WO1999055698A1 - Paroxetine ascorbate - Google Patents

Paroxetine ascorbate Download PDF

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Publication number
WO1999055698A1
WO1999055698A1 PCT/GB1999/001244 GB9901244W WO9955698A1 WO 1999055698 A1 WO1999055698 A1 WO 1999055698A1 GB 9901244 W GB9901244 W GB 9901244W WO 9955698 A1 WO9955698 A1 WO 9955698A1
Authority
WO
WIPO (PCT)
Prior art keywords
paroxetine
ascorbate
paroxetine ascorbate
salt
solution
Prior art date
Application number
PCT/GB1999/001244
Other languages
French (fr)
Inventor
Michael Urquhart
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to EP99918151A priority Critical patent/EP1089995A1/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to IL13908199A priority patent/IL139081A0/en
Priority to KR1020007011809A priority patent/KR20010042977A/en
Priority to EA200001104A priority patent/EA200001104A1/en
Priority to SK1591-2000A priority patent/SK15912000A3/en
Priority to APAP/P/2000/001963A priority patent/AP2000001963A0/en
Priority to JP2000545858A priority patent/JP2002513019A/en
Priority to BR9909868-7A priority patent/BR9909868A/en
Priority to AU36184/99A priority patent/AU3618499A/en
Priority to CA002330055A priority patent/CA2330055A1/en
Publication of WO1999055698A1 publication Critical patent/WO1999055698A1/en
Priority to NO20005352A priority patent/NO20005352D0/en
Priority to BG104940A priority patent/BG104940A/en

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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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • paroxetine ascorbate According to the present invention there is provided paroxetine ascorbate.
  • novel salt of this invention is provided in non-crystalline form, which may a solid or an oil.
  • the oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition
  • Suitable solvents for ascorbic acid include water and lower alcohols.
  • the salt may be isolated in solid form by conventional means from a solution thereof obtained as above.
  • the non-crystalline salt may be prepared by precipitation, spray drying, and freeze drying of solutions, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.
  • the crystalline salt may be prepared by crystallization or recrystallization from appropriate solvents.
  • Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
  • water Prior to the isolation of the paroxetine salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form.
  • suitable solvents for the solution of the salt are those which form an azeotrope with water such as toluene and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
  • crystallization may be carried out from any solvent which allows formation of the desired crystal structure, using seeds of the desired structure where necessary or desirable.
  • individual polymo ⁇ hs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymo ⁇ h using seeds of another polymo ⁇ h may also be carried out.
  • Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. Ascorbic acid is commercially available.
  • the compounds of this invention may be used to treat and prevent the following disorders:
  • the Disorders are herein after referred to as "the Disorders”.
  • the present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a salt of the invention to a sufferer in need thereof.
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of the Disorders which comprises an admixture of a salt of the invention with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a salt of the invention for treating and/or preventing the Disorders.
  • the present invention also provides the use of a salt of the invention in the manufacture of a medicament for treating and/or preventing the Disorders.
  • the present invention is applied to the treatment of depression, OCD and panic.
  • compositions of 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.
  • 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-0- 223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
  • Example 1 Preparation of paroxetine ascorbate
  • the tablets are made satisfactorily on a single punch or a Rotary press.
  • Dihydrate are screened and mixed together in a suitable mixer.

Landscapes

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

Abstract

Paroxetine ascorbate is useful in the treatment of certain CNS disorders.

