WO2000032594A1 - Mixed paroxetine propan-2-ol solvates - Google Patents
Mixed paroxetine propan-2-ol solvates Download PDFInfo
- Publication number
- WO2000032594A1 WO2000032594A1 PCT/GB1999/003993 GB9903993W WO0032594A1 WO 2000032594 A1 WO2000032594 A1 WO 2000032594A1 GB 9903993 W GB9903993 W GB 9903993W WO 0032594 A1 WO0032594 A1 WO 0032594A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- propan
- paroxetine hydrochloride
- solvate
- process according
- solvent
- Prior art date
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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
-
- 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 a mixed paroxetine chloride 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 WO 96/24595 of SmithKline Beecham).
- WO 96/24595 describes the preparation of paroxetine hydrochloride propan-2-ol solvate which is a useful intermediate for the preparation of paroxetine hydrochloride anhydrate Form A.
- paroxetine hydrochloride propan-2-ol solvate has very poor stirring properties, and is very difficult to isolate, wash, and desolvate.
- 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.
- a glass-lined reactor containing a vigorously stirred solution of 20 kg of paroxetine hydrochloride in 160 litres of propan-2-ol was seeded at 48°C. The entire contents set to a thick crystalline mass, and it was necessary to open the man-way and manually dislodge the contents so that the mixture could be stirred and the product collected. 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 a modified paroxetine hydrochloride propan-2-ol solvate which is more easily desolvated than paroxetine hydrochloride propan-2-ol solvate prepared in a conventional manner, and hence more suitable for commercial manufacturing processes.
- a novel compound a crystalline paroxetine hydrochloride which is solvated with propan-2-ol and at least one other solvent.
- Especially the present invention provides crystalline paroxetine hydrochloride acetone propan-2-ol mixed solvate.
- a process for preparing a crystalline paroxetine hydrochloride mixed solvate which comprises contacting crystalline paroxetine hydrochloride propan-2-ol solvate with a transformation solvent.
- the crystalline paroxetine hydrochloride propan-2-ol solvate is typically prepared by providing a solution of paroxetine hydrochloride in propan-2-ol, and crystallising the propan-2-ol solvate from the solution.
- the crystalline paroxetine hydrochloride propan-2-ol solvate may be prepared by adding propan-2-ol to paroxetine hydrochloride, which may be in crystalline or non-crystalline form (e.g. an amo ⁇ hous solid or an oil), and stirring.
- the m xe so vate may be prepared by crystallising paroxetine hydrochloride from a solution in propan-2-ol and a transformation solvent.
- the transformation solvent is a solvent which results in the form of the crystalline product being changed to a mixed solvate, which is more easily desolvated.
- the transformation solvent may be an ether, ketone, chlorinated hydrocarbon, nitrile, lower alcohol, or ester, or a mixture of two or more of these solvents, for example diethyl ether, tetrahydrofuran, acetone, butanone, chloroform, dichloromethane, acetonitrile, methanol, or ethyl acetate.
- a particularly suitable solvent is a mixture of acetone and methanol or acetone alone.
- a suitable concentration of paroxetine hydrochloride in propan-2-ol for the initial crystallisation is one part in between 4 and 40 volumes of propan-2-ol, preferably between 8 and 20 volumes, and more preferably between 10 and 14 volumes.
- the propan-2-ol is anhydrous to suppress formation of paroxetine hydrochloride hemihydrate.
- 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 propan-2-ol solvate prepared by the procedure of this invention or by the procedure of WO 96/24595.
- the transformation solvent may be added to paroxetine hydrochloride propan-2-ol solvate crystals as a slurry in propan-2-ol, or after partial or complete removal of the propan-2-ol mother liquor.
- the resulting slurry is suitably contacted with the transformation solvent for at least 20 minutes, preferably with efficient stirring, more preferably for 2 hours or longer.
- the treatment may be repeated a number of times. For example, using acetone the treatment may be carried out at least two times for three hours in between 3 and 8 volumes of acetone, preferably between 4 and 5 volumes of acetone.
- the treatment with transformation solvent is carried out by a slow perfusion through a packed cake of paroxetine hydrochloride propan- 2-ol solvate.
- This may be carried out conveniently on a manufacturing scale in, for example, a filter drier.
- a proportion of the paroxetine hydrochloride may dissolve. This loss is greater at higher temperatures, but the rate of transformation to mixed solvate is advantageously increased. The loss in yield may be minimised by cooling before final isolation. Consequently, an advantageous implementation of this invention is to carry out the transformation at elevated temperature and to cool before isolation. This procedure is, in effect, a partial or at the extreme, a complete recrystallisation from mixed solvent.
- paroxetine hydrochloride with a bound organic solvent content of less than 1% may be prepared by desolvating the mixed solvate by heating at a temperature not exceeding 70°C in 48 hours or less.
- a su ⁇ rising result of the processes of this invention is that, under comparable desolvation conditions, the product contains less residual organic solvent than is obtained by desolvating the propan-2-ol solvate. This is especially noticable in the case of the mixed propan-2-ol:acetone solvate when compared to the properties of either the pure propan-2-ol solvate or the pure acetone solvate.
