WO2001012623A1 - Procede de preparation d'hydrochlorure de paroxetine anhydre - Google Patents

Procede de preparation d'hydrochlorure de paroxetine anhydre Download PDF

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Publication number
WO2001012623A1
WO2001012623A1 PCT/GB2000/003096 GB0003096W WO0112623A1 WO 2001012623 A1 WO2001012623 A1 WO 2001012623A1 GB 0003096 W GB0003096 W GB 0003096W WO 0112623 A1 WO0112623 A1 WO 0112623A1
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WO
WIPO (PCT)
Prior art keywords
paroxetine hydrochloride
paroxetine
solution
process according
anhydrate form
Prior art date
Application number
PCT/GB2000/003096
Other languages
English (en)
Inventor
David Alan Jones
Neal Ward
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 AU65808/00A priority Critical patent/AU6580800A/en
Publication of WO2001012623A1 publication Critical patent/WO2001012623A1/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
    • 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

Definitions

  • This invention relates to a process for the manufacture of a stable crystalline polymorph of paroxetine hydrochloride anhydrate, which is suitable for large scale commercial operation.
  • Paroxetine hydrochloride has been described as a crystalline hemihydrate (see EP- 0223403) and as various crystalline anhydrate forms (see WO 96/24595).
  • a particularly stable and useful crystalline polymorphic form of paroxetine hydrochloride anhydrate described in WO 96/24595 is paroxetine hydrochloride anhydrate Form C, having a distinctive x-ray powder diffractogram and a melting point of about 164°C.
  • a crystalline form of paroxetine hydrochloride anhydrate having an X-ray powder diffractogram consistent with paroxetine hydrochloride anhydrate Form C is described in Canadian Patent Application 2187128.
  • a solution of paroxetine hydrochloride is formed in a solvent suitable for commercial use, for example by contacting paroxetine base with a source of hydrogen chloride, the solution is if necessary rendered anhydrous, optionally seeded, allowed to crystallise under controlled conditions, and the product isolated, washed and dried.
  • the paroxetine base is in the form of a solution in a solvent which has been carried forward from a previous manufacturing step.
  • the paroxetine base is used in solution in a hydrocarbon (for example toluene), a ketone (for example methyl isobutylketone), an ester (for example ethyl acetate), or an alcohol (for example 1- butanol).
  • the source of hydrogen chloride is aqueous hydrochloric acid, preferably, concentrated hydrochloric acid. It is not necessary to dry the paroxetine base solution before contacting with the source of hydrogen chloride. However, it is important to dry the solution prior to the crystallisation of paroxetine hydrochloride anhydrate Form C, to avoid formation of paroxetine hydrochloride hemihydrate.
  • paroxetine hydrochloride contains water it may be rendered anhydrous by distillation or by use of drying agents.
  • drying step is carried out by distillation using 'Dean and Stark' techniques or by azeotropic distillation.
  • paroxetine hydrochloride anhydrate Form C is typically crystallised from an anhydrous solution of paroxetine hydrochloride at elevated temperature.
  • a high temperature solution of the hydrochloride is optionally dehydrated, for example by distillation, cooled to the crystallisation temperature, optionally seeded with paroxetine hydrochloride anhydrate Form C, then held at the crystallisation temperature for several hours.
  • the crystallisation temperature is less than 85°C, preferably between 35°C and 75°C, more preferably 40-60°C, and most preferably 45-55°C.
  • the crystallisation time is 6-24 hours, preferably 12-18 hours.
  • the paroxetine hydrochloride anhydrate Form C is isolated at a temperature higher than room temperature.
  • the isolation temperature may be the same as or lower than the crystallisation temperature.
  • toluene which is the prefered solvent of this invention is used, we have surprisingly found that solvent levels in the dried product are significantly reduced when the isolation temperature is greater than 35°C, preferably 45-55°C and most preferably 49-51°C.
  • the resultant paroxetine anhydrate Form C desirably contains less than 2% of solvent, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1%.
  • paroxetine anhydrate Form C can be obtained with residual solvent levels below 0.1% and this forms a further aspect of this invention, especially with toluene as solvent.
  • Paroxetine base may be prepared as described US 4,007,196 or EP-0223403.
  • a particularly suitable source of a solution of paroxetine base is described in Example 1 of EP-0223403 whereby (-)-trans-4-(4'-fluorophenyl)-3-(3*-4*-methylenedioxy- phenoxymethyl-N-phenoxycarbonylpiperidine is hydrolysed with potassium hydroxide in refluxing toluene, followed by an aqueous wash.
  • Such a process results in a solution of paroxetine base in wet toluene, which may be used directly in the process of this invention.
  • paroxetine hydrochloride anhydrate Form C is manufactured by crystallisation from a solution of paroxetine hydrochloride generated from amorphous paroxetine hydrochloride or a paroxetine hydrochloride anhydrate hydrate, solvate or mixed solvate, in a suitable solvent such as toluene.
  • the anhydrate may be paroxetine hydrochloride Form A; the hydrate may be the hemihydrate; the solvate may be paroxetine hydrochloride propan-2-ol solvate, and the mixed solvate may be paroxetine hydrochloride propan-2-ol / acetone mixed solvate.
  • the hydrate, solvate or mixed solvate is dissolved in a solvent at elevated temperature, if necessary rendering the solution anhydrous, and employed in the process of the invention.
  • the product may be isolated using conventional equipment such as a centrifuge or a filter drier and dried under vacuum, suitably at 40-50°C.
  • the crystalline paroxetine hydrochloride anhydrate Form C obtainable by this invention may be used in therapy in formulations described in EP-A-0223403 or WO 96/00477.
  • paroxetine hydrochloride anhydrate of this invention include treatment of inter alia : alcoholism, anxiety, depression, obsessive compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders”.
  • OCD obsessive compulsive disorder
  • PMS pre-menstrual syndrome
  • adolescent depression trichotillomania
  • dysthymia substance abuse
  • anhydrate obtainable by the present invention is applied to the treatment of depression, OCD and panic.
  • compositions prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
  • the composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
  • Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.
  • compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
  • Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
  • compositions include those described EP-B- 0223403, and US 4,007,196 in which the anhydrate product of the present invention may be used as the active ingredient.
  • the present invention also provides:
  • compositions for treatment or prophylaxis of the Disorders comprising paroxetine hydrochloride anhydrate Form C obtainable by this invention and a pharmaceutically acceptable carrier;
  • paroxetine hydrochloride anhydrate Form C obtainable by this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders;
  • a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate Form C obtainable by this invention to a person suffering from one or more of the Disorders.
  • paroxetine hydrochloride propan-2-ol solvate (16.9 g) in toluene (200 ml) was heated to reflux and 50 ml of solvent removed by distillation. The resulting solution was cooled to 40-50°C and stirred for 16 hours at this temperature. The product was collected by filtration of the warm solution and dried under vacuum at room temperature for 24 hours to give paroxetine hydrochloride anhydrate Form C as a white solid (14.26g). Toluene level 0.07% (by gas chromatography).
  • the reaction mixture was cooled to 20 to 25°C and demineralized water (50.0 L) added, maintaining the temperature at 20 to 25°C.
  • the mixture was stirred at this temperature for 30 minutes to dissolve the inorganic salts, then the agitator was stopped and the mixture allowed to separate for 30 minutes.
  • the lower, aqueous, phase was separated and discarded.
  • the organic layer was stirred and heated to 60°C and concentrated hydrochloric acid ( 1.4 kg) added.
  • the resulting mixture was heated to reflux under "Dean and Stark” conditions until no further water was collected.
  • the mixture was cooled to 50 to 60°C and stirred at this temperature for 16 hours to complete the crystallisation, then the product was isolated at 50 to 60°C using an "Ellerwerk" centrifuge.
  • the reactor was rinsed with toluene (10 kg) and the toluene used to wash the product.
  • the toluene- wet product was dried in a "Eurovent” agitated vacuum pan drier at 50°C under vacuum for 12 hours to give paroxetine hydrochloride anhydrate Form C (3.23 kg) as a free flowing crystalline powder.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (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)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de cristallisation de la forme C de l'hydrochlorure de paroxétine anhydre. Ce procédé permet d'obtenir un produit à écoulement fluide avec des caractéristiques physiques reproductibles et constantes et de faibles taux de solvants résiduels, qui est particulièrement approprié pour être fabriqué à grande échelle. Une solution d'hydrochlorure de paroxétine est formée dans un solvant approprié pour être utilisé commercialement, par exemple, en plaçant en contact une solution de base de paroxétine avec une source de chlorure d'hydrogène. Si nécessaire, la solution est rendue anhydre, et éventuellement ensemencée, et la forme C peut cristalliser sous conditions contrôlées, en général à une température élevée inférieure à 85 °C. La solution est également isolée à température élevée, en général à 35°. Ce produit présente des taux de solvants résiduels trés faibles.
PCT/GB2000/003096 1999-08-12 2000-08-11 Procede de preparation d'hydrochlorure de paroxetine anhydre WO2001012623A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65808/00A AU6580800A (en) 1999-08-12 2000-08-11 Process for the preparation of paroxetine hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9919001.9 1999-08-12
GBGB9919001.9A GB9919001D0 (en) 1999-08-12 1999-08-12 Novel process

