WO2008035369A2 - Novel form of o-desmethyl venlafaxine - Google Patents
Novel form of o-desmethyl venlafaxine Download PDFInfo
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- WO2008035369A2 WO2008035369A2 PCT/IN2007/000266 IN2007000266W WO2008035369A2 WO 2008035369 A2 WO2008035369 A2 WO 2008035369A2 IN 2007000266 W IN2007000266 W IN 2007000266W WO 2008035369 A2 WO2008035369 A2 WO 2008035369A2
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- desmethyl venlafaxine
- venlafaxine
- desmethyl
- crystalline form
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to novel crystalline polymorphic form of O-desmethyl venlafaxine which is designated as form A and process for the preparation of the same.
- O-desmethyl venlafaxine is ( ⁇ )-l-[2-(dimethylamino)-l-(4-phenol) ethyl] -cyclohexanol, having molecular formula Ci 6 H 25 NO 2 and molecular weight 263.38.
- O- desmethyl venlafaxine is represented by structural formula (I).
- O-desmethyl venlafaxine is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake [Klamerus, K. J. et al., "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite", J. Clin. Pharmacol. 32:716 724 (1992)].
- US 7026508 disclose method of preparation of O-desmethyl venlafaxine which comprises demethylating venlafaxine or a salt thereof with an alkali metal salt of a trialkyl borohydride.
- US 7001920 disclose O-desmethyl venlafaxine formate as well as polymorphs, pharmaceutical compositions, dosage forms, and methods of use.
- 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.
- the polymorphic and pseudopolymorphic solids display different physical properties, including those due to packing, and various thermodynamic, spectroscopic, interfacial and mechanical properties (See H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, N. Y., 1999, pp. 1-2).
- Polymorphic and pseudopolymorphic forms of the drug substance also known as the "active pharmaceutical ingredient” (API)
- API active pharmaceutical ingredient
- a drug product also known as the final or finished dosage form, or as the pharmaceutical composition
- polymorphs of a compound can be characterized by x-ray diffraction pattern, infrared spectrum, DSC etc.
- a process for its bulk manufacture must be developed that reliably provides a uniform and highly pure grade of the compound. Further, the process must deliver a form of the compound that can be suitably formulated for convenient dosage to patients and which is chemically and physically stable over long periods in that formulation.
- a crystalline form of a drug compound has advantages over an amorphous form in several respects.
- the compound can be easily purified by crystallization and recrystallization. Crystallization is a much cheaper and more convenient method of purification to perform on a large scale than other known methods of purification such as chromatography.
- a crystalline form is usually more stable than an amorphous form, both before and during formulation and during subsequent storage.
- when formulating a drug for delivery by inhalation it is generally easier to mill or micronise a crystalline form to a respirable size (generally considered as particles less than 5 microns in diameter) than an amorphous form.
- a primary object of the present invention is to provide a novel crystalline form A of O- desmethyl venlafaxine.
- Another object of the present invention is to provide a process for the preparation of a crystalline form A of O-desmethyl venlafaxine.
- Yet another object of the present invention is to provide a process for the preparation of a crystalline form A of O-desmethyl venlafaxine, which is simple and easy to handle at production and cost effective.
- a further object of the present invention is to provide a process for the preparation of a crystalline form A of O-desrnethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
- Another object of the present invention is to provide a process for the preparation of a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) reacting crude O-desmethyl venlafaxine with acid to form acid addition salt ii) neutralizing acid addition salt obtained in step (i) by combining the acid addition salt with aqueous base
- a process for the preparation of a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
- a process for the preparation of a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) reacting crude O-desmethyl venlafaxine with acid to form acid addition salt ii) neutralizing acid addition salt obtained in step (i) by combining the acid addition salt with aqueous base
- Figure- 1 represents the powder X-ray diffraction (XRD) pattern of crystalline Form A of O- desmethyl venlafaxine.
- Figure-2 represents the differential scanning calorimetry (DSC) thermogram of crystalline Form A of O-desmethyl venlafaxine.
- DSC differential scanning calorimetry
- it provides a process for the preparation of a crystalline form A of O-desmethyl venlafaxine.
- it provides a process for the preparation of a crystalline form A of O-desmethyl venlafaxine, which is simple and easy to handle at production and cost effective.
