WO2007054978A2 - Process for preparing paroxetine hydrochloride hemihydrate - Google Patents
Process for preparing paroxetine hydrochloride hemihydrate Download PDFInfo
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- WO2007054978A2 WO2007054978A2 PCT/IN2006/000446 IN2006000446W WO2007054978A2 WO 2007054978 A2 WO2007054978 A2 WO 2007054978A2 IN 2006000446 W IN2006000446 W IN 2006000446W WO 2007054978 A2 WO2007054978 A2 WO 2007054978A2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- this invention relates to the field of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). More particularly a process for preparing a crystalline paroxetine hydrochloride in hemihydrate form employing a selective solvent system.
- Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI), also useful as a therapeutic agent for various diseases such as depression and Parkinson's diseases.
- Paroxetine is a phenyl piperidine compound identified chemically as (-)-(3S 5 4R)-4-(p-Fluorophenyl)-3-[(3',4'-methylenedioxy phenoxy) methyl] piperidine hydrochloride represented by the Formula 1.
- Paroxetine hydrochloride mainly exist as a crystalline hemihydrate as well as anhydrous forms. Ferrosan first described paroxetine and its salts generically in US 3,912,743 and specifically in US 4,007,196 patent. US' 196 patent claims paroxetine and its salts, discloses their antidepressant properties. In Example 2 of US '196, paroxetine is obtained as a free base and then converted to its maleic acid salt.
- CA 2187128 patent application discloses preparation of three anhydrous forms of paroxetine hydrochloride that is denoted as Form I, Form II and Form III, however
- Form II and Form I are not claimed in the said application.
- Form III is prepared by treating Form I and Form II with methyl isobutyl ketone under inert atmosphere followed by heating up to 90-95 0 C then cooled to obtain precipitates of paroxetine hydrochloride that was recovered by filtration and finally dried.
- Form III can also be prepared by dissolving paroxetine free base in methyl isobutyl ketone and treated with concentrated hydrochloric acid followed by removal of methyl isobutyl ketone under reduced pressure.
- WO 96/24595 discloses paroxetine hydrochloride solvates, other than the propan-2-ol solvate, which are used as precursors in the preparation of paroxetine hydrochloride, substantially free of bound organic solvent.
- WO 96/24595 also discloses four novel forms of paroxetine hydrochloride anhydrates substantially free of bound solvent.
- the main drawback of the above process is that the anhydrous paroxetine hydrochloride prepared is highly hygroscopic and unstable thus make the material extremely difficult to handle.
- Another disadvantage is that the anhydrous material is light and fluffy which create handling problem during pharmaceutical formulation.
- paroxetine hydrochloride in hemihydrate form is prepared by crystallizing paroxetine free base or other salts such as hydrochloride or acetate, using solvent selected from toluene, water, industrial methylated spirit, ethanol, isopropyl alcohol or ethyl acetate.
- solvent selected from toluene, water, industrial methylated spirit, ethanol, isopropyl alcohol or ethyl acetate solvent selected from toluene, water, industrial methylated spirit, ethanol, isopropyl alcohol or ethyl acetate.
- the present invention provides a novel process for preparing paroxetine hydrochloride hemihydrate employing suitable solvent system to achieve stable and non-hygroscopic crystalline paroxetine hydrochloride in hemihydrate form.
- a novel process for preparing crystalline paroxetine hydrochloride in hemihydrate form comprising crystallizing paroxetine hydrochloride employing alcoholic solvent and isolating the crystallized product by optionally adding the secondary solvent.
- a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form comprises taking paroxetine free base in alcoholic solvent containing hydrochloric acid and isolating the product from the resultant by optionally adding secondary solvent.
- a novel process for the preparation of paroxetine hydrochloride in hemihydrate form comprises dissolving paroxetine free base in a solvent, adding hydrochloric acid to the resultant and removing the solvent, dissolving the resulting product in an alcoholic solvent and, isolating the crystallized product from the resultant by optionally adding secondary solvent.