Description

PAROXETINE ASCORBATE
The present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
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 (-)trαrø 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 inter alia depression, obsessive compulsive disorder (OCD) and panic.
We have now surprisingly discovered a novel salt of paroxetine which may be used as an alternative to the currently marketed hydrochloride, or as an intermediate in the preparation of the hydrochloride .
According to the present invention there is provided paroxetine ascorbate.
In one aspect the novel salt of this invention is provided in non-crystalline form, which may a solid or an oil. The oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition
In another aspect the novel salt of this invention is provided in crystalline form. When the crystalline form exists as more than one polymorph, each polymorph forms another aspect of this invention.
Paroxetine ascorbate may be prepared by contacting stoichiometric amounts of ascorbic acid and paroxetine free base. Preferably either the acid or base is in solution, more preferably both are in solution. Elevated temperature may be used to bring the acid into solution, but good yields of the salt are obtained by evaporation of some or all of the solvent or by controlled cooling, preferably in stages. Most commonly used solvents are suitable for mobilizing paroxetine free base, for example toluene, alcohols such as
-1- methanol, ethanol, propan-2-ol, esters such as ethyl acetate, ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran and diethyl ether, but solvents in which ascorbic acid is very insoluble are preferably avoided. Suitable solvents for ascorbic acid include water and lower alcohols.
The salt may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, the non-crystalline salt may be prepared by precipitation, spray drying, and freeze drying of solutions, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid. The crystalline salt may be prepared by crystallization or recrystallization from appropriate solvents.
When the salt is obtained as a solvate, by association with the solvent in which it is dissolved, such solvate forms a further aspect of this invention. Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
Prior to the isolation of the paroxetine salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form. In that case, suitable solvents for the solution of the salt are those which form an azeotrope with water such as toluene and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
More generally, crystallization may be carried out from any solvent which allows formation of the desired crystal structure, using seeds of the desired structure where necessary or desirable. When polymoφhs exist, individual polymoφhs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymoφh using seeds of another polymoφh may also be carried out.
Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. Ascorbic acid is commercially available.
The compounds of this invention may be used to treat and prevent the following disorders:
-2- Alcoholism Anxiety
Depression Obsessive Compulsive Disorder
Panic Disorder Chronic Pain
Obesity Senile Dementia
Migraine Bulimia
Anorexia Social Phobia
Pre-Menstrual Syndrome (PMS) Adolescent Depression
Trichotillomania Dysthymia
Substance Abuse
These disorders are herein after referred to as "the Disorders".
The present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a salt of the invention to a sufferer in need thereof.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of the Disorders which comprises an admixture of a salt of the invention with a pharmaceutically acceptable carrier.
The present invention also provides the use of a salt of the invention for treating and/or preventing the Disorders.
The present invention also provides the use of a salt of the invention in the manufacture of a medicament for treating and/or preventing the Disorders.
Most suitably the present invention is applied to the treatment of depression, OCD and panic.
The compositions of this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
-3- 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.
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-0- 223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
The following Examples illustrate the present invention: Example 1: Preparation of paroxetine ascorbate
A 1.28 mol solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a solution of ascorbic acid (1.12g, 6.38 mmol) in methanol (15 ml). The solvent was removed in vacuo, the residual oil was diluted with toluene (15 ml) and the solvent removed in vacuo. Trituration with diethyl ether (c. 15 ml) and filtration under nitrogen gave a pale yellow solid which was washed with diethyl ether (2 x 10 ml), dried in a vacuum desiccator for 3 hours.
Yield 2.99g.
IR nujol mull:
Bands at 1716, 1603, 1510, 1465, 1377, 1224, 1186, 1136, 1037, 930, 831, 722, 540 cm"1.
Example 2: preparation of tablets
INGREDIENTS 20 mg Tablet 30mg Tablet
Paroxetine ascorbate 20.00 mg 30.0 mg
(based on free base) (based on free base)
Dicalcium Phosphate (DCP) 83.34 mg 125.0 mg
Microcrystalline Cellulose 50.67 mg 76.0 mg
Sodium Starch Glycollate 8.34 mg 12.5 mg
Magnesium Stearate 1.67 mg 2.5 mg
Figure imgf000007_0001
Commercial source of the ingredients
Dicalcium Phosphate Dihydrate Emcompress or Ditab* Microcrystalline Cellulose Avicel PH 102* Sodium Starch Glycollate Explotab.*
* Tradenames
Method
-5- 1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine Ascorbate to the bowl.
3. Add 20 mesh Avicel and Explotab and mix all the powders for 10 minutes. 4. Add magnesium stearate and mix for 5 minutes.
Tablet into Pentagonal Tablets using the following punches:
30 mg Tablet 9.5 mm Circumcircle 20 mg Tablet 8.25 mm Circumcircle
The tablets are made satisfactorily on a single punch or a Rotary press.
Example 3: preparation of tablets
INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet
Paroxetine ascorbate 10 mg 20 mg 30 mg
(as on free base) (as on free base) (as on free base)
Sodium Starch Glycollate 2.98 mg 5.95 mg 8.93 mg
Granular Dicalcium
Phosphate 158.88 mg 317.75 mg 476.63 mg
(DITAB) or Dicafos
Magnesium Stearate 1.75 mg 3.50 mg 5.25 mg
Figure imgf000008_0001
Method
1. Paroxetine ascorbate, Sodium Starch Glycollate and Dicalcium Phosphate
Dihydrate are screened and mixed together in a suitable mixer.
-6- (Planetary, Cuble or High Energy Shear mixer.) 2. Add Magnesium Stearate and compress it into a tablet using a single punch or
Rotary Tablet machine.
-7-

