WO2001012623A1

WO2001012623A1 - Process for the preparation of paroxetine hydrochloride

Info

Publication number: WO2001012623A1
Application number: PCT/GB2000/003096
Authority: WO
Inventors: David Alan Jones; Neal Ward
Original assignee: Smithkline Beecham P.L.C.
Priority date: 1999-08-12
Filing date: 2000-08-11
Publication date: 2001-02-22
Also published as: AU6580800A; GB9919001D0

Abstract

A process for the crystallisation of paroxetine hydrochloride anhydrate Form C which results in a free-flowing product with consistent and reproducible physical characteristics and low levels of residual solvents, and is particularly suitable for large-scale manufacture. A solution of paroxetine hydrochloride is formed in a solvent suitable for commercial use, for example by contacting a solution of paroxetine base with a source of hydrogen chloride, the solution is if necessary rendered anhydrous, optionally seeded, and Form C is allowed to crystallise under controlled conditions, typically at an elevated temperature below 85 °C, and is also isolated at an elevated temperature, typically above 35 °C. The product has surprisingly low levels of residual solvent.

Description

PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE

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.

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',4'- methylenedioxy-phenoxymethyl)-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 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.

No process for the large scale manufacture of paroxetine hydrochloride anhydrate Form C has been described in the prior art. Attempts to crystallise paroxetine hydrochloride anhydrate Form C from those solvents routinely used in large scale manufacture, such as methyl isobutyl ketone or toluene, result in significant levels of residual solvents (see WO 96/24595 Example 18). Furthermore, we have found that the crystallisation of paroxetine hydrochloride anhydrate Form C often proceeds in a slow and unpredictable manner, giving a product of variable crystal size and bulk density. An additional problem we have identified is contamination by co- crystallisation of paroxetine hydrochloride anhydrate Form B. This invention provides a process for the crystallisation of paroxetine hydrochloride anhydrate Form C which results in a free-flowing product with consistent and reproducible physical characteristics and low levels of residual solvents, and is particularly suitable for large-scale manufacture.

In the process of this invention, 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.

Suitably the paroxetine base is in the form of a solution in a solvent which has been carried forward from a previous manufacturing step. Preferably 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).

Suitably 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.

If the solution of paroxetine hydrochloride contains water it may be rendered anhydrous by distillation or by use of drying agents. Preferably the drying step is carried out by distillation using 'Dean and Stark' techniques or by azeotropic distillation.

In the process of this invention, paroxetine hydrochloride anhydrate Form C is typically crystallised from an anhydrous solution of paroxetine hydrochloride at elevated temperature. Suitably 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. Suitably 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. Suitably the crystallisation time is 6-24 hours, preferably 12-18 hours.

Preferably 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. When 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%.

It is surprising that 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.

In a further aspect of the 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. For example, 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.

Suitably 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.

Therapeutic uses of the 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".

Most suitably the anhydrate obtainable by the present invention is applied to the treatment of depression, OCD and panic.

The 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.

The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.

Specific examples of pharmaceutical compositions include those described EP-B- 0223403, and US 4,007,196 in which the anhydrate product of the present invention may be used as the active ingredient.

Accordingly, the present invention also provides:

a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine hydrochloride anhydrate Form C obtainable by this invention and a pharmaceutically acceptable carrier;

the use of paroxetine hydrochloride anhydrate Form C obtainable by this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders; and

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.

The invention is illustrated by the following Examples Example 1

Preparation of paroxetine hydrochloride anhydrate Form C from paroxetine base

Trans (-)-4-(fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-N- phenoxycarbonyl piperidine (25 g) and potassium hydroxide flake (22.5 g) were suspended in toluene (375 ml) and the reaction mixture heated to reflux under nitrogen with vigorous stirring for 3 hours. The suspension was cooled to room temperature, washed with water (250 ml), and the layers separated. The organic layer was warmed to 50°C, then concentrated hydrochloric acid (6 ml) was added and the reaction mixture heated to reflux. Water was removed by azeotropic distillation using a 'Dean and Stark' apparatus. Refluxing was continued for 1.5 hours then the solution was cooled to 48-50°C and held at this temperature for 16 hours. The crystalline product was collected by filtration of the warm solution, washed with toluene and dried under vacuum to give paroxetine hydrochloride anhydrate Form C as a white solid (16.89 g), purity 99.59% by HPLC. Toluene level 0.2% wt/wt by NMR analysis.

Example 2

Preparation of paroxetine hydrochloride anhydrate Form C from paroxetine hydrochloride propan-2-ol solvate

A suspension of 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).

Example 3

Large scale manufacture of paroxetine hydrochloride anhydrate Form C A 250 L glass lined reactor was purged with nitrogen, then charged with toluene (65.0 kg) and potassium hydroxide flake (4.5 kg, 80.2 moles) and the contents stirred at 20°C. Trans (-)-4-(fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-N- phenoxycarbonyl piperidine (5.0 kg, 1 1.1 moles) was then added and the reactor again purged with nitrogen. The vessel contents were brought to reflux over 30 minutes and stirred for 4 hours at this temperature. At this point an in-process check (HPLC) showed that the reaction was complete. 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.

No toluene could be detected in this material by NMR analysis. The infra-red spectrum confirmed that the product was paroxetine hydrochloride anhydrate Form C.

Claims

1. A process for manufacture of paroxetine hydrochloride anhydrate Form C, in which a solution of paroxetine hydrochloride in a hydrocarbon, a ketone, an ester or an alcohol is if necessary rendered anhydrous, optionally seeded, and paroxetine anhydrate Form C is allowed to crystallise at an elevated temperature less than 85°C.

2. A process according to claim 1 in which the crystallisation mixture is maintained at the elevated temperature for a period of 6-24 hours, before collecting the paroxetine hydrochloride anhydrate Form C and drying under vacuum at elevated temperature.

3. A process according to claim 1 or 2 in which crystallisation is carried out at 45-55°C.

4. A process according to claim 1, 2 or 3 in which the solvent is toluene, methyl isobutylketone, ethyl acetate or 1-butanol.

5. A process according to any preceding claim in which the solution of paroxetine hydrochloride is prepared by treating a solution of paroxetine free base with a source of hydrogen chloride.

6. A process according to claim 5 in which the solution of paroxetine base is used directly from a previous processing step in the commercial manufacture of paroxetine.

7. A process according to any one of claims 1 to 4 in which the solution of paroxetine hydrochloride employed is generated from amorphous paroxetine hydrochloride, or an anhydrate, hydrate, solvate or mixed solvate of paroxetine hydrochloride.

8. A process according to any one of claims 1 to 7 in which the solvent is toluene.

9. A process according to any one of claims 1 to 8 in which the crystalline paroxetine hydrochloride anhydrate Form C is isolated at an elevated temperature.

10. Paroxetine hydrochloride anhydrate Form C containing less than 0.1 % by wt. of residual solvent.

1 1. Paroxetine hydrochloride anhydrate Form C containing less than 0.1% by wt. of toluene.

12. Paroxetine hydrochloride anhydrate Form C obtainable by a process according to any one of claims 1 to 9.

13. Use of paroxetine hydrochloride anhydrate as claimed in claim 9, 10 or 11 to manufacture a medicament for the treatment or prophylaxis of the Disorders.