CA2550252A1 - Novel process for the preparation of crystalline venlafaxine hydrochloride - Google Patents
Novel process for the preparation of crystalline venlafaxine hydrochloride Download PDFInfo
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Abstract
The claimed invention provides a novel methods of preparing Venlafaxine hydrochloride Form B. The process comprises the steps of dissolving any form of Venlafaxine hydrochloride either in water or in mixture of water and suitable solvent, azeotropically removing the water from said solution. It also comprises the steps of suspending any form of Venlafaxine Hydrochloride in suitable solvent, seeding Venlafaxine Hydrochloride Form B to said suspension and isolating crystalline Venlafaxine hydrochloride Form B.
Description
NOVEL PROCESS FOR THE PREPARATION OF
CRYSTALLINE VENLAFAXINE HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of crystalline Venlafaxine Hydrochloride Form B. Venlafaxine hydrochloride is chemically known as (t)-1-[2-(Dimethylamino)-1-(4-methyoxyphenyl) ethyl] cyclohexanol hydrochloride of formula (I) and useful for treatment of depression.
N~.HCI
~CH3 OH
HgCO
( BACKGROUND AND PRIOR ART
Venlafaxine selectively inhibits the neuronal uptake of serotonin norepinephrine and to a lesser extent dopamine. Studies indicate that it has comparable or possibly slightly greater efficacy to other selective serotonin reuptake inhibitors (SSRI's). It appears to be as effective as standard antidepressants such as imipramine. Venlafaxine's unique chemical structure and neuro-pharmacological activity give it a broader spectrum of activity than other antidepressants.
Venlafaxine hydrochloride is the first of a class of anti-depressants and marketed as brand name "Effexor". It was first disclosed in EP 0112669. The process for the preparation of Venlafaxine hydrochloride is known in the literature.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes in solid state. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties.
Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures and/or X-Ray diffraction pattern. Polymorphs of a compound can be characterized by X-Ray diffraction pattern, Infrared Spectrum, DSC etc.
Acta Cryst. (2002). E58, 01072-01074 published an article by A.
Sivalakshmidevi et al., which teaches that Venlafaxine hydrochloride, [(~)-N,N-dimethyl-2-(1-hydroxycyclohex-1-yl)-2-(4-methoxyphenyl) ethylamine hydrochloride, C"H28CIN02] is found to crystallize in both orthorhombic and monoclinic crystal systems. The molecular structures in the two polymorphs differ in the conformations of the substituents at the ethylamine group. In the monoclinic crystal structure, the molecules translated along the a axis are linked by CI- ions through O-H.. .CI and N-H~ . ~CI hydrogen bonds to form infinite one-dimensional chains.
It has been reported that Venlafaxine hydrochloride exists in different crystalline polymorphic forms. WO 02/36542 A1 describes four different crystalline polymorphic forms of Venlafaxine hydrochloride designated as Form A, Form B, Form C and Form D. All the different crystalline forms of Venlafaxine are characterized by XRD pattern, IR analysis and DSC.
Also, it discloses the process for the preparation of all the crystalline polymorphic forms of Venlafaxine hydrochloride.
CRYSTALLINE VENLAFAXINE HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of crystalline Venlafaxine Hydrochloride Form B. Venlafaxine hydrochloride is chemically known as (t)-1-[2-(Dimethylamino)-1-(4-methyoxyphenyl) ethyl] cyclohexanol hydrochloride of formula (I) and useful for treatment of depression.
N~.HCI
~CH3 OH
HgCO
( BACKGROUND AND PRIOR ART
Venlafaxine selectively inhibits the neuronal uptake of serotonin norepinephrine and to a lesser extent dopamine. Studies indicate that it has comparable or possibly slightly greater efficacy to other selective serotonin reuptake inhibitors (SSRI's). It appears to be as effective as standard antidepressants such as imipramine. Venlafaxine's unique chemical structure and neuro-pharmacological activity give it a broader spectrum of activity than other antidepressants.
Venlafaxine hydrochloride is the first of a class of anti-depressants and marketed as brand name "Effexor". It was first disclosed in EP 0112669. The process for the preparation of Venlafaxine hydrochloride is known in the literature.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes in solid state. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties.
Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures and/or X-Ray diffraction pattern. Polymorphs of a compound can be characterized by X-Ray diffraction pattern, Infrared Spectrum, DSC etc.
