WO1999040084A1 - Sels de paroxetine - Google Patents

Sels de paroxetine Download PDF

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Publication number
WO1999040084A1
WO1999040084A1 PCT/GB1999/000380 GB9900380W WO9940084A1 WO 1999040084 A1 WO1999040084 A1 WO 1999040084A1 GB 9900380 W GB9900380 W GB 9900380W WO 9940084 A1 WO9940084 A1 WO 9940084A1
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WO
WIPO (PCT)
Prior art keywords
paroxetine
salt
acid
solution
toluene
Prior art date
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PCT/GB1999/000380
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English (en)
Inventor
David Crowe
Deirdre O'keeffe
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.)
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Publication date
Priority claimed from GBGB9802645.3A external-priority patent/GB9802645D0/en
Priority claimed from GBGB9802664.4A external-priority patent/GB9802664D0/en
Priority claimed from GBGB9802639.6A external-priority patent/GB9802639D0/en
Priority claimed from GBGB9802665.1A external-priority patent/GB9802665D0/en
Priority claimed from GBGB9802646.1A external-priority patent/GB9802646D0/en
Priority claimed from GBGB9802657.8A external-priority patent/GB9802657D0/en
Priority claimed from GBGB9802659.4A external-priority patent/GB9802659D0/en
Priority claimed from GBGB9802638.8A external-priority patent/GB9802638D0/en
Priority claimed from GBGB9802698.2A external-priority patent/GB9802698D0/en
Priority claimed from GBGB9802654.5A external-priority patent/GB9802654D0/en
Priority claimed from GBGB9802656.0A external-priority patent/GB9802656D0/en
Priority claimed from GBGB9802658.6A external-priority patent/GB9802658D0/en
Priority claimed from GBGB9802640.4A external-priority patent/GB9802640D0/en
Priority claimed from GBGB9802653.7A external-priority patent/GB9802653D0/en
Priority claimed from GBGB9802661.0A external-priority patent/GB9802661D0/en
Priority claimed from GBGB9802655.2A external-priority patent/GB9802655D0/en
Priority claimed from GBGB9802644.6A external-priority patent/GB9802644D0/en
Priority claimed from GBGB9817340.4A external-priority patent/GB9817340D0/en
Priority claimed from GBGB9817360.2A external-priority patent/GB9817360D0/en
Priority claimed from GBGB9817344.6A external-priority patent/GB9817344D0/en
Priority claimed from GBGB9817321.4A external-priority patent/GB9817321D0/en
Priority claimed from GBGB9817307.3A external-priority patent/GB9817307D0/en
Priority claimed from GBGB9817364.4A external-priority patent/GB9817364D0/en
Priority claimed from GBGB9817359.4A external-priority patent/GB9817359D0/en
Priority claimed from GBGB9817317.2A external-priority patent/GB9817317D0/en
Priority claimed from GBGB9817309.9A external-priority patent/GB9817309D0/en
Priority claimed from GBGB9817320.6A external-priority patent/GB9817320D0/en
Priority claimed from GBGB9817322.2A external-priority patent/GB9817322D0/en
Priority claimed from GBGB9826172.0A external-priority patent/GB9826172D0/en
Priority claimed from GBGB9826173.8A external-priority patent/GB9826173D0/en
Priority claimed from GBGB9827277.6A external-priority patent/GB9827277D0/en
Priority claimed from GBGB9827341.0A external-priority patent/GB9827341D0/en
Priority claimed from GBGB9828775.8A external-priority patent/GB9828775D0/en
Priority to EP99904971A priority Critical patent/EP1053234A1/fr
Priority to BR9907632-2A priority patent/BR9907632A/pt
Priority to CA002319652A priority patent/CA2319652A1/fr
Priority to KR1020007008591A priority patent/KR20010040711A/ko
Priority to APAP/P/2000/001879A priority patent/AP2000001879A0/en
Priority to IL13768499A priority patent/IL137684A0/xx
Priority to SK1181-2000A priority patent/SK11812000A3/sk
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU25288/99A priority patent/AU2528899A/en
Priority to EA200000815A priority patent/EA200000815A1/ru
Priority to JP2000530513A priority patent/JP2002505254A/ja
Publication of WO1999040084A1 publication Critical patent/WO1999040084A1/fr
Priority to NO20003960A priority patent/NO20003960L/no
Priority to BG104737A priority patent/BG104737A/xx

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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
    • 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

