PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE

Abstract: Crystalline paroxetine hydrochloride propan-2-ol solvate having a modified habit that is more easily desolvated to form the anhydrate is obtained by crystallising from a solution of paroxetine hydrochloride in propan-2-ol to which has been added a habit modifier compound. Form A anhydrate is obtained by heating the crystalline solvate of modified habit in a vacuum oven. Suitable habit modifiers are carboxylic acids and amine salts.

Description: PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE The present invention relates to a process for the preparation of a pharmaceutically active compound and intermediates thereof, and to the use of the active compound in therapy. In particular this invention is concerned with a new process for the preparation of paroxetine chloride propan-2-ol solvate and its use to prepare a crystalline anhydrate form of paroxetine hydrochloride. 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-(3",4"- methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of inter alia 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 as various crystalline anhydrate forms (see WO96/24595 of SmithKline Beecham). WO96/24595 describes the preparation of paroxetine hydrochloride propan-2-ol solvate which is a useful intermediate for the preparation of paroxetine hydrochloride anhydrate Form A. When prepared conventionally by crystallisation from anhydrous propan-2-ol, paroxetine hydrochloride propan-2-ol solvate has very poor stirring properties, and is very difficult to isolate, wash, and dry. The desolvation of paroxetine hydrochloride propan-2-ol solvate has been described in WO 96/25495 and EP 0 812 827 Al . It is clear from these publications that desolvation in a vacuum oven is a slow and difficult process. Furthermore, when operated on a scale larger than a few grammes, the time and temperature necessary for substantially complete desolvation increase very greatly, for example EP 0 812 827 Nl states that on a 180 g scale drying for 1 week at 80°C gives a product still containing more than 2% propan-2-ol. and that the temperature must be increased to 110°C before the propan-2-ol residue can be reduced to approximately 0.1%. Lengthy treatment is undesirable for manufacturing because of the costs associated with vessel occupancy, and high temperatures cause degradation and phase transformation in the product. Another undesirable feature of the existing process is the tendency for the product to crystallise in a heavy matted form which is very difficult to stir, transfer, and filter. For example, a glass-lined reactor containing a vigorously stirred solution of 20 kg of paroxetine hydrochloride in 160 litres of propan-2-ol was seeded at 48°C. The entire contents set to a thick crystalline mass, and it was necessary to open the man-way and manually dislodge the contents so that the mixture could be stirred and the product collected. It is therefore evident that the existing process is unsuitable for the large scale manufacture of paroxetine hydrochloride. This invention provides processes for the preparation of paroxetine hydrochloride propan- 2-ol solvate in a form which is more easily desolvated than paroxetine hydrochloride propan-2-ol solvate prepared in a conventional manner, and hence more suitable for commercial manufacturing processes. According to one aspect of the present invention there is provided a process for preparing crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol, adding to the solution a habit modifier compound, and crystallising paroxetine hydrochloride propan-2-ol solvate from the modified solution. Suitable habit modifying compounds are selected from those compounds that are ionic or readily ionisable and are soluble in propan-2-ol. The addition of the indicated habit modifier compound to the solution modifies the habit of the resultant crystals to a form which allows for convenient stirring, filtering and washing on a manufacturing scale, and more effective de-solvation of the crystals. A suitable concentration of paroxetine hydrochloride in propan-2-ol is one part in between 4 and 40 volumes of propan-2-ol, preferably between 8 and 15 volumes, and more preferably between 10 and 14 volumes. Preferably the propan-2-ol is anhydrous to suppress formation of paroxetine hydrochloride hemihydrate. Suitable procedures for preparing paroxetine hydrochloride for dissolution in propan-2-ol for use in the process of this invention include those mentioned in US Patents 4,009,196; 4,721,723; 4,902,801; 4,861,893 and 5,039,803. Examples of suitable habit modifiers are carboxylic acids, preferably acetic acid, and amine salts, particularly hydrochloride or acetate salts, for example diethylamine hydrochloride or ammonium acetate. The amount of carboxylic acid habit modifier used is suitably from 1 to 20% of the solvent volume, preferably from 1 to 10%. N suitable amount of amine salt habit modifier is in the range 5-25 mole %, preferably 10- 20 mole %. Crystallisation may be initiated by conventional procedures such as cooling a heated solution, or removing solvent by evaporation or heating. It may be advantageous to add seeds of crystalline paroxetine hydrochloride propan-2-ol solvate