SK9242000A3 - Process for the preparation of paroxetine hydrochloride - Google Patents

Abstract

A process for the preparation of paroxetine hydrochloride propan-2-ol solvate comprises forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an effective co-solvent, and crystallising paroxetine hydrochloride propan-2-ol solvate from the solution.

Description

Process for the preparation of paroxetine hydrochloride

Technical field

The invention relates to a process for the preparation of a pharmaceutical active substance and to the use of the substance thus prepared in therapy. In particular, the present invention relates to a novel process for the preparation of paroxetine chloride, a propan-2-ol solvate, and its use for preparing the crystalline non-hydrate form of paroxetine hydrochloride.

BACKGROUND OF THE INVENTION

Pharmaceutical products with antidepressant and anti-Parkinsonian properties are described in US-A-3912743 and US-A-4007196. A particularly important compound among the disclosed compounds is paroxetine, the (-) trans isomer of 4- (4'-fluorophenyl) -3 (3 ', 4'-methylenedioxyphenoxymethyl) piperidine. This compound is used in therapy as a hydrochloride salt for the treatment and prevention of, inter alia, depression, obsessive compulsive disorder (OCD) and panic.

Paroxetine hydrochloride has been described in the literature as crystalline hemihydrate (see EP-A-0223403 from Beecham Group) and as various crystalline non-hydrate forms (see WO96 / 24595 from SmithKline Beecham). WO96 / 24595 describes the preparation of anhydrous Form A via an intermediate solvate with an organic solvent such as propan-2-ol.

When prepared by a conventional method (crystallization from anhydrous propan-2-ol), paroxetine hydrochloride, a propan-2-ol solvate, has very poor mixing properties, and is very difficult to isolate, wash and dry. Desolvation by vacuum heat treatment is also very difficult. In WO96 / 24595, the problem that conventional drying techniques are unable to effectively remove the solvent was solved by providing an additional displacement phase before the product was finally dried.

The present invention is based on the discovery that the crystallization of paroxetine hydrochloride from a mixture of propan-2-ol and a co-solvent produces an improved crystalline form that can be more easily mixed, filtered, washed and dried. Surprisingly

It has also been found that it is easier to remove the crystallization solvent by heat treatment.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing paroxetine hydrochloride, a propan-2-ol solvate, which comprises forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an effective cosolvent and crystallizing paroxetine hydrochloride, propan-2-ol solvate from solution.

Typically, the active solvent is one which, upon addition of a solution of paroxetine hydrochloride in propan-2-ol, forms a clear solution and does not form a competitive solvate during crystallization. Suitable co-solvents include toluene, heptane and hexane. Surprisingly, it has been found that toluene is particularly useful, although there may be a toluene solvate of paroxetine hydrochloride.

The cosolvent mixture may be formed prior to the addition of paroxetine hydrochloride or the addition of the cosolvent to the solution of paroxetine hydrochloride in propan-2-ol, or the addition of propan-2-ol to the solution of paroxetine hydrochloride in the active cosolvent. In a preferred method, the final phase of the preparation of paroxetine hydrochloride is carried out in an effective co-solvent to which propan-2-ol can be added for crystallization in accordance with the present invention. For example, if toluene is used as the co-solvent, it can usually be used in the previous step. After washing and acidification, only partial evaporation is required, followed by addition of propan-2-ol and crystallization.

Crystallization can be initiated by conventional methods such as cooling the heated solution or removing the solvent by evaporation or heating. It may be advantageous to add seeds of crystalline paroxetine hydrochloride to the propan-2-ol solvate prepared by the method described in this invention or the method of WO96 / 24595.

Crystalline paroxetine hydrochloride anhydrate may be formed by heating the solvate with propan-2-ol to remove bound propan-2-ol. The resulting product is required to contain less than 2% by weight of solvated solvent, preferably less than 1% by weight, more preferably 0.5% by weight and in particular

Preferably less than 0.1% by weight. Preferably, the crystalline product is Form A anhydrous paroxetine hydrochloride.

Crystalline paroxetine hydrochloride, the product of the invention, can be adapted for therapy as described in EP-A-0223403 or WO96 / 00477.

The therapeutic use of the paroxetine product of the invention includes the 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, trichothilomania, trudomic acid and chemical abuse, hereinafter referred to as “disorders.