Claims

1. Paroxetine ascorbate.
2. A compound according to claim 1 in non-crystalline form.
3. A compound according to claim 1 in crystalline form.
4. A process for the preparation of a compound as claimed in claim 1 or 2 by precipitation, spray drying or freeze drying a solution of paroxetine ascorbate, or by vacuum drying of oils of paroxetine ascorbate, or solidification of melts of paroxetine ascorbate.
5. A process for the preparation of a compound as claimed in claim 1 or 3 by crystallization or re-crystallization from a solution of paroxetine ascorbate.
6. A process according to claim 4 or 5 in which the solution, oil or melt of paroxetine ascorbate is prepared by treating paroxetine free base with ascorbic acid.
7. A method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of paroxetine ascorbate to a sufferer in need thereof.
-8-
PCT/GB1999/001244 1998-04-25 1999-04-23 Paroxetine ascorbate WO1999055698A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
APAP/P/2000/001963A AP2000001963A0 (en) 1998-04-25 1999-04-23 Paroxetine ascorbate.
IL13908199A IL139081A0 (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
KR1020007011809A KR20010042977A (en) 1998-04-25 1999-04-23 Paroxetine Ascorbate
EA200001104A EA200001104A1 (en) 1998-04-25 1999-04-23 Ascorbat Paroxetine
SK1591-2000A SK15912000A3 (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
EP99918151A EP1089995A1 (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
JP2000545858A JP2002513019A (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
CA002330055A CA2330055A1 (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
AU36184/99A AU3618499A (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
BR9909868-7A BR9909868A (en) 1998-04-25 1999-04-23 Paroxetine ascorbate
NO20005352A NO20005352D0 (en) 1998-04-25 2000-10-24 ascorbate
BG104940A BG104940A (en) 1998-04-25 2000-11-13 Paroxetine ascorbate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9808896.6A GB9808896D0 (en) 1998-04-25 1998-04-25 Novel compound
GB9808896.6 1998-04-25

Publications (1)

Publication Number Publication Date
WO1999055698A1 true WO1999055698A1 (en) 1999-11-04

Family

ID=10831008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/001244 WO1999055698A1 (en) 1998-04-25 1999-04-23 Paroxetine ascorbate

Country Status (20)

