WO2000078752A1 - Procede de production de chlorhydrate de paroxetine - Google Patents

Procede de production de chlorhydrate de paroxetine Download PDF

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Publication number
WO2000078752A1
WO2000078752A1 PCT/GB2000/002425 GB0002425W WO0078752A1 WO 2000078752 A1 WO2000078752 A1 WO 2000078752A1 GB 0002425 W GB0002425 W GB 0002425W WO 0078752 A1 WO0078752 A1 WO 0078752A1
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WO
WIPO (PCT)
Prior art keywords
paroxetine
solution
paroxetine hydrochloride
hydrochloride
hydrogen chloride
Prior art date
Application number
PCT/GB2000/002425
Other languages
English (en)
Inventor
David Alan Jones
Original Assignee
Smithkline Beecham P.L.C.
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
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU55509/00A priority Critical patent/AU5550900A/en
Publication of WO2000078752A1 publication Critical patent/WO2000078752A1/fr

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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

Definitions

  • This invention is concerned with a process for conversion of paroxetine maleate to paroxetine hydrochloride, more specifically for the direct conversion of paroxetine maleate to paroxetine hydrochloride.
  • Example 2 of US 4,007,196 describes the preparation of a paroxetine maleate salt.
  • Paroxetine free base is dissolved in ether and treated with a solution of maleic acid in ethyl ether to form a crystalline product, which is recrystallised from 99% ethanol-ether to give a maleate salt melting 136-8°C.
  • PCT/GB99/01 106 describes the preparation of paroxetine maleate 1 : 1 and 2:1 salts and polymorphs.
  • Paroxetine may be isolated and stored in the form of its maleate salt, but for medicinal use the hydrochloride form is preferred, either as the crystalline hemihydrate (as disclosed in EP-A-0223403) or as one of the anhydrate forms (e.g. as disclosed in WO 96/24595).
  • This invention is based on the discovery of a procedure by which paroxetine maleate in suspension is directly converted to solid paroxetine hydrochloride, avoiding formation of paroxetine free base and subsequent re-acidifying with hydrogen chloride.
  • the process surprisingly results in good yield and purity without the complication of large amounts of maleic acid contamination, and so is suitable for large-scale manufacture.
  • paroxetine maleate in propan-2-ol is less than 0.5% by weight, so reactions based on paroxetine maleate in solution would be very volume inefficient and unsuitable for manufacture. Conversion of one solid into another in a slurry is likely to result in incomplete conversion and an impure product. Indeed we have found that if one equivalent of hydrogen chloride is used a mixed product is obtained.
  • this invention provides a process for the preparation of paroxetine hydrochloride in which a suspension of paroxetine maleate is treated with an excess of hydrogen chloride to form a solution containing paroxetine, maleic acid, and hydrochloric acid, and crystallising substantially pure paroxetine hydrochloride from the solution.
  • the hydrogen chloride may be added as an aqueous or non-aqueous solution or in the form of a gas or as an amine hydrochloride salt (for example ammonium chloride or triethylammonium chloride) as a solid or in solution.
  • the hydrogen chloride solution is added slowly.
  • the excess of hydrogen chloride is in the range 5- 100%, more preferably it is in the range 7-15% (on a molar basis).
  • the conversion reaction may be carried out at any temperature between 0°C and 80°C, but most conveniently it is carried out at about 15-25°C.
  • the solution may be filtered or clarified.
  • One surprising feature of the invention is that the product that crystallises from the mixed solution is in fact the more soluble salt.
  • crystallisation is initiated by seeding with crystals of the desired final form of paroxetine hydrochloride, such as the hemihydrate, or the anhydrate Form A, B, or C.
  • paroxetine hydrochloride such as the hemihydrate, or the anhydrate Form A, B, or C.
  • Suitable solvents for the conversion are those from which paroxetine hydrochloride is known to crystallise, for example alcohols, such as propan-2-ol, and ketones, such as butanone, optionally mixed with water, or a hydrocarbon, such as toluene.
  • Suitable volumes of solvent are in the range 5-30 volumes (based on the weight of paroxetine maleate), preferably in the range 10-20 volumes.
  • paroxetine hydrochloride will crystallise as a solvate.
  • the solvent may be removed from the solvate by known methods
  • Paroxetine maleate salts used in this invention may be prepared as disclosed in US 40071 6 or PCT/GB99/01 106.
  • Paroxetine hydrochloride obtainable by the process of this invention may be used to treat and prevent the following disorders:
  • 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 paroxetine hydrochloride obtainable by the process of this 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 paroxetine hydrochloride obtainable by the process of this invention with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of paroxetine hydrochloride obtainable by the process of this invention for treating and/or preventing the Disorders.
  • the present invention also provides the use of paroxetine hydrochloride obtainable by the process of this 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 containing the salt of this invention may be formulated for administration by any route, and examples are oral, sub-lingual, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may, if desired, be designed to give slow release of the paroxetine salt.
  • the medicaments may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • 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.
  • Paroxetine (1:1) Maleate Form B by recrystallization of Form A from butanone.
  • paroxetine maleate Form A 0.5g
  • butanone 4 ml
  • the solution was allowed to cool slowly to room temperature to give a paroxetine maleate Form B as a granular white crystalline solid which was collected by filtration and dried in vacuo over phosphorous pentoxide.
  • NMR showed a ratio of 1 : 1 for paroxetine : maleic acid; butanone content was approximately 0.1% by weight.
  • Paroxetine (1 :1) maleate Form A (5.67 g) in propan-2 -ol (50 ml) was stirred rapidly and treated with a solution of hydrogen chloride in propan-2-ol (2.5 ml of a ca. 5.5 molar solution) over 15 minutes. A solution formed, and was stirred for 30 minutes at room temperature before seeds of paroxetine hydrochloride anhydrate Form A (0.1 g) were added. Crystallisation commenced rapidly giving a thick suspension which was mobilized by the addition of more propan-2-ol (50 ml).
  • Paroxetine maleate Form A (5.00 g) in propan-2-ol (50 ml) was stirred rapidly and treated with a solution of hydrogen chloride in propan-2-ol (2.8 ml of a ca. 5.5 molar solution) over 10 minutes. Insoluble residues were removed by filtration and the resulting clear solution was stirred for 30 minutes at room temperature. Seeds of paroxetine hydrochloride anhydrate Form A were added (0.1 g), causing rapid crystallisation to a thick suspension that was mobilised by adding more propan-2-ol (50 ml).
  • Paroxetine maleate Form A (2.00 g) in methyl 2-pentanone (20 ml) was stirred rapidly and treated with a solution of hydrogen chloride in propan-2-ol under nitrogen (1.35 ml of a ca. 5.5 molar solution). The solid reagents dissolved and the solution was stirred for 30 minutes at room temperature. Seeds of paroxetine hydrochloride anhydrate Form C were added and the reaction mixture was insonicated. Crystallisation occurred and the mixture was stirred at room temperature for 3 hours. The product, paroxetine hydrochloride anhydrate Form C, was collected by filtration, washed with methyl 2- pentanone, and dried under vacuum at 60°C overnight (yield 1.32 g).
  • Example 5 A suspension of paroxetine maleate Form B (2.00 g) in propan-2-ol (50 ml) was stirred rapidly at ambient temperature and treated with 5 molar hydrochloric acid (1.0 ml). The mixture was stirred for 3 hours, filtered, washed with propan-2-ol, and dried under vacuum to give crystalline paroxetine hydrochloride hemihydrate. Yield 1.36 g.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de chlorhydrate de paroxétine consistant à traiter une suspension de maléate de paroxétine avec un excès de chlorure d'hydrogène de manière à obtenir une solution contenant de la paroxétine, de l'acide maléique et de l'acide d'hydrochlorate et à cristalliser en grande partie l'hydrochlorate de paroxétine issu de la solution. Selon ce procédé, le maléate de paroxétine en solution est directement transformé en hydrochlorate de paroxétine solide, on évite ainsi la formation d'une base exempte de paroxétine et sa réacidification avec le chlorure d'hydrogène. On obtient un bon rendement et une bonne pureté sans grosse contamination par l'acide maléique ce qui permet une production à grande échelle.
PCT/GB2000/002425 1999-06-22 2000-06-22 Procede de production de chlorhydrate de paroxetine WO2000078752A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55509/00A AU5550900A (en) 1999-06-22 2000-06-22 Process for the production of paroxetine hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9914585.6A GB9914585D0 (en) 1999-06-22 1999-06-22 Novel process
GB9914585.6 1999-06-22

