OA11635A - 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

1 NOVELPROCESS w 1

The présent invention relates to a process for the préparation of a pharmaceuticallyactive compound, and to the use of the so-prepared compound in therapy. Inparticular this invention is concemed with a new process for the préparation of aparoxetine chloride propan-2-ol solvaté and its use to préparé a crystalline anhydrateform of paroxetine hydrochloride.

Pharmaceutical products with antidepressant and anti-Parkinson properties aredescribed in US-A-3912743 and US-A-4007196. An especially important compoundamong those disclosed is paroxetine, the (-)trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapyas the hydrochloride sait for the treatment and prophylaxis of inter alia dépréssion,obsessive compulsive disorder (OCD) and panic.

Paroxetine hydrochloride has been described in the literature as a crystallinehemihydrate (see EP-A-0223403 of Beecham Group) and as various crystallineanhydrate forms (see WO96/24595 of SmithKline Beecham). WO96/24595 describesthe préparation of the form A anhydrate via an intermediate solvaté with an organicsolvent such as propan-2-ol.

When prepared conventionally (crystallisation ffom anhydrous propan-2-ol),paroxetine hydrochloride propan-2-ol solvaté has very poor stirring properties, and isvery diffîcult to isolate, wash, and dry. It is also very difficult to desolvate by heattreatment under vacuum. In WO96/24595, the problem that conventional dryingtechniques were incapable of efficient removal of solvent was addressed by providingan additional displacement stage before the product was finally dried.

The présent invention is based on the fînding that crystallisation of paroxetinehydrochloride from a mixture of propan-2-ol and a co-solvent produces an improvedcrystalline form which is much easier to stir, filter, wash and dry. Surprisingly it hasalso been found that it is easier to remove solvent of crystallisation by heat treatment.

Accordingly the présent invention provides a process for the préparation of paroxetinehydrochloride propan-2-ol solvaté which comprises forming a solution of paroxetinehydrochloride in a mixture of propan-2-ol and an effective co-solvent, andcrystallising paroxetine hydrochloride propan-2-ol solvaté from the solution. 2 011635

Typically an effective cosolvent is one which will form a clear solution when added toa solution of paroxetine hydrochloride in propan-2-ol and which does not form acompeting solvaté during crystallisation. Suitable cosolvents include toluene, heptaneand hexane. Surprisingly toluene has been found to be particularly useful despite thefact that a toluene solvaté of paroxetine hydrochloride can exist.

The cosolvent mixture may formed before addition of paroxetine hydrochloride, or byaddition of a cosolvent to a solution of paroxetine hydrochloride in propan-2-ol, or byaddition of propan-2-ol to a solution of paroxetine hydrochloride in an effectivecosolvent. In a preferred procedure, the final stage of the préparation of paroxetinehydrochloride is carried out in an effective cosolvent, to which propan-2-ol may beadded for crystallisation in accordance with the invention. For example when tolueneis used as the cosolvent it can be used conveniently in the preceding manufacturingstep. After washing and acidification, only partial évaporation is necessary, foliowedby addition of propan-2-ol and crystallisation.

Crystallisation may be initiated by conventional procedures such as cooling a heatedsolution, or removing solvent by évaporation or heating. It may be advantageous toadd seeds of crystalline paroxetine hydrochloride propan-2-ol solvaté prepared by theprocedure of this invention or by the procedure of WO96/24595. A crystalline anhydrate of paroxetine hydrochloride may be formed by heating thepropan-2-ol solvaté to remove bound propan-2-ol. The résultant product desirablycontains less than 2% of the solvated solvent, preferably less than 1%, morepreferably less than 0.5%, and most preferably less than 0.1%. Advantageously thecrystalline product is the Form A anhydrate of paroxetine hydrochloride.

The crystalline paroxetine hydrochloride product of this invention may be formulatedfor therapy as described in EP-A-0223403 or W096/00477.

Therapeutic uses of the paroxetine product of this invention include treatment of:alcoholism, anxiety, dépréssion, obsessive compulsive disorder, panic disorder,chronic pain, obésitÿ, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent dépréssion, trichotillomania, dysthymia, andsubstance abuse, referred to below as "the disorders".

Accordingly, the présent invention also provides: 3 011635 a pharmaceutical composition for treatment or prophylaxis of the disorderscomprising paroxetine hydrochloride anhydrate prepared by this invention and apharmaceutically acceptable carrier; 5 the use of paroxetine hydrochloride anhydrate prepared by the process of thisinvention to manufacture a médicament for the treatment or prophylaxis of thedisorders; and a method of treating the disorders which comprises administering an effective or 10 prophylactic amount of paroxetine hydrochloride anhydrate prepared by this inventionto a person suffering from one or more of the disorders.