- a novel process for preparing crystalline paroxetine hydrochloride in hemihydrate form comprising crystallizing paroxetine hydrochloride employing alcoholic solvent and isolating the crystallized product by adding the secondary solvent.
- a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form comprises taking paroxetine free base in alcoholic solvent containing hydrochloric acid and isolating the crystallized product by adding secondary solvent.
- a novel process for the preparation of paroxetine hydrochloride in hemihydrate form comprising dissolving paroxetine free base in a solvent, adding hydrochloric acid and removing the solvent, dissolving the resulting product in an alcoholic solvent and, isolating the crystallized product by adding secondary solvent.
- FIG. 1 depicts a powder X-ray diffractogram of crystalline paroxetine hydrochloride hemihydrate according to a prior art process.
- FIG. 2 depicts Infrared absorption spectrum of crystalline paroxetine hydrochloride hemihydrate according to prior art process.
- FIG. 3 depicts a powder X-ray diffractogram of crystalline paroxetine hydrochloride hemihydrate prepared by the inventor.
- FIG. 4 depicts Infrared absorption spectrum of crystalline paroxetine hydrochloride hemihydrate prepared by the inventor.
- the present invention discloses in its aspect novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form, by crystallizing paroxetine hydrochloride from alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent or converting paroxetine free base into paroxetine hydrochloride and then dissolving the resulting product in alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent.
- the crystalline paroxetine hydrochloride hemihydrate of the present invention is characterized by X-ray Powder diffractogram, Infrared and Differential Scanning Calorimetry thermogram.
- the X-ray powder diffractogram of the crystalline paroxetine hydrochloride in hemihydrate form of the present invention are measured on a PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of 2 ⁇ , d-spacing and relative intensities.
- the crystalline paroxetine hydrochloride hemihydrate of the present invention is characterized by PXRD pattern having peaks at 6.36, 7.14, 8.02, 10.80, 11.25, 11.85, 12.70, 13.92, 13.92, 14.25, 15.42, 16.06, 16.30, 16.70, 17.23, 17.46, 18.28, 18.50, 18.60, 19.23, 20.29, 21.43, 21.59, 21.76, 22.01, 22.25, 22.58, 23.16, 23.46, 23.96, 24.16, 24.60, 25.72, 25.94, 26.80, 27.00, 27.52, 27.52, 27.76, 28.52, 29.09, 29.30, 29.87, 30.75, 30.95, 31.57, 31.94, 32.38, 32.94, 33.54, 34.11 34.82, 35.97+0.2° 2 ⁇ .
- the crystalline paroxetine hydrochloride hemihydrate of the present invention is further characterized by Infrared spectrum, which is measured on Thermo Nicolet FT- IR spectrometer using KBr pellets having the characteristic absorption peaks expressed in reciprocal centimeter.
- the identified significant IR peaks are observed around 3404(s), 3338(m), 2955(w), 2924(w), 2815(s) 5 2765(w), 2720 (w), 2669(m), 2545(m), 2493(w), 1606(s), 151 l(s), 1490(s), 1479(m), 1437(m), 1380(m), 1344(m), 1247(m), 1222(s), 1185(s), 1128(m), 1097(s), 1041(s), 1004(m), 930(s), 836(s), 805(m), 780(m), 573(m), 541 (s), 521(w).
- the crystalline paroxetine hydrochloride hemihydrate of the present invention is also characterized by differential scanning calorimetry which is recorded on DSCQlOO equilibrated at 25 0 C to 35O 0 C at 10°C/minute with nitrogen flow rate 60 ml/minute.
- the differential scanning calorimetry thermogram exhibits a significant endotherm peak around 132.9 0 C.
- a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form comprises crystallizing paroxetine hydrochloride from alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent.
- Suitable alcoholic solvent used herein according to the present invention for crystallizing paroxetine hydrochloride are selected from methanol, ethanol, n- propanol, isopropanol or mixture thereof.
