WO2000032595A1 - Process for the production of paroxetine hydrochloride acetone solvate - Google Patents

Process for the production of paroxetine hydrochloride acetone solvate Download PDF

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Publication number
WO2000032595A1
WO2000032595A1 PCT/GB1999/003996 GB9903996W WO0032595A1 WO 2000032595 A1 WO2000032595 A1 WO 2000032595A1 GB 9903996 W GB9903996 W GB 9903996W WO 0032595 A1 WO0032595 A1 WO 0032595A1
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Prior art keywords
paroxetine hydrochloride
acetone solvate
crystalline
microns
acetone
Prior art date
Application number
PCT/GB1999/003996
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French (fr)
Inventor
Andrew Simon Craig
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Smithkline Beecham Plc
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Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP99973028A priority Critical patent/EP1155016A1/en
Priority to AU13981/00A priority patent/AU1398100A/en
Priority to JP2000585237A priority patent/JP2002531453A/en
Publication of WO2000032595A1 publication Critical patent/WO2000032595A1/en

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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
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a process for the preparation of a pharmaceutically active compound and intermediates thereof, and to the use of the active compound in therapy.
  • this invention is concerned with a new process for the preparation of paroxetine chloride acetone solvate and its use to prepare a crystalline anhydrate form of paroxetine hydrochloride.
  • Paroxetine hydrochloride has been described in the literature as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group) and as various crystalline anhydrate forms (see WO96/24595 of SmithKline Beecham).
  • WO96/24595 describes the preparation of paroxetine hydrochloride acetone solvate which is a useful intermediate for the preparation of paroxetine hydrochloride anhydrate Form A.
  • paroxetine hydrochloride acetone solvate When prepared conventionally by crystallisation from anhydrous acetone, paroxetine hydrochloride acetone solvate has poor stirring properties, and is difficult to isolate, wash, and dry.
  • This invention provides processes for the preparation of paroxetine hydrochloride acetone solvate in a form which is more easily desolvated than paroxetine hydrochloride acetone solvate prepared in a conventional manner, and hence more suitable for commercial manufacturing processes.
  • a process for preparing crystalline paroxetine hydrochloride acetone solvate which comprises providing a solution of paroxetine hydrochloride in acetone, adding to the solution a habit modifier compound, and crystallising paroxetine hydrochloride acetone solvate from the modified solution.
  • Suitable habit modifying compounds are selected from those compounds that are ionic or readily ionisable and are soluble in acetone.
  • the addition of the indicated habit modifier compound to the solution modifies the habit of the resultant crystals to a form which allows for convenient stirring, filtering and washing on a manufacturing scale, and more effective de-solvation of the crystals.
  • a suitable concentration of paroxetine hydrochloride in acetone is one part in between 10 and 50 volumes of acetone, preferably between 15 and 40 volumes, and more preferably between 20 and 30 volumes.
  • the acetone is anhydrous to suppress formation of paroxetine hydrochloride hemihydrate.
  • Suitable procedures for preparing paroxetine hydrochloride for dissolution in acetone for use in the process of this invention include those mentioned in US Patents 4,009,196; 4,721,723; 4,902,801; 4,861,893 and 5,039,803.
  • Suitable habit modifiers are carboxylic acids, preferably acetic acid, and amine salts, particularly hydrochloride or acetate salts, for example diethylamine hydrochloride or ammonium acetate.
  • the amount of carboxylic acid habit modifier used is suitably from 1 to 20% of the solvent volume, preferably from 1 to 10%.
  • a suitable amount of amine salt habit modifier is in the range 5-25 mole %, preferably 10- 20 mole %.
  • Crystallisation may be initiated by conventional procedures such as cooling a heated solution, or removing solvent by evaporation or heating. It may be advantageous to add seeds of crystalline paroxetine hydrochloride acetone solvate prepared by the procedure of this invention or by the procedure of WO 96/24595.