The invention is illustrated by the following Examples: 15 Example 1

Paroxetine hydrochloride hemihydrate (160 g) was suspended in a mixture of toluene : (250 mil) and isopropanol (1000 ml) and heated to boiling. Solvent was removed by distillation and replaced by fresh isopropanol (3 x 500 ml). The boiling point was 20 then 81.2°C. Further solvent was removed by distillation until the volume was about1000 ml. The well stirred mixture was allowed to cool to about 70°C, then hexane(500 ml) was added slowly to give a clear solution at 57°C. Seeds of paroxetinehydrochloride isopropanol solvaté were added, and as the crystallisation proceeded thetempérature increased to 60°C. Stirring was continued until the température had 25 fallen to about 30°C, then the product was collected, washed on the filter with hexane(2 x 500 ml) and dried in vacuo at ambient température.

Yield 171g isopropanol content by NMR: 10.5% wt/wt 30 Example 2 (-)-Trans-4-(4-fluorophenyl)-3 -(3 ',4'-methylenedioxyphenoxymethyl)-1 -phenoxycarbonylpiperidine (90 g) is heated with potassium hydroxide (8.5 g) intoluene (1500 ml) at reflux for 3 hours, cooled, washed with hot water, acidified with 35 hydrochloric acid, and distilled to approximately one quarter volume under vacuum.

Hot propan-2-ol (2000 ml) is added and the mixture cooled slowly with vigorousstirring until the température reaches 20°C. After stirring for a further 2 hours, the 4 011635 product is filtered, washed with propan-2-ol, and dried under vacuum, to give paroxetine hydrochloride propan-2-ol solvaté.

Example 3 5

Paroxetine hydrochloride hemihydrate (122 g) was suspended in toluene (1000 ml)and heated to reflux for 2 hours under Dean & Stark apparatus to remove water. Thetoluene solution was concentrated to approximately 250 ml volume at which point itwas still mobile and easy to stir. Warm propan-2-ol was added (1300 ml at about 10 50°C) and the reaction mixture stirred vigorously; the mixture crystallised slowly but did not become unstirrable. After about 30 minutes a further quantity of propan-2-ol(300 ml) and n-heptane (300 ml) was added, and the mixture was cooled to ambienttempérature (approximately 20°C), stirred for a further 30 minutes, filtered and dried. 15 One part of the product was dried under vacuum at approximately 20°C to give paroxetine hydrochloride propan-2-ol solvaté with a composition ratio ofapproximately 1:1.

Another part was dried under vacuum at a final température of 65°C to give 20 paroxetine hydrochloride containing approximately 1.6% propan-2-ol. By comparison, a conventionally prepared sample of solvaté heated ovemight in avacuum oven at 70°C for 24 hours contained 4.1% propan-2-ol.

Example 4 25

Paroxetine hydrochloride hemihydrate (50 g) was heated to reflux with stirring intoluene (500 ml) and the water removed using a Dean and Stark apparatus. Thesolution was allowed to cool to about 40°C, diluted with isopropanol (200 ml), andallowed to crystallize at ambient température. The product was collected, washed 30 with toluene and dried at 40°C to give paroxetine hydrochloride isopropanol solvaté.

Yield 23 g

Claims (6)

1. 4. 011635 Claims F,· •

   1. A process for the préparation of paroxetine hydrochloride propan-2-ol solvatéwhich comprises forming a solution of paroxetine hydrochloride in a mixture of 5 propan-2-ol and an effective co-solvent, and crystallising paroxetine hydrochloridepropan-2-ol solvaté from the solution.
2. 2. A process according to claim 1 wherein the cosolvent comprises toluene,heptane or hexane. 10
3. 3. A process according to claim 1 or 2 wherein the final stage of the préparationof paroxetine hydrochloride is carried out in the cosolvent, to which propan-2-ol issubsequently added for crystallisation. 15 4. A process for the préparation of a crystalline anhydrate of paroxetine hydrochloride which comprises heating a propan-2-ol solvaté , obtained using theprocess of any one of the preceding claims, to remove bound propan-2-ol.
4. 5. A pharmaceutical composition for treatment or prophyIaxis of the disorders 20 comprising paroxetine hydrochloride anhydrate prepared by the process of claim 4 and a pharmaceutically acceptable carrier.
5. 6. The use of paroxetine hydrochloride anhydrate prepared by the process of claim 4to manufacture a médicament for the treatment or prophy Iaxis of the disorders. 25
6. 7. A method of treating the disorders which comprises administering an effective orprophylactic amount of paroxetine hydrochloride anhydrate prepared by the process ofclaim 4 to a person suffering from one or more of the disorders.