- the resulting mixture is cooled at a temperature between 0 to 2O 0 C, preferably between 10 to 15 0 C.
- Secondary solvent selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof is optionally added to the resulting said solution till the solid separates out.
- the resulting precipitate according to the process of the present invention is separated off by conventional method and dried under vacuum at a temperature of 40-70 0 C preferably between 50-60 0 C to a constant weight to afford paroxetine hydrochloride in hemihydrate form.
- a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form comprises taking paroxetine free base in alcoholic solvent containing hydrochloric acid and isolating the crystallized product by optionally adding secondary solvent.
- Suitable alcoholic solvent used herein for dissolving paroxetine free base are selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof. The resulting mixture was stirred at room temperature. Secondary solvent selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof is optionally added to the resulting said solution till the solid separates out.
- the resulting crystallized product is separated off by conventional method and dried under vacuum at a temperature of 40-70 0 C preferably between 50-60 0 C to a constant weight to afford paroxetine hydrochloride in hemihydrate form.
- a novel process for the preparation of paroxetine hydrochloride in hemihydrate form comprises dissolving paroxetine free base in a solvent selected from chlorinated solvent or aromatic hydrocarbon or ester, adding hydrochloric acid and removing the solvent, dissolving the resulting product in an alcoholic solvent and, isolating the crystallized product by adding secondary solvent, wherein the chlorinated solvent is selected from dichloromethane or chloroform, aromatic hydrocarbon is preferably toluene and ester is preferably ethyl acetate or any combination of said solvents.
- Suitable alcoholic solvent used herein for dissolving the resulting product are selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof.
- Secondary solvent selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof is optionally added to the said solution till the solid separates out, the resulting solid was separated by conventional method and dried under vacuum at a temperature of 40-70 0 C preferably between 50-60 0 C to a constant weight to afford paroxetine hydrochloride in hemihydrate form.
- the crystalline paroxetine hydrochloride hemihydrate obtained as per the above process is stable and non-hygroscopic and is well suited for pharmaceutical application.
- the process of the present invention is simple, non-hazardous and well suited for commercial production.
- Paroxetine hydrochloride (10 g) was dissolved in methanol (50 ml) and the resulting solution was cooled at a temperature of 5-1O 0 C.
- diisopropyl ether (100 ml) was added at a temperature between 10-15 0 C under stirring for 1-2 hours.
- the resulting solid was separated and dried under vacuum at 50-60 0 C to afford crystalline paroxetine hydrochloride in hemihydrate form Weight 9.5 g, moisture content (M.C) 2.65 %.
- Paroxetine free base (5 g) was taken in ethyl alcohol (50 ml) and concentrated hydrochloric acid was added. The resulting mixture was stirred to obtain clear solution. To the resulting clear solution, diisopropyl ether (50 ml) was added and stirred for 2 hours. The resulting solid was filtered off and dried under vacuum at 50- 6O 0 C to afford crystalline paroxetine hydrochloride in hemihydrate form. Weight 4 g, moisture content (M.C) 2.50%.
- Paroxetine free base (10 g) was dissolved in dichloromethane (150 ml). Concentrated hydrochloric acid was added. Solvent was distilled off under vacuum at 40-45 0 C. The resulting product was dissolved in methanol (50 ml) and cooled at a temperature of 5- 1O 0 C. To the resulting solution, diisopropyl ether (100 ml) was added at a temperature between 10-15 0 C within 1-2 hours. The resulting solid was filtered off and dried under vacuum at 50-60 0 C to afford crystalline paroxetine hydrochloride in hemihydrate form. Weight 9 g, moisture content (M.C) 2.60%.
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Abstract
Disclosed herein a process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form employing a selective solvent system to achieve stable and non- hygroscopic form which is easy to prepare and convenient to operate on commercial scale.