prepared by the procedure of this invention or by the procedure of WO 96/24595. The crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit obtainable by the process of this invention is a different crystalline form from the previously known product. This novel product forms another aspect of this invention. One characteristic in which the new form differs from the previously known form is in the particle size distribution and mean particle volume. Paroxetine hydrochloride propan-2-ol solvate crystals prepared conventionally are large and long, typically with most of the material in the form of crystals in excess of 300 microns in length, with a length-to- width ratio in excess of 40:1, and a volume as measured by for example laser light scattering, of 10,000 cubic microns or more. By contrast in the novel form of paroxetine hydrochloride propan-2-ol solvate, most of the material is in crystals less than 100 microns long, preferably below 75 microns, and more preferably below 50 microns, and with a length-to- width ratio below 20:1, preferably below 15:1 and more preferably below 10:1, and with a volume below 5,000 cubic microns, preferably below 2,500 cubic microns and more preferably below 1,000 cubic microns. The product of this invention may have either one, two or all three of these desirable characteristics. During the course of our investigations we have discovered that one particular crystallographic axis is critical to the rapid desolvation of paroxetine hydrochloride propan-2-ol solvate. Hence, in another aspect of this invention there is provided paroxetine hydrochloride propan-2-ol solvate of modified habit in which the mean distance between crystal facets characterised by the Miller indices (0, 1 , 0) and (0, 1 , 0) in a monoclinic crystal system, P2, space group is minimised, and is preferably below 100 microns. It has been found that paroxetine hydrochloride propan-2-ol solvate with these characteristics may be processed and desolvated more easily than conventionally produced paroxetine hydrochloride propan-2-ol solvate. The crystallisation process may include if necessary isolating the crystals, optionally washing and drying to remove surface solvent. However advantageously the crystalline solvate is used as a feed material for desolvation to obtain paroxetine hydrochloride anhydrates, especially the Form A anhydrate. Accordingly, in a further aspect the present invention provides a process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating crystalline propan-2-ol solvate obtainable by the process of this invention to remove bound propan-2-ol. Desolvation is conveniently carried out by heating in an oven, preferably in vacuo, suitably at a temperature of about 60°C. The resultant anhydrate desirably contains less than 3% of propan-2-ol, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1%. Advantageously the crystalline anhydrate is the Form A anhydrate of paroxetine hydrochloride. The crystalline paroxetine hydrochloride anhydrate 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: 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 lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg 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 400mg 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 obtainable by this invention and a pharmaceutically acceptable carrier; the use of paroxetine hydrochloride anhydrate 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 obtainable by this invention to a person suffering from one or more of the disorders. The invention is illustrated by the following Examples. In the Examples drying has been carried out under standardised conditions for the purpose of comparison. Conventionally prepared paroxetine hydrochloride propan-2-ol solvate contains approximately 6% propan- 2-ol under these drying conditions. Paroxetine hydrochloride with lower residual propan- 2-ol can be obtained by increasing the drying time or temperature. Comparison example A solution of paroxetine hydrochloride (10 g) in propan-2-ol (170 ml) was heated at reflux under a nitrogen atmosphere and then allowed to cool to room temperature. After 4 hours the crystalline product was collected by filtration. The material was desolvated by heating under vacuum at 60°C for 20 hours. Yield 8.98 g (propan-2-ol content 5.6%). Heating under vacuum for a further 72 hours caused the propan-2-ol content to fall to 3.1%. Crystal length by microscopy 300-500 microns. Example 1 N solution of paroxetine hydrochloride (10 g) in propan-2-ol (170 ml) was heated at reflux for 1 hour then cooled to 60°C and treated with diethylamine hydrochloride (0.5g). The reaction mixture was slowly cooled to room temperature with stirring. After 3.5 hours the resulting white crystalline solid was filtered, washed with propan-2-ol (40 ml) and dried under vacuum at 60°C for 20 hours to give paroxetine hydrochloride, containing 2.5% propan-2-ol by weight. Heating under vacuum for a further 72 hours caused the propan-2- ol content to fall to 1.8%. Example 2 A solution of paroxetine hydrochloride (10 g) in propan-2-ol (170 ml) was heated at reflux for 1 hour then cooled to 60°C and treated with acetic acid (25 ml). The reaction mixture was slowly cooled to room temperature with stirring. The