  • the present invention relates to novel compounds, to processes for preparing them and to their 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 (-)trans 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.
  • OCD obsessive compulsive disorder
  • Tartaric, glutamic, lactic and mandelic acids exist in enantiomeric forms and this invention includes salts with both the D and L-acids and racemic mixtures thereof, as well as with the symmetric me.sO-tartaric acid.
  • Sulphuric, tartaric, oxalic, fumaric, glutamic, and succinic acids are dibasic and the invention therefore includes both salts in which the ratio of paroxetine to acid (by mole) is 1 : 1 and salts in which the ratio of paroxetine to acid (by mole) is 2: 1, as well as mixed salts with, for example, an alkali metal or ammonium cation.
  • Citric and phosphoric acids are tribasic and the invention therefore includes salts in which the ratio of paroxetine to acid (by mole) is 1:1, 2: 1, and 3:1 respectively, as well as mixed salts with, for example, an alkali metal or ammonium cation.
  • novel salts of this invention are provided in non-crystalline form, which may take the form of 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.
  • novel salts of this invention are provided in crystalline form. When the crystalline form exists as more than one polymorph, each polymorph forms another aspect of this invention.
  • -1- Paroxetine salts may be prepared by contacting stoichiometric amounts of the acid (enantiomer or racemic mixture) and paroxetine free base.
  • the base and/or the acid is in solution, more preferably both are in solution.
  • Mixed salts can be prepared by forming the precursor 1 : 1 or hydrogen salt (of paroxetine with the acid, or the metal or ammonium ion with the acid) in situ or using it preformed in solution.
  • paroxetine free base for example toluene, alcohols such as 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.
  • concentration of paroxetine base is preferably in the range 5 to 50% weight/volume, more preferably in the range 10 to 30%.
  • Suitable solvents for the acids used in accordance with the present invention include water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as toluene and benzene, esters such as ethyl acetate, ketones such as acetone, butanone and isobutyl methyl ketone, and halogenated hydrocarbons such as chloroform.
  • the concentration of the acid is preferably in the range 0.1 to 6.0 molar, for example 0.5 to 4.0 molar, in particular 1.0 to 3.0 molar. Elevated temperatures may be used to enhance solubility.
  • the concentration of glutamic acid is preferably in the range 0.01 to 1.0 molar, in particul.ar 0.1 to 0.5 mol.ar.
  • the acids may also be used in the form of a soluble salt such as the ammonium salt or a salt of an amine, for example ethylamine or diethylamine.
  • the paroxetine salts may be isolated in solid form by conventional means from a solution thereof obtained as above.
  • the non-crystalline salts 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 salts may be prepared by directly crystallising from a solvent in which the product has limited solubility, or by triturating or otherwise crystallising a non- crystalline salt.
  • An improved yield of the salt is obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, preferably in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducibity of the production process and the particle size distribution and form of the product.
  • An alternative method of preparing paroxetine salts is to start with a salt of paroxetine with an organic acid, such as acetic acid or maleic acid.
  • Another salt of paroxetine as a starting material is suitable for preparation of the crystalline salt or, if a volatile acid such as acetic acid is used, non-crystalline salts by methods that involve evaporation (such as freeze-drying and spray-drying).
  • 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, pyridine, isopropanol, isobutyl methyl ketone and xylene. 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 polymorphs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymorph using seeds of another polymorph may also be carried out.
  • Sulphate water, butan-1-ol, butan-2-ol. Tartrates: ethanol, methanol, isopropanol, toluene.
  • Oxalates ethanol, methanol, acetone, tetrahydrofuran.
  • Fumarates methanol, butanol, tetrahydrofuran.
  • Propionate hexane, cyclohexane, chloroform.
  • succinates toluene, acetone, or lower alcohols followed by precipitation with ethyl acetate, ether, or hexane.
  • Paroxetine succinate may be recrystallised by cooling and optionally seeding hot solutions in suitable solvents such as butan-1-ol or acetonitrile.
  • Benzoate As used for salt formation.
  • Citrate As used for salt formation.
  • Nitrate toluene, toluene/cyclohexane, isopropanol.
  • Phosphate toluene, ehtanol, tetrahydrofuran, isopropanol.
  • 4-Methylbenzenesulphonate toluene or lower alcohols followed by precipitation with ether or hexane.
  • Hypophosphite toluene or lower alcohols followed by precipitation with ether or hexane.
  • Lactate As used for salt formation.
  • Mandelate isopropanol, toluene.
  • Glycinate As used for salt formation.