Description
PROCESS FOR PREPARING PAROXETINE HYDROCHLORIDE
HEMIHYDRATE
Field of the Invention
In general, this invention relates to the field of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). More particularly a process for preparing a crystalline paroxetine hydrochloride in hemihydrate form employing a selective solvent system.
Background of the Invention
Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI), also useful as a therapeutic agent for various diseases such as depression and Parkinson's diseases. Paroxetine is a phenyl piperidine compound identified chemically as (-)-(3S54R)-4-(p-Fluorophenyl)-3-[(3',4'-methylenedioxy phenoxy) methyl] piperidine hydrochloride represented by the Formula 1.
Paroxetine hydrochloride mainly exist as a crystalline hemihydrate as well as anhydrous forms. Ferrosan first described paroxetine and its salts generically in US 3,912,743 and specifically in US 4,007,196 patent. US' 196 patent claims paroxetine and its salts, discloses their antidepressant properties. In Example 2 of US '196, paroxetine is obtained as a free base and then converted to its maleic acid salt.
CA 2187128 patent application discloses preparation of three anhydrous forms of paroxetine hydrochloride that is denoted as Form I, Form II and Form III, however
Form II and Form I are not claimed in the said application. Form III is prepared by treating Form I and Form II with methyl isobutyl ketone under inert atmosphere
followed by heating up to 90-950C then cooled to obtain precipitates of paroxetine hydrochloride that was recovered by filtration and finally dried. Form III can also be prepared by dissolving paroxetine free base in methyl isobutyl ketone and treated with concentrated hydrochloric acid followed by removal of methyl isobutyl ketone under reduced pressure.
International Journal of Pharmaceutics 42, pp.135-143 (1988), describes the preparation of anhydrous form of the paroxetine hydrochloride. The anhydrous form is produced by crystallizing paroxetine hydrochloride from anhydrous propan-2-ol. Subsequent repetition of this process has resulted in a propan-2-ol solvate of paroxetine hydrochloride, i.e. there is bound propan-2-ol in the product. This bound propan-2-ol cannot be removed by conventional drying techniques such as vacuum oven drying.
International Patent Publication No. WO 96/24595 discloses paroxetine hydrochloride solvates, other than the propan-2-ol solvate, which are used as precursors in the preparation of paroxetine hydrochloride, substantially free of bound organic solvent. WO 96/24595 also discloses four novel forms of paroxetine hydrochloride anhydrates substantially free of bound solvent.
The main drawback of the above process is that the anhydrous paroxetine hydrochloride prepared is highly hygroscopic and unstable thus make the material extremely difficult to handle. Another disadvantage is that the anhydrous material is light and fluffy which create handling problem during pharmaceutical formulation.
The U.S. Pat. No. 4,721,723 describes the preparation of hemihydrate form of paroxetine hydrochloride and its use in treating certain medical disorder. In US '723 patent paroxetine hydrochloride in hemihydrate form is prepared by crystallizing paroxetine free base or other salts such as hydrochloride or acetate, using solvent selected from toluene, water, industrial methylated spirit, ethanol, isopropyl alcohol or ethyl acetate. This invention some extent over come the drawback of the prior arts.
However, yet there is a need for a process to prepare paroxetine hydrochloride hemihydrate overcoming the aforementioned limitation with a better yield and cost effective than the prior disclosed processes.
The present invention provides a novel process for preparing paroxetine hydrochloride hemihydrate employing suitable solvent system to achieve stable and non-hygroscopic crystalline paroxetine hydrochloride in hemihydrate form.
Summary of the Invention It is a principal aspect of the present invention is to provide a novel process for the preparation of stable and non-hygroscopic crystalline paroxetine hydrochloride in hemihydrate form, wherein said process is carried out employing a selective solvent system.
In accordance with another aspect of the present invention, there is provided a novel process to produce crystalline paroxetine hydrochloride in hemihydrate form which is easy to prepare and convenient to operate on commercial scale.
