WO1999052902A1 - Procede de sechage d'un chlorhydrate de paroxetine anhydre - Google Patents
Procede de sechage d'un chlorhydrate de paroxetine anhydre Download PDFInfo
- Publication number
- WO1999052902A1 WO1999052902A1 PCT/JP1999/001914 JP9901914W WO9952902A1 WO 1999052902 A1 WO1999052902 A1 WO 1999052902A1 JP 9901914 W JP9901914 W JP 9901914W WO 9952902 A1 WO9952902 A1 WO 9952902A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- isopropyl alcohol
- paroxetine hydrochloride
- hydrochloride anhydrate
- weight
- drying
- Prior art date
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Definitions
- the present invention relates to a method for drying paroxetine hydrochloride anhydrate. More specifically, the present invention relates to a method for drying paroxetine hydrochloride anhydrate which reduces the residual amount of isopropyl alcohol.
- Paroxetine hydrochloride such as paroxetine hydrochloride anhydrate is a useful compound as an antidepressant.
- paroxetine hydrochloride anhydrate obtained by reacting paroxetine with hydrogen chloride in the presence of isopropyl alcohol contains isopropyl alcohol. Therefore, the paroxetine hydrochloride anhydrate is dried by a vacuum drying method using a vacuum oven temperature-controlled to a temperature lower than 80 ° C. in order to prevent the crystal form from being collapsed. .
- the method has the disadvantage that it takes a long time of about 100 hours or more to dry the isopropyl alcohol content to 5% by weight or less.
- paroxetine hydrochloride anhydrate containing isopropyl alcohol is isolated, dried under vacuum, and free or unbound isopropyl alcohol is separated from the paroxetine hydrochloride ahydrate.
- a method has been proposed in which the isopropyl alcohol bound to the paroxetine hydrochloride anhydrate is replaced with a replacement agent such as water or supercritical carbon dioxide [Japanese Patent Application Laid-Open No. Hei 8- No. 24,562,009, column 9, lines 1 to 9].
- the conventional method for drying paroxetine hydrochloride anhydrate has a drawback that the production efficiency is inferior because a complicated operation and a large-scale apparatus are required.
- An object of the present invention is to reduce the residual amount of isopropyl alcohol in paroxetine hydrochloride anhydrate obtained by crystallization in the presence of isopropyl alcohol without using a large-scale device, etc., in an efficient manner.
- An object of the present invention is to provide a method for drying paroxetine hydrochloride anhydrate which can be reduced well. Disclosure of the invention
- paroxetine hydrochloride anhydrate is further dried in an atmosphere reduced to 2 O mm Hg or less at a temperature of 80 to 110 until the content of isopropyl alcohol becomes 5% by weight or less.
- a method for drying paroxetine hydrochloride anhydrate is provided.
- paroxetine hydrochloride anhydrate is further reduced in an atmosphere reduced to 2 OmmHg or less at a temperature of 80 to 110 ° C. until the content of isopropyl alcohol becomes 5% by weight or less. Drying is performed in two stages: drying.
- the paroxetine hydrochloride anhydrate can be prepared, for example, by dissolving a paroxetine compound in isopropyl alcohol, and then reacting the paroxetine compound with hydrogen chloride. It can be obtained by reacting with hydrogen and crystallization.
- This paroxetine hydrochloride anhydrate usually contains about 30 to 70% by weight of isopropyl alcohol.
- paroxetine compound examples include paroxetine and N-tert-butoxycarbonylparoxetine.
- the N-butyl-butoxycarbonylparoxetine is (3S, 4R) -trans-1-tert-carboxycarbonyl-41- (4-fluorophenyl) -13- [3,4-methylenedioxyphenyl) oxymethyl] Piperidine.
- the amount of hydrogen chloride used in the reaction with the paroxetine compound is preferably about 1 to 5 mol per 1 mol of the paroxetine compound.
- the amount of the paroxetine compound is not particularly limited. Usually, the amount of paroxetine hydrochloride anhydrate is preferably about 5 to 60 parts by weight based on 100 parts by weight of isopropyl alcohol.
- the reaction temperature of the paroxetine compound with hydrogen chloride usually needs to be in the range from room temperature to the boiling point of isopropyl alcohol.
- isopropyl alcohol may be used alone, or may be used as a mixture with another organic solvent or organic acid, for example, as long as the object of the present invention is not hindered. . Further, it is preferable that isopropyl alcohol does not contain water from the viewpoint of shortening the drying time. Therefore, it is preferable that the isopropyl alcohol has substantially no water-containing isopropyl alcohol, that is, the water content is 0.1% or less.
