DESC:Related application
This application claims the benefit of priority of our Indian patent application
numbers 1476/MUM/2014 filed on 28th April 2014 and 3288/MUM/2014 filed on 14th
Oct 2014 which are incorporated herein by reference.
Field of invention
The present invention provides polymorphic forms of Vortioxetine of formula-I
and its pharmaceutically acceptable salts. Specifically the present invention relates
to the novel crystalline forms of Vortioxetine or its pharmaceutically acceptable salts.
Moreover, the present invention also provides an amorphous form of Vortioxetine
hydrobromide and a stable amorphous co-precipitate of Vortioxetine hydrobromide
with pharmaceutically acceptable excipients.
S
N
N H
Formula I
Background of the invention
Vortioxetine hydrobromide (I) is indicated for the treatment of major
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 brand name of BRINTELLIX which contains the beta (ß) polymorph of
Vortioxetine hydrobromide, an antidepressant.
S
N
N H
.HBr
(I)
Vortioxetine was first described in US patent 7144884. It describes
manufacturing process of Vortioxetine. It involves resin base support to prepare
Vortioxetine. Process is as describe in below scheme.
O
O
O
PS
NO2
N H
NH
N H
N
O O
PS
Cl
Cl
Fe Fe
N
N
O O
PS
Cl HS N
NH
S
WO2007144005A1 describes manufacturing process for the preparation of
Vortioxetine. The first step of it involves cross coupling reaction between 2,4-
dimethylthiophenol and 2-bromoiodobenzene using Pd catalysis in presence of
phosphine ligand and base which furnish l-(2-Bromo-phenylsulfanyl)-2,4-dimethylbenzene
which was reacted with unprotected piperazine or protected to furnish
respectively 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine or (4-[2-(2,4-
Dimethyl-phenylsulfanyl)- phenyl]-BOC-piperazine). Protected BOC group was
removed by HCl to produce Vortioxetine. This patent also describes one pot process
for the synthesis of Vortioxetine.
WO2013102573A1 describes one pot process for the preparation of
Vortioxetine. It involves a coupling reaction between 1-iodo-2,4-dimethylbenzene, 2-
bromo thiophenol and piperazine in presence of Pd catalyst, phosphine ligand and
base to furnish 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine.
The above described processes have some limitation and drawback.
Therefore, there is need of process which has industrial feasibility.
Furthermore, WO2007144005 discloses different polymorph of Vortioxetine
base and its salt. They mainly focused on crystalline base, alpha form of
hydrobromide salt, beta form of hydrobromide salt, gamma form of hydrobromide
salt, hemi hydrate of hydrobromide salt, the mixture of the ethyl acetate solvate and
the alpha form of the hydrobromide salt, hydrochloride salt, monohydrate of
hydrochloride salt, mesylate salt, fumarate salt, maleate salt, meso-tartrate salt, L(+)-
tartrate salt, D-(-)-tartrate salt, sulphate salt, phosphate salt, nitrate salt of
Vortioxetine.
WO2010121621A1 discloses AH1, MH1 & MH2 form of Vortioxetine-lactate
and also discloses a, ß, ? and MH form of Vortioxetine DL-lactate.
WO2010094285 discloses Vortioxetine HBr isopropanol solvate.
WO2014044721 discloses delta form of Vortioxetine HBr.
WO2014177491 discloses amorphous form of Vortioxetine hydrobromide with
an adsorbent.
Polymorphism is defined as "the ability of a substance to exist as two or more
crystalline phases that have different arrangement and/or conformations of the
molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different
crystalline structures of the same pure substance in which the molecules have
different arrangements and/or different configurations of the molecules". Different
polymorphs may differ in their physical properties such as melting point, solubility, Xray
diffraction patterns, etc. Although those differences disappear once the
compound is dissolved, they can appreciably influence pharmaceutically relevant
properties of the solid form, such as handling properties, dissolution rate and
stability. Such properties can significantly influence the processing, shelf life, and
commercial acceptance of a polymorph. It is therefore important to investigate all
solid forms of a drug, including all polymorphic forms, and to determine the stability,
dissolution and flow properties of each polymorphic form. Polymorphic forms of a
compound can be distinguished in the laboratory by analytical methods such as Xray
diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared
spectrometry (IR).
The acceptable amount of solvents in an active pharmaceutical ingredient is
strictly regulated e.g. by the ICH guideline for residual solvents. Solvates of
Vortioxetine hydrobromide such as e.g. the ethyl acetate solvate of WO
2007/144005 A1 and the isopropanol solvate of WO 2010/094285 A1 are no suitable
crystalline forms for the preparation of a medicament as they clearly exceed the
recommended solvent amount for class 3 solvents. In summary, solvates of
Vortioxetine hydrobromide know in the art are no suitable forms for the preparation
of a medicament due to the strict limits for residual solvents in an active
pharmaceutical ingredient.
It has been disclosed in the art that the amorphous forms in a number of
drugs exhibit different dissolution characteristics and in some cases different
bioavailability patterns compared to crystalline forms [Konne T., Chem. Pharm. Bull.,
38, 2003-2007 (1990)]. For some therapeutic indications one bioavailability pattern
may be favored over another. The discovery of new polymorphic forms of a
pharmaceutically useful compound provides a new opportunity to improve the
performance characteristics of a pharmaceutical product. It enlarges the repertoire of
materials that a formulation scientist has available for designing, for example, a
pharmaceutical dosage form of a drug with a targeted release profile or other desired
characteristic.
Co-precipitate is characterized by a variety of associated properties such as
stability, flow, and solubility. Typical co-precipitate represents a compromise of the
above properties, as for example, an increase in stability and dissolution properties
of the co-precipitate. Although there is a variety of co-precipitate, there is a continual
search in this field of art for co-precipitate that exhibits an improved mix of
properties.
The existence and possible numbers of polymorphic forms for a given
compound cannot be predicted, and there are no "standard" procedures that can be
used to prepare polymorphic forms of a substance. This is well-known in the art, as
reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8),
August 2004.
The technical problem underlying the present invention is to circumvent the
drawbacks of the known crystalline forms of Vortioxetine hydrobromide disclosed in
the state of the 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 by providing novel polymorphic forms of Vortioxetine
and its pharmaceutically acceptable salts which shows high solubility and is obtained
in polymorphically pure form in an easy and reliable manner.
Summary of the invention
The present inventors have focused on the problems associated with the prior
art polymorphs and have invented several novel polymorphic forms of Vortioxetine
and its pharmaceutically acceptable salts.
In one aspect, the present invention provides a novel crystalline form-A of
Vortioxetine hydrobromide and process of making thereof.
In another aspect, the present invention provides an amorphous form of
Vortioxetine hydrobromide and process of making thereof.
In another aspect, the present invention provides a stable amorphous coprecipitate
of Vortioxetine hydrobromide having enhanced stability, dissolution
properties that can be easily formulated into pharmaceutical compositions and
process of making thereof.
In another aspect, the present invention provides a novel crystalline form-B of
Vortioxetine hydrobromide.
In another aspect present invention also relates to a novel crystalline benzyl
alcohol solvate of Vortioxetine hydrobromide and process for making thereof.
In another aspect, the present invention provides a purification process for
preparation of Vortioxetine hydrobromide using acid base treatment.
Brief description of Drawings
Figure 1: X-ray powder diffraction pattern of Vortioxetine hydrobromide Form A.
Figure 2: X-ray powder diffraction pattern of amorphous form of Vortioxetine
hydrobromide.
Figure 3: X-ray powder diffraction pattern of amorphous Vortioxetine hydrobromide
premix with copovidone.
Figure 4: X-ray powder diffraction pattern of amorphous Vortioxetine hydrobromide
premix with SOLUPLUS.
Figure 5: X-ray powder diffraction pattern of amorphous Vortioxetine hydrobromide
premix with PVP K-90.
Figure 6: X-ray powder diffraction pattern of Vortioxetine hydrobromide Form B.
Figure 7: DSC of Vortioxetine hydrobromide form B.
Figure 8: X-ray powder diffraction pattern of Vortioxetine hydrobromide benzyl
alcohol solvate form C.
Figure 9: Fourier Transform Infrared (FTIR) spectrum of Vortioxetine hydrobromide
benzyl alcohol solvate form C.
Figure 10: Thermogravimetric analyses (TGA) curve of Vortioxetine hydrobromide
benzyl alcohol solvate form C.
Figure 11: Differential Scanning Calorimetry (DSC) of Vortioxetine hydrobromide
benzyl alcohol solvate form C.
Figure 12: X-ray powder diffraction pattern of Vortioxetine adipate.
Figure 13: X-ray powder diffraction pattern of Vortioxetine malonate.