In accordance with one another aspect of the present invention, there is provided a novel process for preparing crystalline paroxetine hydrochloride in hemihydrate form, wherein the process comprises crystallizing paroxetine hydrochloride employing alcoholic solvent and isolating the crystallized product by optionally adding the secondary solvent.
In accordance with further aspect of the present invention, there is provided a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form, the process comprises taking paroxetine free base in alcoholic solvent containing hydrochloric acid and isolating the product from the resultant by optionally adding secondary solvent.
In accordance with one other aspect of the present invention, there is provided a novel process for the preparation of paroxetine hydrochloride in hemihydrate form, the said process comprises dissolving paroxetine free base in a solvent, adding hydrochloric
acid to the resultant and removing the solvent, dissolving the resulting product in an alcoholic solvent and, isolating the crystallized product from the resultant by optionally adding secondary solvent.
In accordance with yet another aspect of the present invention, there is provided a novel process for preparing crystalline paroxetine hydrochloride in hemihydrate form, wherein the process comprises crystallizing paroxetine hydrochloride employing alcoholic solvent and isolating the crystallized product by adding the secondary solvent.
In accordance with another aspect of the present invention, there is provided a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form, the process comprises taking paroxetine free base in alcoholic solvent containing hydrochloric acid and isolating the crystallized product by adding secondary solvent.
In accordance with one other aspect of the present invention, there is provided a novel process for the preparation of paroxetine hydrochloride in hemihydrate form, wherein the process comprises dissolving paroxetine free base in a solvent, adding hydrochloric acid and removing the solvent, dissolving the resulting product in an alcoholic solvent and, isolating the crystallized product by adding secondary solvent.
In accordance with yet another aspect of the present invention, there is provided a novel process for preparing crystalline paroxetine hydrochloride in hemihydrate form, wherein the raw material used herein paroxetine free base or any pharmaceutically acceptable salt, preferably hydrochloride salt of paroxetine.
Brief Description of the Drawing Figure
Further aspect of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the description of preferred embodiments of the present invention which are shown in the accompanying drawing figures.
FIG. 1 depicts a powder X-ray diffractogram of crystalline paroxetine hydrochloride hemihydrate according to a prior art process.
FIG. 2 depicts Infrared absorption spectrum of crystalline paroxetine hydrochloride hemihydrate according to prior art process. FIG. 3 depicts a powder X-ray diffractogram of crystalline paroxetine hydrochloride hemihydrate prepared by the inventor.
FIG. 4 depicts Infrared absorption spectrum of crystalline paroxetine hydrochloride hemihydrate prepared by the inventor.
Description of the Invention
The present invention discloses in its aspect novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form, by crystallizing paroxetine hydrochloride from alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent or converting paroxetine free base into paroxetine hydrochloride and then dissolving the resulting product in alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent.
The crystalline paroxetine hydrochloride hemihydrate of the present invention is characterized by X-ray Powder diffractogram, Infrared and Differential Scanning Calorimetry thermogram.
The X-ray powder diffractogram of the crystalline paroxetine hydrochloride in hemihydrate form of the present invention are measured on a PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of 2Θ, d-spacing and relative intensities.
The crystalline paroxetine hydrochloride hemihydrate of the present invention is characterized by PXRD pattern having peaks at 6.36, 7.14, 8.02, 10.80, 11.25, 11.85, 12.70, 13.92, 13.92, 14.25, 15.42, 16.06, 16.30, 16.70, 17.23, 17.46, 18.28, 18.50, 18.60, 19.23, 20.29, 21.43, 21.59, 21.76, 22.01, 22.25, 22.58, 23.16, 23.46, 23.96, 24.16, 24.60, 25.72, 25.94, 26.80, 27.00, 27.52, 27.52, 27.76, 28.52, 29.09, 29.30, 29.87, 30.75, 30.95, 31.57, 31.94, 32.38, 32.94, 33.54, 34.11 34.82, 35.97+0.2° 2Θ.