Publications (1)

Publication Number Publication Date
WO2001012623A1 true WO2001012623A1 (fr) 2001-02-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/003096 WO2001012623A1 (fr) 1999-08-12 2000-08-11 Procede de preparation d'hydrochlorure de paroxetine anhydre

Country Status (3)

Country Link
AU (1) AU6580800A (fr)
GB (1) GB9919001D0 (fr)
WO (1) WO2001012623A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019209A2 (fr) * 2003-06-12 2005-03-03 Cadila Healthcare Limited Nouvelle forme d'hydrochlorure de paroxetine anhydre et son procede de preparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996024595A1 (fr) * 1995-02-06 1996-08-15 Smithkline Beecham Plc Nouvelles formes de l'hydrochlorure de paroxetine
CA2187128A1 (fr) * 1996-10-04 1997-06-26 K. S. Keshava Murthy Polymorphe nouveau et efficace, a base de chlorhydrate de paroxetine anhydre
WO1999032484A1 (fr) * 1997-12-19 1999-07-01 Smithkline Beecham Plc Procede de preparation d'hydrochlorure de paroxetine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996024595A1 (fr) * 1995-02-06 1996-08-15 Smithkline Beecham Plc Nouvelles formes de l'hydrochlorure de paroxetine
CA2187128A1 (fr) * 1996-10-04 1997-06-26 K. S. Keshava Murthy Polymorphe nouveau et efficace, a base de chlorhydrate de paroxetine anhydre
WO1999032484A1 (fr) * 1997-12-19 1999-07-01 Smithkline Beecham Plc Procede de preparation d'hydrochlorure de paroxetine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019209A2 (fr) * 2003-06-12 2005-03-03 Cadila Healthcare Limited Nouvelle forme d'hydrochlorure de paroxetine anhydre et son procede de preparation
WO2005019209A3 (fr) * 2003-06-12 2005-05-12 Cadila Healthcare Ltd Nouvelle forme d'hydrochlorure de paroxetine anhydre et son procede de preparation

Also Published As

Publication number Publication date
GB9919001D0 (en) 1999-10-13
AU6580800A (en) 2001-03-13

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