WO2000027844A1 - Process for the preparation of paroxetine hydrochloride - Google Patents

Process for the preparation of paroxetine hydrochloride Download PDF

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Publication number
WO2000027844A1
WO2000027844A1 PCT/GB1999/003664 GB9903664W WO0027844A1 WO 2000027844 A1 WO2000027844 A1 WO 2000027844A1 GB 9903664 W GB9903664 W GB 9903664W WO 0027844 A1 WO0027844 A1 WO 0027844A1
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WO
WIPO (PCT)
Prior art keywords
paroxetine hydrochloride
solid
solution
process according
supercritical fluid
Prior art date
Application number
PCT/GB1999/003664
Other languages
French (fr)
Inventor
Ian David Camburn
David Roy Merrifield
Christopher Edmund Valder
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
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU64817/99A priority Critical patent/AU6481799A/en
Publication of WO2000027844A1 publication Critical patent/WO2000027844A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the present invention relates to a process for the preparation of a pharmaceutically active compound, and to use of the so-prepared compound in therapy.
  • this invention is concerned with the preparation of various solid forms of paroxetine hydrochloride.
  • Paroxetine hydrochloride has been described in the literature as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group) and as various crystalline anhydrate forms (see WO96/24595 of SmithKline Beecham pic). These known forms have properties that are not ideal for all pharmaceutical applications, and are prepared by multi-step procedures involving precipitation under carefully controlled conditions, filtration, drying, and homogenisation.
  • the present invention provides a process for isolating a solid form of paroxetine hydrochloride which comprises precipitating paroxetine hydrochloride from a solution thereof in a supercritical or near-critical fluid domain.
  • the solid forms of paroxetine hydrochloride that may be obtained using this procedure include crystalline forms as well as an amorphous precipitated form.
  • This procedure offers the advantage of a more easily controlled precipitation process than is obtained by previously known methods, and better control of surface morphology, porosity, particle size and distribution. These factors are important and affect, for example, the rate of dissolution and the performance of the material in secondary pharmaceutical manufacturing.
  • Paroxetine hydrochloride is prepared for supercritical fluid precipitation by forming a solution in a supercritical fluid such as supercritical carbon dioxide.
  • a supercritical fluid such as supercritical carbon dioxide.
  • Other supercritical fluids such as ethane, n-propane, n-butane, and nitrogen oxide, may also be used.
  • Known solid forms of paroxetine hydrochloride form such solutions with some difficulty. Therefore the paroxetine hydrochloride is preferably first dissolved in an auxiliary solvent, for example ethanol, propan-2-ol, or isobutyl alcohol, compatible with the supercritical fluid, and the solution brought into contact with the supercritical fluid to form a suitable solution for precipitation.
  • an auxiliary solvent for example ethanol, propan-2-ol, or isobutyl alcohol
  • a suitable solution may be prepared from amo ⁇ hous paroxetine hydrochloride or a crystalline anhydrate, hydrate, or solvate of paroxetine hydrochloride, or by dissolving the free base and hydrochloric acid in an aqueous, organic or mixed aqueous and organic solvent. Indeed it may be possible to bring the free base and hydrochloric acid together in the supercritical domain where they may react prior to precipitation of paroxetine hydrochloride.
  • this solvent preferably has an affinity for the supercritical fluid so that both may be effectively removed in a single process.
  • the preferred auxiliary solvents listed above are not ideal in this respect, at least when the supercritical fluid is carbon dioxide, so it may be advantageous to employ an additional entraining solvent to confer suitable properties on the auxiliary solvent.
  • An example of a suitable entraining solvent for use with propan-2-ol and supercritical carbon dioxide is acetone.
  • the entraining solvent may be combined with the auxiliary solvent in a ratio from 1:5 to 20: 1, preferably from 1: 1 to 10:1, and most preferably from 3: 1 to 7: 1.