resulting white crystalline solid was filtered, washed with propan-2-ol (35 ml) and dried in vacuo at 60°C for 20 hours to give paroxetine hydrochloride as acicular crystals, containing 2.8% propan-2-ol by weight. Crystal length by microscopy 40-80 microns. Example 3 A solution of paroxetine hydrochloride (5.0 g) in propan-2-ol (70 ml) and acetic acid (5 ml) was heated at reflux for 10 minutes. The homogeneous solution was then cooled to room temperature under argon without stirring. Seed crystals of paroxetine hydrochloride propan-2-ol solvate (O.lg) were added and the reaction mixture stirred. Rapid crystallisation ensued to give a thick suspension. The suspension was left for 15 minutes and filtered, washed with propan-2-ol (10 ml) and dried in vacuo for 20 hours at 60°C to give paroxetine hydrochloride containing 2.1 % propan-2-ol by weight. Example 4 A solution of paroxetine hydrochloride (5.16 g) in propan-2-ol (70 ml) was heated at reflux, then cooled to 60°C. Ammonium acetate (0.1 g) was added and the mixture further cooled and stirred vigorously at to 35-40°C for 2 hours. The resulting solid was filtered, washed with propan-2-oI (15 ml) and dried in vacuo at 60°C for 20 hours to give paroxetine hydrochloride anhydrate Form A containing 1.6 % ρropan-2-ol. Crystal length by microscopy 30-60 microns; length to width ratio approximately 7:1. Example 5 A solution of paroxetine hydrochloride (4.54 g) in propan-2-ol (70 ml) was heated at reflux then cooled to 60°C. Ammonium chloride (0.1 g) was added and the reaction mixture stirred vigorously and cooled slowly to 45-50°C over 3 hours. The resulting slurry was cooled to ambient temperature, filtered, washed with propan-2-ol (10 ml) and dried in vacuo at 60°C for 20 hours to give paroxetine hydrochloride anhydrate Form A containing 1.1 % propan-2-ol. Crystal length by microscopy 30-60 microns; length to width ratio approximately 6: 1.

Claims: CLAIMS 1. A process for obtaining crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol, adding to the solution a habit modifier compound, and crystallising paroxetine hydrochloride propan-2- ol solvate from the modified solution. 2. A process according to claim 1 in which the habit modifier is an ionic or easily ionisable compound. 3. A process according to claim 1 in which the habit modifier is a carboxylic acid or an amine salt. 4. A process according to claims 1 to 3 for the production of paroxetine hydrochloride propan-2-ol solvate from which more than 50% by weight of the product consists of crystals in which the distance between the facets with Miller indices (0, 1 , 0) and (0, 1, 0) in a monoclinic crystal system, P2, space group, is less than 100 microns. 5. Crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit obtainable by a process according to claim 1 or 2. 6. Crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit in which more than 50% by weight of the material is in crystals less than 100 microns long, preferably below 75 microns, and more preferably below 50 microns. 7. Crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit in which more than 50% by weight of the material is in crystals with a length-to-width ratio below 20:1, preferably below 15:1 and more preferably below 10:1. 8. Crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit in which more than 50% by weight of the material is in crystals with a volume below 5,000 cubic microns, preferably below 2,500 cubic microns and more preferably below 1 ,000 cubic microns. 9. Crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit in which the distance between crystal facets characterised by the Miller indices (0, 1 , 0) and (0, _ l, 0) in a monoclinic crystal system, P2, space group, is below 100 microns for more than 50%> by weight of the product. 10. A process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating crystalline propan-2-ol solvate obtainable by the process of claim 1, 2 or 3 to remove bound propan-2-ol. 11. A pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine hydrochloride anhydrate obtainable by the process of claim 1 , 2 or 3 and a pharmaceutically acceptable carrier; 12. Use of paroxetine hydrochloride anhydrate obtainable by the process of claim 1, 2 or 3 to manufacture a medicament for the treatment or prophylaxis of the disorders; and 13. A method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride anhydrate obtainable by the process of claim 1, 2 or 3 to a person suffering from one or more of the disorders. 14. Paroxetine hydrochloride propan-2-ol solvate that is more easily desolvated, such that in a drying comparison with conventionally crystallised paroxetine hydrochloride propan- 2-ol solvate under standard drying conditions, retains less than 75% of the propan-2-ol in the standard, preferably less than 50%, and more preferably less than 25%. 15. The process of drying paroxetine hydrochloride propan-2-ol solvate claimed in or prepared by the processes claimed in any of the above claims.

Inventors: CRAIG ANDREW SIMON, JONES ALAN DAVID, CRAIG, ANDREW, SIMON, JONES, ALAN, DAVID
Applicants: CRAIG ANDREW SIMON, JONES ALAN DAVID, SMITHKLINE BEECHAM PLC, CRAIG, ANDREW, SIMON, JONES, ALAN, DAVID
Application year: 1999
Main classification: C07D405
IPC codes: A61K31, A61P25, C07D405