- Suitable procedures for preparing paroxetine hydrochloride for dissolution in propan-2-ol 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.
- the crystalline paroxetine hydrochloride propan-2-ol mixed solvates obtainable by the process of this invention are a different crystalline form from the previously known individual solvates.
- paroxetine hydrochloride propan-2-ol mixed solvates may be processed and desolvated more easily than conventionally produced paroxetine hydrochloride propan-2-ol solvate.
- the crystallisation process may include if necessary isolating the propan-2-ol solvate crystals, optionally washing and drying.
- the crystalline propan- 2-ol solvate is not dried, but used as solvent wet cake as a feed material for further processing to obtain a paroxetine hydrochloride anhydrate, especially the Form A anhydrate.
- the present invention provides a process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating a crystalline propan-2-ol mixed solvate of this invention to remove bound propan-2-ol and the transformation solvent.
- Desolvation is conveniently carried out by heating in an oven, preferably in vacuo, suitably at a temperature of about 60°C.
- the resultant anhydrate desirably contains less than 2% of propan-2-ol, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1%.
- 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 inter alia : alcoholism, anxiety, depression, obsessive compulsive disorder
- OCD OCD
- senile dementia migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders”.
- 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
- 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.
- 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:
- compositions 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; 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.
- desolvating has been carried out under standardised conditions of apparatus and temperature for the pu ⁇ ose of comparison.
- greater desolvation is achieved in less time than in the Reference Examples.
- Paroxetine hydrochloride with lower residual propan-2-ol can be obtained by increasing the heating time or temperature.
- paroxetine hydrochloride 5.0 g
- propan-2-ol 70 ml
- acetone 10 ml
- the homogeneous solution was then cooled to room temperature under argon without stirring. Once crystallisation had started, the mixture was stirred and propan-2-ol was added (30 ml).
- the product was collected by filtration, washed with propan-2-ol (15 ml) and desolvated in vacuo for 20 hours at 60°C to give paroxetine hydrochloride anhydrate Form A (4.26 g) containing 3.5% propan-2-ol and 0.1% acetone by weight.
- Acetonitrile 60 ml was added to paroxetine hydrochloride propan-2-ol solvate crystals (10.0 g) and the mixture stirred as a slurry at ambient temperature under a nitrogen atmosphere for 2 hours. The solid was collected by vacuum filtration and desolvated by heating under vacuum at 60°C for 40 hours. Yield 8.7 g (propan-2-ol content 0.2%, acetonitrile content 0.3 %).
- Tetrahydrofuran (5.0 ml) was added to paroxetine hydrochloride propan-2-ol solvate crystals (1.0 g) and the mixture stirred as a slurry at ambient temperature under a nitrogen atmosphere for 2 hours. The solid was collected by vacuum filtration and desolvated by heating under vacuum at 60°C for 40 hours. Yield 0.92 g (propan-2-oI content 0.1 %, tetrahydrofuran content 1.7% ).
- Chloroform (5.0 ml) was added to paroxetine hydrochloride propan-2-ol solvate crystals (0.98 g) and the mixture stirred as a slurry at ambient temperature under a nitrogen atmosphere for 2 hours. The solid was collected by vacuum filtration and desolvated by heating under vacuum at 60°C for 40 hours. Yield 0.78 g (propan-2-ol content 0.1%, chloroform content 2.7%).
- Acetone 200 ml was added to paroxetine hydrochloride propan-2-ol solvate crystals (5.0 g) under a nitrogen atmosphere and the mixture stirred and heated to reflux for 10 minutes. The resulting solution was allowed to cool to ambient temperature and was stirred at this temperature for 1 hour. The crystalline product was collected by vacuum filtration and desolvated by heating at 60°C under vacuum for 1 hour to produce paroxetine hydrochloride anhydrate containing 2.1% acetone and 0.1% propan-2-ol. The acetone content was reduced to 1.0% by heating at 60°C under vacuum for a further 19 hours. Yield 4.10 g.
- Acetone 150 ml was added to the solvent-wet filter cake and the mixture stirred and heated to reflux under a nitrogen atmosphere for 5 minutes. The solution was allowed to cool to room temperature and the resulting crystalline mixed solvate collected by vacuum filtration. The product was desolvated under vacuum at ambient temperature for 16 hours. Yield 11.1 g (propan-2-ol content 1.0%, acetone content 2.9%).
- paroxetine hydrochloride (17.0 kg) in propan-2-ol (137 L) and glacial acetic acid (0.275 kg) was heated to reflux in a 50 gallon glass-lined reactor, held at reflux for 15 minutes, and cooled to 70°C.
- n-Hexane (52 L) and finely powdered seed crystals of paroxetine hydrochloride propan-2-ol solvate (ca 17 g) were added and the well-stirred mixture allowed to crystallise at 60-65 °C for 40 minutes.
- the contents of the reactor were then cooled to about 25 °C and stirred for a further 2 hours.