Acta Cryst. (2002). E58, 01072-01074 published an article by A.
Sivalakshmidevi et al., which teaches that Venlafaxine hydrochloride, [(~)-N,N-dimethyl-2-(1-hydroxycyclohex-1-yl)-2-(4-methoxyphenyl) ethylamine hydrochloride, C"H28CIN02] is found to crystallize in both orthorhombic and monoclinic crystal systems. The molecular structures in the two polymorphs differ in the conformations of the substituents at the ethylamine group. In the monoclinic crystal structure, the molecules translated along the a axis are linked by CI- ions through O-H.. .CI and N-H~ . ~CI hydrogen bonds to form infinite one-dimensional chains.
It has been reported that Venlafaxine hydrochloride exists in different crystalline polymorphic forms. WO 02/36542 A1 describes four different crystalline polymorphic forms of Venlafaxine hydrochloride designated as Form A, Form B, Form C and Form D. All the different crystalline forms of Venlafaxine are characterized by XRD pattern, IR analysis and DSC.
Also, it discloses the process for the preparation of all the crystalline polymorphic forms of Venlafaxine hydrochloride.
2 A1 discloses that the crystalline Venlafaxine hydrochloride prepared by following EP 0112669 having a melting point between 215 and 217°C which is designated as Form C.
WO 02/36542 A1 also discloses that the Form B is thermodynamically more stable than other crystalline forms of Venlafaxine hydrochloride.
Acta. Cryst. (2000), C56, 1009-1010 (D. Vega et. al.) describes the crystallographic study of Venlafaxine hydrochloride.
WO 02/46140 A1 and WO 02/45658 A2 discloses the different crystalline form of Venlafaxine hydrochloride. It is observed that the crystal structure of Venlafaxine hydrochloride disclosed in Acta. Cryst. (2000), C56, 1009-1010, Form I disclosed in WO 02/46140 A1 and Form I disclosed in WO 02/45658 A2 are identical to the crystalline Venlafaxine hydrochloride Form B as designated in WO 02/36542 A1.
The Form B of Venlafaxine hydrochloride is prepared by equilibrating the slurry of Form C of Venlafaxine hydrochloride in isopropanol for around 72 hrs. However, this process requires more time, utility, manpower and results in higher cost of production.
The above patent also discloses another process for the preparation of crystalline Venlafaxine hydrochloride Form B by dissolving Venlafaxine hydrochloride in isopropanol at reflux temperature followed by addition of seeding crystal and cooling it to give desired crystalline form of Venlafaxine hydrochloride.
However, there is a need to have simple, easy to handle and cost efFective improved process for the preparation of Crystalline Venlafaxine hydrochloride Form B
commercially.
OBJECTS OF INVENTION
Thus one object of the present invention is to provide a process for the preparation of crystalline Venlafaxine hydrochloride Form B.
Another object of the present invention is to provide a process for the preparation of crystalline Venlafaxine hydrochloride Farm B, which is simple and easy to handle at production and cost effective.
Further object of the present invention is to characterize Venlafaxine hydrochloride Form B
using XRD, DSC and IR.
SUMMARY OF INVENTION
According to one aspect of the present invention there is provided an improved process for preparation of crystalline Venlafaxine hydrochloride Form B, said process comprising:
(i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution ;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride;
(iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B.
According to one aspect of the present invention there is provided an improved process for preparation of crystalline Venlafaxine hydrochloride Form B, said process comprising (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride;
(iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B.
According to another aspect of the present invention, there is provided an improved process of the preparation of Venlafaxine hydrochloride Form B, said process comprising (i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution ;
(ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
(iii) adding seeding crystals of Venlafaxine hydrochloride Form B;
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B.
According to another aspect of the present invention, there is provided an improved process of the preparation of Venlafaxine hydrochloride Form B, said process comprising (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to the said solution;
(ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
(iii) adding seeding crystals of Venlafaxine hydrochloride Form B;
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B.
According to another aspect of the present invention, there is provided an improved process for the preparation of Venlafaxine hydrochloride Form B, said process comprising (i) suspending Venlafaxine hydrochloride in suitable solvent (ii) adding seeding crystals of Venlafaxine hydrochloride Form B
(iii) stirring the suspension (iv) isolating crystalline Venlafaxine hydrochloride Form B
DETAILED DESCRIPTION OF INVENTION
The term 'Venlafaxine hydrochloride' as used herein is meant to include Venlafaxine hydrochloride in any form, or hydrate, clathrate, solvate or their mixtures and in any state of purity, unless specifically mentioned.