Figure 14: X-ray powder diffraction pattern of Vortioxetine pyruvate.
Figure 15: X-ray powder diffraction pattern Vortioxetine glutarate.
Figure 16: X-ray powder diffraction pattern of Vortioxetine hydrobromide diethyl ether
solvate.
Detailed description of invention
The present invention provides novel polymorphic forms of Vortioxetine and
its pharmaceutically acceptable salts. These solid state forms can be used to
prepare formulations thereof.
In one embodiment the present invention provides a process of preparation of
Vortioxetine of formula-I or pharmaceutically acceptable salts comprising the steps of
N
S
NH
(I)
a. reacting 2,4-dimethyl thiophenol and o-fluoro nitro benzene in presence of
suitable base and suitable solvent to provide compound of formula II.
NO2
S
(II)
b. reducing compound of formula II using suitable reducing agent to prepare
compound of formula III.
NH2
S
(III)
c. converting compound of formula III into Vortioxetine.
Reacting 2,4-dimethyl thiophenol and o-fluoro nitro benzene can be
performed in the presence of suitable base which are one or more of organic or
inorganic bases selected from the group of alkali or alkaline earth metal hydroxide,
carbonate, bicarbonate, for example, NaH, NaOH, KOH, LiOH, NaHCO3, KHCO3,
LiHCO3, Na2CO3, K2CO3, Li2CO3, Mg(OH)2, Ca(OH)2, CaCO3, MgCO3, Ba(OH)2,
Be(OH)2, BaCO3, SrCO3 and the like or mixtures thereof; primary, secondary and
tertiary amines, such as pyridine, piperidine, triethylamine, diisopropyl ethyl amine,
N-methyl morpholine, dimethyl amino pyridine and the like; ammonia and ammonium
salts.
Reacting 2,4-dimethyl thiophenol and o-fluoro nitro benzene can be
performed in the presence of suitable solvent. The term "solvent" includes any
solvent or solvent mixture, including, for example, water, esters, alkanols,
halogenated hydrocarbons, ketones, ethers, nitriles, polar aprotic solvents, or
mixtures thereof. The esters may include one or more of ethyl acetate, n-propyl
acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those
primary, secondary and tertiary alcohols having from one to six carbon atoms.
Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and
butanol. Examples of halogenated hydrocarbons include dichloromethane,
chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl
ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran,
and the like. Examples of nitriles include acetonitrile, benzonitrile. A suitable polar
aprotic solvent includes one or more of N,N-dimethylformamide, N,Ndimethylacetamide,
dimethylsulphoxide, N-methylpyrrolidone, sulfolane and dimethyl
propylene urea.
Reacting 2,4-dimethyl thiophenol and o-fluoro nitro benzene can be
performed preferably at a temperature of from 20 °C to the reflux temperature for a
time period sufficient to complete the reaction, preferably for about 30 minutes to 20
hours.
After the completion of the reaction, the compound of Formula II can be
isolated by a common isolation technique, such as cooling, extraction, one or more
of washing, crystallization, precipitation, filtration, filtration under vacuum,
decantation and centrifugation, or a combination thereof. The isolated compound of
Formula II may be further purified by salt formation, crystallization or
chromatographic methods, or a combination thereof. After the completion of the
reaction one can go in next step without isolation of compound of formula II also.
The compound of Formula II is a suitable intermediate for the preparation of
Vortioxetine.
The reducing agent selected from borane complexes, metals such as iron, tin,
zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel in
presence of hydrogen or hydrogen source selected from ammonium formate, sodium
dihydrogen phosphate, hydrazine; for example, Fe-NH4Cl, Fe-HCl, Fe-CaCl2, Sn-
HCl, NaHS, Zn-AcOH, Pd/C-H2, hydrazine hydrate-Raney Ni, NaBH4-NiCl2.6H2O,
Ni(OAc)2.4H2O, CoCl2 likes metals, metal halides or metal Salts in a solvent
including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones,
ethers, nitriles, polar aprotic solvents, or mixtures thereof. The esters may include
one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl
acetate. Examples of alkanols include those primary, secondary and tertiary alcohols
having from one to six carbon atoms. Suitable alkanol solvents include methanol,
ethanol, n-propanol, isopropanol and butanol. Examples of halogenated
hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of
ethers include diethyl ether, tetrahydrofuran, and the like. Examples of nitriles
include acetonitrile, benzonitrile and the like. A suitable polar aprotic solvent
includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
The reduction is carried out under a suitable reaction temperature for suitable
reaction time. The reaction temperature is preferably from room temperature to
below 100 °C, and the reaction time is generally from 1 hour to several days.
Preferred reaction conditions are disclosed in detail in the examples.
After the reduction is completed the reaction solution is treated and worked up
in a usual way, e.g. by filtering off the solid components, evaporating the filtrate
and/or crystallizing the amino compound or convert into suitable salt using acid. It
can also purify using acid base treatment.
In one more embodiment the present invention provides a process for
preparing Vortioxetine comprising the steps of converting compound of formula III in
to Vortioxetine using Bis (2-chloroethyl) amine hydrochloride or Bis (2-bromoethyl)
amine hydrobromide in presence of suitable solvent and optionally with acid catalyst.
Suitable solvent is selected from water, alcohols, ketones, diols, triols, esters,
amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents,
nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile,
DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol,
propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol
300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-
pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene
glycol monomethyl ether and diethylene glycol ethyl ether, N,N,-dimethyl acetamide,
PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and
ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane
and hexane.
Acid catalyst is one selected from the group consisting of p-toluene sulfonic
acid, methane sulfonic acid, nitric acid, sulphuric acid, hydrochloric acid and mixtures
thereof.
This reaction is carried out under a suitable reaction temperature for suitable
reaction time; preferably at a temperature of from 20 °C to the reflux temperature for
a time period sufficient to complete the reaction, preferably for about 30 minutes to
several days.
The embodiments of present invention are shown in below given scheme-I.
NO2
F
SH +
NO2
S
NH2
S
N
S
NH
K2CO3 Fe powder, NH4Cl
DMF water
PTSA, adipic acid
o-xylene
Bis (2-chloroethyl) amine
hydrochloride
HOOC (CH2)4 COOH
II III
In another embodiment, the present invention provides a purification process
for preparation of Vortioxetine hydrobromide using acid base treatment.
In another embodiment, the present invention provides a process for
purification of Vortioxetine comprising;
a. treating of the Vortioxetine base with a suitable acid;
b. isolating the acid addition salt of Vortioxetine; and
c. treating acid addition salt of Vortioxetine with a suitable base to provide
highly pure Vortioxetine.
Yet, in one more embodiments the present invention provides a purification
process for Vortioxetine compound of formula-I comprising of treating the
Vortioxetine base with a suitable acid followed by treating it with a suitable base in a
suitable solvent to provide highly pure Vortioxetine.
Wherein, the suitable acid is selected from organic acids like acetic acid, citric
acid, para toluene sulfonic acid, malic acid, succinic acid, adipic acid, pyruvic acid,
malonic acid, glutaric acid, trifluoroacetic acid, camphoric acid, napthalene sulfonic
acid, isethionic acid, camphor sulfonic acid and the like; the suitable base is selected
from hydroxides and carbonates of alkali metals or ammonia; the suitable solvent is
selected from water, hydrocarbon solvents, halogenated solvents, alcoholic solvents,
polar-aprotic solvents, ketone solvents and/or their mixtures thereof;
In another embodiment the present invention is to provide Vortioxetine acid
addition salts in crystalline form and process for making them, which comprise:
a) providing a solution of Vortioxetine free base in a suitable solvent or a
mixture of solvents capable of dissolving Vortioxetine;
b) mixing with the solution of organic acid dissolved in the suitable solvent;
c) optionally, filtering the solvent solution to remove any extraneous matter;
and
d) isolating acid addition salt of Vortioxetine.
Yet, another embodiment of the present invention is to get pure crystalline
Vortioxetine adipate salt, Vortioxetine malonate salt, Vortioxetine pyruvate salt and
Vortioxetine glutarate salt.
In another embodiment present invention provides a crystalline Vortioxetine
adipate.
A crystalline form of Vortioxetine adipate having an X-ray powder
diffractogram comprising peaks at 2-theta angles of 7.62± 0.2°, 12.08± 0.2°, 13.35±
0.2°, 13.93± 0.2° and 14.61± 0.2°. The crystalline Vortioxetine adipate has XPRD
pattern as shown in figure 12.