  • the crystalline paroxetine hydrochloride acetone solvate of modified crystal habit obtainable by the process of this invention is a different crystalline form from the previously known product. This novel product forms another aspect of this invention.
  • Paroxetine hydrochloride acetone solvate crystals prepared conventionally are large and long, typically with most of the material in the form of crystals in excess of 300 microns in length, with a length-to-width ratio in excess of 40:1, and a volume of 20,000 cubic microns or more.
  • most of the material is in crystals less than 100 microns long, preferably below 75 microns, and more preferably below 50 microns, and with a length-to-width ratio below 20:1, preferably below 15:1 and more preferably below 10:1, and with a volume below 5,000 cubic microns, preferably below 2,500 cubic microns and more preferably below 1,000 cubic microns.
  • the product of this invention may have either one, two or all three of these desirable characteristics.
  • paroxetine hydrochloride acetone solvate of modified habit in which the mean distance between crystal facets characterised by the Miller indices (0, 1, 0) and (0, 1, 0) in a monoclinic crystal system, P2, space group is minimised, and is preferably below 100 microns.
  • paroxetine hydrochloride acetone solvate with these characteristics may be processed and desolvated more easily than conventionally produced paroxetine hydrochloride acetone solvate.
  • the crystallisation process may include if necessary isolating the crystals, optionally washing and drying to remove surface solvent.
  • the crystalline solvate is used as a feed material for desolvation to obtain paroxetine hydrochloride anhydrates, especially the Form A anhydrate.
  • the present invention provides a process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating crystalline acetone solvate obtainable by the process of this invention to remove bound acetone.
  • Desolvation is conveniently carried out by heating in an oven, preferably in vacuo, suitably at a temperature of about 50°C.
  • the resultant anhydrate desirably contains less than 4% of acetone, preferably less than 2%, more preferably less than 1%, and most preferably less than 0.5%.
  • the crystalline anhydrate is the Form A anhydrate of paroxetine hydrochloride.
  • the crystalline paroxetine hydrochloride anhydrate obtainable by this invention may be used in therapy in formulations described in EP-A-0223403 or WO 96/00477.
  • paroxetine hydrochloride anhydrate of this invention include treatment of: 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
  • the 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 lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg 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 400mg 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.
  • 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: a pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine hydrochloride anhydrate obtainable by this invention and a pharmaceutically acceptable carrier;
  • paroxetine hydrochloride anhydrate 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 obtainable by this invention to a person suffering from one or more of the disorders.
  • the invention is illustrated by the following Examples.
  • drying has been carried out under standardised conditions for the purpose of comparison.
  • Conventionally prepared paroxetine hydrochloride acetone solvate contains approximately 6% acetone under these drying conditions.
  • Paroxetine hydrochloride with lower residual acetone can be obtained by increasing the drying time or temperature.
  • paroxetine hydrochloride 10 g
  • acetone 300 ml
  • diethylamine hydrochloride 0.5g
  • the reaction mixture is slowly cooled to room temperature with stirring.
  • the resulting white crystalline solid is filtered, washed with acetone and dried under vacuum at 45 °C for 20 hours to give paroxetine hydrochloride, containing approximately 1.5% acetone by weight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Crystalline paroxetine hydrochloride acetone solvate having a modified habit that is more easily desolvated to form the anhydrate is obtained by crystallising from a solution of paroxetine hydrochloride in acetone to which has been added a habit modifier compound. Form A anhydrate is obtained by heating the crystalline solvate of modified habit in a vacuum oven. Suitable habit modifiers are carboxylic acids and amine salts.

