MXPA00006040A - 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

PROCEDURE FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE DESCRIPTIVE MEMORY The present invention relates to a process for the preparation of a pharmaceutically active compound, and to the use in therapy of the compound thus prepared. In particular, this invention relates to a novel process for the preparation of a propan-2-ol solvate of paroxetine chloride and its use to prepare a crystalline anhydrate form of paroxetine hydrochloride. Pharmaceuticals with antidepressant and anti-Parkinson properties are described in E.U.A.-A-3912743 and E.U.A.-A-4007196. An especially important compound among those described is paroxetine, the (-) trans isomer of 4- (4, -fluorophenyl) -3- (3 ', 4'-methylenedioxy-phenoxymethyl) -piperidine. This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of, among others, 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 various forms of crystalline anhydrate (see WO96 / 24595 of Smithkline Beecham). WO96 / 24595 describes the preparation of the anhydrate of Form A through an intermediate solvate with an organic solvent such as propan-2-ol.

When prepared conventionally (crystallization from anhydrous propan-2-ol), the propan-2-ol solvate of paroxetine hydrochloride has very poor stirring properties, and is very difficult to isolate, wash and dry. It is also very difficult to solvate by heat treatment under vacuum. In WO96 / 24595, the problem that conventional drying techniques were unable to efficiently remove the solvent was met by providing an additional displacement step before the product finally dried. The present invention is based on the finding that the crystallization of paroxetine hydrochloride from a mixture of propan-2-ol and a co-solvent produces an improved crystalline form which is much easier to agitate, filter, wash and dry . Surprisingly it has been found that it is easy to remove crystallization solvent by heat treatment. Accordingly, the present invention provides a process for the preparation of propan-2-ol solvate of paroxetine hydrochloride comprising the formation of a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an effective cosolvent, and crystallize the propan-2-ol solvate of paroxetine hydrochloride from the solution. Typically, an effective cosolvent is one that forms a clear solution when added to a solution of paroxetine hydrochloride in propan-2-ol and which does not form a competent solvate during crystallization. Suitable co-solvents include toluene, heptane and hexane. Surprisingly, it has been found that toluene is particularly useful in spite of the fact that the toluene solvate of paroxetine hydrochloride can exist. The co-solvent mixture can be formed before the addition of paroxetine hydrochloride, or by the addition of a co-solvent to a solution of paroxetine hydrochloride in propan-2-ol, or by the addition of propan-2-ol to a solution of paroxetine hydrochloride in an effective co-solvent. In a preferred process, the final step of the preparation of paroxetine hydrochloride is carried out in an effective cosolvent, to which propan-2-ol can be added for crystallization according to the invention. For example, when toluene is used as the cosolvent, it can be conveniently used in the previous manufacturing step. Before washing and acidification, only partial evaporation is necessary, followed by the addition of propan-2-ol and crystallization. Crystallization can be initiated by conventional methods such as cooling a heated solution or removing solvent by evaporation or heating. It may be advantageous to add crystals of crystalline paroxetine hydrochloride propan-2-yl solvate prepared by the process of this invention or by the process of WO96 / 24595. A crystalline paroxetine hydrochloride anhydrate can be formed by heating the propan-2-ol solvate to remove bound propan-2-ol. The resulting product desirably contains less than 2% solvated solvent, preferably less than 1%, most preferably less than 0.5%, and most preferably still less than 0.1%. Advantageously, the crystalline product is the form A anhydrate of paroxetine hydrochloride. The crystalline paroxetine hydrochloride product of this invention can be formulated for therapy as described in EP-A-0223403 or WO96 / 00477. Therapeutic uses of the paroxetine product of this invention include the treatment of: alcoholism, anxiety, depression, obsessive-compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS) ), depression in adolescents, trichotillomania, dysthymia and excessive use of substances, referred to below as "the disorders". Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine hydrochloride anhydrate prepared by this invention and a pharmaceutically acceptable carrier; the use of paroxetine hydrochloride anhydrate prepared by the process of this invention to manufacture a medicament for the treatment or prophylaxis of the disorders; and a method of treating disorders comprising administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate prepared by this invention to a person suffering from one or more of the disorders. The invention is illustrated by the following examples: 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 by fresh isopropanol (3 x 500 ml). The boiling point was then 81.2 ° C. The 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. The paroxetine hydrochloride isopropanol solvate grains were added and as crystallization proceeded, the temperature was raised to 60 ° C. Stirring was continued until the temperature had dropped to about 30 ° C, then the product was collected, washed on the filter with hexane (2 x 500 ml) and dried under vacuum at room temperature. Yield: 171 g of isopropanol content by NMR: 10.5% w / w.

