WO2001025230A1 - Process for the preparation of paroxetine hydrochloride acetone solvate - Google Patents
Process for the preparation of paroxetine hydrochloride acetone solvate Download PDFInfo
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- WO2001025230A1 WO2001025230A1 PCT/GB2000/003795 GB0003795W WO0125230A1 WO 2001025230 A1 WO2001025230 A1 WO 2001025230A1 GB 0003795 W GB0003795 W GB 0003795W WO 0125230 A1 WO0125230 A1 WO 0125230A1
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- WIPO (PCT)
- Prior art keywords
- paroxetine
- acetone
- solution
- paroxetine hydrochloride
- solvate
- Prior art date
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- Paroxetine hydrochlo ⁇ de has been described as a crystalline hemihydrate (see EP- 0223403) and as va ⁇ ous crystalline anhydrate forms (see WO 96/24595).
- a particularly useful crystalline form of paroxetine hydrochlo ⁇ de is paroxetine hydrochlo ⁇ de anhydrate Form A, which may be prepared by the desolvation of paroxetine hydrochlo ⁇ de solvates.
- a particularly useful solvate for this purpose is paroxetine hydrochloride acetone solvate.
- Example 9 of WO 96/24595 desc ⁇ bes a laboratory scale preparation of paroxetine hydrochlo ⁇ de acetone solvate which involves the addition of a solution of hydrogen chlo ⁇ de m acetone to a solution of paroxetine free base in acetone
- this procedure is unsuitable for large scale manufacture due to the instability of the solution of hydrogen chloride in acetone
- Example 20 of WO 96/24595 describes the preparation of paroxetine hydrochloride acetone solvate by heating to reflux a suspension of paroxetine hydrochloride anhydrate Form C in acetone.
- This method requires a large amount of solvent (15 volumes), which is an undesirable feature for a manufacturing process, but even at this dilution a clear solution is not obtained. Such a procedure therefore carries the risk of incomplete conversion, particularly on a large scale.
- a procedure which requires paroxetine hydrochloride anhydrate Form C as a starting material involves an additional step in the reaction sequence, and adds to the cost and complexity of the operation.
- This invention is based on the finding that the problems that exist with the known process for preparing paroxetine hydrochloride acetone solvate may be overcome by use an alternative solvent as a carrier solvent for the hydrogen chloride.
- this invention provides a process in which a solution of paroxetine base, or a salt of paroxetine with an organic acid, is treated with acetone and a solution of hydrogen chloride in an carrier solvent, and paroxetine hydrochloride acetone solvate is isolated as a crystalline solid.
- a suitable organic acid is acetic acid.
- Suitable carrier solvents are acetone miscible solvents in which hydrogen chloride is soluble and in which a stable solution of hydrogen chloride is formed.
- Suitable solvents include: alcohols such as methanol or ethanol: esters for example ethylacetate or methylacetate; nitriles for example acetonitrile; ethers for example dioxane or tetrahydrofuran and halogenated hydrocarbons for example dichloromethane or chloroform.
- Preferred carrier solvents are solvents which do not form a solvate with paroxetine hydrochloride anhydrate Form A and hence do not compete with acetone as solvate molecules during the crystallization of paroxetine hydrochloride acetone solvate.
- a particularly preferred carrier solvent on a manufacturing scale is methanol.
- the carrier solvent forms an azeotrope with acetone and may be removed by partial distillation of the paroxetine hydrochloride solution.
- a solvent which forms a solvate with paroxetine hydrochloride anhydrate Form A may be selected for use as the carrier solvent.
- paroxetine hydrochloride acetone solvate may be crystallised using the process of this invention by use of paroxetine free base in a mixed solvent system, that is one which contains a significant proportion of an additional solvent
- the solution of hydrogen chloride in the carrier solvent is added to a solution of paroxetine free base in a mixture of acetone and an additional solvent to afford paroxetine hydrochloride acetone solvate
- a particularly preferred additional solvent on a manufacturing scale is toluene, as a solution of paroxetine free base in toluene may be carried forward from a previous manufacturing step.
- Paroxetine free base and salts may be prepared as described US 4,007,196 or EP-A-0,223,403.
- paroxetine hydrochloride anhydrate Form A is manufactured by desolvating the acetone solvate by procedures described in WO 96/24595.