The crystalline paroxetine hydrochloride hemihydrate of the present invention is further characterized by Infrared spectrum, which is measured on Thermo Nicolet FT- IR spectrometer using KBr pellets having the characteristic absorption peaks expressed in reciprocal centimeter.
The identified significant IR peaks are observed around 3404(s), 3338(m), 2955(w), 2924(w), 2815(s)5 2765(w), 2720 (w), 2669(m), 2545(m), 2493(w), 1606(s), 151 l(s), 1490(s), 1479(m), 1437(m), 1380(m), 1344(m), 1247(m), 1222(s), 1185(s), 1128(m), 1097(s), 1041(s), 1004(m), 930(s), 836(s), 805(m), 780(m), 573(m), 541 (s), 521(w).
The crystalline paroxetine hydrochloride hemihydrate of the present invention is also characterized by differential scanning calorimetry which is recorded on DSCQlOO equilibrated at 250C to 35O0C at 10°C/minute with nitrogen flow rate 60 ml/minute. The differential scanning calorimetry thermogram exhibits a significant endotherm peak around 132.90C.
According to one aspect of the present invention there is provided a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form, the said process comprises crystallizing paroxetine hydrochloride from alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent.
Suitable alcoholic solvent used herein according to the present invention for crystallizing paroxetine hydrochloride are selected from methanol, ethanol, n- propanol, isopropanol or mixture thereof. The resulting mixture is cooled at a temperature between 0 to 2O0C, preferably between 10 to 150C. Secondary solvent selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof is optionally added to the resulting said solution till the solid separates out.
The resulting precipitate according to the process of the present invention is separated off by conventional method and dried under vacuum at a temperature of 40-700C preferably between 50-600C to a constant weight to afford paroxetine hydrochloride in hemihydrate form.
In accordance with another aspect of the present invention, there is provided a novel process for the preparation of crystalline paroxetine hydrochloride in hemihydrate form, the process comprises taking paroxetine free base in alcoholic solvent containing hydrochloric acid and isolating the crystallized product by optionally adding secondary solvent.
Suitable alcoholic solvent used herein for dissolving paroxetine free base are selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof. The resulting mixture was stirred at room temperature. Secondary solvent selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof is optionally added to the resulting said solution till the solid separates out.
The resulting crystallized product is separated off by conventional method and dried under vacuum at a temperature of 40-700C preferably between 50-600C to a constant weight to afford paroxetine hydrochloride in hemihydrate form.
In accordance with one other aspect of the present invention, there is provided a novel process for the preparation of paroxetine hydrochloride in hemihydrate form, the said process comprises dissolving paroxetine free base in a solvent selected from chlorinated solvent or aromatic hydrocarbon or ester, adding hydrochloric acid and removing the solvent, dissolving the resulting product in an alcoholic solvent and, isolating the crystallized product by adding secondary solvent, wherein the chlorinated solvent is selected from dichloromethane or chloroform, aromatic hydrocarbon is preferably toluene and ester is preferably ethyl acetate or any combination of said solvents. Suitable alcoholic solvent used herein for dissolving the resulting product are selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof. Secondary solvent selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof is optionally added to the said solution till the solid separates out, the resulting solid was separated by conventional method and dried under vacuum at a temperature of 40-700C preferably between 50-600C to a constant weight to afford paroxetine hydrochloride in hemihydrate form.
The crystalline paroxetine hydrochloride hemihydrate obtained as per the above process is stable and non-hygroscopic and is well suited for pharmaceutical application. The process of the present invention is simple, non-hazardous and well suited for commercial production.
The examples that follow are not intended to limit the scope of the invention as defined hereinabove or as claimed below.