A polymorphic form may be referred to herein as being characterized by
graphical data "as shown in" a Figure. Such data include, for example, powder X-ray
diffractograms. The graphical data potentially provides additional technical
information to further define the respective solid state form which can not necessarily
be described by reference to numerical values or peak positions. In any event, the
skilled person will understand that such graphical representations of data may be
subject to small variations, e.g., in peak relative intensities and peak positions due to
factors such as variations in instrument response and variations in sample
concentration and purity, which factors are well known to the skilled person.
Nonetheless, the skilled person would readily be capable of comparing the graphical
data in the Figures herein with graphical data generated for an unknown crystal form
and confirming whether the two sets of graphical data characterize the same solid
state form or two different solid state forms. The skilled person would understand
that a solid state form referred to herein as being characterized by graphical data "as
shown in" a Figure would include any solid state form of the same chemical
characterized by graphical data substantially similar to the Figure except for such
small variations, the potential occurrence of which is well known to the skilled
person.
In another embodiment present invention provides process for preparation of
Vortioxetine adipate comprising the step of treatment of Vortioxetine with adipic acid.
In another embodiment present invention also provides crystalline forms of
Vortioxetine malonate. A crystalline form of Vortioxetine malonate having an X-ray
powder diffractogram comprising peaks at 2-theta angles of 10.78 ± 0.2°, 11.97 ±
0.2°, 14.57 ± 0.2°, 15.44 ± 0.2° and 15.72 ± 0.2°. A crystalline Vortioxetine
malonate has XPRD pattern as shown in figure 13.
In another embodiment present invention also provides crystalline
Vortioxetine pyruvate.
A crystalline form of Vortioxetine pyruvate having an X-ray powder
diffractogram comprising peaks at 2-theta angles of 7.39 ± 0.2°, 12.81 ± 0.2°, 14.82
± 0.2°, 16.33 ± 0.2° and 17.94 ± 0.2°. A crystalline Vortioxetine pyruvate has XPRD
pattern as shown in figure 14.
In another embodiment present invention also provides crystalline
Vortioxetine glutarate.
A crystalline form of Vortioxetine glutarate having an X-ray powder
diffractogram comprising peaks at 2-theta angles of 11.10 ± 0.2°, 15.53 ± 0.2°, 16.14
± 0.2°, 17.24 ± 0.2° and 23.79 ± 0.2°.A crystalline Vortioxetine pyruvate has XPRD
pattern as shown in figure 15.
In another embodiment the present invention provides a novel, pure and
stable amorphous form of Vortioxetine Hydrobromide characterized by X-ray
diffraction pattern as depicted in Figure 2.
In another embodiment of the present invention, a process is provided for
preparation of a stable and substantially pure amorphous form of Vortioxetine
Hydrobromide, which comprises:
a) providing a solution of Vortioxetine Hydrobromide in a suitable solvent or a
mixture of solvents capable of dissolving Vortioxetine Hydrobromide;
b) optionally, filtering the solvent solution to remove any extraneous matter;
and
c) substantially removing the solvent from the solution to afford amorphous
form of Vortioxetine Hydrobromide.
In another embodiment of the present invention, a process is provided for
preparation of a stable and substantially pure amorphous form of Vortioxetine
Hydrobromide, which comprises:
a) providing a solution of Vortioxetine free base in a suitable solvent or a
mixture of solvents capable of dissolving Vortioxetine;
b) mixing with the solution of Hydrobromic acid dissolved in the suitable
solvent;
c) optionally, filtering the solvent solution to remove any extraneous matter;
and
d) substantially removing the solvent from the solution to afford amorphous
form of Vortioxetine Hydrobromide.
The present invention discloses a process for the preparation of amorphous
form of Vortioxetine Hydrobromide, which includes one or more of the following
steps:
a) providing a solution of Vortioxetine Hydrobromide in one or more solvents;
b) adding a suitable anti-solvent; and
c) isolating the amorphous form of Vortioxetine Hydrobromide.
The solution of Vortioxetine Hydrobromide can be obtained by the known
methods that include direct use of a reaction mixture containing Vortioxetine
Hydrobromide that is obtained in the course of its synthesis, or dissolving
Vortioxetine Hydrobromide in a suitable solvent or mixture of solvents.
Suitable solvents in all process may include but are not limited to water;
alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl
alcohol, 1-pentanol, 2- pentanol, amyl alcohol, ethylene glycol, glycerol and the like;
ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone,
methyl isobutyl ketone, and the like; esters such as ethyl formate, methyl acetate,
ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, hydrocarbons like
toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the
like, nitriles like acetonitrile, ethers like diethyl ether, diisopropyl ether, t-butyl methyl
ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol. Polar aprotic
solvents like N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine,
formic acid, acetic acid, propionic acid and the like; and mixtures thereof.
Suitable anti-solvents may include one or more of hydrocarbons like hexanes,
n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like; aromatic
hydrocarbons like toluene, xylene, chlorobenzene, ethylbenzene and the like; ethers
like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether,
tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, and the like.
The process can produce amorphous Vortioxetine Hydrobromide in
substantially pure form.
The term "substantially pure amorphous form of Vortioxetine Hydrobromide "
refers to the amorphous form of Vortioxetine Hydrobromide having purity greater
than about 98%, specifically greater than about 99%, more specifically greater than
about 99.5% and still more specifically greater than about 99.9% (measured by
HPLC).
The amorphous Vortioxetine Hydrobromide obtained by the process disclosed
herein is consistently reproducible and has good flow properties, and which is
particularly suitable for bulk preparation and handling, and so, the amorphous
Vortioxetine Hydrobromide obtained by the process disclosed herein is suitable for
formulating Vortioxetine Hydrobromide.
Step-(a) of providing a solution of Vortioxetine Hydrobromide includes
dissolving Vortioxetine Hydrobromide in the solvent, or obtaining an existing solution
from a previous processing step. Preferably the Vortioxetine Hydrobromide is
dissolved in the solvent at a temperature of below about boiling temperature of the
solvent used, more preferably at about 20 °C to about 110 °C, and still more
preferably at about 25 °C to about 80 °C.
The solution in step-(a) may also be prepared by reacting Vortioxetine free
base with Hydrobromic acid to produce a solution containing Vortioxetine
Hydrobromide, or optionally subjecting the solution to usual work up such as
washings, extractions etc., and dissolving the resulting Vortioxetine Hydrobromide in
a suitable solvent at a temperature of below about boiling temperature of the solvent
used, more preferably at 200C to about 1100C, and still more preferably at about
250C to about 800C.
The solution obtained in step-(a) may optionally be subjected to carbon
treatment. The carbon treatment can be carried out by methods known in the art, for
example by stirring the solution with finely powdered carbon at a temperature of
below about 70 °C for at least 15 minutes, preferably at a temperature of about 25 °C
to about 70 °C for at least 30 minutes; and filtering the resulting mixture through hyflo
to obtain a filtrate containing Vortioxetine Hydrobromide by removing charcoal.
Preferably, finely powdered carbon is an active carbon.
The solution obtained in step-(a) or step-(b) is optionally stirred at a
temperature of about 30 °C to the reflux temperature of the solvent used for at least
20 minutes, and preferably at a temperature of about 40 °C to the reflux temperature
of the solvent used from about 30 minutes to about 4 hours.
Removal of solvent in step-(c) is accomplished by, for example, substantially
complete evaporation of the solvent, concentrating the solution and filtering the solid
under inert atmosphere. Alternatively, the solvent may also be removed by
evaporation.
Evaporation can be achieved at sub-zero temperatures by the lyophilisation or
freeze- drying technique. The solution may also be completely evaporated in, for
example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional
reactor under vacuum above about 720 mm Hg by flash evaporation techniques by
using an agitated thin film dryer ("ATFD"), or evaporated by spray drying.
The distillation process can be performed at atmospheric pressure or reduced
pressure. Preferably the solvent is removed at a pressure of about 760 mm Hg or
less, more preferably at about 400 mm Hg or less, still more preferably at about 80
mm Hg or less, and most preferably from about 30 to about 80 mm Hg.
The substantially pure amorphous Vortioxetine Hydrobromide obtained by the
above process may be further dried in, for example, Vacuum Tray Dryer, Rotocon
Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor, to further lower
residual solvents.
In one more embodiment of the present invention provides Vortioxetine
Hydrobromide co-precipitate having enhanced stability and dissolution properties
and process for preparation thereof.
The term “co-precipitate” herein refers to a composition prepared by
dissolving a Vortioxetine hydrobromide in an organic solvent or mixture of organic
solvents with one or more pharmaceutically acceptable carriers and converting the
solution to a solid form.