The term 'suitable solvent' used herein is meant to include solvent which form azeotrope with water such as toluene, xylene, methyl isobutyl ketone, n-butanol and the like or mixtures thereof. The preferable suitable solvent is toluene.
WO 02/36542 A1 also discloses that the Form B is thermodynamically more stable than other crystalline forms of Venlafaxine hydrochloride.
Acta. Cryst. (2000), C56, 1009-1010 (D. Vega et. al.) describes the crystallographic study of Venlafaxine hydrochloride.
WO 02/46140 A1 and WO 02/45658 A2 discloses the different crystalline form of Venlafaxine hydrochloride. It is observed that the crystal structure of Venlafaxine hydrochloride disclosed in Acta. Cryst. (2000), C56, 1009-1010, Form I disclosed in WO 02/46140 A1 and Form I disclosed in WO 02/45658 A2 are identical to the crystalline Venlafaxine hydrochloride Form B as designated in WO 02/36542 A1.
The Form B of Venlafaxine hydrochloride is prepared by equilibrating the slurry of Form C of Venlafaxine hydrochloride in isopropanol for around 72 hrs. However, this process requires more time, utility, manpower and results in higher cost of production.
The above patent also discloses another process for the preparation of crystalline Venlafaxine hydrochloride Form B by dissolving Venlafaxine hydrochloride in isopropanol at reflux temperature followed by addition of seeding crystal and cooling it to give desired crystalline form of Venlafaxine hydrochloride.
However, there is a need to have simple, easy to handle and cost efFective improved process for the preparation of Crystalline Venlafaxine hydrochloride Form B
commercially.
OBJECTS OF INVENTION
Thus one object of the present invention is to provide a process for the preparation of crystalline Venlafaxine hydrochloride Form B.
Another object of the present invention is to provide a process for the preparation of crystalline Venlafaxine hydrochloride Farm B, which is simple and easy to handle at production and cost effective.
Further object of the present invention is to characterize Venlafaxine hydrochloride Form B
using XRD, DSC and IR.
SUMMARY OF INVENTION
According to one aspect of the present invention there is provided an improved process for preparation of crystalline Venlafaxine hydrochloride Form B, said process comprising:
(i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution ;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride;
(iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B.
According to one aspect of the present invention there is provided an improved process for preparation of crystalline Venlafaxine hydrochloride Form B, said process comprising (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride;
(iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B.
According to another aspect of the present invention, there is provided an improved process of the preparation of Venlafaxine hydrochloride Form B, said process comprising (i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution ;
(ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
(iii) adding seeding crystals of Venlafaxine hydrochloride Form B;
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B.
According to another aspect of the present invention, there is provided an improved process of the preparation of Venlafaxine hydrochloride Form B, said process comprising (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to the said solution;
(ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
(iii) adding seeding crystals of Venlafaxine hydrochloride Form B;
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B.
According to another aspect of the present invention, there is provided an improved process for the preparation of Venlafaxine hydrochloride Form B, said process comprising (i) suspending Venlafaxine hydrochloride in suitable solvent (ii) adding seeding crystals of Venlafaxine hydrochloride Form B
(iii) stirring the suspension (iv) isolating crystalline Venlafaxine hydrochloride Form B
DETAILED DESCRIPTION OF INVENTION
The term 'Venlafaxine hydrochloride' as used herein is meant to include Venlafaxine hydrochloride in any form, or hydrate, clathrate, solvate or their mixtures and in any state of purity, unless specifically mentioned.
The term 'suitable solvent' used herein is meant to include solvent which form azeotrope with water such as toluene, xylene, methyl isobutyl ketone, n-butanol and the like or mixtures thereof. The preferable suitable solvent is toluene.
In the present invention, the process for the preparation of crystalline Venlafaxine hydrochloride Form B, characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8 and 22.710.2 degree two-theta comprises (i) dissolving Venlafaxine hydrochloride in a mixture of water and suitable solvent to form solution ;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride (iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B
In the present invention, the process for the preparation of crystalline Venlafaxine hydrochloride Form B, characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8 and 22.710.2 degree two-theta comprises (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride;
(iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B
Venlafaxine hydrochloride is dissolved in mixture of water and toluene at about 20° C to about 35°C under stirring to obtain a solution. The solution is optionally charcoalized and filtered.