- paroxetine hydrochloride anhydrate Form A obtainable by this invention may be used in therapy in formulations described in EP-A-0223403 or WO 96/00477.
- paroxetine hydrochloride anhydrate obtainable by this invention include treatment of inter alia : alcoholism, anxiety, depression, obsessive compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders”.
- OCD obsessive compulsive disorder
- PMS pre-menstrual syndrome
- adolescent depression trichotillomania
- dysthymia substance abuse
- anhydrate obtainable by the present invention is applied to the treatment of depression, OCD and panic.
- compositions prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
- the composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
- Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.
- the compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
- Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
- compositions include those described EP-B- 0223403, and US 4,007,196 in which the anhydrate product of the present invention may be used as the active ingredient.
- the present invention also provides:
- compositions for treatment or prophylaxis of the Disorders comprising paroxetine hydrochloride anhydrate Form A obtainable by this invention and a pharmaceutically acceptable carrier;
- paroxetine hydrochloride anhydrate Form A obtainable by this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders;
- a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate Form A obtainable by this invention to a person suffering from one or more of the Disorders.
- IR bands at cm" 1 3631, 3406, 1713, 1631, 1604, 1563, 1513, 1493, 1466, 1341, 1286, 1248, 1220, 1 195, 1 170, 1132, 1091, 1068, 1034, 1005, 982, 965, 924, 907, 887, 839, 806, 783, 761, 722, 665, 614, 592, 571, 539, 512.
- N-phenoxycarbonyl paroxetine (19.4 g), potassium hydroxide (17.5 g) and toluene (300 ml) is heated to reflux under a nitrogen atmosphere for 3 hours.
- the mixture is cooled to room temperature, washed with water (200 ml) and the organic layer separated, dried over magnesium sulphate and concentrated to a total volume of 75 ml.
- the solution is diluted with dry acetone (100 ml) and a solution hydrochloric acid in methanol (5.5 N, 8.0 ml) is added to the mixture under a nitrogen atmosphere.
- the mixture is stirred for 30 minutes and the product collected by filtration, washed with acetone (50 ml) and dried under vacuum at 60°C for 20 hours.
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- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
A process for preparing paroxetine hydrochloride acetone solvate, in which a solution of paroxetine base, or a salt of paroxetine with an organic acid, is treated with acetone and a solution of hydrogen chloride in a carrier solvent, and paroxetine hydrochloride acetone solvate is isolated as a crystalline solid.
Description
NOVEL PROCESS
PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE ACETONE SOLVATE
Pharmaceutical products with antidepressant and anti-Parkinson properties are descπbed in US-A-3912743 and US-A-4007196 An especially important compound among those disclosed is paroxetine, the (-)trans isomer of 4-(4'-fluorophenyl)-3',4'- methylenedιoxy-phenoxymethyl)-pιpeπdιne. This compound is used in therapy as the hydrochloπde salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic
Paroxetine hydrochloπde has been described as a crystalline hemihydrate (see EP- 0223403) and as vaπous crystalline anhydrate forms (see WO 96/24595). A particularly useful crystalline form of paroxetine hydrochloπde is paroxetine hydrochloπde anhydrate Form A, which may be prepared by the desolvation of paroxetine hydrochloπde solvates. A particularly useful solvate for this purpose is paroxetine hydrochloride acetone solvate.
Example 9 of WO 96/24595 descπbes a laboratory scale preparation of paroxetine hydrochloπde acetone solvate which involves the addition of a solution of hydrogen chloπde m acetone to a solution of paroxetine free base in acetone Although it is possible to carry out this procedure on a small scale by rapid addition of a freshly prepared solution of hydrogen chloride in acetone to a solution of paroxetine free base, this procedure is unsuitable for large scale manufacture due to the instability of the solution of hydrogen chloride in acetone
It is well documented that hydrogen chloπde promotes aldol condensation reactions of ketones such as acetone, hence a solution of hydrogen chloπde in acetone at ambient temperature will undergo self-condensation reactions and further reactions with the condensation products, leading to a cascade of side-reactions. Such a series of uncontrolled side reactions is a highly undesirable feature for a manufacturing process
and can lead to non-reproducible reactions, and problems of contamination of the required product with impurities.
Water is generated as a side product of the aldol condensation reactions, the presence of which in the crystallization process has been found to lead to the formation of paroxetine hydrochloride hemihydrate.
