EP1155016A1 - Verfahren zur herstellung von paroxetinhydrochlorid-acetonsolvat - Google Patents
Verfahren zur herstellung von paroxetinhydrochlorid-acetonsolvatInfo
- Publication number
- EP1155016A1 EP1155016A1 EP99973028A EP99973028A EP1155016A1 EP 1155016 A1 EP1155016 A1 EP 1155016A1 EP 99973028 A EP99973028 A EP 99973028A EP 99973028 A EP99973028 A EP 99973028A EP 1155016 A1 EP1155016 A1 EP 1155016A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- paroxetine hydrochloride
- acetone solvate
- crystalline
- microns
- acetone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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 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.
- 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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9826178.7A GB9826178D0 (en) | 1998-11-30 | 1998-11-30 | Novel process |
GB9826178 | 1998-11-30 | ||
PCT/GB1999/003996 WO2000032595A1 (en) | 1998-11-30 | 1999-11-30 | Process for the production of paroxetine hydrochloride acetone solvate |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1155016A1 true EP1155016A1 (de) | 2001-11-21 |
Family
ID=10843290
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99973028A Withdrawn EP1155016A1 (de) | 1998-11-30 | 1999-11-30 | Verfahren zur herstellung von paroxetinhydrochlorid-acetonsolvat |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1155016A1 (de) |
JP (1) | JP2002531453A (de) |
AU (1) | AU1398100A (de) |
GB (1) | GB9826178D0 (de) |
WO (1) | WO2000032595A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9923445D0 (en) * | 1999-10-04 | 1999-12-08 | Smithkline Beecham Plc | Novel process |
GB9923439D0 (en) * | 1999-10-04 | 1999-12-08 | Smithkline Beecham Plc | Novel process |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
GB8430581D0 (en) * | 1984-12-04 | 1985-01-09 | Ferrosan As | Treatment |
EP0223403B1 (de) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidinderivat, seine Herstellung und seine Verwendung als Arzneimittel |
SK283608B6 (sk) * | 1995-02-06 | 2003-10-07 | Smithkline Beecham Plc | Bezvodý hydrochlorid paroxetínu, spôsob jeho výroby a použitie |
EP1394160A1 (de) * | 1996-06-13 | 2004-03-03 | SUMIKA FINE CHEMICALS Co., Ltd. | Verfahren zur Herstellung von kristallinem Paroxetin-Hydrochlorid |
HU221921B1 (hu) * | 1996-07-08 | 2003-02-28 | Richter Gedeon Vegyészeti Gyár Rt. | N-benzil-piperidin- és tetrahidropiridinszármazékok és eljárás azok előállítására |
-
1998
- 1998-11-30 GB GBGB9826178.7A patent/GB9826178D0/en not_active Ceased
-
1999
- 1999-11-30 AU AU13981/00A patent/AU1398100A/en not_active Abandoned
- 1999-11-30 EP EP99973028A patent/EP1155016A1/de not_active Withdrawn
- 1999-11-30 WO PCT/GB1999/003996 patent/WO2000032595A1/en not_active Application Discontinuation
- 1999-11-30 JP JP2000585237A patent/JP2002531453A/ja active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO0032595A1 * |
Also Published As
Publication number | Publication date |
---|---|
GB9826178D0 (en) | 1999-01-20 |
JP2002531453A (ja) | 2002-09-24 |
WO2000032595A1 (en) | 2000-06-08 |
AU1398100A (en) | 2000-06-19 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
Effective date: 20010809 |
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AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
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AX | Request for extension of the european patent |
Free format text: AL;LT;LV;MK;RO;SI |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: SMITHKLINE BEECHAM PLC |
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17Q | First examination report despatched |
Effective date: 20070201 |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 20070601 |