 0.5%, preferably less than about 0.1%,
preferably less than about 0.05%, preferably as measured by HPLC.
10
In an embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising Vortioxetine or or a pharmaceutically acceptable salt thereof which comprises formulating Vortioxetine or a pharmaceutically acceptable salt, wherein the purity of the composition is tested using compound of formula-IV according to the 5 invention as a reference marker or reference standard.
In an embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising Vortioxetine or or a pharmaceutically acceptable salt thereof which comprises formulating Vortioxetine or a pharmaceutically acceptable salt, wherein the amount of 10 compound of formula-IV in the composition is tested using compound of formula-IV according to the invention as a reference marker or reference standard.
In an embodiment, the present invention provides determination of purity of Vortioxetine or or a pharmaceutically acceptable salt in a 15 pharmaceutical dosage form comprising Vortioxetine or a pharmaceutically acceptable salt, using compound of formula-IV as reference marker or reference standard.
In an embodiment, the present invention provides a chromatographic method for testing the purity of a sample of vortioxetine 20 by determining the presence of compound of formula-IV in a sample comprising vortioxetine, said method comprising:
(a) dissolving a sample of vortioxetine or a dosage form comprising vortioxetine in a solvent to produce a sample solution; (b) dissolving a sample of compound of formula-IV in a solvent to produce 25 a reference marker solution; (c) subjecting the sample solution and the reference solution to a chromatographic technique; and (d) determining the presence of compound of formula-IV in the sample by
11
reference to the presence of the known compound(s) present in the
reference solution.
In an embodiment, the present invention provides a
chromatographic method for testing the purity of a sample of vortioxetine
5 by determining the presence of compound of formula-IV in a sample
comprising vortioxetine by any known methods to the person skilled in the
art.
In one embodiment, the chromatographic method is a liquid
chromatographic method such as a HPLC, LC-MS or LC-MS/MS method.
10 In an embodiment, present invention provides a method to prepare
intermediate compound of formula II from compound of formula-III by
reduction reaction as shown below.
NO2
S
NH2
S
Formula-III Formula-II
15 In an embodiment, the reduction of nitro compound (formula-III) to
amino (formula-II) is carried out using raney nickel, raney nickel, Pd/C,
palladium(II) acetate, iron powder in glacial acetic acid, iron powder in HCl,
Iron/NH4Cl, tin(II)chloride dihydrate, Tin chloride in HCl, tin(II)chloride
dihydrate in concentrated hydrochloric acid, Zn in presence of ammonium
20 chloride, Zn/HOAc, SnCl2, SnCl2 in ethanol, hydrazine compound as
reducing agent in the presence of an metal compound, combination of
palladium(II) acetate, aqueous potassium fluoride, and
polymethylhydrosiloxane (PMHS).
The hydrazine compound for use in the reduced according to
25 present invention is generally NH2NH2, including its hydrate or salts such
12
as hydrazine monohydrate or its aqueous solution; the metal compound used in combination with hydrazine compounds is palladium, platinum, raney nickel, or a iron compound, the iron compound is preferably ferrous or ferric compound such as iron oxide, ferric halides, ferric sulphate, ferric nitrate, anhydrate or hydrate form of iron compounds. 5
Further an activated carbon may be used in the said reduction reaction to accelerating the reaction.
Further a reaction solvent may be used in the said reduction reaction and there is no particular limitation and any solvent may be used, insofar as it does not bring about any problem on process operations, and 10 it doesn’t hinder the reaction or any solvent which doesn’t adversely affect the reaction.
In Another embodiment of present invention is to prepare beta crystalline form of vortioxetine hydrobromide is as shown in below scheme. 15
13
NO2
F
SH
+
NO2
S
NH2
S
N
S
N
H
Na2CO3 Fe powder, NH4Cl
Dimehyl Acetamide water
PTSA, adipic acid
o-xylene
Bis (2-chloroethyl) amine
hydrochloride
HOOC (CH2)4 COOH
S
N
N
H
cyclohexane, NaOH
Aq. HBr soln.