EXAMPLE 2 (-) - Trans-4- (4-fluorophenyl) -3- (3,, 4'-methylenedioxyphenoxymethyl) -1-phenoxycarbonylpiperidine (90 g) is heated with potassium hydroxide (8.5 g) in toluene ( 1500 ml) is refluxed for 3 hours, cooled, washed with hot water, acidified with hydrochloric acid and distilled to a volume of 1 liter under vacuum. Warm propan-2-ol (2000 ml) is added and the mixture is cooled slowly with vigorous stirring until the temperature reaches 20 ° C. After stirring for a further 2 hours, the product is filtered, washed with propan-2-ol and dried under vacuum to give propan-2-ol solvate of paroxetine hydrochloride.

EXAMPLE 3 Paroxetine hydrochloride hemihydrate (122 g) was suspended in toluene (1000 ml) and heated to reflux for 2 hours in a Dean & Stark to remove water. The toluene solution was concentrated to approximately a volume of 250 ml, at which point it was still mobile and easy to stir. Warm propan-2-oI (1300 ml at about 50 ° C) was added and the reaction mixture was stirred vigorously; the mixture crystallized slowly but did not become inagitable. After approximately 320 minutes an additional amount of propan-2-ol (300 ml) and n-heptane (300 ml) was added and the mixture was cooled to room temperature (about 20 ° C), stirring was added for 30 minutes, it was filtered and dried. A part of the product was dried under vacuum at approximately ° C to give propan-2-ol solvate of paroxetine hydrochloride with a composition ratio of about 1: 1. Another part was dried under vacuum at a final temperature of 65 ° C to give paroxetine hydrochloride containing about 1.6% propan-2-ol. By way of comparison, a conventionally prepared sample of solvate was heated overnight in a vacuum oven at 70 ° C for 24 hours containing 4.1% propan-2-ol.

EXAMPLE 4 Paroxetine hydrochloride hemihydrate (50 g) was heated to reflux with stirring in toluene (500 ml) and the water was moved using a Dean and Stark apparatus. The solution was allowed to cool to about 40 ° C, diluted with isopropanol (200 ml), and allowed to crystallize at room temperature. The product was collected, washed with toluene and dried at 40 ° C to give paroxetine hydrochloride isopropanol solvate. Yield: 23 g.

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of propan-2-ol solvate of paroxetine hydrochloride which consists of forming a solution of paroxetine hydrochloride in a mixture of propan-2-oI and an effective co-solvent, and crystallizing the propan solvate -2-ol of paroxetine hydrochloride from the solution.

2. A process according to claim 1, further characterized in that the co-solvent comprises toluene, heptane or hexane.

3. A process according to claim 1 or 2, further characterized in that the final step of the preparation of paroxetine hydrochloride is carried out in the cosolvent, to which propan-2-ol is subsequently added for crystallization.

4. A process for the preparation of crystalline paroxetine hydrochloride anhydrate consisting of heating a propan-2-ol solvate, obtained using the method of any of the preceding claims, to remove bound propan-2-ol.

5. A pharmaceutical composition for the treatment or prophylaxis of the disorders, comprising paroxetine hydrochloride anhydrate prepared by the process of claim 4 and a pharmaceutically acceptable carrier.

6. The use of paroxetine hydrochloride anhydrate prepared by the method of claim 4 to manufacture a medicament for the treatment or prophylaxis of disorders.

7. The use of paroxetine hydrochloride anhydrate prepared by the method of claim 4 for the manufacture of a medicament for treating alcoholism, anxiety, depression, obsessive-compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine , bulimia, anorexia, social phobia, premenstrual syndrome (PMS), depression in adolescents, trichotillomania, dysthymia and excessive use of substances in a patient.