In one more embodiment of the present invention provides an amorphous coprecipitate
of Vortioxetine Hydrobromide with pharmaceutically acceptable excipients
wherein the pharmaceutically acceptable excipients may be one or more selected
from copovidone, povidone, ethyl cellulose, hydroxypropyl methylcellulose,
polyethylene glycol, soluplus, starch, microcrystalline cellulose, crosspovidone,
methylcellulose, cellulose ethers, sodium carboxymethylcellulose, dextrose, lactose,
sucrose, sorbitol, mannitol, polyvinylpyrrolidone, polyacrylamides,
polyvinyloxoazolidone, polyvinylalcohols, carmellose, carmellose sodium, glycerol
monosterate or starch.
In an embodiment, a pharmaceutical composition comprising a therapeutically
effective amount of an amorphous co-precipitate of Vortioxetine Hydrobromide and
one or more pharmaceutically acceptable carriers, excipients, or diluents.
In one more embodiment a process for preparation of a stable amorphous coprecipitate
of Vortioxetine hydrobromide comprising the steps of:
a) preparing a solution comprising a mixture of Vortioxetine hydrobromide
and one or more pharmaceutically acceptable excipients;
b) removing the solvent to obtain amorphous co-precipitate of Vortioxetine
hydrobromide in combination with a pharmaceutically acceptable
excipients.
In an embodiment, the present invention provides a stable amorphous coprecipitate
of Vortioxetine Hydrobromide having enhanced stability, dissolution
properties that can be easily formulated into pharmaceutical compositions.
According to present invention, the ratio of Vortioxetine Hydrobromide to
excipients is in a range of 1:0.1 to 1: 10.
The term "substantially removing" the solvent refers to at least 80%,
specifically greater than about 85%, more specifically greater than about 90%, still
more specifically greater than about 99%, and most specifically essentially complete
(100%), removal of the solvent from the solvent solution.
According to present invention, the solvent employed in step (a) is selected
from the group comprising of alcohols, carboxylic acids, chlorinated hydrocarbons,
ketones, amides, sulphoxides, ethers, nitriles, water or mixtures thereof. Examples of
alcohols may include methanol, ethanol, 1-propanol, 1-butanol or 2- butanol.
Examples of carboxylic acids may include formic acid, acetic acid or propionic acid.
Examples of chlorinated hydrocarbons may include dichloromethane or chloroform.
Examples of ketones may include acetone, dimethyl ketone, ethyl methyl ketone or
methyl iso-butyl ketone. Examples of ethers may include diethyl ether, ethyl methyl
ether, di-isopropyl ether, tetrahydrofuran or 1,4-dioxane. Examples of amides may
include N,N-dimethylformamide or N,N-dimethylacetaniide. Examples of sulphoxides
may include dimethyl sulfoxide or diethyl sulphoxide. Examples of cyclic ethers may
include tetrahydrofuran, Examples of nitriles include acetonitrile, benznitrile. More
preferably dichloromethane is used.
The reaction of step (a) is carried out at a temperature of 0 to 50 °C,
preferably at 5 to 45 °C and more preferably selected from 20 to 30 °C.
The suitable excipients of step (a) can be any pharmaceutically acceptable
excipient(s) discussed in the specification includes but not limited to diluents,
lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures
thereof.
Exemplary pharmaceutically acceptable excipients include, but are not limited
to starch, pregelatinized starch, lactose, mannitol, sorbitol, xylitol, sucrose, dextrates,
dextrin, dextrose, microcrystalline cellulose, powdered cellulose, calcium carbonate,
calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, alginic acid,
sodium alginate, crosspovidone, sodium starch glycolate, crosscarmellose,
methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethylcellulose,
polyethylene glycol, polyvinylpyrrolidone, pectins, gelatin, polyacrylamides,
polyvinyloxoazolidone, polyvinylalcohols, polyvinyl pyrrolidone (PVP), polyethylene
glycol (PEG), pectin, pullulan, mannan, gelatin, gum arabic, a cyclodextrin, agar, a
polyoxysorbitan fatty acid ester, an alginate or cellulose derivatives, hypromellose
(HPMC), hydroxypropyl cellulose (HPC), hypromellose phthalate (HPMCP),
hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose acetate
succinate cellulose (HPMCAS), hydroxyethyl cellulose, carmellose (CMC),
carmellose sodium (CMC-Na), carmellose calcium (CMC-Ca), croscarmellose
sodium and low-substituted hydroxypropyl cellulose (L-HPC), candela wax, carnauba
wax, glycerol monosterate, copovidone, povidone, povidone 12, povidone 25,
povidone 30, povidone 90, PEG-4000, PEG-6000, PEG-8000, poloxamer, hydroxy
propyl cellulose, hydroxy ethyl cellulose, hydroxy propyl methyl cellulose, hydroxy
propyl methyl cellulose acetate succinate, soluplus, corn starch, lactose,
maltodextrin, more preferably copovidone, polyvinylpyrrolidone or SOLUPLUS is
used. This list is not intended to be comprehensive, as many other excipient
substances are useful in the invention.
Removal of solvent in step (b) is accomplished, for example, by substantially
complete evaporation of the solvent, concentrating the solution or distillation of
solvent, under inert atmosphere to obtain the stable amorphous co-precipitate of
Vortioxetine Hydrobromide.
In another embodiment, the solvent is removed by evaporation. Evaporation
can be achieved at sub-zero temperatures by lyophilisation or freeze-drying
techniques. The solution may also be completely evaporated in, for example, a pilot
plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum
above about 720 mm Hg by flash evaporation techniques by using an agitated thin
film dryer ("ATFD"), or evaporated by spray drying to obtain a dry amorphous
powder.
The distillation process can be performed at atmospheric pressure or reduced
pressure. Specifically, the solvent is removed at a pressure of about 760 mm Hg or
less, more specifically at about 400 mm Hg or less, still more specifically at about 80
mm Hg or less, and most specifically from about 30 to about 80 mm Hg.
According to present invention, a stable amorphous co-precipitate of
Vortioxetine hydrobromide can be formed using Fusion Method, Solvent Evaporation
Method, Spray Drying, Lyophilisation(freeze drying), Hot-melt extrusion, Electrostatic
Spinning Method, Coating on sugar beads using fluidized bed-coating system,
Supercritical Fluid Technology, more preferably spray drying technique is used.
According to present invention, solvent is removed by the known techniques
such as spray dry, evaporation, distillation, lyophilisation, agitated thin film drier
(ATFD) or Alteration. Preferably solvent is removed by spray dry at a temperature
about 30 °C to about 150 °C, specifically from about 65 °C to about 110 °C.
In another embodiment, the invention provides a process for preparation of a
stable co-precipitate of amorphous Vortioxetine hydrobromide comprising the steps
of:
a) providing solution of crystalline Vortioxetine adipate in a solvent or mixture
thereof;
b) adding a base into the resulting solution of step-a);
c) adding an aqueous solution of hydrobromic acid into resulting solution of
step-b);
d) adding suitable pharmaceutical acceptable excipient; into organic layer of
resulting solution of step-c);
e) substantially removing solvent from step-d) to a get stable amorphous coprecipitate
of Vortioxetine hydrobromide.
According to present invention, base can be selected from, but not limited to,
Inorganic bases like sodium hydroxide, potassium hydroxide, ammonium hydroxide,
sodium carbonate, ammonia gas, ammonia solution or mixtures thereof, more
preferably sodium hydroxide is used.
The amorphous co-precipitate of Vortioxetine hydrobromide with copovidone
is having the X-ray powder diffraction (XRD) pattern substantially as depicted in
figure 3.
The amorphous co-precipitate of Vortioxetine hydrobromide with soluplus is
having the X-ray powder diffraction (XRD) pattern substantially as depicted in figure
4.
The amorphous co-precipitate of Vortioxetine hydrobromide with PVP K-90 is
having the X-ray powder diffraction (XRD) pattern substantially as depicted in figure
5.
In yet another embodiment; the present invention relates to isolated
Vortioxetine impurities such as N-oxide impurity and their use as reference
standards in a chromatographic method for testing the purity of a Vortioxetine active
pharmaceutical ingredient or dosage form.
S
N
NH
CH3
CH3
O.
In yet another embodiment; the present invention provides a crystalline form-
A of Vortioxetine hydrobromide.
In yet another embodiment; the present invention provides a crystalline form-
A of Vortioxetine hydrobromide having an X-ray powder diffractogram comprising at
least one peak at diffraction 2-theta angle selected from 11.35 ± 0.2°, 15.30 ± 0.2°
and 19.80 ± 0.2°. The crystalline form-A of has an X-ray powder diffraction pattern
with characteristics peaks at 11.35 ± 0.2°, 15.30 ± 0.2°, 18.67 ± 0.2° and 19.80 ±
0.2°. A crystalline Vortioxetine hydrobromide form-A has XPRD pattern as shown in
figure 1.