Description

PROCESS FOR THE PRODUCTION OF PAROXETINE HYDROCHLORIDE ACETONE SOLVATE
The present invention relates to a process for the preparation of a pharmaceutically active compound and intermediates thereof, and to the use of the active compound in therapy. In particular this invention is concerned with a new process for the preparation of paroxetine chloride acetone solvate and its use to prepare a crystalline anhydrate form of paroxetine hydrochloride.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described 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-(3",4"- methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of mter alia depression, obsessive compulsive disorder (OCD) and panic.
Paroxetine hydrochloride has been described in the literature as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group) and as various crystalline anhydrate forms (see WO96/24595 of SmithKline Beecham). WO96/24595 describes the preparation of paroxetine hydrochloride acetone solvate which is a useful intermediate for the preparation of paroxetine hydrochloride anhydrate Form A. When prepared conventionally by crystallisation from anhydrous acetone, paroxetine hydrochloride acetone solvate has poor stirring properties, and is difficult to isolate, wash, and dry.
The desolvation of paroxetine hydrochloride acetone solvate in a vacuum oven is a slow and difficult process. Furthermore, when operated on a scale larger than a few grammes, the time and temperature necessary for substantially complete desolvation increase very greatly. Lengthy treatment is undesirable for manufacturing because of the costs associated with vessel occupancy, and high temperatures cause degradation and phase transformation in the product.
Another undesirable feature of the existing process is the tendency for the product to crystallise in a heavy matted form which is very difficult to stir, transfer, and filter. It is therefore evident that the existing process is unsuitable for the large scale manufacture of paroxetine hydrochloride.
This invention provides processes for the preparation of paroxetine hydrochloride acetone solvate in a form which is more easily desolvated than paroxetine hydrochloride acetone solvate prepared in a conventional manner, and hence more suitable for commercial manufacturing processes.
According to one aspect of the present invention there is provided a process for preparing crystalline paroxetine hydrochloride acetone solvate which comprises providing a solution of paroxetine hydrochloride in acetone, adding to the solution a habit modifier compound, and crystallising paroxetine hydrochloride acetone solvate from the modified solution. Suitable habit modifying compounds are selected from those compounds that are ionic or readily ionisable and are soluble in acetone.
The addition of the indicated habit modifier compound to the solution modifies the habit of the resultant crystals to a form which allows for convenient stirring, filtering and washing on a manufacturing scale, and more effective de-solvation of the crystals.
A suitable concentration of paroxetine hydrochloride in acetone is one part in between 10 and 50 volumes of acetone, preferably between 15 and 40 volumes, and more preferably between 20 and 30 volumes. Preferably the acetone is anhydrous to suppress formation of paroxetine hydrochloride hemihydrate.
Suitable procedures for preparing paroxetine hydrochloride for dissolution in acetone for use in the process of this invention include those mentioned in US Patents 4,009,196; 4,721,723; 4,902,801; 4,861,893 and 5,039,803.
Examples of suitable habit modifiers are carboxylic acids, preferably acetic acid, and amine salts, particularly hydrochloride or acetate salts, for example diethylamine hydrochloride or ammonium acetate. The amount of carboxylic acid habit modifier used is suitably from 1 to 20% of the solvent volume, preferably from 1 to 10%.
A suitable amount of amine salt habit modifier is in the range 5-25 mole %, preferably 10- 20 mole %.
Crystallisation may be initiated by conventional procedures such as cooling a heated solution, or removing solvent by evaporation or heating. It may be advantageous to add seeds of crystalline paroxetine hydrochloride acetone solvate prepared by the procedure of this invention or by the procedure of WO 96/24595.