Water is removed from said solution by azeotropic distillation using dean stark condenser at about 90 °C to about 105°C. When water is almost distilled off from the solution, Venlafaxine hydrochloride crystallized out. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then cooled to room temperature from about 20 °C to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
Alternatively, Venlafaxine hydrochloride is dissolved in water at about 20°C to about 35° C under stirring to obtain a solution. The solution is optionally charcoalized and filtered. Toluene is added to the said solution followed by azeotropic distillation of water from the solution by dean stark condenser at about 90 to about 105° C. When water is almost distilled off from the solution, Venlafaxine hydrochloride crystallized out. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and cooled to room temperature from about 20 to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
Another aspect of the invention is to provided the new process of preparing Venlafaxine hydrochloride Form B characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8, 22.710.2 degree two-theta, which comprises (i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution ;
(ii) removing about 70% to about 95% of water from said solution by azeotropic distillation (iii) adding seeding crystals of Venlafaxine hydrochloride Form B
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B
Another aspect of the invention is to provided the new process of preparing Venlafaxine hydrochloride Form B characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8, 22.710.2 degree two-theta, which comprises (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
(ii) removing about 70% to about 95% of water from said solution by azeotropic distillation;
(iii) adding seeding crystals of Venlafaxine hydrochloride Form B;
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B.
Venlafaxine hydrochloride is dissolved in mixture of water and toluene at about 20°C to about 35° C under stirring to obtain a solution. The solution is optionally charcoalized and filtered.
About 70 to about 95%, more preferably about 90 to about 95% of water is removed from the said solution by azeotropic distillation using dean stark condenser at about 90°C to about 105°C. Venlafaxine hydrochloride Form B seeding crystals are added to the said solution.
Then, remaining water is almost distilled off from the slurry. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then cooled to room temperature from about 20°C to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
Alternatively Venlafaxine hydrochloride is dissolved in water at about 20°C to about 35°C under stirring to obtain a solution. The solution is optionally charcoalized and filtered. Toluene is added to the said solution followed by azeotropic distillation of water from the solution by dean stark condenser at about 90 to about 105°C. Venlafaxine hydrochloride Form B
seeding crystals are added to the said solution to initiate crystallization. The remaining water is almost distilled off form the solution. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then cooled to room temperature from about 20 to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
In the present invention there is provided yet another process for the preparation of Venlafaxine hydrochloride Form B characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8 and 22.710.2 degree two-theta, which comprises (i) suspending Venlafaxine hydrochloride in suitable solvent (ii) adding seeding crystals of Venlafaxine hydrochloride Form B
(iii) stirring the suspension (iv) isolating crystalline Venlafaxine hydrochloride Form B
Venlafaxine hydrochloride is suspended in toluene at about 20°C to about 35°C. Venlafaxine hydrochloride Form B seeding crystals are added to the suspension. The suspension is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then it is cooled to room temperature from about 20°C to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
The volume of suitable solvent used can be up to 10-30 times the amount of Venlafaxine Hydrochloride used.
Crystalline Venlafaxine hydrochloride Form B is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
The wet cake of crystalline Venlafaxine hydrochloride Form B may be washed with toluene and other conventional solvent.
Crystalline Venlafaxine hydrochloride Form B obtained by the present invention is characterized by its XRD pattern, IR spectra and DSC.
The process of the present invention is described by the following examples, which are illustrative only and should ,not be construed so as to limit the scope of the invention in any manner.
Venlafaxine hydrochloride used in the examples is prepared according to methods reported in the literature and prior art.
BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Figure 1 represents the powder X-ray diffraction (XRD) pattern of crystalline Venlafaxine hydrochloride Form B.
Figure 2 represents Infra Red (IR) spectra of crystalline Venlafaxine hydrochloride Form B.
Figure 3 represents Differential Scanning Calorimetric (DSC) thermogram of crystalline Venlafaxine hydrochloride Form B.
Example: 1 100gm Venlafaxine hydrochloride is dissolved in DM water (100 ml) at 20-35°C under stirring till the solid is completely dissolved. 1 gm activated charcoal is added to the solution under stirring and then the solution is filtered. 2000m1 of Toluene is added to filtrate and water is distilled out azeotropically using Dean-Stark condenser at 90-105°C. When the product starts to crystallizes out, the reflux is continued for 2-3 hours under stirring. Then the solution is cooled to 25-30°C
under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 85-95g.