In yet another embodiment; the present invention provides a pharmaceutical
composition comprising the crystalline form-A of Vortioxetine hydrobromide and at
least one pharmaceutically acceptable excipient.
In yet another embodiment; the present invention provides a process for
preparation of crystalline form-A of Vortioxetine hydrobromide comprising the steps
of;
a) providing the solution of Vortioxetine hydrobromide in suitable solvent;
b) contacting the solution of step(a) with water; and
c) isolating crystalline form-A of Vortioxetine hydrobromide.
In an illustrative embodiments of the present invention; suitable solvents is
selected from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl
alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone,
butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone,
ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl
acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene,
acetonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether,
tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,Ndimethylacetamide,
N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane,
formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic
acid or mixtures thereof.
In yet another embodiment; the present invention provides a crystalline form-
B of Vortioxetine hydrobromide in that the molar ratio of Vortioxetine and the
Hydrobromic acid is in the range of from 1:0.5 to 1:1.2, and preferably is
approximately 1:0.6.
A crystalline form-B of Vortioxetine hydrobromide has an X-ray powder
diffractogram comprising peaks at 2-theta angles of 8.42 ± 0.2°, 12.20 ± 0.2°, 14.20
± 0.2°, and 14.91 ± 0.2°. The crystalline form-B of Vortioxetine hydrobromide has
XPRD pattern as shown in figure 6.
In illustrative embodiments of the present invention; a process for preparation
of crystalline form-B of Vortioxetine hydrobromide comprising the steps of:
a) passing dry Hydrobromic acid gas in to the solution of Vortioxetine base in
the suitable solvent; and
b) isolating the crystalline form-B of Vortioxetine hydrobromide.
Wherein suitable solvent is selected from acetone, N,N-dimethylformamide
dimethylsulfoxide, acetonitrile, tetrahydrofuran, methylene dichloride, ethyl acetate,
butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone,
ethyl formate, methyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate,
ethylene dichloride, chlorobenzene, diethyl ether, diisopropyl ether, t-butyl methyl
ether, dibutyl ether, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylacetamide, Nmethylpyrrolidone,
sulfolane, formamide, acetamide, propanamide, hexane,
cyclohexane, pentane, toluene, xylene or mixtures thereof.
In another embodiment; the present invention encompasses the solvates
isolated in pure form or when admixed with other materials, for example other
isomers and/or polymorphic forms and/or salt forms or any other material.
Solvates have some variability in the exact molar ratio of their components
depending on a variety of conditions understood to a person of skill in the art. For
example, a molar ratio of components within a solvate provides a person of skill in
the art information as to the general relative quantities of the components of the
solvate and in many cases the molar ratio may vary by about plus or minus 20%
from a stated range. For example, a molar ratio of 1:1 is understood to include the
ratio 1:0.8 as well as 1:1.2 as well as all of the individual ratios in between.
The present invention relates to solvates of Vortioxetine hydrobromide with
benzyl alcohol, propylene glycol, dimethyl sulphoxide and diethyl ether.
In specific embodiment the present invention relates to a crystalline benzyl
alcohol solvate of Vortioxetine hydrobromide wherein the molar ratio of Vortioxetine
hydrobromide to benzyl alcohol is approximately 1:0.5; more specifically, crystalline
form-C of Vortioxetine hydrobromide benzyl alcohol solvate.
The present invention also relates, at least in part, to a crystalline benzyl
alcohol solvate of Vortioxetine hydrobromide wherein the molar ratio of Vortioxetine
hydrobromide to benzyl alcohol is approximately 1:1. The crystalline solvates of the
present invention may have advantages relative to other known forms of Vortioxetine
hydrobromide, including chemical stability, polymorphic stability and/or varying
solubility.
The crystalline form-C of Vortioxetine hydrobromide benzyl alcohol solvate of
present invention can be characterized by showing an X-ray powder diffractogram
comprising characteristic peaks (expressed in 2? ± 0.2° ?, CuKa radiation) at 8.85 ±
0.2°, 11.84 ± 0.2°, 14.22 ± 0.2°, 14.75 ± 0.2° and 15.00 ± 0.2°. A representative
diffractogram is displayed in figure 8.
In illustrative embodiments of present invention, there is provided a Form C of
Vortioxetine hydrobromide benzyl alcohol solvate described herein characterized by
a Diffraction Scanning Calorimetry as depicted in figure 11.
The DSC thermogram for form-C of Vortioxetine hydrobromide benzyl alcohol,
shown in figure 11, indicates an endotherm onset at 140-150° C, at scan rate of 10
°C/min.
In illustrative embodiments of the present invention, there is provided a
process for preparation of Vortioxetine hydrobromide benzyl alcohol solvate, the
process comprising:
a. contacting Vortioxetine free base with benzyl alcohol in solution or
suspension;
b. treating the resulting solution or suspension of step-a with hydrobromic
acid;
c. crystallizing the benzyl alcohol solvate of Vortioxetine hydrobromide;
d. isolating the solvate.
In illustrative embodiments of the present invention; Vortioxetine free base
solution or suspension can be prepared by dissolving it in solvent like water, esters,
alkanols, aliphatic and cyclic hydrocarbons, halogenated hydrocarbons, ketones,
ethers, nitriles, polar aprotic solvents, carboxylic acid or mixtures thereof. The esters
may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and nbutyl
acetate. Examples of alkanols include those primary, secondary and tertiary
alcohols having from one to six carbon atoms. Suitable alkanol solvents include
methanol, ethanol, n-propanol, isopropanol and butanol. Examples of aliphatic
hydrocarbons include hexane, heptane, and octane. Examples of cyclic
hydrocarbons include cylohexane, cycloheptane and cyclooctane. Examples of
halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-
dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the
like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like.
Examples of nitriles include acetonitrile, benzonitrile. A suitable polar aprotic solvent
includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone, Examples of carboxylic
acid include acetic acid, propionic acid, fumaric acid.
In illustrative embodiments of the present invention, hydrobromic acid may be
provided as a gas or as a solution in an organic or aqueous solvent.
In illustrative embodiments of the present invention, crystallizing
the benzyl alcohol solvate may be induced by cooling and/or seeding. Following
crystallization, a suspension may be formed and the suspension may be maintained
at a temperature of about 20°C to about 40°C prior to isolation of the crystals.
In illustrative embodiments of the present invention, Vortioxetine
hydrobromide benzyl alcohol solvate can be crystallized by use of solvent like water,
esters, alkanols, aliphatic and cyclic hydrocarbons, halogenated hydrocarbons,
ketones, ethers, polar aprotic solvents, carboxylic acids or mixtures thereof. The
esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate,
and n-butyl acetate. Examples of alkanols include those primary, secondary and
tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents
include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of
aliphatic hydrocarbons include hexane, heptane, and octane. Examples of cyclic
hydrocarbons include cylohexane, cycloheptane and cyclooctane. Examples of
halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-
dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the
like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A
suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,Ndimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Examples of carboxylic acids include acetic acid, propionic acid, fumaric acid. More
preferably hydrocarbons like hexane, heptanes, cyclohexane is used.
In illustrative embodiments of the present invention, the Vortioxetine
hydrobromide benzyl alcohol solvate can be isolated by using technique like filtration
or distillation.
In illustrative embodiments of the present invention, there is provided a
process for preparation of Vortioxetine hydrobromide benzyl alcohol solvate, the
process comprising:
a. contacting Vortioxetine hydrobromide with benzyl alcohol;
b. crystallizing the benzyl alcohol solvate of Vortioxetine hydrobromide;
c. isolating the solvate.
In illustrative embodiments of the present invention, there is provided a
process for preparation of Vortioxetine hydrobromide benzyl alcohol solvate, the
process comprising:
a. contacting Vortioxetine acid addition salt with base in solution;
b. treating the resulting solution of step-a with hydrobromic acid;
c. treating the resulting solution of step-b with benzyl alcohol in solution;
d. crystallizing the benzyl alcohol solvate of Vortioxetine hydrobromide;
e. isolating the solvate.
In illustrative embodiments of the present invention, Vortioxetine acid addition
salt includes but not limited to Vortioxetine adipate, Vortioxetine pyruvate,
Vortioxetine malonate and Vortioxetine glutarate.
In illustrative embodiments of the present invention, base can be selected
from inorganic base or organic base. Examples of inorganic base includes but not
limited to KOH, NaOH, K2CO3, Na2CO3, NH3. Examples of organic base includes but
not limited to triethyl amine, methyl amine, pyridine, histidine. More preferably
sodium hydroxide is used.