  • the salt may obtained as a solvate or hydrate, when during isolation from solution it becomes associated with the solvent in which it is dissolved. Any such solvate or hydrate 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.
  • Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0223403. The acids are commercially available.
  • the compounds of this invention may be used to treat and prevent the following disorders:
  • PMS Pre-Menstrual Syndrome
  • 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.
  • 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.
  • 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 200 mg 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.
  • 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.
  • 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.
  • Specific examples of pharmaceutical compositions include those described EP-B-
  • Example 2 preparation of tablets
  • Paroxetine salt, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer. (Planetary, Cuble or High Energy Shear mixer.)
  • Example 3 Paroxetine sulphate 1 : 1 salt.
  • Aqueous sulphuric acid (1.5 ml , 2 molar) was added to a solution of paroxetine free base (1.0 g) in propan-2-ol (10 ml) and the mixture stirred at ambient temperature for three hours. The solvent was removed by evaporation and the residue was stirred in a mixture of hexane (10 ml) and butan-1-ol (10 ml) until the product crystallised. Finally, the crystals were filtered, washed with hexane and dried in vacuo. m.pt 128-130°C IR nujol mull:
  • Example 4 Paroxetine sulphate 2: 1 salt.
  • Aqueous sulphuric acid 1.5 ml , 2 molar
  • paroxetine free base 2.1 g
  • the mixture was diluted with hexane (40 ml) and butanol (20 ml) and stirred rapidly, as a result the form of the crystalline solid improved.
  • the crystals were filtered, washed with hexane and dried in vacuo.
  • Paroxetine base (54.9 g) was dissolved in a mixture of propan-2-ol (500 ml) and water (20 ml). To the stirred, clear solution was added slowly a mixture of sulphuric acid (8.3 g,
  • Example 6 Preparation of non-crystalline paroxetine sulphate (2:1) Concentrated sulphuric acid (1.6 g) was diluted to 10 ml with water, and the solution added slowly to a stirred mixture of paroxetine base (11.0 g) and water (20 ml). The clear solution was evaporated at reduced pressure to form a white, crisp glassy solid.
  • Example 7 Preparation of paroxetine sulphate (2: 1)
  • Example 8 crystallisation of non-crystalline paroxetine sulphate (2:1)
  • the non-crystalline paroxetine sulphate prepared in Example 6 was suspended in propan-2- ol (200 ml), stirred vigorously, and gradually heated to reflux. After 2 hours the paroxetine sulphate could be seen to have changed form, so the mixture was cooled, filtered, washed with cold propan-2-ol, and dried under vacuum to give crystalline paroxetine sulphate (2:1). Yield 8.5 g.
  • Example 9 Paroxetine L(+) tartrate 1 : 1 salt.
  • L(+)-tartaric acid (1.25 g) was dissolved in propan-2-ol (10 ml) with heating, and mixed with a stirred solution of paroxetine base (2 g) in toluene (20 ml). A crystalline suspension formed which was stirred for a further 1 hour at room temperature. Finally, the product was filtered, washed with acetone and dried under reduced pressure. Yield 2.65 g.
  • Example 10 Paroxetine L(+) tartrate 1 : 1 salt.
  • a solution of L(+)-t.art.aric acid (1.0 g) in methanol (10 ml) was mixed with a solution of paroxetine base (1.75 g) in methanol (15ml) and the mixture stirred at ambient temperature. Crystals separated within a few minutes and the suspension was stirred for a further 1 hour at ambient temperature. Finally the crystals were filtered, washed with acetone and dried under reduced pressure. Yield 2.01 g.
  • Example 11 Larger scale preparation of paroxetine L(+) tartrate 1: 1 salt.
  • L(+) tartaric acid 25 g was dissolved in propan-2-ol (200 ml) with heating and mixed with a solution of paroxetine base (42 g) in toluene (400 ml).
  • a crystalline precipitate formed, which was stirred for 1 hour at ambient temperature then at 0°C for a further 1 hour.
  • the crystals were filtered, washed with acetone and dried under reduced pressure. Yield 59.88g. m.pt 176-178°C.
  • IR nujol mull IR nujol mull
  • Example 12 Paroxetine D(-) tartrate 1 : 1 salt.
  • D(-)-tartaric acid (1.25 g) was dissolved in propan-2-ol (10 ml) with heating, and mixed with a stirred solution of paroxetine base (2.1 g) in toluene (20 ml). A crystalline suspension soon formed which was stirred for another hour at room temperature. The product was then filtered, washed with acetone and dried under reduced pressure. Yield 2.70 g.
  • Example 13 Larger scale preparation of paroxetine D(-)-tartrate 1 : 1 salt.
  • D(-) tartaric acid 25 g was dissolved in propan-2-ol (200 ml) by heating and added rapidly to a solution of paroxetine base (42 g) in toluene (400 ml).
  • a crystalline precipitate soon formed, and was stirred for 1 hour at ambient temperature then at 0°C for a further 1 hour.
  • the crystals were then filtered, washed with toluene and dried under reduced pressure. Yield 57.59g. m. pt 174-176°C.
  • IR nujol mull IR nujol mull
  • Example 14 Preparation of non-crystalline 2: 1 salt with L(+)-tartaric acid.