- it provides a process for the preparing a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in an organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
- it provides a process for the preparing a crystalline form A of O- desmethyl venlafaxine comprising steps of: i) converting venlafaxine to crude O-desmethyl venlafaxine ii) dissolving crude O-desmethyl venlafaxine in an organic solvent iii) refluxing the solution obtain in step (ii) iv) cooling the solution obtain in step (iii)
- it provides a process for the preparing a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) reacting crude O-desmethyl venlafaxine with acid to form acid addition salt ii) neutralizing acid addition salt obtained in step (i) by combining the acid addition salt with aqueous base
- it provides novel salts of O-desmethyl venlafaxine except succinate and formate.
- the examples of salts of O-desmethyl venlafaxine as mention hereinabove includes inorganic acid and organic acid addition salts except succinate and formate.
- inorganic acid addition salt includes but not limited to hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid and the like.
- organic acid addition salt includes but not limited to trifluoroacetic acid, fumaric acid, acetic acid, benzene sulfonic acid, tartaric acid, maleic acid, oxalic acid, malonic acid, methanesulfonic acid, phthalic acid, ascorbic acid, p- toluenesulfonic acid, ethanesulfonic acid, malic acid, citric acid and the like.
- FIG. 1 depicts the X-ray powder diffraction spectrum of a crystalline form A of O- desmethyl venlafaxine.
- a crystalline form A of O-desmethyl venlafaxine characterized by differential scanning calorimetry (DSC) thermogram endotherm peak occurs in the temperature range from about 224 0 C to about 228 0 C and normally occurs at 225.9 0 C.
- DSC differential scanning calorimetry
- Figure-2 depicts the differential scanning calorimetry thermogram endotherm of a crystalline form A of O-desmethyl venlafaxine.
- O-desmethyl venlafaxine in another embodiment, it provides a crystalline form A of O-desmethyl venlafaxine having a particle size wherein d o . 5 less than 20 ⁇ m.
- the meaning of term 'crude O-desmethyl venlafaxine' as used hereinabove includes O-desmethyl venlafaxine in any form, or hydrate, clathrate, solvate or their mixtures and in any state of purity, unless specifically mentioned.
- Organic solvent' as used hereinabove includes alcohol, ketones, esters, chlorinated solvent, water, polar aprotic solvent and the like or mixtures thereof.
- the preferred polar aprotic solvent is Dimethylformamide.
- the meaning of term 'acid addition salt' as used hereinabove includes inorganic acid addition salts like hydrochloric acid, hydrobromic acid sulphuric acid and the like. Hydrochloric acid is preferred.
- 'aqueous base' as used hereinabove includes ammonium hydroxide, potassium hydroxide, and sodium hydroxide.
- Sodium hydroxide is preferred.
- the venlafaxine which is used as the starting material may be the free base of venlafaxine.
- suitable base include ammonium hydroxide, potassium hydroxide, and sodium hydroxide and sodium hydride.
- a crystalline form A of O-desmethyl venlafaxine is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
- a crystalline form A of O-desmethyl venlafaxine obtained by the present invention is characterized by its XRD pattern, DSC thermogram.
- Venlafaxine used in the examples is prepared according to methods reported in the literature and prior art.
- the crude O-desmethyl venlafaxine (36 gm) obtained in example 1 was dissolved in isopropanol (800ml) under reflux condition to get solution.
- the said solution is treated with activated charcoal at hot condition and filtered through hyflo bed.
- the filtrate was chilled to 10-20 0 C and filtered to get crystalline form A of O-desmethyl venlafaxine (28gm). Purity ⁇ 99.5%
- the crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in methyl ethyl ketone (1800ml) under reflux condition to get solution.
- the said solution is treated with activated charcoal at hot condition and filtered through hyflo bed.
- the filtrate was chilled to 10-20 0 C and filtered to get crystalline form A of O-desmethyl venlafaxine (25.2gm). Purity - 99.4 %
- the crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in mixture of ethanol (900ml) and acetone (900ml) under reflux condition to get solution.
- the said solution is treated with activated charcoal at hot condition and filtered through hyflo bed.
- the filtrate was chilled to 10-20 0 C and filtered to get crystalline form A of O-desmethyl venlafaxine (12.6gm).
- the crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in dimethylformamide (216ml) under reflux condition to get solution.
- the said solution is treated with activated charcoal at hot condition and filtered through hyflo bed.
- the filtrate was chilled to 10-20 0 C and filtered to get crystalline form A of O-desmethyl venlafaxine
Abstract
The present invention relates to novel crystalline polymorphic form of O-desmethyl venlafaxine which is designated as form A and process for the preparation of the same.