- the white crystals were transferred under nitrogen to a Guedu filter drier and washed with hexane (2 x 33.5 L). Acetone (126 L) was allowed to permeate slowly through the filter cake over a period of 4 hours. The product was then desolvated under vacuum (ca 30 mbar) in the filter drier at 35 - 40°C for 11 hours, agitating for 5 minutes each hour.
- the solvated paroxetine hydrochloride was desolvated by increasing the drying temperature to 60°C over a period of 11 hours, and continuing the vacuum drying at 60 - 70 °C for a further 13 hours with constant agitation.
- paroxetine hydrochloride anhydrate was found to contain 0.8% propan-2-ol.
- the acetone content was less than 0.1%.
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- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99973027A EP1135383B1 (en) | 1998-11-30 | 1999-11-30 | Mixed paroxetine propan-2-ol solvates |
AU13979/00A AU1397900A (en) | 1998-11-30 | 1999-11-30 | Mixed paroxetine propan-2-ol solvates |
JP2000585236A JP2002531452A (en) | 1998-11-30 | 1999-11-30 | Mixed paroxetine propan-2-ol solvate |
DE69913377T DE69913377T2 (en) | 1998-11-30 | 1999-11-30 | Mixed paroxetine-propan-2-ol solvates |
AT99973027T ATE255577T1 (en) | 1998-11-30 | 1999-11-30 | MIXED PAROXETINE-PROPANE-2-OL SOLVATE |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9826182.9A GB9826182D0 (en) | 1998-11-30 | 1998-11-30 | Novel process |
GB9916257.0 | 1999-07-12 | ||
GB9826182.9 | 1999-07-12 | ||
GBGB9916257.0A GB9916257D0 (en) | 1999-07-12 | 1999-07-12 | Novel compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000032594A1 true WO2000032594A1 (en) | 2000-06-08 |
Family
ID=26314751
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/003993 WO2000032594A1 (en) | 1998-11-30 | 1999-11-30 | Mixed paroxetine propan-2-ol solvates |
Country Status (9)
Country | Link |
---|---|
EP (2) | EP1408039A3 (en) |
JP (1) | JP2002531452A (en) |
AT (1) | ATE255577T1 (en) |
AU (1) | AU1397900A (en) |
DE (1) | DE69913377T2 (en) |
DK (1) | DK1135383T3 (en) |
ES (1) | ES2211232T3 (en) |
PT (1) | PT1135383E (en) |
WO (1) | WO2000032594A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6686473B2 (en) | 2001-02-21 | 2004-02-03 | Synthon Bct Technologies, Llc | Process for the production of paroxetine |
WO2007054978A2 (en) * | 2005-11-10 | 2007-05-18 | Jubilant Organosys Limited | Process for preparing paroxetine hydrochloride hemihydrate |
Citations (6)
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 |
-
1999
- 1999-11-30 JP JP2000585236A patent/JP2002531452A/en not_active Withdrawn
- 1999-11-30 AT AT99973027T patent/ATE255577T1/en active
- 1999-11-30 AU AU13979/00A patent/AU1397900A/en not_active Abandoned
- 1999-11-30 WO PCT/GB1999/003993 patent/WO2000032594A1/en not_active Application Discontinuation
- 1999-11-30 PT PT99973027T patent/PT1135383E/en unknown
- 1999-11-30 DK DK99973027T patent/DK1135383T3/en active
- 1999-11-30 DE DE69913377T patent/DE69913377T2/en not_active Expired - Lifetime
- 1999-11-30 EP EP03078795A patent/EP1408039A3/en not_active Withdrawn
- 1999-11-30 EP EP99973027A patent/EP1135383B1/en not_active Withdrawn - After Issue
- 1999-11-30 ES ES99973027T patent/ES2211232T3/en not_active Expired - Lifetime
Patent Citations (6)
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)
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 (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6686473B2 (en) | 2001-02-21 | 2004-02-03 | Synthon Bct Technologies, Llc | Process for the production of paroxetine |
WO2007054978A2 (en) * | 2005-11-10 | 2007-05-18 | Jubilant Organosys Limited | Process for preparing paroxetine hydrochloride hemihydrate |
WO2007054978A3 (en) * | 2005-11-10 | 2008-01-03 | Jubilant Organosys Ltd | Process for preparing paroxetine hydrochloride hemihydrate |
Also Published As
Publication number | Publication date |
---|---|
ATE255577T1 (en) | 2003-12-15 |
AU1397900A (en) | 2000-06-19 |
PT1135383E (en) | 2004-04-30 |
EP1135383B1 (en) | 2003-12-03 |
JP2002531452A (en) | 2002-09-24 |
EP1408039A2 (en) | 2004-04-14 |
DE69913377T2 (en) | 2004-12-30 |
ES2211232T3 (en) | 2004-07-01 |
DK1135383T3 (en) | 2004-04-05 |
EP1135383A1 (en) | 2001-09-26 |
EP1408039A3 (en) | 2004-05-12 |
DE69913377D1 (en) | 2004-01-15 |
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