There are further problems with the use of hydrogen chloride gas to prepare the solutions of hydrogen chloride in acetone on a manufacturing scale, for example the cost of the necessary capital equipment, the dangers of toxic gas handling, and the inability to store the solutions.
Example 20 of WO 96/24595 describes the preparation of paroxetine hydrochloride acetone solvate by heating to reflux a suspension of paroxetine hydrochloride anhydrate Form C in acetone. This method requires a large amount of solvent (15 volumes), which is an undesirable feature for a manufacturing process, but even at this dilution a clear solution is not obtained. Such a procedure therefore carries the risk of incomplete conversion, particularly on a large scale. Furthermore, a procedure which requires paroxetine hydrochloride anhydrate Form C as a starting material involves an additional step in the reaction sequence, and adds to the cost and complexity of the operation.
This invention is based on the finding that the problems that exist with the known process for preparing paroxetine hydrochloride acetone solvate may be overcome by use an alternative solvent as a carrier solvent for the hydrogen chloride.
In its broadest aspect this invention provides a process in which a solution of paroxetine base, or a salt of paroxetine with an organic acid, is treated with acetone and a solution of hydrogen chloride in an carrier solvent, and paroxetine hydrochloride acetone solvate is isolated as a crystalline solid.
A suitable organic acid is acetic acid.
Suitable carrier solvents are acetone miscible solvents in which hydrogen chloride is soluble and in which a stable solution of hydrogen chloride is formed. Suitable solvents include: alcohols such as methanol or ethanol: esters for example ethylacetate or methylacetate; nitriles for example acetonitrile; ethers for example dioxane or tetrahydrofuran and halogenated hydrocarbons for example dichloromethane or chloroform.
Preferred carrier solvents are solvents which do not form a solvate with paroxetine hydrochloride anhydrate Form A and hence do not compete with acetone as solvate molecules during the crystallization of paroxetine hydrochloride acetone solvate. A particularly preferred carrier solvent on a manufacturing scale is methanol.
In an alternative aspect of the invention the carrier solvent forms an azeotrope with acetone and may be removed by partial distillation of the paroxetine hydrochloride solution. In this case a solvent which forms a solvate with paroxetine hydrochloride anhydrate Form A may be selected for use as the carrier solvent.
Surprisingly we have found that paroxetine hydrochloride acetone solvate may be crystallised using the process of this invention by use of paroxetine free base in a mixed solvent system, that is one which contains a significant proportion of an additional solvent
Thus in a further aspect of the invention the solution of hydrogen chloride in the carrier solvent is added to a solution of paroxetine free base in a mixture of acetone and an additional solvent to afford paroxetine hydrochloride acetone solvate
A particularly preferred additional solvent on a manufacturing scale is toluene, as a solution of paroxetine free base in toluene may be carried forward from a previous manufacturing step.
Paroxetine free base and salts may be prepared as described US 4,007,196 or EP-A-0,223,403.
In a further aspect of the invention paroxetine hydrochloride anhydrate Form A is manufactured by desolvating the acetone solvate by procedures described in WO 96/24595.
The paroxetine hydrochloride anhydrate Form A obtainable by this invention may be used in therapy in formulations described in EP-A-0223403 or WO 96/00477.
Therapeutic uses of the paroxetine hydrochloride anhydrate obtainable by this invention include treatment of inter alia : alcoholism, anxiety, depression, obsessive compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders".
Most suitably the anhydrate obtainable by the present invention is applied to the treatment of depression, OCD and panic.
The compositions prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
The composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.
The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
Specific examples of pharmaceutical compositions include those described EP-B- 0223403, and US 4,007,196 in which the anhydrate product of the present invention may be used as the active ingredient.
Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine hydrochloride anhydrate Form A obtainable by this invention and a pharmaceutically acceptable carrier;
the use of paroxetine hydrochloride anhydrate Form A obtainable by this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders; and
a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate Form A obtainable by this invention to a person suffering from one or more of the Disorders.
The invention is illustrated by the following Examples
Example 1
Dry acetone (60 ml) was added paroxetine free base (10.0 g) and the mixture stirred until a clear solution was obtained. A solution of hydrogen chloride in methanol (5.5N, 5.5 ml) was added and the mixture stirred for 30 minutes. The product was collected by filtration, washed with acetone (20 ml) and dried at 60°C for 20 hours.