Example: 2 100gm Venlafaxine hydrochloride is dissolved in DM water (100 ml) and toluene (2000 ml) at 20-35°C under stirring. 1 gm activated charcoal is added to the solution under stirring and then the solution is filtered. Water is distilled out azeotropically using Dean-Stark condenser at 90-105°C. When the product starts to crystallized out, the reflux is continued for 2-3 hours under stirring. Then the solution is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 85-95g Example: 3 100gm Venlafaxine hydrochloride is dissolved in DM water (100 ml) and toluene (2000 ml) at 20-35°C under stirring. 1gm activated charcoal is added to the solution under stirring and then the solution is filtered. About 90-95 ml of water is distilled out azeotropically using Dean-Stark condenser at 90-105°C. 5gm seeding crystals of Venlafaxine hydrochloride Form B is added to the solution and the distillation is continued till complete removal of water.
The reaction mass is stirred further for 2-3 hours at reflux temperature.
Then the solution is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 95-98g Example: 4 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C. 5gm seeding crystals of Venlafaxine hydrochloride Form B is added to the suspension and the suspension is heated to reflux at abut 110-115°C. The reaction mass is stirred further for 2-3 hours at reflux temperature. Then the slurry is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~
95-98g.
Example: 5 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C & is heated to reflux at about 110-115°C. The reaction mass is stirred further for about 5 to about 10 hours at reflux temperature. Then the slurry is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~
95-98g.
Example: 6 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C. 5gm seeding crystals of Venlafaxine hydrochloride Form B is added to the suspension and the suspension is stirred at ambient temperature for 24-30 hours. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 95-98g.
Example: 7 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C & stirred at ambient temperature for 70-80 hours. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 95-98g.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride (iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B
In the present invention, the process for the preparation of crystalline Venlafaxine hydrochloride Form B, characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8 and 22.710.2 degree two-theta comprises (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
(ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride;
(iii) stirring the suspension and cooling it; and (iv) isolating crystalline Venlafaxine hydrochloride Form B
Venlafaxine hydrochloride is dissolved in mixture of water and toluene at about 20° C to about 35°C under stirring to obtain a solution. The solution is optionally charcoalized and filtered.
Water is removed from said solution by azeotropic distillation using dean stark condenser at about 90 °C to about 105°C. When water is almost distilled off from the solution, Venlafaxine hydrochloride crystallized out. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then cooled to room temperature from about 20 °C to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
Alternatively, Venlafaxine hydrochloride is dissolved in water at about 20°C to about 35° C under stirring to obtain a solution. The solution is optionally charcoalized and filtered. Toluene is added to the said solution followed by azeotropic distillation of water from the solution by dean stark condenser at about 90 to about 105° C. When water is almost distilled off from the solution, Venlafaxine hydrochloride crystallized out. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and cooled to room temperature from about 20 to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
Another aspect of the invention is to provided the new process of preparing Venlafaxine hydrochloride Form B characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8, 22.710.2 degree two-theta, which comprises (i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution ;
(ii) removing about 70% to about 95% of water from said solution by azeotropic distillation (iii) adding seeding crystals of Venlafaxine hydrochloride Form B
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B
Another aspect of the invention is to provided the new process of preparing Venlafaxine hydrochloride Form B characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8, 22.710.2 degree two-theta, which comprises (i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
(ii) removing about 70% to about 95% of water from said solution by azeotropic distillation;
(iii) adding seeding crystals of Venlafaxine hydrochloride Form B;
(iv) azeotropically removing remaining water from said solution, stirring the suspension and cooling it; and (v) isolating crystalline Venlafaxine hydrochloride Form B.
Venlafaxine hydrochloride is dissolved in mixture of water and toluene at about 20°C to about 35° C under stirring to obtain a solution. The solution is optionally charcoalized and filtered.
About 70 to about 95%, more preferably about 90 to about 95% of water is removed from the said solution by azeotropic distillation using dean stark condenser at about 90°C to about 105°C. Venlafaxine hydrochloride Form B seeding crystals are added to the said solution.