  • L(+) tartaric acid (1.0 g) was heated in propan-2-ol (10 ml) to form a solution, and mixed with a solution of paroxetine base (5.0 g) in toluene (20 ml). The resulting solution was stirred at ambient temperature and then hexane (50 ml) was added.and a white solid precipitated. The suspension was stirred for a further 1 hour then the solid was filtered, washed with hexane and dried under reduced pressure. This solid was shown by X-ray diffraction to be non-crystalline. Yield 4.32g.
  • Example 15 Preparation of crystalline 2: 1 salt with D(-)-tartaric acid.
  • D(-) tartaric acid (1 g) was heated in propan-2-ol to form a solution. This solution was mixed with a stirred solution of paroxetine base (5.0 g) in toluene (20 ml). Crystallization commenced within two minutes, and the suspension was stirred at ambient temperature for a further 1 hour. Finally the product was filtered, washed with toluene and dried under reduced pressure. Yield 5.69 g.
  • Example 16 Larger scale preparation of crystalline 2: 1 salt with D(-)-tartaric acid.
  • D(-) tartaric acid (10 g) was dissolved in propan-2-ol (100 ml) by heating and then mixed with a stirred solution of paroxetine base (50.4 g) in toluene (200 ml). Within 5 minutes
  • Example 17 Preparation of crystalline 2: 1 salt with L(+)-tartaric acid.
  • L(+)-potassium hydrogen tartrate (1.0 g) was heated in a mixture of ethanol (120 ml) and water (40 ml) to form a solution.
  • Paroxetine base (4.2 g) in toluene (10 ml) was added and the mixture stirred at ambient temperature for several hours but remained clear. The solvent was therefore removed by evaporation and the residue redissolved in toluene. The evaporation procedure was repeated and the residue stirred with fresh toluene for 30 minutes to form a crystalline product, which was filtered, washed in toluene and dried under reduced pressure. Yield 2.18 g.
  • IR nujol mull (0.05 g) was added to form a solution.
  • Example 18 Preparation of paroxetine 1: 1 mesotartrate
  • a solution of meso-tartaric acid (2.14 g) in water (19 ml) was prepared by heating to reflux temperature.
  • Propan-2-ol (20 ml) and paroxetine base (4.2 g) in toluene (20 ml) were added and the mixture stirred, then the solvents were removed by distillation at reduced pressure.
  • Toluene (20 ml) was added and the distillation repeated to yield the 1: 1 meso-tartrate as a non-crystalline solid.
  • Trituration with heptane caused the solid to crystallise, and the white powdery product was filtered, washed with heptane and dried under reduced pressure. Yield 3.52 g
  • Example 19 Preparation of paroxetine oxalate (1: 1) Oxalic acid (1.15 g) was dissolved in methanol (50 ml) with heating. A solution of paroxetine base in toluene (4.2 g in 20 ml) was added and the reaction mixture stirred at room temperature. The solvents were removed in vacuo to afford a white glassy solid of non-crystalline paroxetine oxalate. Trituration with heptane caused the produce to crystallise to a white powdery solid, which was filtered, washed with heptane and dried at reduced pressure. Yield 2.93g
  • Example 20 Preparation of paroxetine oxalate (2: 1) Oxalic acid (1.15 g) was added to methanol (40 ml) and the mixture heated to achieve total dissolution of the acid. Paroxetine base in toluene (8.4 g in 40 ml) was added and the solution stirred at room temperature. White crystals separated rapidly. The product was filtered, washed with heptane and dried at reduced pressure. Yield 7.34 g. Melting point 207-211°C
  • Fumaric acid (0.3 g) was heated in a mixture of toluene (5 ml) and propan-2-ol (5 ml) to form a solution. This solution was mixed with a solution of paroxetine free base (1 g) in toluene (10 ml) while stirring. Crystals separated within 2 minutes and the suspension was stirred at ambient temperature for a further 1 hour. Finally the product was filtered, washed in toluene and dried at reduced pressure.
  • Example 22 Larger scale preparation of 1 : 1 salt.
  • Fumaric acid (30 g) was heated in propan-2-ol until the solid dissolved and the warm solution was mixed with a solution of paroxetine free base (84 g) in toluene (500 ml) with stirring. Crystals separated rapidly and the suspension was stirred for 1 hour at ambient temperature then 1 hour at 0°C (ice/water bath). Finally the crystals were filtered, washed in toluene and dried at reduced pressure.
  • Fumaric acid (0.3 g) was heated in propan-2-ol (10 ml) until the solid dissolved and this solution was mixed with paroxetine free base (2.1 g) in toluene (20 ml). The mixture was stirred for 1 hour at room temperature and a gel began to separate. Diethyl ether (20 ml) was added and the product crystallised. The suspension was stirred for a further 1 hour.
  • Example 24 Larger scale preparation of 2: 1 salt. Fumaric acid (9 g) was heated in propan-2-ol (200 ml) until the solid dissolved, and the warm solution was added to a solution of paroxetine free base (63 g) in toluene (600 ml).
  • Example 25 Preparation of non-crystalline salt.
  • Paroxetine fumarate (2 g) (prepared as Example 22) was heated in methanol (50 ml) to form a solution. The solvent was removed by evaporation at a water bath temperature of between 70 and 80°C. The product was a glassy solid which was shown by X-ray diffraction to be non-crystalline.
  • Example 27 Propionic acid (15 ml) was added to a solution of paroxetine free base (63 g) in toluene (150 ml). The mixture was diluted with hexane (1500 ml) and an oil formed which began to crystallise within a few minutes. The suspension was stirred for 1 hour at ambient temperature then 1 hour at 0°C (ice/water bath). The product was filtered, washed with