Example 1
Preparation of paroxetine hydrochloride hemihvdrate
Paroxetine hydrochloride (10 g) was dissolved in methanol (50 ml) and the resulting solution was cooled at a temperature of 5-1O0C. To the resulting solution, diisopropyl ether (100 ml) was added at a temperature between 10-150C under stirring for 1-2 hours. The resulting solid was separated and dried under vacuum at 50-600C to afford crystalline paroxetine hydrochloride in hemihydrate form Weight 9.5 g, moisture content (M.C) 2.65 %.
Example 2
Preparation of paroxetine hydrochloride hemihvdrate
Paroxetine free base (5 g) was taken in ethyl alcohol (50 ml) and concentrated hydrochloric acid was added. The resulting mixture was stirred to obtain clear solution. To the resulting clear solution, diisopropyl ether (50 ml) was added and stirred for 2 hours. The resulting solid was filtered off and dried under vacuum at 50- 6O0C to afford crystalline paroxetine hydrochloride in hemihydrate form. Weight 4 g, moisture content (M.C) 2.50%.
Example 3
Preparation of paroxetine hydrochloride hemihvdrate
Paroxetine free base (10 g) was dissolved in dichloromethane (150 ml). Concentrated hydrochloric acid was added. Solvent was distilled off under vacuum at 40-450C. The resulting product was dissolved in methanol (50 ml) and cooled at a temperature of 5- 1O0C. To the resulting solution, diisopropyl ether (100 ml) was added at a temperature between 10-150C within 1-2 hours. The resulting solid was filtered off and dried under vacuum at 50-600C to afford crystalline paroxetine hydrochloride in hemihydrate form. Weight 9 g, moisture content (M.C) 2.60%.
Certain modifications and improvements of the disclosed invention would occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.
Claims
1. A process for the preparation of paroxetine hydrochloride in hemihydrate form comprising crystallizing paroxetine hydrochloride employing an alcoholic solvent and isolating the crystallized product by optionally adding secondary solvent.
2. The process according to claim 1, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof.
3. The process according to claim 1, wherein the secondary solvent is selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof.
4. The process according to claim 1, wherein the product is crystallized at a temperature of 0-200C.
5. The process according to claim 1, wherein the product is crystallized at a temperature of 10-150C.
6. A process for the preparation of paroxetine hydrochloride in hemihydrate form comprising taking paroxetine free base in alcoholic solvent containing hydrogen chloride and isolating the crystallized product by optionally adding secondary solvent.
7. The process according to claim 6, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof.
8. The process according to claim 6, wherein the secondary solvent is selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof.
9. A process for the preparation of paroxetine hydrochloride in hemihydrate form comprising dissolving paroxetine free base in a solvent selected from chlorinated solvent or aromatic hydrocarbon or ester, adding hydrochloric acid and removing the solvent from the resultant, further dissolving the resulting product in an alcoholic solvent and isolating the resultant crystallized product by optionally adding secondary solvent.
10. The process according to claim 9, wherein the chlorinated solvent is selected from dichloromethane or chloroform or mixture thereof.
11. The process according to claim 9, wherein the aromatic hydrocarbon is selected from toluene.
12. The process according to claim 9, wherein the ester is selected from ethyl acetate.
13. The process according to claim 9, wherein the said secondary solvent is selected from diisopropyl ether or methyl tertiary butyl ether or mixture thereof.
14. A process for the preparation of paroxetine hydrochloride in hemihydrate form comprising crystallizing paroxetine hydrochloride employing an alcoholic solvent and isolating the crystallized product by adding secondary solvent.
15. A process for the preparation of paroxetine hydrochloride in hemihydrate form comprising taking paroxetine free base in alcoholic solvent containing hydrogen chloride and isolating the crystallized product by adding secondary solvent.
16. A process for the preparation of paroxetine hydrochloride in hemihydrate form comprising dissolving paroxetine free base in a solvent selected from chlorinated solvent or aromatic hydrocarbon or ester, adding hydrochloric acid and removing the solvent from the resultant, further dissolving the resulting product in an alcoholic solvent and isolating the resultant crystallized product by adding secondary solvent.