The crystalline paroxetine hydrochloride acetone solvate of modified crystal habit obtainable by the process of this invention is a different crystalline form from the previously known product. This novel product forms another aspect of this invention.
One characteristic in which the new form differs from the previously known form is in the particle size distribution and mean particle volume. Paroxetine hydrochloride acetone solvate crystals prepared conventionally are large and long, typically with most of the material in the form of crystals in excess of 300 microns in length, with a length-to-width ratio in excess of 40:1, and a volume of 20,000 cubic microns or more. By contrast in the novel form of paroxetine hydrochloride acetone solvate, most of the material is in crystals less than 100 microns long, preferably below 75 microns, and more preferably below 50 microns, and with a length-to-width ratio below 20:1, preferably below 15:1 and more preferably below 10:1, and with a volume below 5,000 cubic microns, preferably below 2,500 cubic microns and more preferably below 1,000 cubic microns. The product of this invention may have either one, two or all three of these desirable characteristics.
During the course of our investigations we have discovered that one particular crystallographic axis is critical to the rapid desolvation of paroxetine hydrochloride acetone solvate. Hence, in another aspect of this invention there is provided paroxetine hydrochloride acetone solvate of modified habit in which the mean distance between crystal facets characterised by the Miller indices (0, 1, 0) and (0, 1, 0) in a monoclinic crystal system, P2, space group is minimised, and is preferably below 100 microns.
It has been found that paroxetine hydrochloride acetone solvate with these characteristics may be processed and desolvated more easily than conventionally produced paroxetine hydrochloride acetone solvate.
The crystallisation process may include if necessary isolating the crystals, optionally washing and drying to remove surface solvent. However advantageously the crystalline solvate is used as a feed material for desolvation to obtain paroxetine hydrochloride anhydrates, especially the Form A anhydrate.
Accordingly, in a further aspect the present invention provides a process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating crystalline acetone solvate obtainable by the process of this invention to remove bound acetone.
Desolvation is conveniently carried out by heating in an oven, preferably in vacuo, suitably at a temperature of about 50°C.
The resultant anhydrate desirably contains less than 4% of acetone, preferably less than 2%, more preferably less than 1%, and most preferably less than 0.5%. Advantageously the crystalline anhydrate is the Form A anhydrate of paroxetine hydrochloride.
The crystalline paroxetine hydrochloride anhydrate 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 of this invention include treatment of: 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 lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg 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 400mg 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 obtainable by this invention and a pharmaceutically acceptable carrier;
the use of paroxetine hydrochloride anhydrate 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 obtainable by this invention to a person suffering from one or more of the disorders.
The invention is illustrated by the following Examples. In the Examples drying has been carried out under standardised conditions for the purpose of comparison. Conventionally prepared paroxetine hydrochloride acetone solvate contains approximately 6% acetone under these drying conditions. Paroxetine hydrochloride with lower residual acetone can be obtained by increasing the drying time or temperature.
Example
A solution of paroxetine hydrochloride (10 g) in acetone (300 ml) is heated at reflux then cooled to 45°C and treated with diethylamine hydrochloride (0.5g). The reaction mixture is slowly cooled to room temperature with stirring. The resulting white crystalline solid is filtered, washed with acetone and dried under vacuum at 45 °C for 20 hours to give paroxetine hydrochloride, containing approximately 1.5% acetone by weight.