  • Paroxetine Propionate characterising data m. pt 89-91°C.
  • Example 28 Preparation of crystalline paroxetine formate A solution of paroxetine base in toluene (2 ml, 2.55 mmol) was added to a solution of formic acid (0.12g, 2.50 mmol) in toluene (10 ml). The solvent was removed at reduced pressure to yield a white solid. Trituration with diethyl ether (c. 10 ml) and filtration under nitrogen gave a white solid which was washed with diethyl ether (2 x 10 ml) and dried. Yield 0.84g.
  • Example 29 Larger scale preparation of crystalline salt.
  • a solution of paroxetine base in toluene 120 ml, 153.0 mmol was added to a solution of formic acid (7.2g, 156.0 mmol) in toluene (300 ml). The solvent was removed at reduced pressure to yield a white solid. Trituration with diethyl ether (c. 400 ml) and filtration gave a white solid which was washed with diethyl ether (2 x 100 ml) and dried at reduced pressure. Yield 56. lOg. l H NMR (CDCI3) showed a ratio between formic acid and paroxetine of 1:1. m.p. 100 - 103°C.
  • IR nujol mull IR nujol mull
  • Example 30 Preparation of non-crystalline paroxetine L-glutamate A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a suspension of L- glutamic acid (0.94 g, 6.38 mmol) in hot methanol (45 ml). The mixture was heated at reflux for 1 hour, allowed to cool, filtered and the solvent was removed at reduced pressure. The residual oil was diluted with toluene (15 ml) and the solvent removed at reduced pressure. Trituration with diethyl ether (c.
  • Example 31 Preparation of non-crystalline paroxetine D-glutamate A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a suspension of D-glutamic acid (0.94 g, 6.38 mmol) in hot methanol (45 ml). The mixture was heated at reflux for lhour, allowed to cool, filtered and the solvent removed at reduced pressure. The residual oil was diluted with toluene (30 ml) and the solvent removed at reduced pressure. Trituration with diethyl ether (c. 20 ml) and filtration under nitrogen gave a pale brown solid which was washed with diethyl ether (2 x 10 ml) and vacuum dried. Yield 2.65g. 1H NMR (DMSO) shows a ratio between D-glutamic acid and paroxetine of 1 : 1. IR nujol mull:
  • Example 32 Preparation of crystalline 1 : 1 salt with L-glutamic acid.
  • Paroxetine free base (2.1 g) in toluene (5 ml) was added to a suspension of L-glutamic acid (0.8 g) in propan-2-ol (90 ml) and water (15 ml), stirred, and diluted further with toluene (100 ml).
  • the mixture was gently heated to dissolve the acid, and the solution evaporated.
  • the residue from evaporation was stirred at ambient temperature with a mixture of toluene (50 ml) and n-hexane (50 ml) until the product appeared to have crystallised and then for another hour. Finally, the crystals were collected by filtration, washed with hexane and dried at reduced pressure, m.pt 92-98°C.
  • IR nujol mull IR nujol mull
  • Example 33 Preparation of crystalline paroxetine D-glutamate 1 : 1 salt
  • a solution of paroxetine base (4.2 g) in toluene (10 ml) was added to a suspension of D- glutamic acid (1.88 g, 12.76 mmoles) in water (35 ml) and toluene (40 ml).
  • the reaction mixture was stirred and brought to reflux temperature and all of the water was removed using a Dean and Stark apparatus. Almost immediately a solid separated.
  • the mixture was cooled to 0°C, and the reaction mixture was diluted with propan-2-ol (80 ml) with stirring, to afford paroxetine D-glutamate 1 : 1 salt as a white crystalline solid.
  • Example 34 Preparation of crystalline 1 : 1 paroxetine succinate Succinic acid (0.35 g) was dissolved in propan-2-ol (5 ml) with heating and mixed with a solution of paroxetine base (1 g) in toluene (10 ml). The solution was diluted with ethyl acetate (15 ml) and hexane (20 ml). An oil formed initially, but this crystallised within 15 minutes following scratching and ultrasonication. The suspension was stirred at approximately 20°C for a further hour then the crystals were filtered, washed with ethyl acetate and dried at reduced pressure. Yield 0.92 g.
  • Example 35 Larger scale preparation of crystalline 1 : 1 paroxetine succinate. Succinic acid (20 g) was dissolved in propan-2-ol (300 ml) with heating and then mixed witht a solution of paroxetine base (60 g) in toluene 500 ml. The warm solution was diluted with ethyl acetate (500 ml) and hexane (800 ml) and stirred vigorously. Crystals began to separate out within a few minutes, and stirring at approximately 20°C was continues for an hour, and then at 0°C for a further hour. Finally the crystals were filtered, washed with ethyl acetate and dried at reduced pressure. Yield 66.24g.
  • Example 36 Alternative preparation of crystalline 1 : 1 paroxetine succinate.
  • Succinic acid (0.7 g) was heated in propan-2-ol (10 ml) to form a solution, which was then added to a solution of paroxetine free base (4.2 g) in toluene (10 ml).
  • the mixture was diluted with diethyl ether (30 ml) and hexane (30 ml) and the resulting oil was scratched and ultrasonicated until it crystallised.
  • the suspension was stirred for a further 1 hour, filtered, washed with diethyl ether and dried at reduced pressure. Yield 0.99g.