Accordingly, the present invention also provides:

a pharmaceutical composition for treating or preventing a disorder comprising paroxetine hydrochloride anhydrate prepared according to the invention and a pharmaceutically acceptable carrier;

the use of paroxetine hydrochloride anhydrate prepared by the process of the invention for the manufacture of a medicament for the treatment or prevention of disorders; and a method of treating a disorder comprising administering an effective or preventive amount of paroxetine hydrochloride anhydrate prepared according to the invention to a person suffering from one or more of these disorders.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Paroxetine hydrochloride hemihydrate (160 g) was suspended in a mixture of toluene (250 mL) and isopropanol (1000 mL) and heated to boiling. The solvent was removed by distillation and replaced with fresh isopropanol (3 x 500 mL). The boiling point was then 81.2 ° C. Additional solvent was removed by distillation until the volume was about 1000 ml. The well stirred mixture was allowed to cool to about 70 ° C, then hexane (500 mL) was slowly added to give a clear solution at 57 ° C. Seeds of paroxetine hydrochloride, an isopropanol solvate, were added and the temperature rose to 60 ° C as crystallization proceeded. Stirring continued until

The temperature was not dropped to about 30 ° C, then the product was collected, washed on a filter with hexane (2 x 500 mL) and dried under vacuum at ambient temperature.

The yield was 171 g, isopropanol content by NMR: 10.5% by weight.

EXAMPLE 2 (-) - trans [7S-4- (4-Fluorophenyl) -3- (3 ', 4'-methylenedioxyphenoxymethyl) phenoxycarbonylpiperidine (90 g) was heated with potassium hydroxide (8.5 g) in toluene (1500 ml) ) under reflux for 3 hours, cooled, washed with hot water, acidified with hydrochloric acid and distilled to approximately one quarter of the amount under vacuum. Hot propan-2-ol (2000 mL) was added and the mixture was cooled slowly with vigorous stirring until the temperature reached 20 ° C. After stirring for a further 2 hours, the product was filtered off, washed with propan-2-ol and dried under vacuum to give paroxetine hydrochloride, propan-2-ol solvate.

Example 3

Paroxetine hydrochloride hemihydrate (122 g) was suspended in toluene (1000 mL) and heated at reflux in a Dean and Stark apparatus to remove water for 2 hours. The solution was concentrated to approximately 250 mL, while still mobile and easily miscible. Warm propan-2-ol (1300 mL at about 50 ° C) was added and the reaction mixture was vigorously stirred; the mixture slowly crystallized but did not become immiscible. After about 30 minutes, an additional amount of propan-2-ol (300 mL) and n-heptane (300 mL) were added and the mixture was cooled to ambient temperature (about 20 ° C), stirred for an additional 30 minutes, filtered and dried.

One portion of the product was dried under vacuum at about 20 ° C to give paroxetine hydrochloride, a propan-2-ol solvate, in a mixture of about 1: 1.

Another portion was dried under vacuum at a final temperature of 65 ° C to give paroxetine hydrochloride containing about 1.6% propan-2-ol by weight. By comparison, a conventional prepared sample of the solvate heated overnight in a vacuum oven at 70 ° C for 24 hours contained 4.1% propan-2-ol.

-5Example 4

Paroxetine hydrochloride hemihydrate (50 g) was heated under reflux by stirring in toluene (500 mL) and water was removed using a Dean and Stark apparatus. The solution was allowed to cool to approximately 40 ° C, diluted with isopropanol (200 mL), and allowed to crystallize at ambient temperature. The product was collected, washed with toluene and dried at 40 ° C to give paroxetine hydrochloride, an isopropanol solvate.

Claims (7)

PATENT CLAIMS A process for the preparation of paroxetine hydrochloride, a propan-2-ol solvate, comprising forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an effective cosolvent and crystallizing paroxetine hydrochloride, propan-2-ol solvate from solution . The process according to claim 1, wherein the co-solvent comprises toluene, heptane or hexane. Process according to claim 1 or 2, characterized in that the last phase of the preparation of paroxetine hydrochloride is carried out in a co-solvent to which propan-2-ol is later added for crystallization. A process for the preparation of crystalline paroxetine hydrochloride anhydrous, comprising heating the solvate with propan-2-ol, obtained using any of the methods of the preceding claims, thereby removing bound propan-2-ol. 5. A pharmaceutical composition for the treatment or prevention of a disorder comprising paroxetine hydrochloride anhydrate prepared by the process of claim 4 and a pharmaceutically acceptable carrier. Paroxetine hydrochloride prepared by the method of claim 4 for the manufacture of a medicament for the treatment or prevention of disorders. The use of paroxetine hydrochloride anhydrate prepared by the method of claim 4 for the manufacture of a medicament for the treatment or prevention of disorders.