Then, remaining water is almost distilled off from the slurry. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then cooled to room temperature from about 20°C to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
Alternatively Venlafaxine hydrochloride is dissolved in water at about 20°C to about 35°C under stirring to obtain a solution. The solution is optionally charcoalized and filtered. Toluene is added to the said solution followed by azeotropic distillation of water from the solution by dean stark condenser at about 90 to about 105°C. Venlafaxine hydrochloride Form B
seeding crystals are added to the said solution to initiate crystallization. The remaining water is almost distilled off form the solution. The slurry is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then cooled to room temperature from about 20 to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
In the present invention there is provided yet another process for the preparation of Venlafaxine hydrochloride Form B characterized by powder X-ray diffraction peaks at about 6.7, 10.3, 13.5, 15.4, 15.6, 18.3, 19.8, 20.3, 21.8 and 22.710.2 degree two-theta, which comprises (i) suspending Venlafaxine hydrochloride in suitable solvent (ii) adding seeding crystals of Venlafaxine hydrochloride Form B
(iii) stirring the suspension (iv) isolating crystalline Venlafaxine hydrochloride Form B
Venlafaxine hydrochloride is suspended in toluene at about 20°C to about 35°C. Venlafaxine hydrochloride Form B seeding crystals are added to the suspension. The suspension is stirred at about ambient temperature to about reflux temperature for about 1 hour to about 36 hours and then it is cooled to room temperature from about 20°C to about 35°C under stirring. It is further filtered, washed with suitable solvent and dried to obtain crystalline Venlafaxine hydrochloride Form B.
The volume of suitable solvent used can be up to 10-30 times the amount of Venlafaxine Hydrochloride used.
Crystalline Venlafaxine hydrochloride Form B is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
The wet cake of crystalline Venlafaxine hydrochloride Form B may be washed with toluene and other conventional solvent.
Crystalline Venlafaxine hydrochloride Form B obtained by the present invention is characterized by its XRD pattern, IR spectra and DSC.
The process of the present invention is described by the following examples, which are illustrative only and should ,not be construed so as to limit the scope of the invention in any manner.
Venlafaxine hydrochloride used in the examples is prepared according to methods reported in the literature and prior art.
BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Figure 1 represents the powder X-ray diffraction (XRD) pattern of crystalline Venlafaxine hydrochloride Form B.
Figure 2 represents Infra Red (IR) spectra of crystalline Venlafaxine hydrochloride Form B.
Figure 3 represents Differential Scanning Calorimetric (DSC) thermogram of crystalline Venlafaxine hydrochloride Form B.
Example: 1 100gm Venlafaxine hydrochloride is dissolved in DM water (100 ml) at 20-35°C under stirring till the solid is completely dissolved. 1 gm activated charcoal is added to the solution under stirring and then the solution is filtered. 2000m1 of Toluene is added to filtrate and water is distilled out azeotropically using Dean-Stark condenser at 90-105°C. When the product starts to crystallizes out, the reflux is continued for 2-3 hours under stirring. Then the solution is cooled to 25-30°C
under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 85-95g.
Example: 2 100gm Venlafaxine hydrochloride is dissolved in DM water (100 ml) and toluene (2000 ml) at 20-35°C under stirring. 1 gm activated charcoal is added to the solution under stirring and then the solution is filtered. Water is distilled out azeotropically using Dean-Stark condenser at 90-105°C. When the product starts to crystallized out, the reflux is continued for 2-3 hours under stirring. Then the solution is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 85-95g Example: 3 100gm Venlafaxine hydrochloride is dissolved in DM water (100 ml) and toluene (2000 ml) at 20-35°C under stirring. 1gm activated charcoal is added to the solution under stirring and then the solution is filtered. About 90-95 ml of water is distilled out azeotropically using Dean-Stark condenser at 90-105°C. 5gm seeding crystals of Venlafaxine hydrochloride Form B is added to the solution and the distillation is continued till complete removal of water.
The reaction mass is stirred further for 2-3 hours at reflux temperature.
Then the solution is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 95-98g Example: 4 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C. 5gm seeding crystals of Venlafaxine hydrochloride Form B is added to the suspension and the suspension is heated to reflux at abut 110-115°C. The reaction mass is stirred further for 2-3 hours at reflux temperature. Then the slurry is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~
95-98g.
Example: 5 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C & is heated to reflux at about 110-115°C. The reaction mass is stirred further for about 5 to about 10 hours at reflux temperature. Then the slurry is cooled to 25-30°C under stirring. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~
95-98g.