- the reaction time is not particularly limited.
- the reaction time may be generally until the reaction is completed.
- the resulting reaction solution of paroxetine hydrochloride anhydrate may contain impurities.
- the reaction solution can be treated with activated carbon to remove such impurities.
- the obtained crystals of paroxetine hydrochloride anhydrate contain isopropyl alcohol.
- the crystals of paroxetine hydrochloride anhydrate containing isopropyl alcohol are very unstable thermally.
- paroxetine hydrochloride anhydrate crystals containing the isopropyl alcohol are dried at a temperature of 8 (TC or more, a part of the paroxetine hydrochloride anhydrate crystals is dissolved by the contained isopropyl alcohol.
- TC temperature of 8
- the crystal form collapses or a desired crystal form cannot be obtained (see Comparative Example 2 described later).
- paroxetine hydrochloride anhydrate containing isopropyl alcohol is treated with isopropyl alcohol at a temperature of 60 ° C. or less at a pressure of normal pressure or less in an atmosphere containing substantially no water. Dry until the content is less than 15% by weight.
- the present invention has one major feature in that such an operation is employed.
- paroxetine hydrochloride anhydrate is dried, paroxetine hydrochloride anhydrate is replaced with paroxetine hydrochloride when isopropyl alcohol is replaced with water (steam) as in the conventional method.
- water (steam) there is no danger of conversion to hemihydrate.
- after replacement with water (steam) there is an advantage that a complicated operation of removing the replaced water by vacuum drying or the like is not required.
- the atmosphere containing substantially no water means that the relative humidity (20 ° C.) of the atmosphere is 10% or less, preferably 5% or less.
- the atmosphere that does not substantially contain moisture include dry air, and inert gases such as nitrogen gas and argon gas. Among them, an inert gas such as a nitrogen gas or an argon gas is preferable because an atmosphere substantially free of moisture can be easily formed.
- the pressure of the atmosphere may be normal pressure or less.
- a drying method a drying method in an open system such as ventilation drying and a drying method in a closed system such as drying under reduced pressure can be employed.
- the pressure in the system should be 20 OmmHg or less, preferably 10 OmmHg or less, and more preferably 50 mmHg or less, from the viewpoint of increasing the drying efficiency.
- the pressure is adjusted so as to be not more than g.
- the temperature at which paroxetine hydrochloride anhydrate is dried is at most 60 ° C, preferably at most 50 ° C, from the viewpoint of maintaining the crystalline form of paroxetine hydrochloride ahydrate.
- the temperature is preferably 15 ° C. or more, and more preferably 20 ° C. or more, from the viewpoint of increasing the drying efficiency.
- the paroxetine hydrochloride anhydrate is dried until the content of isopropyl alcohol in the paroxetine hydrochloride anhydrate becomes 15% by weight or less, preferably 13% by weight or less.
- the lower limit of the content of isopropyl alcohol after drying is not particularly limited. However, according to the following heating and drying operation, paroxetine hydrochloride anhydrate can be dried quickly. Therefore, from the viewpoint of shortening the time required for drying, the content of isopropyl alcohol is 8 to 1%. After reaching about 5% by weight, it is preferable to carry out the following heating and drying operation.
- paroxetine hydrochloride anhydrate is obtained in a substantially water-free atmosphere at normal pressure and at a temperature of 60 ° C or less until the content of isopropyl alcohol becomes 15% by weight or less.
- paroxetine hydrochloride anhydrate will be converted to paroxetine hydrochloride anhydrate even if it is further dried at a high temperature of 80 to 110 ° C. No deformation occurs in the crystal.
- Paroxetine hydrochloride If drying is completed before the content of isopropyl alcohol in the non-hydrated product becomes 15% by weight or less, paroxetine hydrochloride anhydrous when subsequently dried at a high temperature of 80 ° C or more The crystals of the object are deformed.
- the content of isopropyl alcohol in paroxetine hydrochloride anhydrate during the drying operation can be confirmed by, for example, gas chromatography, nuclear magnetic resonance spectrum (NMR), or the like.
- the paroxetine hydrochloride anhydrate is dried until the content of isopropyl alcohol in the anhydrous paroxetine is 15 weight or less, the paroxetine hydrochloride anhydrate is dried in an atmosphere reduced in pressure to 20 mmHg or less. It is further dried at a temperature of 80 to 110 ° C. until the content of isopropyl alcohol becomes 5% by weight or less.