In illustrative embodiments of the present invention, Vortioxetine acid addition
solution can be prepared by dissolving Vortioxetine acid addition salt in solvent like
water, esters, alkanols, aliphatic and cyclic hydrocarbons, halogenated
hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The
esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate,
and n-butyl acetate. Examples of alkanols include those primary, secondary and
tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents
include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of
aliphatic hydrocarbons include hexane, heptane, and octane. Examples of cyclic
hydrocarbons include cylohexane, cycloheptane and cyclooctane. Examples of
halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-
dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the
like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A
suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,Ndimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. More
preferably water is used.
In illustrative embodiments of the present invention, the hydrobromic acid may
be provided as a gas or as a solution in an organic or aqueous solvent.
In illustrative embodiments of the present invention, crystallizing
the benzyl alcohol solvate may be induced by cooling and/or seeding. Following
crystallization, a suspension may be formed and the suspension may be maintained
at a temperature of about 20 °C to about 40 °C prior to isolation of the crystals.
In illustrative embodiments of the present invention, Vortioxetine
hydrobromide benzyl alcohol solvate can be crystallized by use of solvent like water,
esters, alkanols, aliphatic and cyclic hydrocarbons, halogenated hydrocarbons,
ketones, ethers, polar aprotic solvents, or mixtures thereof. The esters may include
one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl
acetate. Examples of alkanols include those primary, secondary and tertiary alcohols
having from one to six carbon atoms. Suitable alkanol solvents include methanol,
ethanol, n-propanol, isopropanol and butanol. Examples of aliphatic hydrocarbons
include hexane, heptane, and octane. Examples of cyclic hydrocarbons include
cylohexane, cycloheptane and cyclooctane. Examples of halogenated hydrocarbons
include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones
include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl
ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or
more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide,
acetonitrile and N-methylpyrrolidone. More preferably hydrocarbons like hexane,
heptanes, cyclohexane is used.
Yet another embodiment of the present invention provides a novel solvate
Vortioxetine hydrobromide diethyl ether solvate.
A process for preparation of Vortioxetine diethyl ether solvate comprising; the
step of achieving a solution of Vortioxetine hydrobromide in diethyl ether.
A crystalline form of Vortioxetine hydrobromide diethyl ether solvate of
present invention can be characterized by showing an X-ray powder diffractogram
comprising characteristic peaks at 2-theta angles of 8.34 ± 0.2°, 12.98 ± 0.2°, 15.30
± 0.2°, 16.67 ± 0.2° and 17.20 ± 0.2°. A crystalline Vortioxetine hydrobromide
diethyl ether solvate has XPRD pattern as shown in as shown in figure 16.
In another embodiment the Vortioxetine Hydrobromide disclosed herein for
use in the pharmaceutical compositions of the present invention, wherein 90 volumepercent
of the particles (D90) have a size of less than or equal to about 500 microns,
specifically less than or equal to about 300 microns, more specifically less than or
equal to about 200 microns, still more specifically less than or equal to about 100
microns, and most specifically less than or equal to about 15 microns.
Examples
The following examples are provided to enable one skilled in the art to
practice the invention and are merely illustrate the process of this invention.
However, it is not intended in any way to limit the scope of the present invention.
1H NMR spectra are recorded at 300 MHz on a Bruker Avance III instrument.
Dimethyl sulfoxide (99.8% D) is used as solvent, and tetramethylsilane (TMS) is
used as internal reference standard.
The melting points are measured using Differential Scanning Calorimetry
(DSC). The equipment is a TA-Instruments DSC-Q1000 calibrated at 10°/min to give
the melting point as onset value. About 2 mg of sample is heated 10°/min in a
loosely closed pan under nitrogen flow.
Thermo gravimetric analysis (TGA) used for estimation of solvent/water
content of dried material is performed using a TA-instruments TGA-Q500 about 10
mg sample is heated 10°/min in an open pan under nitrogen flow.
X-Ray powder diffractograms were measured on a PANalytical X'Pert PRO XRay
Diffractometer using CuKa1 radiation. The samples were measured in reflection
mode in the 2?-range 2.5-40° using an X' celerator detector.
The FTIR spectrum was collected at 4 cm resolution using a Perkin Elmer
Paragon 1100 single beam FTIR instrument. The samples were intimately mixed in
an approximately 1 :100 ratio (w/w) with potassium bromide using an agate mortar
and pestle to a fine consistency; the mixture was compressed in a pellet die at a
pressure of 5 to 10 tonnes for a time period between 2 and 5 minutes. The resulting
disk was scanned 5 times versus a collected background. Data was baseline
corrected and normalized.
Example-1: Preparation of 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene.
2,4-dimethylbenzenethiol (5.0 g), 1-fluoro-2-nitrobenzene (5.2 g), potassium
carbonate (10.0 g) and Dimethyl formamide (50ml) were introduced into round
bottom flask at temperature 30±5 °C. The reaction mixture was heated at 85±5 °C for
two hr. After completion reaction mixture was cooled to 25±5 °C. Process water (250
ml) was added into reaction mixture at 0-5 °C. Reaction mixture was stirred for 30
min at 0-10 °C. Reaction mixture was filtered and process water (250 ml) was added
at 20-25 °C. Reaction mixture was heated to 45±5 °C for 15 min. Solid material was
isolated by filtration and dried it at 60 °C.
Example-2: Preparation of 2-[(2,4-dimethylphenyl)sulfanyl]aniline
2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (52.5 g)), iron powder (52.5
g), ammonium chloride (10.5 g) and water (1050 ml) was added into round bottom
flask at 30±5 °C. The reaction mixture was heated to 85±5 °C for about 3-4 hrs. After
completion of reaction, the reaction mixture was cooled to room temperature, filtered
to remove metal catalyst and the compound was extracted with toluene (2 x 1050
ml). Toluene was distilled out under vacuum to give the desired compound. Residual
mass was dissolved in dichloromethane and into this resulting solution, Methanolic
HCl (128 ml, Assay=7.7%, 1.25 eq) was added at 30±5 °C. The reaction mixture was
stirred for 40 °C for 15-30 minutes then, Dichloromethane and methanol was distilled
out under vacuum at 55 °C. Cyclohexane was added into resulting solid mass and
stirred it for 1 hr at 30±5 °C. Resulting mixture was filtered and then solid mass was
dissolved in acetone at reflux temperature for 1 hr then reaction mixture was cooled
to 30±5 °C. Resulting reaction mixture was filtered and it was dissolved in
dichloromethane, into this solution 10% NaOH solution was added (pH >10). Organic
layer was separated out and was distilled out to collect 2-[(2,4-
dimethylphenyl)sulfanyl]aniline.
Example-3: Preparation of Vortioxetine adipate.
2-[(2,4-dimethylphenyl)sulfanyl]aniline (20 g), o-Xylene (60 ml), Bis(2-
chloroethyl)amine hydrochloride (15.59 g) and PTSA (0.5 g) was added into round
bottom flask. The reaction mixture was heated at 140±7 °C. Reaction mixture was
stirred for 30 hr at reflux temperature. Reaction mixture was cooled to 30±5 °C and
then, o-Xylene (200 ml) and water (160 ml) was added to the reaction mixture at
30±5 °C. Resulting reaction mixture was basified with 10% NaOH (pH > 7.0) at 30±5
°C. Organic layer was separated out and into resulting organic layer, adipic acid
solution (12.8 g) in Acetone (306 ml) was added at 40 °C. Resulting reaction mixture
was stirred for 2 hr at 30±5 °C. Reaction mixture was filtered and solid mass was
washed with acetone (20 ml) and dried it under vacuum for 6-8 hrs at 55±5 °C.
Resulting crude Vortioxetine adipate salt was added in THF (500 ml) at 30±5 °C.
Resulting reaction mixture was heated to reflux temperature for 5-10 mins. Resulting
reaction mixture was cooled to 30±5 °C and stirred it for 1 hr at 30±5 °C and pure
Vortioxetine adipate salt was collected by filtration.
Example-4: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine malonate.
Vortioxetine adipate (5 gm) and water (25 ml) were added into round bottom
flask at 30±5 °C. Into this reaction mixture, ethyl acetate (10 ml) was added at 30±5
°C. Resulting reaction mixture was basified using 10% NaOH solution (pH>7.0) (7.5
ml) at 30±5 °C and was stirred it for 10 min. Organic layer was separated and it was
heated up to reflux temperature. Malonic acid solution (malonic acid solution is
prepared by dissolving 1.13 g malonic acid into Ethyl acetate (14 ml) at reflux
temperature) was added into this organic layer and reaction mixture was stirred for
15-30 mins at reflux temperature. Reaction mixture was cooled to 30±5 °C. Reaction
mixture was filtered to get solid mass and was dried under vacuum for 6-8 hrs at
55±5 °C.
Example-5: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine pyruvate.
