PROCESS FOR THE PRODUCTION OF PAROXETINE HYDROCHLORIDE PROPAN-2-OL SOLVATE

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 under intense insonation conditions, or in a continuous crystalliser, or which has been seeded with crystals of a paroxetine hydrochloride solvate or anhydrate, especially Form A anhydrate.

Description: PROCESS FOR THE PRODUCTION OF PAROXETINE HYDROCHLORIDE PROPAN-2-OL SOLVATE 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 oϊ 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 Al 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, and crystallising paroxetine hydrochloride propan-2-ol solvate under conditions of intense insonation. Advantageously, insonation is carried out during slow cooling through the metastable zone, and is maintained during cooling to ambient temperature. These conditions provide a continuous flux of freshly generated nuclei, and result in crystallisation of paroxetine hydrochloride propan-2-ol solvate in a modified crystal habit which is easy to stir, wash and filter, and surprisingly is more readily desolvated than conventionally crystallised paroxetine hydrochloride propan-2-ol solvate. Suitably crystallization is carried out in a vessel provided with one or more high intensity ultrasonic probes, for example with titanium alloy resonant horns which enable acoustic energy to be coupled to the crystallizing medium at a frequency of 20 kHz and an amplitude of 12 microns or more, and with a device that modifies the power output according to the acoustic parameters of the load. Insonation may be intermittent, limited to part of the apparatus, or discontinued once sufficient nuclei have been generated. In another aspect of this invention, rapid crystallisation onto a dense flux of freshly generated nuclei may be achieved by causing rapid crystallisation in a continuous flow crystallisation apparatus. Suitably, the crystallisation may be achieved by bringing together two liquid streams, for example a solution of paroxetine hydrochloride in propan- 2-ol and an anti-solvent such as hexane or heptane, or by rapid cooling of a single solvent stream, or by insonation of a saturated solvent stream, or by a combination of some or all of these techniques. In the case where two streams are combined, generation of nuclei and crystallisation takes place in a reaction zone, which may vary from a specially designed vortex mixer to a simple Y-tube. According to another aspect of the present invention there is provided a process for crystallising paroxetine hydrochloride propan-2-ol solvate with modified habit from a solution of paroxetine hydrochloride in propan-2-ol in the presence of a dense flux of nuclei supplied by the addition of seeds. Suitable seeds are obtained from a wide range of paroxetine hydrochloride solvates such as, for example, the solvate with pyridine, acetic acid, p-xylene, N,N'-dimethylformamide, chloroform, dichloromethane, dichloroethane, acetonitrile, propan-1-ol, ethanol, propan-2-ol, acetone, tetrahydrofuran, 1,4-dioxane, or the Form "A" anhydrate. Advantageously seeding is carried out with very finely powdered paroxetine hydrochloride anhydrate or solvate at elevated temperature. The seeds should preferably be less than 30 microns in length, and median particle volume below 120 cubic microns. Seeding should preferably be carried out within the metastable zone, hence at a 6-8% concentration the preferred temperature for crystallisation is from 40 to 70°C, more preferably from 55 to 65°C, and optimally from 58 to 62°C. The efficiency of external seeding may be greatly increased by very vigorous stirring, since secondary nuclei are generated by attrition of larger seed crystals, resulting in an increased flux of suitable nuclei. In certain cases a sufficient flux of nuclei may be generated by particularly vigorous stirring alone, although this procedure is unlikely to be as effective unless the crystallisation vessel is routinely used for the crystallisation of paroxetine hydrochloride propan-2-ol solvate and so is in effect saturated with seed crystals. Suitable apparatus includes stirrers designed to operate at high torque with high shear rate and vessels with optimal hydrodynamic design including the use of baffles and bladed stirrers. These procedures for crystallisation in a flux of freshly generated nuclei modify the habit of the resultant crystals to a form which allows more effective de-solvation of the crystals. Furthermore, the procedures result in a controlled crystallisation in which the product can be stirred efficiently and continuously without the use of specialised apparatus, and without forming dense unstirrable zones in the crystallizer. A suitable concentration of paroxetine hydrochloride in propan-2-ol is one part in from 4 to 40 volumes of propan-2-ol, preferably from 8 to 15 volumes, and more preferably from 10 to 14 volumes. Preferably the propan-2-ol is anhydrous to suppress formation of paroxetine hydrochloride hemihydrate. The preparation of crystalline paroxetine hydrochloride anhydrate, for use as seed crystals in one of the processes of this invention, is described in WO 96/24595. 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. In addition to the procedures described above, crystallisation may be assisted by conventional techniques such as cooling, or removing solvent by evaporation or distillation. 