- the present invention also has one feature in that the second drying step is performed following the first drying step.
- the crystals of paroxetine hydrochloride anhydrate are deformed at a temperature of 80 ° C. or higher.
- the crystal form of paroxetine hydrochloride anhydrate which cannot be expected from the prior art, does not collapse, The desired crystals can be obtained.
- the isopropyl alcohol present on the surface is removed by performing the first-stage drying operation.
- isopropyl alcohol present on the surface is removed in advance, it is considered that the crystal form of paroxetine hydrochloride anhydrate is destroyed.
- the crystals can be efficiently dried without dissolving the crystals in isopropyl alcohol without causing deformation of the crystals.
- the object of the present invention cannot be achieved simply by heating to a temperature of 80 ° C. or higher in order to remove isopropyl alcohol taken in the inside of the crystal.
- the second-stage drying operation is performed in an atmosphere having a reduced pressure of 2 OmmHg or less, the external isopropyl alcohol is sequentially and efficiently discharged from the inside of the crystal. It is considered that drying can be performed well.
- the atmosphere may be decompressed to 2 OmmHg or less.
- the temperature may be adjusted to 110 ° C.
- the temperature may be raised in multiple stages or continuously. Good.
- the temperature at which paroxetine hydrochloride anhydrate is dried is 80 ° C or higher, preferably 90 ° C, from the viewpoint of improving the drying efficiency, and the melting point of paroxetine hydrochloride anhydrate is 115. Taking into account that it is ⁇ 120 ° C, it is 110 ° C or less, preferably 100 ° C or less.
- the atmospheric pressure at the time of drying paroxetine hydrochloride anhydrate is preferably as low as possible from the viewpoint of shortening the drying time and maintaining the crystal form. From such a viewpoint, the pressure of the atmosphere is 2 OmmHg or less, preferably 1 OmmHg or less.
- the first-stage drying step and the second-stage drying step are preferably performed consecutively in the same system in order to efficiently perform drying.
- the content of isopropyl alcohol contained in paroxetine hydrochloride anhydrate is reduced to 5% by weight or less without disturbing the crystal form of paroxetine hydrochloride anhydrate. Can be dried quickly.
- the paroxetine hydrochloride anhydrate is dried until the content of isopropyl alcohol is 5% by weight or less, because the paroxetine hydrochloride anhydrate can be suitably used as a pharmaceutical.
- Production Example 1 (1) (3S, 4R)-1 obtained according to the method described in the specification of European Patent Application Publication No. 8 1 282 7 (19997) Yuichii butyloxycarbonyl—4- (4-fluorophenyl) -13- (3,4-methylenedioxyphenyl) oxymethylbiperidine] 16.5 g of isopropyl alcohol 1 37m This was dissolved in 1 to obtain a solution.
- the crystals of paroxetine hydrochloride anhydrate containing 53.5% by weight of isopropyl alcohol obtained in Production Example 1 were dried at room temperature (about 20 ° C) under reduced pressure of 2 to 2 OmmHg for 12 hours. Then, the content of isopropyl alcohol was adjusted to 9.8% by weight.
- the temperature of the crystals was adjusted to 85 to 90 ° C., and the crystals were dried under a reduced pressure of 2 to 2 OmmHg for 10 hours.
- the content of isopropyl alcohol in the dried crystals was 2.4% by weight. X-ray diffraction and infrared absorption spectrum Therefore, examination revealed no deformation.
- Example 2 From the above results, according to the method of Example 1, the residual amount of isopropyl alcohol in the crystals of paroxetine hydrochloride anhydrate containing isopropyl alcohol was reduced to about 22 hours without using a large-scale apparatus. It can be seen that it can be efficiently reduced to less than 2.5% by weight in a relatively short time.
- Example 2
- paroxetine hydrochloride anhydrate crystals were dried at 80 ° C. for 18 hours under a reduced pressure of 1 to 3 mm Hg to obtain crystals of paroxetine hydrochloride anhydrate containing 2.9% by weight of isopropyl alcohol. Was done.
- the crystal form of the obtained paroxetine hydrochloride anhydrate was examined by powder X-ray diffraction and infrared absorption spectrum, but no deformation was observed.
- Example 3 From the above results, according to the method of Example 2, the residual amount of isopropyl alcohol in the crystals of paroxetine hydrochloride anhydrate containing isopropyl alcohol was reduced to 42 without using a large-scale apparatus. It can be seen that it can be efficiently reduced to less than 3.0% by weight in a relatively short period of time.