Description
NOVEL FORM OF O-DESMETHYL VENLAF AXINE
FIELD OF THE INVENTION:
The present invention relates to novel crystalline polymorphic form of O-desmethyl venlafaxine which is designated as form A and process for the preparation of the same.
BACKGROUND OF THE INVENTION:
The chemical name of O-desmethyl venlafaxine is (±)-l-[2-(dimethylamino)-l-(4-phenol) ethyl] -cyclohexanol, having molecular formula Ci6H25NO2 and molecular weight 263.38. O- desmethyl venlafaxine is represented by structural formula (I).
(I)
O-desmethyl venlafaxine is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake [Klamerus, K. J. et al., "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite", J. Clin. Pharmacol. 32:716 724 (1992)].
US 6673838 disclose O-desmethyl venlafaxine succinate as well as polymorphs, pharmaceutical compositions, dosage forms, and methods of use.
US 7026508 disclose method of preparation of O-desmethyl venlafaxine which comprises demethylating venlafaxine or a salt thereof with an alkali metal salt of a trialkyl borohydride.
US 7001920 disclose O-desmethyl venlafaxine formate as well as polymorphs, pharmaceutical compositions, dosage forms, and methods of use.
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. The polymorphic and pseudopolymorphic solids display different physical properties, including those due to packing, and various thermodynamic, spectroscopic, interfacial and mechanical properties (See H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, N. Y., 1999, pp. 1-2). Polymorphic and pseudopolymorphic forms of the drug substance (also known as the "active pharmaceutical ingredient" (API)), as administered by itself or formulated as a drug product (also known as the final or finished dosage form, or as the pharmaceutical composition) are well known and may affect, for example, the solubility, stability, flowability, fractability, and compressibility of drug substances and the safety and efficacy of drug products, (see, e.g., Knapman, K Modem Drug Discoveries, March 2000: 53). Polymorphs of a compound can be characterized by x-ray diffraction pattern, infrared spectrum, DSC etc.
Before a drug compound can be commercialized, a process for its bulk manufacture must be developed that reliably provides a uniform and highly pure grade of the compound. Further, the process must deliver a form of the compound that can be suitably formulated for convenient dosage to patients and which is chemically and physically stable over long periods in that formulation.
A crystalline form of a drug compound has advantages over an amorphous form in several respects. For example, the compound can be easily purified by crystallization and recrystallization. Crystallization is a much cheaper and more convenient method of purification to perform on a large scale than other known methods of purification such as chromatography. Further, a crystalline form is usually more stable than an amorphous form, both before and during formulation and during subsequent storage. Further, when formulating a drug for delivery by inhalation, it is generally easier to mill or micronise a crystalline form to a respirable size (generally considered as particles less than 5 microns in diameter) than an amorphous form.
One important physical property that can vary between two polymorphic forms is solubility, which can affect the bioavailability of the drug. Therefore there is a need to develop new polymorphic forms particularly crystalline form of a drug since it provides new opportunity to improve the performance characteristics of a pharmaceutical product.
It has now been surprisingly found that a crystalline form of (±)-l-[2-(dimethylamino)-l-(4- phenol) ethylj-cyclohexanol exists and may be prepared using the processes outlined hereinbelow.
OBJECTS OF THE INVENTION:
A primary object of the present invention is to provide a novel crystalline form A of O- desmethyl venlafaxine.
Another object of the present invention is to provide a process for the preparation of a crystalline form A of O-desmethyl venlafaxine.
Yet another object of the present invention is to provide a process for the preparation of a crystalline form A of O-desmethyl venlafaxine, which is simple and easy to handle at production and cost effective.
A further object of the present invention is to provide a process for the preparation of a crystalline form A of O-desrnethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
Another object of the present invention is to provide a process for the preparation of a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) reacting crude O-desmethyl venlafaxine with acid to form acid addition salt
ii) neutralizing acid addition salt obtained in step (i) by combining the acid addition salt with aqueous base
SUMMARY OF THE INVENTION: According to one aspect of the present invention there is provided a novel crystalline form A of O-desmethyl venlafaxine.
According to another aspect of the present invention there is provided a process for the preparation of a crystalline form A of O-desmethyl venlafaxine.
According to another aspect of the present invention there is provided a process for the preparation of a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
According to further aspect of the present invention there is provided a process for the preparation of a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) reacting crude O-desmethyl venlafaxine with acid to form acid addition salt ii) neutralizing acid addition salt obtained in step (i) by combining the acid addition salt with aqueous base
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure- 1 represents the powder X-ray diffraction (XRD) pattern of crystalline Form A of O- desmethyl venlafaxine.