  • the concentration of paroxetine hydrochloride in the auxiliary solvent may be from 0.5% to 25%, but is preferably in the range 1% to 10%, for example from 2.5% to 5%.
  • the supercritical solution for precipitation is formed by combining the paroxetine hydrochloride solution with supercritical fluid in its liquid phase in a ratio of from 1 :2 to 1 :200, preferably in the range from 1 : 10 to 1 :50, most preferably in the range 1 : 15 to 1:30.
  • a chamber containing a spray device is maintained at a temperature and pressure such that carbon dioxide (or other fluid) is supercritical.
  • the temperature is controlled using an oven, and the pressure is controlled using a back pressure regulator at the chamber exit.
  • a solution of paroxetine hydrochloride is prepared in a suitable solvent system and this solution and a supercritical fluid are separately metered to the spray device using high pressure pumps.
  • the supercritical fluid effectively removes the solvent from the paroxetine hydrochloride solution, giving a precipitate which is deposited in the collection chamber.
  • the delivery of paroxetine hydrochloride solution is stopped.
  • the paroxetine hydrochloride particles are rinsed with supercritical fluid to remove final traces of solvent and the apparatus is depressurised to harvest the product.
  • the paroxetine hydrochloride is dissolved in the supercritical fluid or solvent-modified supercritical fluid using a saturator chamber.
  • the resultant supercritical fluid solution is sprayed through a spray device into a second chamber at atmospheric or slightly above atmospheric pressure and particles of paroxetine hydrochloride are formed.
  • the temperature of the precipitation is generally from 15°C to 150°C, preferably from 45°C to 100°C, and the pressure is maintained in the range 25 to 300 bar, preferably from 100 to 200 bar.
  • a crystalline product When a crystalline product is desired, improved control of the precipitation process may be achieved by the addition of seeds.
  • the desired product is a hydrate such as paroxetine hydrochloride hemihydrate, an amount of water should be present in excess of the amount required according to theory.
  • the solid product of this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595. Free-flowing solids are advantageous for the preparation of solid formulations. Easily soluble solids are suitable for the preparation of solutions for parenteral use.
  • paroxetine product of this invention includes treatment of: 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, and substance abuse, referred to below as "the disorders”. Accordingly, the present invention also provides:
  • compositions for treatment or prophylaxis of the disorders comprising solid paroxetine hydrochloride obtained by the process of this invention and a pharmaceutically acceptable carrier or a solution of the obtained solid paroxetine hydrochloride;
  • a method of treating the disorders which comprises administering an effective or prophylactic amount of solid paroxetine hydrochloride obtained by the process of this invention, or a solution thereof, to a person suffering from one or more of the disorders.
  • a particle collection chamber inco ⁇ orating a spray device was maintained at a temperature of 45°C and a pressure of 95 bar.
  • a 2% solution of paroxetine hydrochloride in a 50: 10 acetone/propan-2-ol mixture containing 1.6% water was metered to the spray device at 0.40 ml/min.
  • Supercritical carbon dioxide was also metered to the spray device at 9.0 ml/min.
  • Paroxetine hydrochloride was deposited as low bulk density white powder.
  • a particle collection chamber with a spray device was maintained at 50°C and 125 bar.
  • a 2% solution of paroxetine hydrochloride in 110: 10 acetone/propan-2-ol was metered to the spray device at 0.27 ml min.
  • Supercritical carbon dioxide was also metered to the spray device at 6.0 ml/min.
  • Paroxetine hydrochloride was deposited as a dense white powder.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Solid forms of paroxetine hydrochloride (crystalline as well as amorphous) are obtained by precipitation from a supercritical or near-critical fluid such as carbon dioxide. This procedure offers the advantage of a more easily controlled precipitation process than is obtained by previously known methods, and better control of surface morphology, porosity, particle size and distribution.