- Example 3
- Paroxetine hydrochloride anhydrate was produced in the same manner as in Production Example 1 to obtain 1423.5 g of paroxetine hydrochloride anhydrate crystals.
- the crystals contained 59.3% by weight of isopropyl alcohol.
- the paroxetine hydrochloride anhydrate crystals containing the isopropyl alcohol were dried at a temperature of 50 to 60 ° C. under a reduced pressure of 3 to 15011111118 for 18 hours. As a result, the content of isopropyl alcohol in the crystals of paroxetine hydrochloride anhydrate was 10.8% by weight.
- the temperature of the crystals of the paroxetine hydrochloride anhydrate was adjusted to 85 to 110 ° C., dried under reduced pressure of + to 3 mmHg for 10 hours, and paroxetine hydrochloride anhydrous containing 0.9% by weight of isopropyl alcohol was used. Crystals of the hydrate were obtained. The crystal form of the obtained paroxetine hydrochloride nonhydrate was examined by powder X-ray diffraction and infrared absorption spectrum, but no deformation was observed.
- Example 4 From the above results, according to the method of Example 3, the residual amount of isopropyl alcohol in paroxetine hydrochloride anhydrate crystallized in the presence of isopropyl alcohol was reduced without using a large-scale apparatus. It can be seen that it can be efficiently reduced to less than 1.0% by weight in a relatively short time of about time.
- Example 4
- paroxetine hydrochloride anhydrate was produced in the same manner as in Production Example 1, the obtained isopropyl alcohol solution containing paroxetine hydrochloride anhydrate crystals was passed through a compression filter (Dryuk filter) under nitrogen gas. Under pressure filtration. 26.0 kg of the obtained crystals of paroxetine hydrochloride anhydrate contained 58.5% by weight of isopropyl alcohol.
- the crystals of paroxetine hydrochloride anhydrate containing 58.5% by weight of the isopropyl alcohol were dried in the compression filter at a temperature of 50 ° C. under a reduced pressure of 10 to 8 0111111 ⁇ 18 for 12 hours.
- the content of isopropyl alcohol was adjusted to 13.1% by weight.
- the temperature of the paroxetine hydrochloride anhydrate was further adjusted to 85 ° C., and the crystal was dried under reduced pressure of 1 to 3 mmHg for about 12 hours to dry the paroxetine hydrochloride anhydrate.
- Isopropyl alcohol content in the dried crystals was 2.3 weight.
- the crystal form of the obtained paroxetine hydrochloride anhydrate was examined by powder X-ray diffraction and infrared absorption spectrum, but no deformation was observed.
- Example 2 The crystals containing 12.6% by weight of isopropyl alcohol obtained in Example 2 were dried at 70 ° C. under a reduced pressure of 1-3 mmHg at 70 ° C. for the same 18 hours as in Example 2, but the content of isopropyl alcohol was It was 9.6% by weight.
- Paroxetine hydrochloride anhydrate containing 53.5% by weight of isopropyl alcohol obtained in Example 1 was dried at 90 ° C. under a reduced pressure of 54 to 85 mmHg for 13 hours to obtain crystals. Was melted and the crystal form was broken.
- the obtained crystals were subjected to IR analysis and the water content was measured. As a result, the crystals were 1Z dihydrate of paroxetine hydrochloride.