Figure-2 represents the differential scanning calorimetry (DSC) thermogram of crystalline Form A of O-desmethyl venlafaxine.
DETAIL DESCRIPTION OF PRESENT INVENTION:
According to one aspect of present invention, it provides a novel crystalline form A of O- desmethyl venlafaxine.
According to another aspect of present invention, it provides a process for the preparation of a crystalline form A of O-desmethyl venlafaxine.
According to another aspect of present invention, it provides a process for the preparation of a crystalline form A of O-desmethyl venlafaxine, which is simple and easy to handle at production and cost effective.
According to further aspect of present invention, it provides a process for the preparing a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in an organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
According to further aspect, it provides a process for the preparing a crystalline form A of O- desmethyl venlafaxine comprising steps of: i) converting venlafaxine to crude O-desmethyl venlafaxine ii) dissolving crude O-desmethyl venlafaxine in an organic solvent iii) refluxing the solution obtain in step (ii) iv) cooling the solution obtain in step (iii)
In an embodiment of present invention, it provides a process for the preparing a crystalline form A of O-desmethyl venlafaxine comprising steps of: i) reacting crude O-desmethyl venlafaxine with acid to form acid addition salt ii) neutralizing acid addition salt obtained in step (i) by combining the acid addition salt with aqueous base
In another embodiment of present invention, it provides novel salts of O-desmethyl venlafaxine except succinate and formate. The examples of salts of O-desmethyl venlafaxine as mention hereinabove includes inorganic acid and organic acid addition salts except succinate and formate.
The examples of inorganic acid addition salt includes but not limited to hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid and the like. The examples of organic acid addition salt includes but not limited to trifluoroacetic acid, fumaric acid, acetic acid, benzene sulfonic acid, tartaric acid, maleic acid, oxalic acid, malonic acid, methanesulfonic acid, phthalic acid, ascorbic acid, p- toluenesulfonic acid, ethanesulfonic acid, malic acid, citric acid and the like.
In another embodiment of the present invention, it provides a crystalline form A of O- desmethyl venlafaxine, characterized by an X-ray powder diffraction spectrum having peaks at about 12.1, 13.2, 15.9, 19.6, 20.4, 22.4, 24.4, 25.1, 26.6 and 28.6 ±0.2 degree two-theta. Figure- 1 depicts the X-ray powder diffraction spectrum of a crystalline form A of O- desmethyl venlafaxine.
In another embodiment of present invention, it provides a crystalline form A of O-desmethyl venlafaxine, characterized by differential scanning calorimetry (DSC) thermogram endotherm peak occurs in the temperature range from about 2240C to about 228 0C and normally occurs at 225.90C. Figure-2 depicts the differential scanning calorimetry thermogram endotherm of a crystalline form A of O-desmethyl venlafaxine.
In another embodiment of present invention, it provides a crystalline form A of O-desmethyl venlafaxine having a particle size wherein do.5 less than 20 μm.
For the purpose of this specification, the meaning of term 'crude O-desmethyl venlafaxine' as used hereinabove includes O-desmethyl venlafaxine in any form, or hydrate, clathrate, solvate or their mixtures and in any state of purity, unless specifically mentioned.
For the purpose of this specification, the meaning of term Organic solvent' as used hereinabove includes alcohol, ketones, esters, chlorinated solvent, water, polar aprotic solvent and the like or mixtures thereof. The preferred polar aprotic solvent is Dimethylformamide.
For the purpose of this specification, the meaning of term 'converting' as used hereinabove includes conversion of venlafaxine to O-desmethyl venlafaxine according to methods reported in the literature and prior art.
For the purpose of this specification, the meaning of term 'acid addition salt' as used hereinabove includes inorganic acid addition salts like hydrochloric acid, hydrobromic acid sulphuric acid and the like. Hydrochloric acid is preferred.
For the purpose of this specification, the meaning of term 'aqueous base' as used hereinabove includes ammonium hydroxide, potassium hydroxide, and sodium hydroxide. Sodium hydroxide is preferred.
The venlafaxine which is used as the starting material may be the free base of venlafaxine. Alternatively, it is possible to start with an acid addition salt of venlafaxine. In this case, it may be preferred to add suitable base to the venlafaxine salt-organic solvent mixture to liberate the free base of venlafaxine. Suitable bases include ammonium hydroxide, potassium hydroxide, and sodium hydroxide and sodium hydride.