Description

PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLOR IDE
The present invention relates to a process for the preparation of a pharmaceutically active compound, and to use of the so-prepared compound in therapy. In particular this invention is concerned with the preparation of various solid forms of paroxetine hydrochloride.
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 - methylene-dioxyphenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
Paroxetine hydrochloride has been described in the literature as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group) and as various crystalline anhydrate forms (see WO96/24595 of SmithKline Beecham pic). These known forms have properties that are not ideal for all pharmaceutical applications, and are prepared by multi-step procedures involving precipitation under carefully controlled conditions, filtration, drying, and homogenisation.
There remains a need for a more easily controlled precipitation process than is obtained by previously known methods, and better control of surface morphology, porosity, particle size and distribution
As the basis of this invention, we have devised a procedure for the isolation of solid forms of paroxetine hydrochloride whereby the precipitation takes place in or from a supercritical or near-critical phase, i.e. a phase that has properties similar to a gas but has density and solvation power similar to a liquid.
Accordingly, in its broadest aspect, the present invention provides a process for isolating a solid form of paroxetine hydrochloride which comprises precipitating paroxetine hydrochloride from a solution thereof in a supercritical or near-critical fluid domain.
The solid forms of paroxetine hydrochloride that may be obtained using this procedure include crystalline forms as well as an amorphous precipitated form. This procedure offers the advantage of a more easily controlled precipitation process than is obtained by previously known methods, and better control of surface morphology, porosity, particle size and distribution. These factors are important and affect, for example, the rate of dissolution and the performance of the material in secondary pharmaceutical manufacturing.
Paroxetine hydrochloride is prepared for supercritical fluid precipitation by forming a solution in a supercritical fluid such as supercritical carbon dioxide. Other supercritical fluids such as ethane, n-propane, n-butane, and nitrogen oxide, may also be used. Known solid forms of paroxetine hydrochloride form such solutions with some difficulty. Therefore the paroxetine hydrochloride is preferably first dissolved in an auxiliary solvent, for example ethanol, propan-2-ol, or isobutyl alcohol, compatible with the supercritical fluid, and the solution brought into contact with the supercritical fluid to form a suitable solution for precipitation. A suitable solution may be prepared from amoφhous paroxetine hydrochloride or a crystalline anhydrate, hydrate, or solvate of paroxetine hydrochloride, or by dissolving the free base and hydrochloric acid in an aqueous, organic or mixed aqueous and organic solvent. Indeed it may be possible to bring the free base and hydrochloric acid together in the supercritical domain where they may react prior to precipitation of paroxetine hydrochloride.
In order to achieve successful precipitation of paroxetine hydrochloride from a supercritical fluid by a method that uses an auxiliary solvent, this solvent preferably has an affinity for the supercritical fluid so that both may be effectively removed in a single process. The preferred auxiliary solvents listed above are not ideal in this respect, at least when the supercritical fluid is carbon dioxide, so it may be advantageous to employ an additional entraining solvent to confer suitable properties on the auxiliary solvent. An example of a suitable entraining solvent for use with propan-2-ol and supercritical carbon dioxide is acetone.
The entraining solvent may be combined with the auxiliary solvent in a ratio from 1:5 to 20: 1, preferably from 1: 1 to 10:1, and most preferably from 3: 1 to 7: 1. The concentration of paroxetine hydrochloride in the auxiliary solvent may be from 0.5% to 25%, but is preferably in the range 1% to 10%, for example from 2.5% to 5%. The supercritical solution for precipitation is formed by combining the paroxetine hydrochloride solution with supercritical fluid in its liquid phase in a ratio of from 1 :2 to 1 :200, preferably in the range from 1 : 10 to 1 :50, most preferably in the range 1 : 15 to 1:30. In a typical procedure, a chamber containing a spray device is maintained at a temperature and pressure such that carbon dioxide (or other fluid) is supercritical. The temperature is controlled using an oven, and the pressure is controlled using a back pressure regulator at the chamber exit. A solution of paroxetine hydrochloride is prepared in a suitable solvent system and this solution and a supercritical fluid are separately metered to the spray device using high pressure pumps. Within, or close to the spray device, the supercritical fluid effectively removes the solvent from the paroxetine hydrochloride solution, giving a precipitate which is deposited in the collection chamber. When sufficient material has accumulated in the collection chamber the delivery of paroxetine hydrochloride solution is stopped. The paroxetine hydrochloride particles are rinsed with supercritical fluid to remove final traces of solvent and the apparatus is depressurised to harvest the product.
In an alternative method of operation the paroxetine hydrochloride is dissolved in the supercritical fluid or solvent-modified supercritical fluid using a saturator chamber. The resultant supercritical fluid solution is sprayed through a spray device into a second chamber at atmospheric or slightly above atmospheric pressure and particles of paroxetine hydrochloride are formed.
The temperature of the precipitation is generally from 15°C to 150°C, preferably from 45°C to 100°C, and the pressure is maintained in the range 25 to 300 bar, preferably from 100 to 200 bar.
When a crystalline product is desired, improved control of the precipitation process may be achieved by the addition of seeds. When the desired product is a hydrate such as paroxetine hydrochloride hemihydrate, an amount of water should be present in excess of the amount required according to theory.
The solid product of this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595. Free-flowing solids are advantageous for the preparation of solid formulations. Easily soluble solids are suitable for the preparation of solutions for parenteral use.
Therapeutic uses of the paroxetine product of this invention include treatment of: 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, and substance abuse, referred to below as "the disorders". Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the disorders comprising solid paroxetine hydrochloride obtained by the process of this invention and a pharmaceutically acceptable carrier or a solution of the obtained solid paroxetine hydrochloride;
the use of solid paroxetine hydrochloride obtained by the process of this invention to manufacture a medicament in solid or liquid form for the treatment or prophylaxis of the disorders; and
a method of treating the disorders which comprises administering an effective or prophylactic amount of solid paroxetine hydrochloride obtained by the process of this invention, or a solution thereof, to a person suffering from one or more of the disorders.
The invention is illustrated by the following Examples:
Example 1
A particle collection chamber incoφorating a spray device was maintained at a temperature of 45°C and a pressure of 95 bar. A 2% solution of paroxetine hydrochloride in a 50: 10 acetone/propan-2-ol mixture containing 1.6% water was metered to the spray device at 0.40 ml/min. Supercritical carbon dioxide was also metered to the spray device at 9.0 ml/min. Paroxetine hydrochloride was deposited as low bulk density white powder.
Example 2
A particle collection chamber with a spray device was maintained at 50°C and 125 bar. A 2% solution of paroxetine hydrochloride in 110: 10 acetone/propan-2-ol was metered to the spray device at 0.27 ml min. Supercritical carbon dioxide was also metered to the spray device at 6.0 ml/min. Paroxetine hydrochloride was deposited as a dense white powder.