Country Link
EP (1) EP1089995A1 (en)
JP (1) JP2002513019A (en)
KR (1) KR20010042977A (en)
CN (1) CN1297448A (en)
AP (1) AP2000001963A0 (en)
AU (1) AU3618499A (en)
BG (1) BG104940A (en)
BR (1) BR9909868A (en)
CA (1) CA2330055A1 (en)
EA (1) EA200001104A1 (en)
GB (1) GB9808896D0 (en)
HU (1) HUP0102116A3 (en)
ID (2) ID26083A (en)
IL (1) IL139081A0 (en)
NO (1) NO20005352D0 (en)
PL (1) PL343677A1 (en)
SK (1) SK15912000A3 (en)
TR (1) TR200003084T2 (en)
WO (1) WO1999055698A1 (en)
ZA (1) ZA200005912B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058449A1 (en) * 2000-02-11 2001-08-16 Smithkline Beecham Plc Water dispersible formulation of paroxetine
WO2002102382A1 (en) * 2001-06-14 2002-12-27 Teva Pharmaceutical Industries Ltd. A PROCESS FOR PREPARING PAROXETINE HCl WHICH LIMITS FORMATION OF PINK COLORED COMPOUNDS
US7893297B2 (en) 2002-01-09 2011-02-22 Emisphere Technologies, Inc. Amorphous sodium 4-[4-chloro-2-hydroxybenzoyl)amino]butanoate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020088481A1 (en) * 2018-10-30 2020-05-07 中国科学院化学研究所 Method for preparing drug or drug intermediate single crystal or amorphous substance

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3912743A (en) * 1973-01-30 1975-10-14 Ferrosan As 4-Phenylpiperidine compounds
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
US5276042A (en) * 1993-04-16 1994-01-04 Crenshaw Roger T Treatment of premature ejaculation
WO1997031915A1 (en) * 1996-02-29 1997-09-04 Ferrer Internacional, S.A. NEW PROCESS FOR PREPARING (-)-TRANS-N-p-FLUOROBENZOYLMETHYL-4-(p-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]-PIPERIDINE

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3912743A (en) * 1973-01-30 1975-10-14 Ferrosan As 4-Phenylpiperidine compounds
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
US5276042A (en) * 1993-04-16 1994-01-04 Crenshaw Roger T Treatment of premature ejaculation
WO1997031915A1 (en) * 1996-02-29 1997-09-04 Ferrer Internacional, S.A. NEW PROCESS FOR PREPARING (-)-TRANS-N-p-FLUOROBENZOYLMETHYL-4-(p-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]-PIPERIDINE

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058449A1 (en) * 2000-02-11 2001-08-16 Smithkline Beecham Plc Water dispersible formulation of paroxetine
AU2001232079B2 (en) * 2000-02-11 2004-11-25 Smithkline Beecham Plc Water dispersible formulation of paroxetine
WO2002102382A1 (en) * 2001-06-14 2002-12-27 Teva Pharmaceutical Industries Ltd. A PROCESS FOR PREPARING PAROXETINE HCl WHICH LIMITS FORMATION OF PINK COLORED COMPOUNDS
US7893297B2 (en) 2002-01-09 2011-02-22 Emisphere Technologies, Inc. Amorphous sodium 4-[4-chloro-2-hydroxybenzoyl)amino]butanoate

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NO20005352L (en) 2000-10-24
CN1297448A (en) 2001-05-30
HUP0102116A3 (en) 2002-12-28
ZA200005912B (en) 2001-12-19
JP2002513019A (en) 2002-05-08
SK15912000A3 (en) 2001-04-09
ID26654A (en) 2001-01-25
HUP0102116A2 (en) 2002-05-29
BG104940A (en) 2001-09-28
AP2000001963A0 (en) 2000-12-31
EA200001104A1 (en) 2001-04-23
IL139081A0 (en) 2001-11-25
KR20010042977A (en) 2001-05-25
NO20005352D0 (en) 2000-10-24
EP1089995A1 (en) 2001-04-11
TR200003084T2 (en) 2001-02-21
PL343677A1 (en) 2001-08-27
BR9909868A (en) 2000-12-19
GB9808896D0 (en) 1998-06-24
AU3618499A (en) 1999-11-16
CA2330055A1 (en) 1999-11-04
ID26083A (en) 2000-11-23

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