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 by for example laser light scattering, of 20,000 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 3,000 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 200 mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg 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 400 mg 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 these 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. (20 hours at 60°C). Paroxetine hydrochloride with lower residual propan-2-ol for commercial use 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 60DC 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%. Example 1 Paroxetine hydrochloride propan-2-ol solvate (100 g) and propan-2-ol (800 ml) was charged to a 1 litre jacketed vessel equiped with a mechanical stirrer and a high intensity ultrasonic probe. The mixture was stirred and heated to 75°C under a nitrogen atmosphere to afford a clear solution which was then allowed to cool. When the temperature of the solution reached 70°C, insonation (frequency 20 kHz, amplitude 12 microns) was started. At 65°C the solution became cloudy and this temperature was maintained with continous insonation for ten minutes. The mixture was then cooled to ambient temperature, with continous insonation over a period of 45 minutes.The product was collected by filtration and dried under vacuum at 60°C for 20 hours. Weight of product 81.5g (propan-2-ol content 1.5% by weight, acicular crystals 10 - 50 microns in length, no agglomeration.) Particle sizing by laser light scattering: more than 50% of material below 700 cubic microns. Example 2 Paroxetine hydrochloride propan-2-ol solvate (68 g) and propan-2-ol (925 ml) were charged to a 1 litre jacketed vessel equiped with a mechanical stirrer and a high intensity ultrasonic probe. The mixture was stirred and heated to 65°C under a nitrogen atmosphere to afford a clear solution, insonation (frequency 20 kHz, amplitude 12 microns) was started and the solution allowed to cool. At 59°C the solution became cloudy and this temperature was maintained with continous insonation for ten minutes. The suspension was cooled to 40°C, with insonation, over a period of 20 minutes and then cooled to ambient temperature without further insonation. The product was collected by filtration and dried under vacuum at 60°C for 20 hours. Weight of product 60.7g (propan-2-ol content 2.8% by weight, acicular crystals 5 - 100 microns in length, no agglomeration.) Particle sizing by laser light scattering: more than 50% of material below 1150 cubic microns. Example 3 A solution paroxetine free base (120 g) in propan-2-ol (800 ml) was charged to a 1 litre jacketed vessel equiped with a mechanical stirrer and a high intensity ultrasonic probe. The mixture was stirred at ambient temperature under a nitrogen atmosphere and insonation (frequency 20 kHz, amplitude 12 microns) started. A solution of hydrogen chloride in propan-2-ol (5-6N, 65 ml) was added over a period of thirty minutes with continous insonation of the mixture during the addition and for a further 30 minutes afterwards. The product was collected by filtration and dried under vacuum at 60°C for 20 hours. Weight of product 118 g (propan-2ol content 2.3% wt/wt). Example 4 A solution of paroxetine hydrochloride (4.4 g) in propan-2-ol (70 ml) was heated at reflux under argon then cooled to 60°C and, with very vigorous stirring, treated with seed crystals of paroxetine hydrochloride anhydrate Form A (0.25 g) which had been ground to a fine powder. Rapid crystallisation ocurred, and propan-2-ol was added (30 ml) before filtering the white crystalline solid which formed. The product was filtered, washed with propan-2- ol (15 ml) and dried at 60°C for 20 hours to give paroxetine hydrochloride containing 2.8% propan-2-ol by weight. Example 5 A solution of paroxetine hydrochloride (5.17 g) in propan-2-ol (70 ml) was heated at reflux under argon then cooled to 60-63°C. Then, with very vigorous stirring, seed crystals of paroxetine hydrochloride anhydrate Form A (O.lg) which had been ground to a fine powder were added. Rapid crystallisation took place and the precipitate was stirred for 30 minutes, filtered, washed with propan-2-ol and dried at 60°C for 20 hours to give paroxetine hydrochloride containing 2.7% propan-2-ol by weight. Example 6 A mixture of (-)-trans-N-phenoxycarbonyl-4-(4'-fluorophenyl)-3-(3",4 H - methylenedioxyphenoxymethyl)piperidine (25 g) and potassium hydroxide flake (22.5 g) in toluene (375 ml) was heated at reflux under a nitrogen atmosphere for three hours and then the mixture allowed to cool to 20-30°C. Water (250 ml) was added and the organic layer was separated, dried with magnesium sulphate, and filtered. The resulting filtrate was evaporated to an oil, then redissolved in propan-2-ol (50 ml), and re-evaporated. Then the oil was re-dissolved in propan-2-ol (200 ml), warmed to 60-67°C and a solution of hydrogen chloride in propan-2-ol added (5-6N, 15 ml). Very vigorous stirring was applied to initiate nucleation while the temperature was reduced in stages to 55-60°C over 30 minutes then to 40-50°C over 1 hour. The resulting product was collected by filtration, washed with propan-2-ol (30 ml) and dried in vacuo at 60°C for 20 hours to give paroxetine hydrochloride (12.5 g) containing 1.1% propan-2-ol by weight. Particle size by microscopy: most crystals less than 100 microns in length, no agglomeration, length to width ratio approximately 7:1.