  • Example 37 Preparation of crystalline 1 : 1 paroxetine succinate.
  • a solution of succinic acid (0.35 g) in hot propan-2-ol was mixed with a solution of paroxetine base (1 g) in toluene (10 ml). The mixture was stirred at approximately 20°C
  • Example 38 Preparation of 2: 1 paroxetine succinate.
  • a solution of succinic acid (0.35 g) in methanol (10 ml) was added to a solution of paroxetine free base (2.1g) in toluene (10 ml). The solvent was removed by evaporation under reduced pressure to yield a white crisp foam.
  • Diethyl ether (25 ml) and hexane (25 ml) were added and the solid triturated to give a solid, easily stirrable product. After stirring for 30 minutes, the product was filtered, washed in diethyl ether and dried at reduced pressure.
  • Example 39 Preparation of paroxetine benzoate Paroxetine base (2.1 g) in toluene (5 ml) was added to a suspension of benzoic acid (0.78 g, 6.38 mmol) in toluene (15 ml) and stirred vigorously. The solvent was removed from the resulting clear solution by evaporation under high vacuum to afford paroxetine benzoate. Yield 2.9g
  • Example 40 Preparation of paroxetine citrate (1: 1) A solution of paroxetine base (4.2 g) in toluene (25 ml) was added to a suspension of citric acid (2.45 g) in water (4 ml), and the mixture was heated to reflux to form a clear solution. The water was removed by heating at reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent decanted. Fresh toluene (20 ml) was added to the solid residue, and the mixture heated once again at reflux in a Dean and Stark apparatus. Finally the toluene was removed at reduced pressure and the residue stirred with heptane overnight, filtered and dried to produce paroxetine citrate 1 : 1 salt as a yellowish powder.
  • Example 41 Preparation of paroxetine citrate (2:1) A solution of paroxetine base (4.2 g) in toluene (30 ml) was added to a suspension of citric acid (1.23 g) in water (2 ml), and the mixture was heated to reflux to form a clear solution. The water was removed by heating at reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent decanted. Propan-2-ol (30 ml) was added to the solid residue and the mixture stirred and heated to reflux temperature for 30 minutes, then cooled to room temperature (approximately 22°C), whereupon a yellowish precipitate was
  • paroxetine citrate 2 1, was collected by filtration under an atmosphere of nitrogen and dried under vacuum.
  • IR spectrum (nujol mull): Bands at 2970, 2360, 1738, 1622, 1487, 1134, 929, 830, 668 cm '1 .
  • paroxetine base (6.3 g) in toluene (25 ml) was added to a suspension of citric acid (1.23 g) in water (2.5 ml), and the mixture was heated to reflux to form a clear solution. The water was removed by heating at reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent decanted. Residual toluene was removed at reduced pressure and the solid product stirred with heptane overnight, filtered and dried at reduced pressure to give paroxetine citrate 3: 1 salt as a yellowish powder.
  • IR spectrum (nujol mull): Bands at 2970, 2359, 1738, 1558, 1487, 1366, 1035, 929, 720 cm '1 .
  • Example 44 Paroxetine phosphate 1 : 1 salt.
  • a solution of paroxetine base (2.1 g) in toluene (20 ml) was diluted with acetone (20 ml).
  • Orthophosphoric acid in propan-2-ol (1.5 ml, 3.675molar) was added and the mixture diluted further with propan-2-ol (20 ml) and stirred for 1 hour at ambient temperature.
  • the product crystallised and was filtered, washed with propan-2-ol and dried in vacuo. Yield 1.92 g.
  • Example 46 Preparation of paroxetine phosphate 2:1 salt.
  • a solution of paroxetine base (4.2 g) in toluene (20 ml) was treated with a solution of orthophosphoric acid in propan-2-ol (1.5 ml, 3.675 molar).
  • Propan-2-ol (20 ml) was added and a white solid precipitated.
  • the suspension was stirred for 1 hour at ambient temperature, and then the product was filtered, washed with propan-2-ol and dried in vacuo. Yield 3.40 g.
  • IR nujol mull Bands at 1573, 1466, 1225, 1189, 1039, 876, 834, 782, 720, 547 cm- 1 .
  • Example 47 Preparation of non-crystalline paroxetine phosphate 2: 1 salt.
  • Paroxetine base (4.2 g) in toluene (10 ml) was added to a suspension of aqueous orthophosphoric acid (0.37 ml, 14.6 molar, 85%) in methanol (50 ml), with stirring to form a clear solution.
  • the solvents were removed by distillation in vacuo to produce an oil, which was dissolved in toluene (30 ml) and the solvent removed once more. The resulting
  • Example 48 Crystallisation of paroxetine phosphate 2:1 salt.
  • Example 51 Preparation of paroxetine hypophosphite Paroxetine base (4.2 g) in toluene (10 ml) was added to a 50% aqueous solution of hypophosphorous acid (1.32 ml, 9.7 molar) and the mixture stirred at approximately 20°C. The solvents were then removed by distillation at reduced pressure to produce non- crystalline paroxetine hypophosphite as a crisp glassy solid. This solid was triturated with heptane to form the crystalline salt as a white solid, which was filtered under nitrogen and dried in vacuo.
  • IR nujol mull Bands at 1647, 1588, 1464, 1377, 1195, 1038, 930, 785, 721cm '1 .
  • X-ray diffractogram (CuK2 ) CuK2
  • IR nujol mull Bands at 1617, 1463, 1267, 1183, 1015, 984, 870, 735, 539, 516 cm- 1 .
  • X-ray diffractogram major peaks (Cu K2 ) Cu K2