A crystalline form A of O-desmethyl venlafaxine is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
A crystalline form A of O-desmethyl venlafaxine obtained by the present invention is characterized by its XRD pattern, DSC thermogram.
Venlafaxine used in the examples is prepared according to methods reported in the literature and prior art.
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.
Example 1
Preparation of crude O-desmethyl venlafaxine
In a 3 necked 2 liter round bottom flask equipped with mechanical stirrer thermometer pocket, reflux condenser and nitrogen inlet tube was charged with dimethylformamide (200ml), venlafaxine (40gm) and ethane thiol (53ml) and stirred it. The reaction mixture was heated to 4O0C. Sodium hydride (31.3gm) was added in portions during 3 hours at 25-40 0C. The temperature of the reaction mixture was raised to 150 0C very slowly and maintained for 6 hours. The reaction mixture was cooled to ambient temperature and ethyl acetate (280ml) was added and stirred for 60 minutes. The insoluble mass was filtered out. The filtrate was distilled out under vacuum at 100 0C. The reaction mixture was cooled to ambient temperature and water (240ml) was added and stirred it vigorously for an hour. Filter the solid and washed with water and dried to get crude O-desmethyl venlafaxine (36 gm). Purity ~ 97.5 %
Example 2
Preparation of crystalline form A of O-desmethyl venlafaxine in Isoprpanol
The crude O-desmethyl venlafaxine (36 gm) obtained in example 1 was dissolved in isopropanol (800ml) under reflux condition to get solution. The said solution is treated with activated charcoal at hot condition and filtered through hyflo bed. The filtrate was chilled to 10-20 0C and filtered to get crystalline form A of O-desmethyl venlafaxine (28gm). Purity ~ 99.5%
Example 3 Preparation of crystalline form A of O-desmethyl venlafaxine in Methyl ethyl ketone
The crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in methyl ethyl ketone (1800ml) under reflux condition to get solution. The said solution is treated with activated charcoal at hot condition and filtered through hyflo bed. The filtrate was chilled to 10-20 0C and filtered to get crystalline form A of O-desmethyl venlafaxine (25.2gm). Purity - 99.4 %
Example 4
Preparation of crystalline form A of O-desmethyl venlafaxine in mixture of Methanol and Dicliloromethane The crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in mixture of methanol (828ml) and dichloromethane (828ml) under reflux condition to get solution. The said solution is treated with activated charcoal at hot condition and filtered through hyflo bed. The filtrate was chilled to 10-20 0C and filtered to get crystalline form A of O-desmethyl venlafaxine (23.4gm). Purity ~ 99.6%
Example 5
Preparation of crystalline form A of O-desmethyl venlafaxine in mixture of Ethanol and
Acetone
The crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in mixture of ethanol (900ml) and acetone (900ml) under reflux condition to get solution. The said solution is treated with activated charcoal at hot condition and filtered through hyflo bed. The filtrate was chilled to 10-20 0C and filtered to get crystalline form A of O-desmethyl venlafaxine (12.6gm).
Purity ~ 99.4%
Example 6
Preparation of crystalline form A of O-desmethyl venlafaxine in Dimethylformamide
The crude O-desmethyl venlafaxine (36gm) obtained in example 1 was dissolved in dimethylformamide (216ml) under reflux condition to get solution. The said solution is treated with activated charcoal at hot condition and filtered through hyflo bed. The filtrate was chilled to 10-20 0C and filtered to get crystalline form A of O-desmethyl venlafaxine
(23.4gm).
Purity ~ 99.5%
Example 7
Preparation of crystalline form A of O-desmethyl venlafaxine
Sodium hydride (51.2gm) was charged in dimethyl formamide under nitrogen atmosphere at 15-200C. The reaction mixture was stirred at 15-200C for an hour. Ethane thiol (79.42gm) was added slowly to reaction mixture. The mixture was stirred for 2 hours at 15-200C followed by addition of venlafaxine hydrochloride (10Og). The mixture was heated at 1500C and maintained it fo* 25 hours. The reaction mixture was cooled to 25-300C followed by addition of D. M. Water (2500ml). pH of mixture was adjusted to 2 by concentrated hydrochloric acid and then activated carbon (5gm) was added, stirred it for 30 min., filtered it through hyflo. pH of mixture was adjusted to 8-9 by 20% sodium hydroxide solution, stirred
it for an hour and then filtered, washed and dried to get crystalline form A of O-desmethyl venlafaxine (80gm).