.HBr
Beta Form of Vortioxetine HBr
Vortioxetine adipate
Benzyl alcohol
1/2 Benzyl alcohol
Vortioxetine HBr Benzyl alcohol hemisolvate
S
N
N
H
.HBr
cyclohexane, NaOH
aq. HBr
The invention is further exemplified by the following non-limiting examples, which
are illustrative representing the preferred modes of carrying out the invention.
The invention's scope is not limited to these specific embodiments only but
5 should be read in conjunction with what is disclosed anywhere else in the
specification together with those information and knowledge which are within the
general understanding of the person skilled in the art.
14
Examples
Example 1: Preparation of 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene.
N,N-Dimethyl acetamide (300 ml) and 2,4-dimethylbenzenethiol (100 g) were charged into round bottom flask at temperature 30±5 °C. Sodium 5 bicarbonate (46 g) was added to reaction mixture at 30±5 °C and reaction mass was heated to 80±2.5°C. 2,4-Dimethylbenzenethiol (100 g) was added to above resulting reaction mass and stirred it for one hour at 80±2.5°C. Reaction mass was cooled to 5±5°C and process water (1500 ml) was added into it and heated up to 30±5°C. Reaction mass was stirred 10 for 60 min at 30±5°C. Reaction mass was filtered at 30±5°C and wet cake was charged into reaction vessel containing process water (600 ml) at 30±5°C. Reaction mass temperature was increased to 45±5°C and stirred it for 30 min at 45±5°C. Reaction mass was filtered and washed with the water (200 ml) at 30±5°C. Solid was dried in air oven for 10 hr at 70±5°C. 15
Example 2: Preparation of 2-[(2,4-dimethylphenyl)sulfanyl]aniline.
Water (1000 ml) was charged into reaction vessel at 30 ±5°C. 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (100 g, stage-I) was added into reaction vessel at 30 ±5°C. Ammonium chloride (20.0 g) was added into above reaction vessel at 30 ±5°C. Activated Iron Powder (70 g) was 20 added into reaction mass at 30 ±5°C and temperature of reaction mass was increased to 87.5±2.5°C and maintained at 87.5±2.5°C for 4 hours. Reaction mass was cooled to 40±5°C. Toluene (800 ml) was added to the reaction mass and stirred it for 15 min. at 40±5°C. Reaction mass was cooled to 30±5°C and filtered through hyflo at 30±5°C. Reaction mass was 25 settled at 30±5°C and organic layer was separated out. Process water (300 ml) was added to organic layer at 30±5°C and stirred it for 15 mins at 30±5°C. Reaction mass was settled for 10 min at 30±5°C and organic layer was separated out. Toluene was distilled out from organic layer
15
under vacuum and degassed the residue for 3 hrs at 65±5°C under vacuum.
Example 3: Preparation of Vortioxetine adipate.
o-Xylene (400 ml), {2-[(2,4-dimethylphenyl)sulfanyl]aniline} (100 g), Bis (2-chloro ethyl) amine hydrochloride (78 g) and PTSA (2.5 g) were charged 5 into reaction vessel at 30±5°C. Reaction mass was heated up to reflux temperature (147±3°C) and stirred it for 20 hours at reflux temperature (147±3°C). Reaction mass was cooled to 30±5°C. Then o-Xylene (1000 ml) was added to the reaction mass at 30±5°C and then process water (800 ml) was added to the reaction mass at 30±5°C. Solution of NaOH (35 10 g in NaOH in 350 ml water) was added to the reaction mass at 30±5°C. Reaction mass was stirred for 15 min at 30±5°C. Reaction mass was settled at 30±5°C. Organic layer was separated out. Process water (500 ml) was added to resulting organic layer at 30±5°C and stirred it for 15 min at 30±5°C. Reaction mass was settled and organic layer was separated 15 out and filtered it through hyflo at 30±5°C. Organic layer was heated to 45±5°C. Traces of water were separated out from resulting organic layer. Into resulting orgaic acid layer, Adipic acid (64 g adipic acid in 1530 ml acetone) was added at 45±5°C and reaction mass was stirred for 2 hrs at 30±5°C. Solid mass was filtered at 30±5°C and washed with acetone (2 x 20 100 ml) dried the solid under vacuum for 10hrs at 82±3°C to get vortioxetine adipate.