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, and crystallising paroxetine hydrchloride propan-2-ol solvate under conditions of intense insonation. 2. A process according to claim 1 in which the insonation is carried out during slow cooling through the metastable zone, and is maintained during cooling to ambient temperature. 3. A process according to claims 1 or 2 in which the crystallization is carried out in a vessel provided with one or more high intensity ultrasonic probes, for example with titanium alloy resonant horns which enable acoustic energy to be coupled to the crystallizing medium at a frequency of 20 kHz and an amplitude of 12 microns or more, and with a device that modifies the power output according to the acoustic parameters of the load. 4. A process according to claims 1, 2, or 3 in which the insonation is intermittent or limited to part of the apparatus, or discontinued once sufficient nuclei have been generated. 5. A process for obtaining crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol, and crystallising paroxetine hydrchloride propan-2-ol solvate in a continuous flow crystallisation apparatus. 6. A process according to claim 5 in which the crystallisation is achieved by bringing together two liquid streams, such as a solution of paroxetine hydrochloride in propan-2-ol and an anti-solvent such as hexane or heptane. 7. A process according to claim 5 in which the crystallisation is achieved by rapid cooling of a single solvent stream, or by insonation of a saturated solvent stream. 8. A process according to claim 5, 6, or 7 in which the crystallisation takes place in a reaction zone, such as a vortex mixer or a Y-tube. 9. A process for obtaining crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol, and crystallising paroxetine hydrchloride propan-2-ol solvate in the presence of crystallisation nuclei supplied by the addition of seeds. 10. A process according to claim 9 in which the seeds are obtained from paroxetine hydrochloride solvates with pyridine, acetic acid, p-xylene, N,N'-dimethylformarnide, chloroform, dichloromethane, dichloroethane, acetonitrile, propan-1-ol, ethanol, propan-2- ol, acetone, tetrahydrofuran, or 1,4-dioxane, or the Form "A" anhydrate. 11. A process according to claims 9 or 10 in which the seed is very finely powdered. 12. A process according to claims 9, 10, or 11 in which the finely powdered seed consists mainly of crystals less than 30 microns in length or median particle volume below 120 cubic microns. 13. A process according to claims 9, 10, 11, or 12 in which seeding is carried out within the metastable zone. 14. A process according to claims 9 to 13 in which seeding and crystallisation is carried out at a temperature of from 40 to 70°C, more preferably from 55 to 65°C, and optimally from 58 to 62°C. 15. A process according to any of claims 1 to 14 in which nucleation is augmented by very vigorous stirring. 16. A process for obtaining crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol , and generating crystallisation nuclei by very vigorous stirring in a vessel previously used for the preparation of paroxetine hydrochloride propan-2-ol solvate. 17. A process according to claim 16 in which the apparatus includes stirrers designed to operate at high torque with high shear rate and vessels with optimal hydrodynamic design including the use of baffles and bladed stirrers. 18. Crystalline paroxetine hydrochloride propan-2-ol solvate of modified crystal habit obtainable by a process according to any of claims 1 to 17. 19. A process according to claims 1 to 17 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. 20. 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. 21 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. 22. 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. 23. 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. 24. A process for preparing a crystalline anhydrate of paroxetine hydrochloride by heating crystalline propan-2-ol solvate obtainable by the process of claim 1 to 17 or 19 to remove bound propan-2-ol 25. A pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine hydrochloride anhydrate obtainable by the process of claim 1 to 17 or 19 and a pharmaceutically acceptable carrier; 26. Use of paroxetine hydrochloride anhydrate obtainable by the process of claim 1 to 17 or 19 to manufacture a medicament for the treatment or prophylaxis of the disorders; and 27. 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 to 17 or 19 to a person suffering from one or more of the disorders. 28. 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%. 29. 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 DAVID ALAN, CRAIG, ANDREW, SIMON, JONES, DAVID, ALAN
Applicants: CRAIG ANDREW SIMON, JONES DAVID ALAN, SMITHKLINE BEECHAM PLC, CRAIG, ANDREW, SIMON, JONES, DAVID, ALAN
Application year: 1999
Main classification: C07D405
IPC codes: A61K31, A61P25, C07D405