WO2000032597A1 - Process for the production of paroxetine hydrochloride propan-2-ol solvate - Google Patents
Process for the production of paroxetine hydrochloride propan-2-ol solvate Download PDFInfo
- Publication number
- WO2000032597A1 WO2000032597A1 PCT/GB1999/004000 GB9904000W WO0032597A1 WO 2000032597 A1 WO2000032597 A1 WO 2000032597A1 GB 9904000 W GB9904000 W GB 9904000W WO 0032597 A1 WO0032597 A1 WO 0032597A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- propan
- paroxetine hydrochloride
- solvate
- process according
- microns
- 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
- 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 propan-2-ol 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 propan-2-ol solvate which is a useful intermediate for the preparation of paroxetine hydrochloride anhydrate Form A.
- paroxetine hydrochloride propan-2-ol solvate When prepared conventionally by crystallisation from anhydrous propan-2-ol, paroxetine hydrochloride propan-2-ol solvate has very poor stirring properties, and is very difficult to isolate, wash, and dry.
- 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 paroxetine hydrochloride propan- 2-ol solvate in a form 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 process for preparing crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol, and crystallising paroxetine hydrochloride propan-2-ol solvate under conditions of intense insonation.
- insonation is carried out during slow cooling through the metastable zone, and is maintained during cooling to ambient temperature.
- These conditions provide a continuous flux of freshly generated nuclei, and result in crystallisation of paroxetine hydrochloride propan-2-ol solvate in a modified crystal habit which is easy to stir, wash and filter, and surprisingly is more readily desolvated than conventionally crystallised paroxetine hydrochloride propan-2-ol solvate.
- Suitably crystallization is carried out in a vessel provided with one or more high intensity ultrasonic probes, for example with titanium alloy resonant horns which enable acoustic energy to be coupled to the crystallizing medium at a frequency of 20 kHz and an amplitude of 12 microns or more, and with a device that modifies the power output according to the acoustic parameters of the load.
- Insonation may be intermittent, limited to part of the apparatus, or discontinued once sufficient nuclei have been generated.
- rapid crystallisation onto a dense flux of freshly generated nuclei may be achieved by causing rapid crystallisation in a continuous flow crystallisation apparatus.
- the crystallisation may be achieved by bringing together two liquid streams, for example a solution of paroxetine hydrochloride in propan- 2-ol and an anti-solvent such as hexane or heptane, or by rapid cooling of a single solvent stream, or by insonation of a saturated solvent stream, or by a combination of some or all of these techniques.
- generation of nuclei and crystallisation takes place in a reaction zone, which may vary from a specially designed vortex mixer to a simple Y-tube.
- Suitable seeds are obtained from a wide range of paroxetine hydrochloride solvates such as, for example, the solvate with pyridine, acetic acid, p-xylene, N,N'-dimethylformamide, chloroform, dichloromethane, dichloroethane, acetonitrile, propan-1-ol, ethanol, propan-2-ol, acetone, tetrahydrofuran, 1,4-dioxane, or the Form "A" anhydrate.
- Advantageously seeding is carried out with very finely powdered paroxetine hydrochloride anhydrate or solvate at elevated temperature.
- the seeds should preferably be less than 30 microns in length, and median particle volume below 120 cubic microns. Seeding should preferably be carried out within the metastable zone, hence at a 6-8% concentration the preferred temperature for crystallisation is from 40 to 70°C, more preferably from 55 to 65°C, and optimally from 58 to 62°C.
- the efficiency of external seeding may be greatly increased by very vigorous stirring, since secondary nuclei are generated by attrition of larger seed crystals, resulting in an increased flux of suitable nuclei.
- a sufficient flux of nuclei may be generated by particularly vigorous stirring alone, although this procedure is unlikely to be as effective unless the crystallisation vessel is routinely used for the crystallisation of paroxetine hydrochloride propan-2-ol solvate and so is in effect saturated with seed crystals.
- Suitable apparatus includes stirrers designed to operate at high torque with high shear rate and vessels with optimal hydrodynamic design including the use of baffles and bladed stirrers.
- a suitable concentration of paroxetine hydrochloride in propan-2-ol is one part in from 4 to 40 volumes of propan-2-ol, preferably from 8 to 15 volumes, and more preferably from 10 to 14 volumes.
- the propan-2-ol is anhydrous to suppress formation of paroxetine hydrochloride hemihydrate.
- 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.
- crystallisation may be assisted by conventional techniques such as cooling, or removing solvent by evaporation or distillation.
- the crystalline paroxetine hydrochloride propan-2-ol 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 propan-2-ol 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 by for example laser light scattering, 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 3,000 cubic microns.
- the product of this invention may have either one, two or all three of these desirable characteristics.
- paroxetine hydrochloride propan-2-ol 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 propan-2-ol solvate with these characteristics 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 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 propan-2-ol solvate obtainable by the process of this invention to remove bound propan-2-ol.
- 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 3% of propan-2-ol, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1%.
- 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
- 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 200 mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50mg 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 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. In these Examples drying has been carried out under standardised conditions for the purpose of comparison. Conventionally prepared paroxetine hydrochloride propan-2-ol solvate contains approximately 6% propan- 2-ol under these drying conditions. (20 hours at 60°C). Paroxetine hydrochloride with lower residual propan-2-ol for commercial use can be obtained by increasing the drying time or temperature.
- Paroxetine hydrochloride propan-2-ol solvate 100 g
- propan-2-ol 800 ml
- the mixture was stirred and heated to 75°C under a nitrogen atmosphere to afford a clear solution which was then allowed to cool.