Claims

CLAIMS:
1. A process for isolating a solid form of paroxetine hydrochloride which comprises precipitating paroxetine hydrochloride from a solution thereof in a supercritical or near-critical fluid
2. A process according to claim 1 in which the solid form of paroxetine hydrochloride is crystalline.
3. A process according to claim 1 or 2 in which the supercritical fluid is carbon dioxide or ethane, n-propane, n-butane, or nitrogen oxide.
4. A process according to claim 1 , 2 or 3 in which the paroxetine hydrochloride is first dissolved in an auxiliary solvent compatible with the supercritical fluid, and the solution brought into contact with the supercritical fluid to form a suitable solution for precipitation.
5. A process according to claim 4 in which the auxiliary solvent is ethanol, propan- 2-ol, or isobutyl alcohol.
6. A process according to claim 4 or 5 in which an additional entraining solvent is employed to confer suitable properties on the auxiliary solvent.
7. A process according to claim 6 in which the supercritical fluid is carbon dioxide, the auxiliary solvent is propan-2-ol, and the entraining solvent is acetone.
8. A pharmaceutical composition for treatment or prophylaxis of the disorders comprising solid paroxetine hydrochloride obtained by the process of this invention and a pharmaceutically acceptable carrier or a solution of the obtained solid paroxetine hydrochloride.
9. The use of solid paroxetine hydrochloride obtained by the process of this invention to manufacture a medicament in solid or liquid form for the treatment or prophylaxis of the disorders.
10. A method of treating the disorders which comprises administering an effective or prophylactic amount of solid paroxetine hydrochloride obtained by the process of this invention, or a solution thereof, to a person suffering from one or more of the disorders.
PCT/GB1999/003664 1998-11-05 1999-11-05 Process for the preparation of paroxetine hydrochloride WO2000027844A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64817/99A AU6481799A (en) 1998-11-05 1999-11-05 Process for the preparation of paroxetine hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9824298.5A GB9824298D0 (en) 1998-11-05 1998-11-05 Novel process
GB9824298.5 1998-11-05

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WO2000027844A1 true WO2000027844A1 (en) 2000-05-18

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032462A1 (en) * 2000-10-19 2002-04-25 Separex Method for making very fine particles consisting of a principle inserted in a host molecule
US7390411B2 (en) 2001-10-12 2008-06-24 Pierre Fabre Medicament Method for preparing a compound of interaction of active substances with a porous support using supercritical fluid
US8741346B2 (en) 2003-04-25 2014-06-03 Pierre Fabre Medicament Method for the preparation of molecular complexes

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
WO1995001221A1 (en) * 1993-07-01 1995-01-12 University Of Bradford Method and apparatus for the formation of particles
WO1996024595A1 (en) * 1995-02-06 1996-08-15 Smithkline Beecham Plc New forms of paroxetin hydrochloride
EP0810224A1 (en) * 1996-05-30 1997-12-03 Asahi Glass Company Ltd. Method of producing amorphous paroxetine hydrochloride
WO1998031365A1 (en) * 1997-01-15 1998-07-23 Smithkline Beecham Plc Paroxetine compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
WO1995001221A1 (en) * 1993-07-01 1995-01-12 University Of Bradford Method and apparatus for the formation of particles
WO1996024595A1 (en) * 1995-02-06 1996-08-15 Smithkline Beecham Plc New forms of paroxetin hydrochloride
EP0810224A1 (en) * 1996-05-30 1997-12-03 Asahi Glass Company Ltd. Method of producing amorphous paroxetine hydrochloride
WO1998031365A1 (en) * 1997-01-15 1998-07-23 Smithkline Beecham Plc Paroxetine compositions

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032462A1 (en) * 2000-10-19 2002-04-25 Separex Method for making very fine particles consisting of a principle inserted in a host molecule
FR2815540A1 (en) * 2000-10-19 2002-04-26 Separex Sa A method and apparatus for making very fine particles containing a complex of an active principle and a cyclodextrin for e.g. pharmaceutical use by placing them in a solvent or solvents and contacting with a supercritical liquid
US7291296B2 (en) 2000-10-19 2007-11-06 Separex (Societe Anonyme) Method for making very fine particles consisting of a principle inserted in a host molecule
US7390411B2 (en) 2001-10-12 2008-06-24 Pierre Fabre Medicament Method for preparing a compound of interaction of active substances with a porous support using supercritical fluid
US8741346B2 (en) 2003-04-25 2014-06-03 Pierre Fabre Medicament Method for the preparation of molecular complexes

Also Published As

Publication number Publication date
AU6481799A (en) 2000-05-29
GB9824298D0 (en) 1998-12-30

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