CZ20002256A3 - Process for preparing paroxetine hydrochloride - Google Patents

Abstract

Process for preparing propan-2-ol solvate paroxetine hydrochloride comprises preparing the solution paroxetine hydrochloride in propan-2-ol mixture and active cosolvent, and lrystallization of the propan-2-ol solvate paroxetine hydrochloride solution.

Description

Process for the preparation of paroxetine hydrochloride

Technical field

The present invention relates to a process for the preparation of a pharmaceutically active compound and to the use of the compound thus prepared in therapy. In particular, the present invention is directed to a novel process for the preparation of a 2-propanol paroxetine chloride solvate and its use for the preparation of crystalline paroxetine hydrochloride anhydrate.

BACKGROUND OF THE INVENTION

Pharmaceutical products having anti-depressant and anti-Parkinson's properties are described in US-A-3 912 743 and US-A4 007 196. A particularly important compound among those described 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 prophylaxis of, inter alia. depression, obesively-compulsive disorder (OKP) and panic conditions.

Paroxetine hydrochloride has been described in the literature as crystalline hemihydrate (see EP-A-0 223 403 from Beecham Group) and as various forms of anhydrates (see WO96 / 24595 from SmithKline Beecham). WO96 / 24595 describes the preparation of Form A anhydrate via an intermediate solvate with an organic solvent such as propan-2-ol.

When prepared usually (by crystallization from anhydrous propan-2-ol), the propan-2-ol solvate of paroxetine hydrochloride has very poor mixing properties, and it is very difficult to isolate, wash and dry. It is also very difficult to heat the solvent under the heat under vacuum. In WO96 / 24595, the problem that conventional drying techniques were not able to effectively remove the solvent forced the insertion of an additional displacement step before the final drying of the product.

SUMMARY OF THE INVENTION

The present invention is based on the discovery that crystallization of paroxetine hydrochloride from a mixture of propan-2-ol and a co-solvent produces an improved crystalline form that is much easier to mix, filter, wash and dry. Surprisingly, it has also been found that it is easier to remove the crystallization solvent by heat treatment.

Thus, the present invention provides a process for the preparation of a paroxetine hydrochloride propane-2-ol solvate which comprises forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an active cosolvent, and crystallizing the paroxetine hydrochloride propan-2-ol solvate from 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 that does not form a competitive solvate during crystallization. Suitable heptane and hexane. Surprisingly particularly useful despite the co-solvent include toluene, it has been found that toluene was a fact that there may be a toluene solvate of paroxetine hydrochloride.

The co-solvent mixture may be formed prior to the addition of paroxetine hydrochloride, the addition of the co-solvent 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 co-solvent. In a preferred process, the final phase of the preparation of the final phase 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 invention. For example, when toluene is used as a cosolvent, it can usually be used in a previous manufacturing 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 means, such as cooling the heated solution or removing the solvent by evaporation or heating. It may be advantageous to add seed crystals of the crystalline paroxetine hydrochloride propan-2-ol solvate prepared by the process of the invention or the process of WO96 / 24595.

Crystalline paroxetine hydrochloride anhydrate can be formed by heating the propan-2-ol solvate to remove bound propan-2-ol. It is desirable that the resulting product contain less than 2% solvated solvent, preferably less than 1%, more preferably less than 0.5% and most preferably less than 0.1%. Preferably, crystalline product A is the paroxetine hydrochloride anhydrate form.

The crystalline paroxetine hydrochloride product of the invention can be formulated for therapy as described in EP-A-0 223 403 or WO96 / 00477.

The therapeutic use of the paroxetine products of the invention includes the treatment of alcoholism, anxiety, depression, forced behavioral disorders, panic conditions, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), puberty depression, trichotillomania, thyroid disorders, and substance abuse hereinafter referred to as "disorders.

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Thus, the present invention also provides: a pharmaceutical composition for the treatment or prophylaxis of "disorders" comprising paroxetine hydrochloride anhydrate prepared according to the invention and a pharmaceutically acceptable carrier;

the use of paroxetine hydrochloride anhydrate prepared by the method of the invention for the manufacture of a medicament for the treatment or prophylaxis of "disorders; and a method of treating "disorders" comprising administering to a subject suffering from one or more "disorders" an effective or prophylactic amount of paroxetine hydrochloride anhydrate prepared according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

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 with new isopropanol (3 x 500 mL). The boiling point was then 81.2 ° C. Additional solvent was removed by distillation to a volume of about 1000 ml. The well-stirred mixture was then cooled to about 70 ° C, then hexane (500 mL) was slowly added to give a clear solution at 57 ° C. Seed crystals of paroxetine hydrochloride isopropanol solvate were added and the temperature was increased to 60 ° C as crystallization continued. Stirring was continued until the temperature dropped to about 30 ° C, then the product was separated, washed on the filter with hexane (2 x 500 mL) and dried in vacuo at room temperature.

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Yield 171 g, 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) ) under reflux for 3 hours, cooled, washed with hot water, acidified with hydrochloric acid, and distilled to about one quarter of the volume under vacuum. Hot 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 an additional 2 hours, the product is filtered, washed with propan-2-ol and dried under vacuum to obtain the 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 apparatus to remove water. The toluene solution was concentrated to a volume of approximately 250 ml, at which point it was still liquid and easily stirred. Warm propan-2-ol (1300 mL at about 50 ° C) was added and the reaction mixture was vigorously stirred, the mixture crystallized slowly but did not become immiscible. After about 30 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), stirred for an additional 30 minutes, filtered and dried.

One portion of the product was vacuum dried at about 20 ° C to obtain the paroxetine hydrochloride propan-2-ol solvate with a component ratio of about 1: 1.

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

Example 4

Paroxetine hydrochloride hemihydrate with a reflux condenser with stirring in toluene water using a Dean-Stark apparatus, about 40 ° C, diluted with isopropanol to crystallize at room temperature, washed with toluene and dried at 40 ° C to give the paroxetine hydrochloride solvate.

(50 g) was heated under (500 mL) and removed

The solution was cooled to (200 mL) and left

The product was collected, isopropanol was obtained

Yield 23 g.

Claims (7)

PATENT CLAIMS A process for the preparation of paroxetine hydrochloride propan-2-ol solvate, comprising forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an active cosolvent, and crystallizing the paroxetine hydrochloride propan-2-ol solvate from solution. 2. The process of claim 1 wherein the co-solvent comprises toluene, heptane, or hexane. Process according to claim 1 or 2, characterized in that the final preparation stage of paroxetine hydrochloride is carried out in a co-solvent to which propan-2-ol is added sequentially. A process for preparing crystalline paroxetine hydrochloride anhydrate, comprising heating the propan-2-ol solvate obtained using the methods of any one of the preceding claims to remove bound propan-2-ol. A pharmaceutical composition for the treatment or prophylaxis of "disorders" comprising paroxetine hydrochloride anhydrate prepared by the process of claim 4 and a pharmaceutically acceptable carrier. Use of the paroxetine hydrochloride anhydrate prepared by the process of claim 4 for the manufacture of a medicament for the treatment or prophylaxis of "disorders". • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · A method of treating "disorders" comprising administering an effective or prophylactic amount of a paroxetine hydrochloride anhydrate prepared by the method of claim 4 to a person suffering from one or more "disorders."