Vortioxetine adipate (5 gm) and water (25 ml) were added into round bottom
flask at 30±5 °C. Into this reaction mixture, ethyl acetate (10 ml) was added at 30±5
°C. Resulting reaction mixture was basified using 10% NaOH solution (pH>7.0) (7.5
ml) at 30±5 °C and was stirred it for 10 min. Organic layer was separated and it was
heated up to reflux temperature. Pyruvic acid solution (pyruvic acid solution is
prepared by dissolving 0.96 g pyruvic acid into Ethyl acetate (5.5 ml) at reflux
temperature) was added into this organic layer and reaction mixture was stirred for
15-30 mins at reflux temperature. Reaction mixture was cooled to 30±5 °C. Reaction
mixture was filtered to get solid mass and was dried under vacuum for 6-8 hr at 55±5
°C.
Example-6: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine glutarate.
Vortioxetine adipate (5 gm) and water (25 ml) were added into round bottom
flask at 30±5 °C. Into this reaction mixture, ethyl acetate (10 ml) was added at 30±5
°C. Resulting reaction mixture was basified using 10% NaOH solution (pH>7.0) (7.5
ml) at 30±5 °C and was stirred it for 10 min. Organic layer was separated and it was
heated up to reflux temperature. Glutaric acid solution (glutaric acid solution is
prepared by dissolving 1.29 g glutaric acid into Ethyl acetate (60 ml) at reflux
temperature) was added into this organic layer and reaction mixture was stirred for
15-30 mins at reflux temperature. Reaction mixture was cooled to 30±5 °C. Reaction
mixture was filtered to get solid mass and was dried under vacuum for 6-8 hrs at
55±5 °C.
Example-7: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine hydrobromide form-B.
Vortioxetine adipate (30.0 g) and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and
distilled out from reaction mixture to remove water azeotropically to get clear
solution. Dichloromethane (300 ml) was added into above clear solution and stirred it
for 10 min. Dry HBr was purged into the resulting reaction mixture for 1 hr. After
completion of reaction dichloromethane was distilled out and dried under vacuum for
6 hr at 40 °C to get Vortioxetine hydrobromide Form-B.
Example-8: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine hydrobromide diethylether solvate.
Vortioxetine adipate (30.0 g) and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and into
this organic layer, aqueous HBr (12.0 g) was added and stirred it for 30 min. Organic
layer was separated out and distilled out from reaction mixture to remove water
azeotropically to get clear solution. Dichloromethane (300 ml) was added into above
clear solution. Reaction mixture was stirred for 10 min. Resulting reaction mixture
was added into cooled diethyl ether (1500 ml) solvent at -65 to -70 °C and was
stirred it for 30 min. Reaction mixture was distilled out to get solid mass and dried it
at 40 °C under vacuum for 6 hour to get Vortioxetine hydrobromide diethyl ether
solvate.
Example-9: Preparation of amorphous form of Vortioxetine Hydrobromide.
Vortioxetine adipate (30.0 g).and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out. Aqueous
HBr (11.48 g) was added into the organic layer and stirred it for 30 min. Organic
layer was separated out and distilled out dichloromethane to remove water
azeotropically; Dichloromethane (300 ml) was added into above clear solution and
was stirred it for 10 min. The reaction mixture was filtered through hyflo at 30±5 °C
and spray dried to get amorphous Vortioxetine hydrobromide. Solid was dried at
40°C for 6 hours.
Condition of spray drying
Feeding rate of solution: 6 rpm to 10 rpm.
Nitrogen/Air pressure: 3 kg to 5 kg
Temperature of spray gun inlet: 55 to 60 °C
Vacuum of spray dryer: 50-90 mmHg
Humidity of working area: less than 40 % RH
Example-10a: Preparation of an amorphous co-precipitate of Vortioxetine
hydrobromide with copovidone.
Vortioxetine adipate (30.0 g).and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out. Aqueous
HBr (11.48 g) was added into organic layer and stirred it for 30 min. After completion
of reaction dichlormethane was distilled out to remove water azeotropically;
Dichloromethane (300 ml) and copovidone (12.8 g) were added into it and stirred it
for 10 min. The reaction mixture was filtered through hyflo at 30±5 °C and spray
dried to get an amorphous co-precipitate Vortioxetine hydrobromide with
copovidone. The resulting solid was dried at 60°C under vacuum for 6 hours.
Condition of spray drying
Feeding rate of solution: 6 rpm to 10 rpm.
Nitrogen/Air pressure: 3 kg to 5 kg
Temperature of spray gun inlet: 55 to 60 °C
Vacuum of spray dryer: 50-90 mmHg
Humidity of working area: less than 40 % RH
Example-10b: Preparation of an amorphous co-precipitate of Vortioxetine
hydrobromide with copovidone.
Vortioxetine adipate (30.0 g).and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and was
distilled out to remove water azeotropically; Dichloromethane (250) and HBr in acetic
acid (16.83 g) were added into resulting clear solution and stirred it for 10 min.
Copovidone (12.8 g) was added into it and stirred it for 10 min. The reaction mixture
was filtered through hyflo at 30±5 °C and spray dried to get an amorphous coprecipitate
of vortioxetine hydrobromide with copovidone. The resulting solid was
dried at 60°C under vacuum for 6 hours.
Condition of spray drying
Feeding rate of solution: 6 rpm to 10 rpm.
Nitrogen/Air pressure: 3 kg to 5 kg
Temperature of spray gun inlet: 55 to 60° C
Vacuum of spray dryer: 50-90 mmHg
Humidity of working area: less than 40 % RH
Example-11: Preparation of an amorphous co-precipitate of Vortioxetine
hydrobromide with starch.
Vortioxetine hydrobromide (1.0g) and starch (1.0g) was dissolved in 250 ml
water at 65-70 °C in lyophiliser glass chamber. Suddenly cool the reaction mass to -
70 to -78 °C for thin layer preparation. Evaporate the water from reaction mass in
lyophiliser till completely water removed from reaction mass. Drying of solid gives an
amorphous co-precipitate of Vortioxetine hydrobromide (1.7 g).
Example-12: Preparation of an amorphous co-precipitate of Vortioxetine
hydrobromide with Maize starch.
Vortioxetine hydrobromide (1.0g) and maize starch (1.0g) was dissolved in
250 ml water at 65-70 °C in lyophiliser glass chamber. Suddenly cool the reaction
mass to -70 to -78 °C for thin layer preparation. Evaporate the water from reaction
mass in lyophiliser till completely water removed from reaction mass. Drying of solid
gives an amorphous co-precipitate of Vortioxetine hydrobromide (1.6 g).
Example 13: Preparation of an amorphous co-precipitate of Vortioxetine
Hydrobromide with PVP K-90.
Vortioxetine adipate (30.0 g).and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and was
distilled out to remove water azeotropically; Dichloromethane (250) and HBr in acetic
acid (16.83 g) were added into resulting clear solution and stirred it for 10 min. PVP
K-90 (12.8 g) was added into it and stirred it for 10 min. The reaction mixture was
filtered through hyflo at 30±5 °C and spray dried to get an amorphous co-precipitate
of Vortioxetine hydrobromide with PVP K-90. The resulting solid was dried at 60°C
under vacuum for 6 hours.
Condition of spray drying
Feeding rate of solution: 6 rpm to 10 rpm.
Nitrogen/Air pressure: 3 kg to 5 kg
Temperature of spray gun inlet: 55 to 60 °C
Vacuum of spray dryer: 50-90 mmHg
Humidity of working area: less than 40 %RH
Example 14: Preparation of an amorphous co-precipitate of Vortioxetine
Hydrobromide with SOLUPLUS.
Vortioxetine adipate (30.0 g).and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and was
distilled out to remove water azeotropically; Dichloromethane (250) and HBr in acetic
acid (16.83 g) were added into resulting clear solution and stirred it for 10 min.
SOLUPLUS (12.8 g) was added into it and stirred it for 10 min. The reaction mixture
was filtered through hyflo at 30±5 °C and spray dried to get an amorphous coprecipitate
of vortioxetine hydrobromide with SOLUPLUS. The resulting solid was
dried at 60°C under vacuum for 6 hours.
Condition of spray drying:
Feeding rate of solution: 6 rpm to 10 rpm.
Nitrogen/Air pressure: 3 kg to 5 kg
Temperature of spray gun inlet: 55 to 60 °C
Vacuum of spray dryer: 50-90 mmHg
Humidity of working area: less than 40 % RH
Example-15a: Preparation of Vortioxetine hydrobromide benzyl alcohol
solvate.
Vortioxetine adipate (30.0 g) and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and into
this organic layer, aqueous HBr (9.8 g) was added and stirred it for 30 min.