- insonation frequency 20 kHz, amplitude 12 microns
- the solution became cloudy and this temperature was maintained with continous insonation for ten minutes.
- Paroxetine hydrochloride propan-2-ol solvate (68 g) and propan-2-ol (925 ml) were charged to a 1 litre jacketed vessel equiped with a mechanical stirrer and a high intensity ultrasonic probe.
- the mixture was stirred and heated to 65°C under a nitrogen atmosphere to afford a clear solution, insonation (frequency 20 kHz, amplitude 12 microns) was started and the solution allowed to cool. At 59°C the solution became cloudy and this temperature was maintained with continous insonation for ten minutes.
- the suspension was cooled to 40°C, with insonation, over a period of 20 minutes and then cooled to ambient temperature without further insonation.
- the product was collected by filtration and dried under vacuum at 60°C for 20 hours. Weight of product 60.7g (propan-2-ol content 2.8% by weight, acicular crystals 5 - 100 microns in length, no agglomeration.)
- Particle sizing by laser light scattering more than 50% of material below 1150 cubic microns.
- paroxetine hydrochloride (4.4 g) in propan-2-ol (70 ml) was heated at reflux under argon then cooled to 60°C and, with very vigorous stirring, treated with seed crystals of paroxetine hydrochloride anhydrate Form A (0.25 g) which had been ground to a fine powder. Rapid crystallisation ocurred, and propan-2-ol was added (30 ml) before filtering the white crystalline solid which formed. The product was filtered, washed with propan-2- ol (15 ml) and dried at 60°C for 20 hours to give paroxetine hydrochloride containing 2.8% propan-2-ol by weight.
- paroxetine hydrochloride containing 2.7% propan-2-ol by weight.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000585239A JP2002531454A (en) | 1998-11-30 | 1999-11-30 | Process for preparing paroxetine hydrochloride propan-2-ol solvate |
AU13985/00A AU1398500A (en) | 1998-11-30 | 1999-11-30 | Process for the production of paroxetine hydrochloride propan-2-ol solvate |
EP99973030A EP1135384A1 (en) | 1998-11-30 | 1999-11-30 | Process for the production of paroxetine hydrochloride propan-2-ol solvate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9826242.1 | 1998-11-30 | ||
GBGB9826242.1A GB9826242D0 (en) | 1998-11-30 | 1998-11-30 | Novel process |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000032597A1 true WO2000032597A1 (en) | 2000-06-08 |
Family
ID=10843335
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/004000 WO2000032597A1 (en) | 1998-11-30 | 1999-11-30 | Process for the production of paroxetine hydrochloride propan-2-ol solvate |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1135384A1 (en) |
JP (1) | JP2002531454A (en) |
AU (1) | AU1398500A (en) |
GB (1) | GB9826242D0 (en) |
WO (1) | WO2000032597A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6482438B1 (en) | 1998-12-24 | 2002-11-19 | Smithkline Beecham Corporation | Apparatus and process for preparing crystalline particles |
US7128784B2 (en) | 2001-07-30 | 2006-10-31 | Basf Aktiengesellschaft | Small particle-adjustment crystallization process |
GB2461028A (en) * | 2007-06-18 | 2009-12-23 | Prosonix Ltd | Process for preparation of crystalline active |
CN102366679A (en) * | 2011-08-31 | 2012-03-07 | 华南理工大学 | Horizontal spiral push-type supersonic cooling crystallization machine |
US9855538B2 (en) | 2013-03-08 | 2018-01-02 | The Board Of Trustees Of The University Of Illinois | Ultrasonic method and apparatus for producing particles having a controlled size distribution |
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 |
-
1998
- 1998-11-30 GB GBGB9826242.1A patent/GB9826242D0/en not_active Ceased
-
1999
- 1999-11-30 EP EP99973030A patent/EP1135384A1/en not_active Withdrawn
- 1999-11-30 WO PCT/GB1999/004000 patent/WO2000032597A1/en not_active Application Discontinuation
- 1999-11-30 JP JP2000585239A patent/JP2002531454A/en active Pending
- 1999-11-30 AU AU13985/00A patent/AU1398500A/en not_active Abandoned
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 (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6482438B1 (en) | 1998-12-24 | 2002-11-19 | Smithkline Beecham Corporation | Apparatus and process for preparing crystalline particles |
US7128784B2 (en) | 2001-07-30 | 2006-10-31 | Basf Aktiengesellschaft | Small particle-adjustment crystallization process |
GB2461028A (en) * | 2007-06-18 | 2009-12-23 | Prosonix Ltd | Process for preparation of crystalline active |
GB2461028B (en) * | 2007-06-18 | 2011-12-07 | Prosonix Ltd | Process for Making Crystals |
US9278323B2 (en) | 2007-06-18 | 2016-03-08 | Prosonix Limited | Process for making crystals |
CN102366679A (en) * | 2011-08-31 | 2012-03-07 | 华南理工大学 | Horizontal spiral push-type supersonic cooling crystallization machine |
US9855538B2 (en) | 2013-03-08 | 2018-01-02 | The Board Of Trustees Of The University Of Illinois | Ultrasonic method and apparatus for producing particles having a controlled size distribution |
Also Published As
Publication number | Publication date |
---|---|
JP2002531454A (en) | 2002-09-24 |
EP1135384A1 (en) | 2001-09-26 |
GB9826242D0 (en) | 1999-01-20 |
AU1398500A (en) | 2000-06-19 |
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