Example: 6 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C. 5gm seeding crystals of Venlafaxine hydrochloride Form B is added to the suspension and the suspension is stirred at ambient temperature for 24-30 hours. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 95-98g.
Example: 7 100gm Venlafaxine hydrochloride is suspended in 1000 ml toluene at 20-35°C & stirred at ambient temperature for 70-80 hours. The slurry is filtered at the same temperature and washed with toluene or other conventional solvent and dried at 60 to 65°C to obtain crystalline Venlafaxine hydrochloride Form B. Yield: ~ 95-98g.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims (7)
1. A process for preparing Venlafaxine hydrochloride Form B, comprising steps of:
i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution;
ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride B;
iii) stirring the suspension and cooling it; and iv) isolating crystalline Venlafaxine hydrochloride Form B.
i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution;
ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride B;
iii) stirring the suspension and cooling it; and iv) isolating crystalline Venlafaxine hydrochloride Form B.
2. A process for preparing Venlafaxine hydrochloride Form B, comprising steps of:
i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride B;
iii) stirring the suspension and cooling it; and iv) isolating crystalline Venlafaxine hydrochloride Form B.
i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to said solution;
ii) azeotropically removing water from said solution to crystallize Venlafaxine hydrochloride B;
iii) stirring the suspension and cooling it; and iv) isolating crystalline Venlafaxine hydrochloride Form B.
3. A process for preparing Venlafaxine hydrochloride Form B, comprising steps of:
i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution;
ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
iii) adding seeding crystals of Venlafaxine hydrochloride Form B
iv) azeotropically removing remaining water from said solution to crystallize Venlafaxine hydrochloride B;
v) stirring the suspension and cooling it; and vi) isolating crystalline Venlafaxine hydrochloride Form B.
i) dissolving Venlafaxine hydrochloride in mixture of water and suitable solvent to form solution;
ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
iii) adding seeding crystals of Venlafaxine hydrochloride Form B
iv) azeotropically removing remaining water from said solution to crystallize Venlafaxine hydrochloride B;
v) stirring the suspension and cooling it; and vi) isolating crystalline Venlafaxine hydrochloride Form B.
4. A process for preparing Venlafaxine hydrochloride Form B, comprising steps of:
i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to the said solution;
ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
iii) adding seeding crystals of Venlafaxine hydrochloride Form B
iv) azeotropically removing remaining water from said solution to crystallize Venlafaxine hydrochloride B;
v) stirring the suspension and cooling it; and vi) isolating crystalline Venlafaxine hydrochloride Form B.
i) dissolving Venlafaxine hydrochloride in water to form solution and then adding suitable solvent to the said solution;
ii) removing about 70 to about 95% of water from said solution by azeotropic distillation;
iii) adding seeding crystals of Venlafaxine hydrochloride Form B
iv) azeotropically removing remaining water from said solution to crystallize Venlafaxine hydrochloride B;
v) stirring the suspension and cooling it; and vi) isolating crystalline Venlafaxine hydrochloride Form B.
5. A process for preparing Venlafaxine hydrochloride Form B, comprising steps of:
i) suspending Venlafaxine hydrochloride in suitable solvent;
ii) adding seeding crystals of Venlafaxine hydrochloride Form B;
iii) stirring the suspension; and iv) isolating crystalline Venlafaxine hydrochloride Form B.
i) suspending Venlafaxine hydrochloride in suitable solvent;
ii) adding seeding crystals of Venlafaxine hydrochloride Form B;
iii) stirring the suspension; and iv) isolating crystalline Venlafaxine hydrochloride Form B.
6. The process according to any preceding claims, wherein the suitable solvents used is selected from the group comprising of toluene, xylene, methyl isobutyl ketone, n-butanol and the like or mixtures thereof.
7. The process according to any preceding claims, wherein the suitable solvent is toluene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN733MU2005 | 2005-06-22 | ||
| IN733/MUM/2005 | 2005-06-22 |
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| Publication Number | Publication Date |
|---|---|
| CA2550252A1 true CA2550252A1 (en) | 2006-12-22 |
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ID=39343605
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002550252A Abandoned CA2550252A1 (en) | 2005-06-22 | 2006-06-15 | Novel process for the preparation of crystalline venlafaxine hydrochloride |
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| Country | Link |
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| CA (1) | CA2550252A1 (en) |
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2006
- 2006-06-15 CA CA002550252A patent/CA2550252A1/en not_active Abandoned
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