17. The process according to any of claim 14 or 15, wherein said alcoholic solvent is selected from methanol, ethanol, n-propanol or isopropanol alone or combination thereof.
18. The process according to claim 16, wherein the chlorinated solvent is selected from dichloromethane or chloroform or mixture thereof.
19. The process according to claim 16, wherein the aromatic hydrocarbon is selected from toluene.
20. The process according to claim 16, wherein the ester is selected from ethyl acetate.
21. The process according to any of claim 14, 15 or 16, wherein the said secondary solvent is selected from alkyl ether, preferably diisopropyl ether or methyl tertiary butyl ether or mixture thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3007/DEL/2005 | 2005-11-10 | ||
| IN3007DE2005 | 2005-11-10 |
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| WO2007054978A2 true WO2007054978A2 (en) | 2007-05-18 |
| WO2007054978A3 WO2007054978A3 (en) | 2008-01-03 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1726591A2 (en) * | 2005-05-26 | 2006-11-29 | Apotecnia , S.A. | Process for manufacturing paroxetine hydrochloride hemihydrate |
| JP2010260826A (en) * | 2009-05-08 | 2010-11-18 | Sumitomo Chemical Co Ltd | Method of manufacturing paroxetine hydrochloride semihydrate |
| US7943582B2 (en) | 2006-12-04 | 2011-05-17 | Mitsubishi Tanabe Pharma Corporation | Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate |
| US8853385B2 (en) | 2008-01-17 | 2014-10-07 | Mitsubishi Tanabe Pharma Corporation | Combination therapy comprising SGLT inhibitors and DPP4 inhibitors |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4721723A (en) * | 1985-10-25 | 1988-01-26 | Beecham Group P.L.C. | Anti-depressant crystalline paroxetine hydrochloride hemihydrate |
| US5856493A (en) * | 1995-02-06 | 1999-01-05 | Smithkline Beecham Corporation | Process for making novel form of paroxeting hydrochloride anhydrate |
| WO2000032594A1 (en) * | 1998-11-30 | 2000-06-08 | Smithkline Beecham Plc | Mixed paroxetine propan-2-ol solvates |
-
2006
- 2006-11-10 WO PCT/IN2006/000446 patent/WO2007054978A2/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4721723A (en) * | 1985-10-25 | 1988-01-26 | Beecham Group P.L.C. | Anti-depressant crystalline paroxetine hydrochloride hemihydrate |
| US5856493A (en) * | 1995-02-06 | 1999-01-05 | Smithkline Beecham Corporation | Process for making novel form of paroxeting hydrochloride anhydrate |
| WO2000032594A1 (en) * | 1998-11-30 | 2000-06-08 | Smithkline Beecham Plc | Mixed paroxetine propan-2-ol solvates |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1726591A2 (en) * | 2005-05-26 | 2006-11-29 | Apotecnia , S.A. | Process for manufacturing paroxetine hydrochloride hemihydrate |
| EP1726591A3 (en) * | 2005-05-26 | 2007-07-25 | Apotecnia , S.A. | Process for manufacturing paroxetine hydrochloride hemihydrate |
| US7943582B2 (en) | 2006-12-04 | 2011-05-17 | Mitsubishi Tanabe Pharma Corporation | Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate |
| US8513202B2 (en) | 2006-12-04 | 2013-08-20 | Mitsubishi Tanabe Pharma Corporation | Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate |
| US8853385B2 (en) | 2008-01-17 | 2014-10-07 | Mitsubishi Tanabe Pharma Corporation | Combination therapy comprising SGLT inhibitors and DPP4 inhibitors |
| JP2010260826A (en) * | 2009-05-08 | 2010-11-18 | Sumitomo Chemical Co Ltd | Method of manufacturing paroxetine hydrochloride semihydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007054978A3 (en) | 2008-01-03 |
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