Example 4: Preparation of Vortioxetine Hydrobromide benzyl alcohol hemi solvate crude.
Vortioxetine adipate (100.0 g) and cyclohexane (1500 ml) were charged 25 into reaction vessel at 30±5°C. Solution of NaOH (27.67 g in 500 ml water) was added into reaction vessel at 30±5°C. Reaction mass was heated to 75±3°C and stirred for 60 min at 75±3°C. Reaction mass was settled for 10 min at 75±3°C. Organic layer was separate out at 70±3°C. Water (500 ml)
16
was charged into resulting organic layer at 70±3°C and reaction mass was stirred for 10 min at 70±3°C. Reaction mass was settled for 10 min at 75±3°C. Organic layer was separated out at 70±3°C and filtered it through hyflo bed at 70±3°C and washed hyflo bed with cyclohexane (200 ml) at 70±3°C. Benzylalcohol was charged (150 ml) to filtrate at 50-70°C. 5 Cyclohexane was distilled out from reaction mass at up to 70 °C. Reaction mass was degassed at 70°C for 1 hour. Reaction mass was cooled to (-5)±3°C under nitrogen. Aqueous HBr was added to above resulting reaction mass within 30 min at (-5) ±3°C under nitrogen. Reaction mass was stirred for under nitrogen till solid came out. Reaction mass 10 temperature was raised to 0±3°C under nitrogen. Cyclohexane (500 ml) was added to the reaction mass at 0±3°C under nitrogen. Reaction mass was heated to 25±2°C under nitrogen. Cyclohexane was distilled out from reaction mass below 27°C. Reaction mass was at 25±2°C for 3 hours. Cyclohexane (500 ml) was added to reaction mass at 25±2°C under 15 nitrogen and stirred it for 30 mins at 25±2°C under nitrogen. Reaction mass was filtered at 25±2°C under nitrogen and solid was washed with cyclohexane (200 ml) at 25±2°C under nitrogen. Solid was dried at 30±2°C under vacuum for 6 hours to obtain Vortioxetine Hydrobromide benzyl alcohol hemi solvate. 20
Example 5: Preparation of Vortioxetine Hydrobromide benzyl alcohol hemi solvate.
Vortioxetine Hydrobromide benzyl alcohol hemi solvate crude (100.0 g) and cyclohexane (1500 ml) were charged into reaction vessel at 30±5°C. Solution of NaOH (27.67 g in 500 ml water) was added into reaction vessel 25 at 30±5°C. Reaction mass was heated to 75±3°C and stirred for 60 min at 75±3°C. Reaction mass was settled for 10 min at 75±3°C. Organic layer was separate out at 70±3°C. Water (500 ml) was charged into resulting organic layer at 70±3°C and reaction mass was stirred for 10 min at 70±3°C. Reaction mass was settled for 10 min at 75±3°C. Organic layer 30
17
was separated out at 70±3°C and filtered it through hyflo bed at 70±3°C and washed hyflo bed with cyclohexane (200 ml) at 70±3°C. Benzylalcohol was charged (150 ml) to filtrate at 50-70°C. Cyclohexane was distilled out from reaction mass at up to 70 °C. Reaction mass was degassed at 70°C for 1 hour. Reaction mass was cooled to (-5 )±3°C under nitrogen. 5 Aqueous HBr was added to above resulting reaction mass within 30 min at (-5)±3°C under nitrogen. Reaction mass was stirred for under nitrogen till solid came out. Reaction mass temperature was raised to 0±3°C under nitrogen. Cyclohexane (500 ml) was added to the reaction mass at 0±3°C under nitrogen. Reaction mass was heated to 25±2°C under nitrogen. 10 Cyclohexane was distilled out from reaction mass below 27°C. Reaction mass was at 25±2°C for 3 hours. Cyclohexane (500 ml) was added to reaction mass at 25±2°C under nitrogen and stirred it for 30 mins at 25±2°C under nitrogen. Reaction mass was filtered at 25±2°C under nitrogen and solid was washed with cyclohexane (200 ml) at 25±2°C under 15 nitrogen. Solid was dried under nitrogen for 30 min. Cyclohexane (500 ml) was added to resulting solid at 25±2°C under nitrogen and stirred it for 30 mins at 25±2°C under nitrogen. Reaction mass was filtered at 25±2°C under nitrogen and solid was washed with cyclohexane (200 ml) at 25±2°C under nitrogen. Solid was dried at 30±2°C under vacuum for 6 hours to 20 obtain Vortioxetine Hydrobromide benzyl alcohol hemi solvate.