Publications (1)

Publication Number Publication Date
WO2000078752A1 true WO2000078752A1 (fr) 2000-12-28

Family

ID=10855843

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/002425 WO2000078752A1 (fr) 1999-06-22 2000-06-22 Procede de production de chlorhydrate de paroxetine

Country Status (3)

Country Link
AU (1) AU5550900A (fr)
GB (1) GB9914585D0 (fr)
WO (1) WO2000078752A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223403A2 (fr) * 1985-10-25 1987-05-27 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
WO1996024595A1 (fr) * 1995-02-06 1996-08-15 Smithkline Beecham Plc Nouvelles formes de l'hydrochlorure de paroxetine
WO1998056787A1 (fr) * 1997-06-10 1998-12-17 Synthon B.V. Composes 4-phenylpiperidine
WO1999052901A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Plc Maleate de paroxetine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223403A2 (fr) * 1985-10-25 1987-05-27 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
WO1996024595A1 (fr) * 1995-02-06 1996-08-15 Smithkline Beecham Plc Nouvelles formes de l'hydrochlorure de paroxetine
WO1998056787A1 (fr) * 1997-06-10 1998-12-17 Synthon B.V. Composes 4-phenylpiperidine
WO1999052901A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Plc Maleate de paroxetine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BUXTON P C ET AL: "SOLID-STATE FORMS OF PAROXETINE HYDROCHLORIDE", INTERNATIONAL JOURNAL OF PHARMACEUTICS,NL,AMSTERDAM, vol. 42, 1988, pages 135 - 143, XP000572028, ISSN: 0378-5173 *

Also Published As

Publication number Publication date
AU5550900A (en) 2001-01-09
GB9914585D0 (en) 1999-08-25

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