Claims

1. A process for obtaining crystalline paroxetine hydrochloride acetone solvate which comprises providing a solution of paroxetine hydrochloride in acetone, adding to the solution a habit modifier compound, and crystallising paroxetine hydrochloride acetone solvate from the modified solution.
2. A process according to claim 1 in which the habit modifier is an ionic or easily ionisable compound.
3. A process according to claim 1 in which the habit modifier is a carboxylic acid or an amine salt.
4. A process according to claims 1 to 3 for the production of paroxetine hydrochloride acetone solvate from which more than 50% by weight of the product consists of crystals in which the distance between the facets with Miller indices (0, 1, 0) and (0, ~1, 0) in a monoclinic crystal system, P2, space group, is less than 100 microns.
5. Crystalline paroxetine hydrochloride acetone solvate of modified crystal habit obtainable by a process according to claim 1 or 2.
6. Crystalline paroxetine hydrochloride acetone solvate of modified crystal habit in which more than 50% by weight of the material is in crystals less than 100 microns long, preferably below 75 microns, and more preferably below 50 microns.
7. Crystalline paroxetine hydrochloride acetone solvate of modified crystal habit in which more than 50% by weight of the material is in crystals with a length-to-width ratio below 20: 1 , preferably below 15:1 and more preferably below 10:1.
8. Crystalline paroxetine hydrochloride acetone solvate of modified crystal habit in which more than 50% by weight of the material is in crystals with a volume below 5,000 cubic microns, preferably below 2,500 cubic microns and more preferably below 1,000 cubic microns.
9. Crystalline paroxetine hydrochloride acetone solvate of modified crystal habit in which the distance between crystal facets characterised by the Miller indices (0, 1, 0) and (0, _1,
0) in a monoclinic crystal system, P2, space group, is below 100 microns for more than 50% by weight of the product.
10. A process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating crystalline acetone solvate obtainable by the process of claim 1, 2 or 3 to remove bound acetone.
11. A pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine hydrochloride anhydrate obtainable by the process of claim 1, 2 or 3 and a pharmaceutically acceptable carrier;
12. Use of paroxetine hydrochloride anhydrate obtainable by the process of claim 1, 2 or 3 to manufacture a medicament for the treatment or prophylaxis of the disorders; and
13. A method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate obtainable by the process of claim 1 , 2 or 3 to a person suffering from one or more of the disorders.
14. Paroxetine hydrochloride acetone solvate that is more easily desolvated, such that in a drying comparison with conventionally crystallised paroxetine hydrochloride acetone solvate under standard drying conditions, retains less than 75% of the acetone in the standard, preferably less than 50%, and more preferably less than 25%.
15. The process of drying paroxetine hydrochloride acetone solvate claimed in or prepared by the processes claimed in any of the above claims.
PCT/GB1999/003996 1998-11-30 1999-11-30 Process for the production of paroxetine hydrochloride acetone solvate WO2000032595A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP99973028A EP1155016A1 (en) 1998-11-30 1999-11-30 Process for the production of paroxetine hydrochloride acetone solvate
AU13981/00A AU1398100A (en) 1998-11-30 1999-11-30 Process for the production of paroxetine hydrochloride acetone solvate
JP2000585237A JP2002531453A (en) 1998-11-30 1999-11-30 Preparation of paroxetine hydrochloride acetone solvate

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Application Number Priority Date Filing Date Title
GBGB9826178.7A GB9826178D0 (en) 1998-11-30 1998-11-30 Novel process
GB9826178.7 1998-11-30

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001025232A1 (en) * 1999-10-04 2001-04-12 Smithkline Beecham Plc Process for the preparation of paroxetine hydrochloride acetone solvate
WO2001025230A1 (en) * 1999-10-04 2001-04-12 Smithkline Beecham Plc Process for the preparation of paroxetine hydrochloride acetone solvate

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0188081A2 (en) * 1984-12-04 1986-07-23 Novo Nordisk A/S Use of paroxetine for the manufacture of a medicament for the treatment of obesity
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
WO1996024595A1 (en) * 1995-02-06 1996-08-15 Smithkline Beecham Plc New forms of paroxetin hydrochloride
EP0812827A1 (en) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Piperidine derivative as intermediates for the preparation of paroxetine and process for their preparation
WO1998001424A1 (en) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. N-benzylpiperidine and tetrahydropyridine derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0188081A2 (en) * 1984-12-04 1986-07-23 Novo Nordisk A/S Use of paroxetine for the manufacture of a medicament for the treatment of obesity
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
WO1996024595A1 (en) * 1995-02-06 1996-08-15 Smithkline Beecham Plc New forms of paroxetin hydrochloride
EP0812827A1 (en) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Piperidine derivative as intermediates for the preparation of paroxetine and process for their preparation
WO1998001424A1 (en) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. N-benzylpiperidine and tetrahydropyridine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
P. C. BUXTON ET AL.: "Solid-state forms of paroxetine hydrochloride", INTERNTIONAL JOURNAL OF PHARMACEUTICS, vol. 42, 1988, pages 135 - 143, XP000572028 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001025232A1 (en) * 1999-10-04 2001-04-12 Smithkline Beecham Plc Process for the preparation of paroxetine hydrochloride acetone solvate
WO2001025230A1 (en) * 1999-10-04 2001-04-12 Smithkline Beecham Plc Process for the preparation of paroxetine hydrochloride acetone solvate

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EP1155016A1 (en) 2001-11-21
AU1398100A (en) 2000-06-19
JP2002531453A (en) 2002-09-24

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