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Abstract

L'invention concerne des sels de paroxétine avec un acide sélectionné dans le groupe constitué d'acides sulfurique, tartrique, oxalique, fumarique, propionique, formique, glutamique, succinique, benzoïque, nitrique, phosphorique, 4-méthylbenzène sulfonique, hypophosphoreux, lactique et mandélique ainsi que de glycine. Ce sel peut servir au traitement et à la prévention de certains troubles du système nerveux central.
PCT/GB1999/000380 1998-02-06 1999-02-05 Sels de paroxetine WO1999040084A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR9907632-2A BR9907632A (pt) 1998-02-06 1999-02-05 Sais de paroxetina
SK1181-2000A SK11812000A3 (sk) 1998-02-06 1999-02-05 Soli paroxetínu, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitie
IL13768499A IL137684A0 (en) 1998-02-06 1999-02-05 Salts of paroxetine
APAP/P/2000/001879A AP2000001879A0 (en) 1998-02-06 1999-02-05 Salts of paroxetine.
EA200000815A EA200000815A1 (ru) 1998-02-06 1999-02-05 Соли пароксетина
EP99904971A EP1053234A1 (fr) 1998-02-06 1999-02-05 Sels de paroxetine
AU25288/99A AU2528899A (en) 1998-02-06 1999-02-05 Salts of paroxetine
JP2000530513A JP2002505254A (ja) 1998-02-06 1999-02-05 パロキセチン塩
CA002319652A CA2319652A1 (fr) 1998-02-06 1999-02-05 Sels de paroxetine
KR1020007008591A KR20010040711A (ko) 1998-02-06 1999-02-05 파록세틴의 염
NO20003960A NO20003960L (no) 1998-02-06 2000-08-04 Salter av paroxsetine
BG104737A BG104737A (en) 1998-02-06 2000-08-30 Salts of paroxetine

Applications Claiming Priority (66)

Application Number Priority Date Filing Date Title
GB9802698.2 1998-02-06
GBGB9802661.0A GB9802661D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802645.3 1998-02-06
GBGB9802655.2A GB9802655D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802644.6A GB9802644D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802645.3A GB9802645D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802653.7A GB9802653D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802640.4A GB9802640D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802654.5 1998-02-06
GB9802655.2 1998-02-06
GBGB9802658.6A GB9802658D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802656.0 1998-02-06
GB9802665.1 1998-02-06
GB9802664.4 1998-02-06
GB9802657.8 1998-02-06
GBGB9802656.0A GB9802656D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802654.5A GB9802654D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802639.6 1998-02-06
GB9802644.6 1998-02-06
GBGB9802698.2A GB9802698D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802638.8A GB9802638D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802659.4A GB9802659D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802638.8 1998-02-06
GBGB9802657.8A GB9802657D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802646.1A GB9802646D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802665.1A GB9802665D0 (en) 1998-02-06 1998-02-06 Novel compounds
GBGB9802639.6A GB9802639D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802658.6 1998-02-06
GB9802659.4 1998-02-06
GB9802661.0 1998-02-06
GB9802646.1 1998-02-06
GBGB9802664.4A GB9802664D0 (en) 1998-02-06 1998-02-06 Novel compounds
GB9802653.7 1998-02-06
GB9802640.4 1998-02-06
GB9817364.4 1998-08-08
GB9817317.2 1998-08-08
GB9817359.4 1998-08-08
GBGB9817309.9A GB9817309D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817340.4 1998-08-08
GBGB9817317.2A GB9817317D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817340.4A GB9817340D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817359.4A GB9817359D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817344.6 1998-08-08
GB9817309.9 1998-08-08
GB9817360.2 1998-08-08
GBGB9817364.4A GB9817364D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817307.3 1998-08-08
GBGB9817307.3A GB9817307D0 (en) 1998-08-08 1998-08-08 Novel compound
GBGB9817321.4A GB9817321D0 (en) 1998-08-08 1998-08-08 Novel compound
GB9817321.4 1998-08-08
GBGB9817344.6A GB9817344D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817360.2A GB9817360D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817320.6A GB9817320D0 (en) 1998-08-10 1998-08-10 Novel compounds
GBGB9817322.2A GB9817322D0 (en) 1998-08-10 1998-08-10 Novel compounds
GB9817320.6 1998-08-10
GB9817322.2 1998-08-10
GBGB9826173.8A GB9826173D0 (en) 1998-11-30 1998-11-30 Novel compounds
GBGB9826172.0A GB9826172D0 (en) 1998-11-30 1998-11-30 Novel compound
GB9826172.0 1998-11-30
GB9826173.8 1998-11-30
GB9827277.6 1998-12-11
GBGB9827341.0A GB9827341D0 (en) 1998-12-11 1998-12-11 Novel compounds
GB9827341.0 1998-12-11
GBGB9827277.6A GB9827277D0 (en) 1998-12-11 1998-12-11 Novel compound
GB9828775.8 1998-12-29
GBGB9828775.8A GB9828775D0 (en) 1998-12-29 1998-12-29 Novel compounds

Publications (1)

Publication Number Publication Date
WO1999040084A1 true WO1999040084A1 (fr) 1999-08-12

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Application Number Title Priority Date Filing Date
PCT/GB1999/000380 WO1999040084A1 (fr) 1998-02-06 1999-02-05 Sels de paroxetine

Country Status (11)