Example 8 Preparation of crystalline form A of O-desmethyl venlafaxine in Methanol
The crude O-desmethyl venlafaxine prepared according to the procedure of example 1 (50gm) was dissolved in methanol (1500 ml) under reflux condition to get solution. The said solution is treated with activated charcoal at hot condition and filtered through hyflo bed. The filtrate was distilled upto between 1/3 to 2/3 volume and cooled in between temperature - 100C to 50 0C and stirred and filtered to get crystalline form A of O-desmethyl venlafaxine (40gm). Purity ~ 99.5%
Claims
1. Form A of O-desmethyl venlafaxine, characterized by an X-ray powder diffraction spectrum having peaks at about 12.1, 13.2, 15.9, 19.6, 20.4, 22.4, 24.4, 25.1, 26.6 and 28.6 ±0.2 degree two-theta.
2. Form A of O-desmethyl venlafaxine, characterized by differential scanning calorimetry (DSC) thermogram endotherm peak occurs in the temperature range from about 2240C to about 228 0C.
3. Form A of O-desmethyl Venlafaxine according to claim 2, characterized by differential scanning calorimetry (DSC) thermogram endotherm peak occurs at 225.9 0C.
4. Form A of O-desmethyl venlafaxine having a particle size wherein do.5 less than 20 μm.
5. A process for the preparing form A of O-desmethyl venlafaxine comprising steps of: i) dissolving crude O-desmethyl venlafaxine in an organic solvent ii) refluxing the solution obtain in step (i) iii) cooling the solution obtain in step (ii)
6. A process for the preparing form A of O-desmethyl venlafaxine comprising steps of: i) converting venlafaxine to crude O-desmethyl venlafaxine ii) dissolving crude O-desmethyl venlafaxine in an organic solvent iii) refluxing the solution obtain in step (ii) 1 iv) cooling the solution obtain in step (iii)
7. The process according to claim 4 and 5, wherein the organic solvent used is selected from the group consisting of alcohol, ketones, esters, chlorinated solvent, water, polar aprotic solvent and mixtures thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009027766A2 (en) * | 2006-12-22 | 2009-03-05 | Medichem, S.A. | New crystalline solid forms of o-desvenlafaxine base |
| CN106995376A (en) * | 2017-04-21 | 2017-08-01 | 上海华源医药科技发展有限公司 | A kind of industrialized producing technology of desmethylvenlafaxine |
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| US20030105358A1 (en) * | 2001-12-04 | 2003-06-05 | Wyeth | Methods for preparing O-desmethylvenlafaxine |
| WO2007071404A1 (en) * | 2005-12-20 | 2007-06-28 | Synthon B.V. | Process for making desvenlafaxine |
| WO2007120923A1 (en) * | 2006-04-17 | 2007-10-25 | Teva Pharmaceutical Industries Ltd. | Substantially pure o-desmethylvenlafaxine and processes for preparing it |
| US20080033051A1 (en) * | 2006-04-17 | 2008-02-07 | Sigalit Levi | Crystal forms of o-desmethylvenlafaxine |
-
2007
- 2007-06-28 WO PCT/IN2007/000266 patent/WO2008035369A2/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030105358A1 (en) * | 2001-12-04 | 2003-06-05 | Wyeth | Methods for preparing O-desmethylvenlafaxine |
| WO2003048104A1 (en) * | 2001-12-04 | 2003-06-12 | Wyeth | Methods for preparing o-desmethylvenlafaxine |
| WO2007071404A1 (en) * | 2005-12-20 | 2007-06-28 | Synthon B.V. | Process for making desvenlafaxine |
| WO2007120923A1 (en) * | 2006-04-17 | 2007-10-25 | Teva Pharmaceutical Industries Ltd. | Substantially pure o-desmethylvenlafaxine and processes for preparing it |
| US20080033051A1 (en) * | 2006-04-17 | 2008-02-07 | Sigalit Levi | Crystal forms of o-desmethylvenlafaxine |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009027766A2 (en) * | 2006-12-22 | 2009-03-05 | Medichem, S.A. | New crystalline solid forms of o-desvenlafaxine base |
| WO2009027766A3 (en) * | 2006-12-22 | 2009-04-23 | Medichem Sa | New crystalline solid forms of o-desvenlafaxine base |
| CN106995376A (en) * | 2017-04-21 | 2017-08-01 | 上海华源医药科技发展有限公司 | A kind of industrialized producing technology of desmethylvenlafaxine |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008035369A3 (en) | 2008-05-15 |
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