Dichloromethane was distilled out to remove water azeotropically; dichloromethane
(90 ml) and benzyl alcohol (40 ml) were added into it. Reaction mixture was stirred
for 10 min. Dichloromethane was distilled out to get solid mass. Cyclohexane
(150ml) was added into solid residue and stirred it for 1 hour. Resulting mixture was
filtered to get solid mass and dried it at 60 °C under vacuum for 6 hour to get
Vortioxetine hydrobromide benzyl alcohol solvate.
Example-15b: Preparation of Vortioxetine hydrobromide benzyl alcohol
solvate.
Vortioxetine adipate (30.0 g) and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and
distilled out to remove water azeotropically; Acetic acid (100 ml) was added into
above clear solution. Dichloromethane was distilled out from resulting reaction
mixture and HBr in acetic acid (15.2 g) was added into resulting reaction mixture.
Benzyl alcohol (40 ml) was added into reaction mixture and stirred it for 10 min.
Acetic acid was distilled out from reaction mixture and cyclohexane (150 ml) was
added into resulting reaction residue and stirred it for 1 hr. Reaction mixture was
filtered and solid was dried under vacuum at 60 °C for 8 hr to get solid vortioxetine
hydrobromide benzyl alcohol solvate.
Example-15c: Preparation of Vortioxetine hydrobromide benzyl alcohol
solvate.
Prepared a solution of 10g of Vortioxetine hydrobromide in 10ml of benzyl
alcohol and allowed to crystallise at room temperature. Stirred the slurry with 20ml
hexane and then filtered the solid.
Example-16a: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine hydrobromide Form A.
Vortioxetine adipate (30.0 g) and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and into
this organic layer, aqueous HBr (11.5 g) was added and stirred it for 30 min.
Dichloromethane was distilled out to remove water azeotropically. Acetic acid (200
ml) and water (50 ml) were added into this clear solution and resulting mixture of this
was added into round bottom flask containing water (1250 ml) at 7±3 °C. Resulting
reaction mixture was stirred for 30 minutes at 20±2°C and reaction mixture was
filtered and residual solid was washed with water (50 ml). Solid was dried under
vacuum for 6-8 hrs at 45±3°C to get Vortioxetine hydrobromide Form A.
Example-16b: Preparation of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-
piperazine hydrobromide Form A.
Vortioxetine adipate (30.0 g) and dichloromethane (450 ml) were charged in
round bottom flask. The reaction mixture was stirred for 5 min then it was basified
with NaOH solution (8.1 g in 300 ml water). Solution of NaCl (7.5 g in 75 ml water)
was added into above reaction mixture. Organic layer was separated out and into
this organic layer; HBr in acetic acid (18 g) was added to above organic layer and
stirred for 30 min. Dichloromethane was distilled out atmospherically from reaction
mixture. Acetic acid (200 ml) and water (50 ml) were added into this reaction mixture
and resulting mixture of this was added into round bottom flask containing water
(1250 ml) at 7±3 °C. Resulting reaction mixture was stirred for 30 minutes at 20±2°C
and reaction mixture was filtered and residual solid was washed with water (50 ml).
Solid was dried under vacuum for 6-8 hrs at 45±3°C to get Vortioxetine
hydrobromide Form A. ,CLAIMS:1. A crystalline form-A of Vortioxetine hydrobromide.
2. A crystalline form-A of Vortioxetine hydrobromide having an X-ray powder
diffractogram comprising at least one peak at diffraction 2-theta angle
selected from 11.35 ± 0.2°, 15.30 ± 0.2° and 19.80 ± 0.2°.
3. The crystalline form-A of claim 1, having an X-ray powder diffraction
pattern with characteristics peaks at 11.35 ± 0.2°, 15.30 ± 0.2°, 18.67 ±
0.2° and 19.80 ± 0.2°.
4. A crystalline Vortioxetine hydrobromide according to claim 1, having
XPRD pattern as shown in figure 1.
5. A process for preparation of crystalline form-A of Vortioxetine
hydrobromide comprising the steps of;
a) providing the solution of Vortioxetine hydrobromide in suitable solvent;
b) contacting the solution of step(a) with water; and
c) isolating crystalline form-A of Vortioxetine hydrobromide.
6. The process according to claim 5, wherein suitable solvent is selected
from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl
alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol,
acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone,
methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl
acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene
dichloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether,
diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-
dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,Ndimethylacetamide,
N-methylpyrrolidone, pyridine, dimethylsulfoxide,
sulfolane, formamide, acetamide, propanamide, pyridine, formic acid,
acetic acid, propionic acid or mixtures thereof.
7. A crystalline form-B of Vortioxetine hydrobromide.
8. The crystalline compound of claim 7, characterized in that the molar ratio
of Vortioxetine and the Hydrobromic acid is in the range of from 1:0.5 to
1:1.2, and preferably is approximately 1:0.6.
9. A crystalline form-B of Vortioxetine hydrobromide according to claim 7,
having an X-ray powder diffractogram comprising peaks at 2-theta angles
of 8.42 ± 0.2°, 12.20 ± 0.2°, 14.20 ± 0.2°, and 14.91 ± 0.2°.
10.The crystalline form-B of Vortioxetine hydrobromide according to claim 7,
having XPRD pattern as shown in figure 6.
11.A process for preparation of crystalline form-B of Vortioxetine
hydrobromide comprising the steps of:
a) passing dry Hydrobromic acid gas in to the solution of Vortioxetine
base in the suitable solvent; and
b) isolating the crystalline form-B of Vortioxetine hydrobromide.
12.The process according to claim 11, wherein suitable solvent is selected
from acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone,
methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl
acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, cyclohexane,
methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile,
diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether,
tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide,
sulfolane, formamide, acetamide, propanamide, pyridine, formic acid,
acetic acid, propionic acid, hexane, cyclohexane, pentane or mixtures
thereof
13.A Crystalline Vortioxetine hydrobromide benzyl alcohol solvate.
14.A crystalline form-C of Vortioxetine hydrobromide benzyl alcohol solvate.
15.The crystalline benzyl alcohol solvate of Vortioxetine hydrobromide of
claim 13, wherein the molar ratio of Vortioxetine hydrobromide to benzyl
alcohol is approximately 1:0.5.
16.The crystalline form of Vortioxetine hydrobromide benzyl alcohol solvate
according to claim 14, having an X-ray powder diffractogram comprising
peaks at 2-theta angles of 8.85 ± 0.2°, 11.84 ± 0.2°, 14.22 ± 0.2°, 14.75 ±
0.2° and 15.00 ± 0.2°.
17.The crystalline Vortioxetine hydrobromide benzyl alcohol solvate
according to claim 14, having XPRD pattern as shown in figure 8.
18.A process for preparation of crystalline Vortioxetine hydrobromide benzyl
alcohol solvate comprising the step of;
a) contacting Vortioxetine hydrobromide with benzyl alcohol;
b) crystallizing the benzyl alcohol solvate of Vortioxetine hydrobromide;
c) optionally treating with suitable solvent; and
d) isolating the solvate.
19.The process according to claim 18, wherein suitable solvent is selected
from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl
alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol,
acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone,
methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl
acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene
dichloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether,
diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-
dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,Ndimethylacetamide,
N-methylpyrrolidone, pyridine, dimethylsulfoxide,
sulfolane, formamide, acetamide, propanamide, pyridine, formic acid,
acetic acid, propionic acid or mixtures thereof.
20.A process for purification of Vortioxetine comprising;
a) treating of the Vortioxetine base with a suitable acid;
b) isolating the acid addition salt of Vortioxetine;
c) treating acid addition salt of Vortioxetine with a suitable base to provide
highly pure Vortioxetine.
21.The process according to claim 20, wherein the suitable acid is selected
from organic acids like acetic acid, citric acid, para toluene sulfonic acid,
malic acid, succinic acid, adipic acid, pyruvic acid, malonic acid, glutaric
acid, trifluoroacetic acid, camphoric acid, napthalene sulfonic acid,
isethionic acid, camphor sulfonic acid.
22.The process according to claim 20, wherein the suitable base is selected
from hydroxides, carbonates of alkali metals and ammonia.
23.Crystalline Vortioxetine adipate.
24.A crystalline form of Vortioxetine adipate according to claim 23, having an
X-ray powder diffractogram comprising peaks at 2-theta angles of 7.62 ±
0.2°, 12.08 ± 0.2°, 13.35 ± 0.2°, 13.93 ± 0.2° and 14.61 ± 0.2°.
25.The crystalline Vortioxetine adipate according to claim 23, having XPRD
pattern as shown in figure 12.
26.A process for preparation of Vortioxetine adipate comprising the step of
treatment of Vortioxetine with adipic acid.