Example 6: Preparation of Beta form of Vortioxetine Hydrobromide.
Vortioxetine hydrobromide benzyl alcohol hemisolvate (100 g) and cyclohexane (1500 ml) were charged into reaction vessel at 30±5°C. Solution of NaOH (27.67 g in 500 ml DM water) was added into reaction 25 vessel at 30±5°C. Reaction mass was heated up to 75±3°C and stirred it for 60 min at 75±3°C. Reaction mass was settled for 10 min at 75±3°C. Organic layer was separated out 70±3°C and into this DM water (500 ml) was added at 70±3°C. Organic layer was filtered through hyflo bed at 70±3°C and washed hyflo bed with cyclohexane (200 ml) at 70±3°C. 30
18
Organic layer was added into aqueous HBr solution in 30 min at 65-70°C. Reaction mass was cooled to 42±3°C and maintained it for 1 hr at 42±3°C. Reaction mass was filtered at 42±3°C and washed the solid with water (2*200 ml) at 42±3°C. Solid was dried at 77±3°C under vacuum for 8 hours to obtain beta form of vortioxetine hydrobromide. 5
Example 7: Preparation of compound of formula-IV
Vortioxetine Base (1.0 g) was heated with Fumaric acid (0.78 g) in DMSO (3 ml) at 120oC for 24 hrs. This reaction mass was dumped in crushed ice and ,CLAIMS:1. A process for preparation of beta form of Vortioxetine Hydrobromide
comprising
a) providing solution of vortioxetine using hydrocarbon solvent.
5 b) adding hydrobromic acid into step-a;
c) collecting beta form of vortioxetine hydrobromide
2. The process of preparation according to claim 1, wherein step a)
comprising dissolving vortioxetine or its pharmaceutical acceptable
salts or solvates thereof into hydrocarbon solvent or mixture
10 thereof.
3. The process of preparation according to claim 1, wherein the
hydrocarbon solvent is selected from cycloheptane, cyclohexane,
cyclohexene, cyclooctane, cyclopentane, pentane, hexane,
heptane, benzene, xylene, toluene, methylcyclohexane, petroleum
15 ether, pentamethylbenzene, octadecene or mixtures thereof.
4. A compound having formula-IV
N
S
N
OH
O
HO
O
Formula-IV
5. A process for preparation of compound having formula-IV
20 comprising reacting Vortioxetine Base with Fumaric acid in a
suitable solvent and under suitable reaction conditions.
6. The process for preparation of compound having formula-IV
according to claim 5, wherein the suitable solvent is DMSO and the
suitable reaction condition is temperature of 1200C.
20
7. A compound according to claim 4, for use as a reference marker or reference standard in testing the purity of a sample of Vortioxetine or pharmaceutically acceptable salts or a pharmaceutical composition comprising Vortioxetine or pharmaceutically acceptable salts or a pharmaceutical dosage form comprising Vortioxetine or 5 pharmaceutically acceptable salts.
8. Pharmaceutical composition comprising Vortioxetine or pharmaceutically acceptable salts which is substantially free of compound of formula-IV.