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EP (1) EP1053234A1 (fr)
JP (1) JP2002505254A (fr)
KR (1) KR20010040711A (fr)
BG (1) BG104737A (fr)
CA (1) CA2319652A1 (fr)
EA (1) EA200000815A1 (fr)
IL (1) IL137684A0 (fr)
NO (1) NO20003960L (fr)
PL (1) PL342295A1 (fr)
SK (1) SK11812000A3 (fr)
WO (1) WO1999040084A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001692A1 (fr) * 1998-07-02 2000-01-13 Smithkline Beecham Plc Sels de paroxetine
WO2000008016A1 (fr) * 1998-08-08 2000-02-17 Smithkline Beecham Plc Sels de paroxetine
WO2000035910A1 (fr) * 1998-12-11 2000-06-22 Smithkline Beecham Plc Derive paroxetinique
WO2000078290A2 (fr) * 1999-06-22 2000-12-28 Smithkline Beecham P.L.C. Nouvelle preparation
EP1020464B1 (fr) * 1998-07-02 2001-07-04 Smithkline Beecham Plc Méthanesulfonate de paroxetine
WO2001077106A1 (fr) * 2000-04-07 2001-10-18 Richter Gedeon Vegyészeti Gyár Rt. Nouveau sel de paroxetine et nouveau produit pharmaceutique le contenant
WO2002053561A1 (fr) * 2001-01-05 2002-07-11 Eli Lilly And Company Antagonistes du recepteur d'acide amine excitateur
WO2003020717A1 (fr) * 2001-08-02 2003-03-13 Spurcourt Limited Sel d'isethionate de paroxetine, procede de preparation et utilisation dans le traitement de la depression
US7229980B2 (en) 2004-09-21 2007-06-12 Chong Kun Dang Pharmaceutical Corp. Paroxetine cholate or cholic acid derivative salts, and composition comprising paroxetine and cholic acid or derivative thereof
US20210038590A1 (en) * 2018-03-08 2021-02-11 Hefei Keda Bio-Technology Co. Ltd Memantine paroxetine cocrystal salt and its preparation method, pharmaceutical composition and application

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0188081A2 (fr) * 1984-12-04 1986-07-23 Novo Nordisk A/S Utilisation de paroxétine pour l'obtention d'un medicament pour le traitement del'obèsitè
EP0223403A2 (fr) * 1985-10-25 1987-05-27 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
EP0810224A1 (fr) * 1996-05-30 1997-12-03 Asahi Glass Company Ltd. Procédé de préparation de l'hydrochlorure de paroxétine amorphe
WO1998001424A1 (fr) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. Derives de n-benzylpiperidine et de tetrahydropyridine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0188081A2 (fr) * 1984-12-04 1986-07-23 Novo Nordisk A/S Utilisation de paroxétine pour l'obtention d'un medicament pour le traitement del'obèsitè
EP0223403A2 (fr) * 1985-10-25 1987-05-27 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
EP0810224A1 (fr) * 1996-05-30 1997-12-03 Asahi Glass Company Ltd. Procédé de préparation de l'hydrochlorure de paroxétine amorphe
WO1998001424A1 (fr) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. Derives de n-benzylpiperidine et de tetrahydropyridine

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001692A1 (fr) * 1998-07-02 2000-01-13 Smithkline Beecham Plc Sels de paroxetine
EP1020464B1 (fr) * 1998-07-02 2001-07-04 Smithkline Beecham Plc Méthanesulfonate de paroxetine
WO2000008016A1 (fr) * 1998-08-08 2000-02-17 Smithkline Beecham Plc Sels de paroxetine
WO2000035910A1 (fr) * 1998-12-11 2000-06-22 Smithkline Beecham Plc Derive paroxetinique
WO2000078290A2 (fr) * 1999-06-22 2000-12-28 Smithkline Beecham P.L.C. Nouvelle preparation
WO2000078290A3 (fr) * 1999-06-22 2001-05-25 Smithkline Beecham Plc Nouvelle preparation
WO2001077106A1 (fr) * 2000-04-07 2001-10-18 Richter Gedeon Vegyészeti Gyár Rt. Nouveau sel de paroxetine et nouveau produit pharmaceutique le contenant
WO2002053561A1 (fr) * 2001-01-05 2002-07-11 Eli Lilly And Company Antagonistes du recepteur d'acide amine excitateur
WO2003020717A1 (fr) * 2001-08-02 2003-03-13 Spurcourt Limited Sel d'isethionate de paroxetine, procede de preparation et utilisation dans le traitement de la depression
US7229980B2 (en) 2004-09-21 2007-06-12 Chong Kun Dang Pharmaceutical Corp. Paroxetine cholate or cholic acid derivative salts, and composition comprising paroxetine and cholic acid or derivative thereof
US20210038590A1 (en) * 2018-03-08 2021-02-11 Hefei Keda Bio-Technology Co. Ltd Memantine paroxetine cocrystal salt and its preparation method, pharmaceutical composition and application
US11839607B2 (en) * 2018-03-08 2023-12-12 Hefei Keda Bio-Technology Co. Ltd Memantine paroxetine cocrystal salt and its preparation method, pharmaceutical composition and application

Also Published As

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NO20003960L (no) 2000-09-25
IL137684A0 (en) 2001-10-31
BG104737A (en) 2001-07-31
KR20010040711A (ko) 2001-05-15
SK11812000A3 (sk) 2001-08-06
CA2319652A1 (fr) 1999-08-12
JP2002505254A (ja) 2002-02-19
NO20003960D0 (no) 2000-08-04
EA200000815A1 (ru) 2001-02-26
EP1053234A1 (fr) 2000-11-22
PL342295A1 (en) 2001-06-04

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