Weight of product: 8.9 g. Analysis by 1H-NMR indicated the presence of acetone, 1.5% wt/wt.
IR (nujol mull) bands at cm"1 : 3631, 3406, 1713, 1631, 1604, 1563, 1513, 1493, 1466, 1341, 1286, 1248, 1220, 1 195, 1 170, 1132, 1091, 1068, 1034, 1005, 982, 965, 924, 907, 887, 839, 806, 783, 761, 722, 665, 614, 592, 571, 539, 512.
Example 2
A stirred mixture of N-phenoxycarbonyl paroxetine (19.4 g), potassium hydroxide (17.5 g) and toluene (300 ml) is heated to reflux under a nitrogen atmosphere for 3 hours. The mixture is cooled to room temperature, washed with water (200 ml) and the organic layer separated, dried over magnesium sulphate and concentrated to a total volume of 75 ml. The solution is diluted with dry acetone (100 ml) and a solution hydrochloric acid in methanol (5.5 N, 8.0 ml) is added to the mixture under a nitrogen atmosphere. The mixture is stirred for 30 minutes and the product collected by filtration, washed with acetone (50 ml) and dried under vacuum at 60°C for 20 hours.
Claims
1. A process for preparing paroxetine hydrochloride acetone solvate, in which a solution of paroxetine base, or a salt of paroxetine with an organic acid, is treated with acetone and a solution of hydrogen chloride in an carrier solvent, and paroxetine hydrochloride acetone solvate is isolated as a crystalline solid.
2. A process according to claim 1 in which the carrier solvent is selected from: alcohols such as methanol or ethanol: esters for example ethylacetate or methylacetate; nitriles for example acetonitrile; ethers for example dioxane or tetrahydrofuran and halogenated hydrocarbons for example dichloromethane or chloroform.
3. A process according to claim 1 in which the carrier solvent forms an azeotrope with acetone and is removed by partial distillation of the paroxetine hydrochloride solution.
4. A process according to any one of claims 1 to 3 in which the solution of hydrogen chloride in the carrier solvent is added to a solution of paroxetine free base in a mixture of acetone and an additional solvent to afford paroxetine hydrochloride acetone solvate
5. A process according to any one of claims 1 to 4 in which the crystalline product is desolvated to obtain paroxetine hydrochloride anhydrate Form A.
6. A method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate Form A obtainable by this invention to a person suffering from one or more of the Disorders.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU75422/00A AU7542200A (en) | 1999-10-04 | 2000-10-04 | Process for the preparation of paroxetine hydrochloride acetone solvate |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9923445.2 | 1999-10-04 | ||
| GBGB9923445.2A GB9923445D0 (en) | 1999-10-04 | 1999-10-04 | Novel process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001025230A1 true WO2001025230A1 (en) | 2001-04-12 |
Family
ID=10862098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2000/003795 WO2001025230A1 (en) | 1999-10-04 | 2000-10-04 | Process for the preparation of paroxetine hydrochloride acetone solvate |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7542200A (en) |
| GB (1) | GB9923445D0 (en) |
| WO (1) | WO2001025230A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996024595A1 (en) * | 1995-02-06 | 1996-08-15 | Smithkline Beecham Plc | New forms of paroxetin hydrochloride |
| WO2000032595A1 (en) * | 1998-11-30 | 2000-06-08 | Smithkline Beecham Plc | Process for the production of paroxetine hydrochloride acetone solvate |
-
1999
- 1999-10-04 GB GBGB9923445.2A patent/GB9923445D0/en not_active Ceased
-
2000
- 2000-10-04 WO PCT/GB2000/003795 patent/WO2001025230A1/en active Application Filing
- 2000-10-04 AU AU75422/00A patent/AU7542200A/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996024595A1 (en) * | 1995-02-06 | 1996-08-15 | Smithkline Beecham Plc | New forms of paroxetin hydrochloride |
| WO2000032595A1 (en) * | 1998-11-30 | 2000-06-08 | Smithkline Beecham Plc | Process for the production of paroxetine hydrochloride acetone solvate |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7542200A (en) | 2001-05-10 |
| GB9923445D0 (en) | 1999-12-08 |
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