- the paxoxetine hydrochloride anhydrate obtained by the production method of the present invention can be suitably used as an intermediate as an antidepressant.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69909207T DE69909207T2 (de) | 1998-04-13 | 1999-04-12 | Verfahren zur trocknung von paroxetinhydrochlorid |
CA002294716A CA2294716C (en) | 1998-04-13 | 1999-04-12 | Method for drying anhydrous paroxetine hydrochloride |
EP99945685A EP0990655B1 (en) | 1998-04-13 | 1999-04-12 | Method for drying anhydrous paroxetine hydrochloride |
US09/445,598 US6541637B1 (en) | 1998-04-13 | 1999-04-12 | Method for drying anhydrous paroxetine hydrochloride |
AU52656/99A AU730652B2 (en) | 1998-04-13 | 1999-04-12 | Method for drying anhydrous paroxetine hydrochloride |
AT99945685T ATE244237T1 (de) | 1998-04-13 | 1999-04-12 | Verfahren zur trocknung von paroxetinhydrochlorid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10/101058 | 1998-04-13 | ||
JP10105898A JP3796351B2 (ja) | 1998-04-13 | 1998-04-13 | パロキセチン塩酸塩無水和物の乾燥方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999052902A1 true WO1999052902A1 (fr) | 1999-10-21 |
Family
ID=14290525
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/001914 WO1999052902A1 (fr) | 1998-04-13 | 1999-04-12 | Procede de sechage d'un chlorhydrate de paroxetine anhydre |
Country Status (10)
Country | Link |
---|---|
US (1) | US6541637B1 (ja) |
EP (1) | EP0990655B1 (ja) |
JP (1) | JP3796351B2 (ja) |
AT (1) | ATE244237T1 (ja) |
AU (1) | AU730652B2 (ja) |
CA (1) | CA2294716C (ja) |
DE (1) | DE69909207T2 (ja) |
ES (1) | ES2199592T3 (ja) |
PT (1) | PT990655E (ja) |
WO (1) | WO1999052902A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1384720A1 (en) * | 1996-06-13 | 2004-01-28 | SUMIKA FINE CHEMICALS Co., Ltd. | Process for drying paroxetine hydrochloride |
ID27914A (id) * | 1998-08-07 | 2001-05-03 | Smithkline Beecham Plc | Proses untuk penyiapan bentuk anhidrat paroksetina hidroklorida bukan kristal |
US20080033050A1 (en) * | 2006-08-04 | 2008-02-07 | Richards Patricia Allison Tewe | Method of treating thermoregulatory disfunction with paroxetine |
US9138430B2 (en) * | 2007-12-27 | 2015-09-22 | Mylan Specialty L.P. | Formulation and method for the release of paroxetine in the large intestine |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08245620A (ja) * | 1995-02-06 | 1996-09-24 | Smithkline Beecham Plc | 新規化合物 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5856493A (en) * | 1995-02-06 | 1999-01-05 | Smithkline Beecham Corporation | Process for making novel form of paroxeting hydrochloride anhydrate |
EP1384720A1 (en) * | 1996-06-13 | 2004-01-28 | SUMIKA FINE CHEMICALS Co., Ltd. | Process for drying paroxetine hydrochloride |
JP3819532B2 (ja) | 1996-06-13 | 2006-09-13 | 住友化学株式会社 | ピペリジン誘導体およびその製造方法 |
ID27914A (id) | 1998-08-07 | 2001-05-03 | Smithkline Beecham Plc | Proses untuk penyiapan bentuk anhidrat paroksetina hidroklorida bukan kristal |
-
1998
- 1998-04-13 JP JP10105898A patent/JP3796351B2/ja not_active Expired - Fee Related
-
1999
- 1999-04-12 US US09/445,598 patent/US6541637B1/en not_active Expired - Fee Related
- 1999-04-12 CA CA002294716A patent/CA2294716C/en not_active Expired - Fee Related
- 1999-04-12 AT AT99945685T patent/ATE244237T1/de active
- 1999-04-12 ES ES99945685T patent/ES2199592T3/es not_active Expired - Lifetime
- 1999-04-12 EP EP99945685A patent/EP0990655B1/en not_active Expired - Lifetime
- 1999-04-12 DE DE69909207T patent/DE69909207T2/de not_active Expired - Lifetime
- 1999-04-12 PT PT99945685T patent/PT990655E/pt unknown
- 1999-04-12 WO PCT/JP1999/001914 patent/WO1999052902A1/ja active IP Right Grant
- 1999-04-12 AU AU52656/99A patent/AU730652B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08245620A (ja) * | 1995-02-06 | 1996-09-24 | Smithkline Beecham Plc | 新規化合物 |
Also Published As
Publication number | Publication date |
---|---|
EP0990655B1 (en) | 2003-07-02 |
JP3796351B2 (ja) | 2006-07-12 |
JP2001072677A (ja) | 2001-03-21 |
EP0990655A4 (en) | 2001-10-04 |
AU730652B2 (en) | 2001-03-08 |
ATE244237T1 (de) | 2003-07-15 |
CA2294716A1 (en) | 1999-10-21 |
CA2294716C (en) | 2004-08-03 |
DE69909207D1 (de) | 2003-08-07 |
PT990655E (pt) | 2003-11-28 |
ES2199592T3 (es) | 2004-02-16 |
DE69909207T2 (de) | 2004-04-22 |
EP0990655A1 (en) | 2000-04-05 |
US6541637B1 (en) | 2003-04-01 |
AU5265699A (en) | 1999-11-01 |
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