JP2002531450A - Process for producing paroxetine hydrochloride - Google Patents

Abstract

  (57) [Summary] By crystallizing from a solution of paroxetine hydrochloride in propan-2-ol to which a crystal habit modifier compound has been added, crystalline paroxetine having a modified crystal habit that more easily desolvates to form an anhydride. A hydrochloride / propan-2-ol solvate is obtained. Heating a crystalline solvate having a modified crystal habit in a vacuum oven gives Form A anhydride. Suitable crystal habit modifiers are carboxylic acids and amine salts.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of a pharmaceutically active compound and its intermediates, and to the use of said active compound in therapy. In particular, the present invention relates to a novel process for preparing paroxetine chloride-propan-2-ol solvate and its use for preparing the crystalline anhydrous form of paroxetine hydrochloride.

[0002] Pharmaceutical products having antidepressant and anti-Parkinson properties are disclosed in US Pat.
No. 3 and No. 4007196. Of particular interest among the disclosed compounds is 4- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxy-
Paroxetine, which is the (-) trans isomer of phenoxymethyl) -piperidine. This compound is used in therapy where the hydrochloride salt is, inter alia, for the treatment and prevention of depression, obsessive-compulsive disorder (OCD) and panic.

[0003] Paroxetine hydrochloride is a crystalline hemihydrate (Beecham Group).
Group EP-A-0223403) and various crystalline anhydrous forms (see SmithKline Beecham, WO 96/24595). WO96 / 24595 includes paroxetine / hydrochloride / anhydride Form A (Fo
rm A), an intermediate useful for the production of paroxetine hydrochloride propane-2-
The preparation of all solvates is disclosed. When prepared conventionally by crystallization from anhydrous propan-2-ol, paroxetine hydrochloride propan-2-ol
All solvates have very poor agitation properties and are very difficult to isolate, wash and dry.

The desolvation of paroxetine / hydrochloride / propan-2-ol solvate is described in WO 96/2
5495 and EP 0 812 827 A1. It is clear from these documents that desolvation in a vacuum oven is a slow and difficult process. Furthermore, when operating on a scale of more than a few grams, the time and temperature required for substantially complete desolvation increase significantly, for example, EP 0 812 827 A1, on a scale of 180 g, Drying at 80 ° C. for 1 week yields a product still containing more than 2% of propan-2-ol, and the propane-2-ol must be raised to 110 ° C.
It is disclosed that the all residue cannot be reduced to about 0.1%. Very long processing is undesirable for manufacturing due to the costs associated with container occupancy, and high temperatures cause product decomposition and phase transitions.

[0005] Another undesirable feature of current methods is the tendency of the product to crystallize in a heavy, mat-like form that is very difficult to stir, move, and filter. For example, 20 kg of paroxetine hydrochloride in 160 liters of propan-2-ol was seeded at 48 ° C. in a glass lined reactor containing a vigorously stirred solution. All contents are
It solidified into a thick crystalline mass, which required opening the man-way, forcibly moving the contents by hand and stirring the mixture to recover the product. Thus, the current methods have proven unsuitable for large-scale production of paroxetine hydrochloride.

[0006] The present invention provides paroxetine / hydrochloride in a form that is more easily desolvated than paroxetine / hydrochloride / propan-2-ol solvate prepared by conventional means and is therefore more suitable for commercial production processes. Provided is a method for producing a salt / propan-2-ol solvate.

According to one aspect of the present invention, a solution of paroxetine hydrochloride in propan-2-ol is prepared, a crystal habit modifier compound is added to the solution, and paroxetine hydrochloride. Provided is a method for producing crystalline paroxetine hydrochloride propan-2-ol solvate, comprising crystallizing propan-2-ol solvate. Suitable crystal habit modifying compounds are selected from ionic compounds or compounds that can be easily ionized and can be dissolved in propan-2-ol.

[0008] Upon the addition of a given crystal habit modifier compound to the solution, the resulting crystal habit forms a form that allows for convenient stirring, filtration and washing on a production scale, and more effective desolvation of the crystals. Changes to

[0009] A suitable concentration of paroxetine hydrochloride in propan-2-ol is
2-ol 4 to 40 volumes, preferably 8 to 15 volumes, more preferably 10 to 10 volumes
It is one capacity part in 14 capacities. Preferably, propan-2-ol is anhydrous to suppress the formation of paroxetine hydrochloride hemihydrate.

A suitable method for preparing paroxetine hydrochloride for dissolution in propan-2-ol for use in the method of the present invention is described in US Pat. Nos. 4,009,196;
Nos. 21,723; 4,902,801; 4,861,893 and 5,039,803.

Examples of suitable crystal habit modifiers are carboxylic acids, preferably acetic acid, and amine salts,
In particular, hydrochloride or acetate, for example diethylamine hydrochloride or ammonium acetate.

The amount of the carboxylic acid crystal habit modifier used is suitably 1 to 20% by volume of the solvent, preferably 1 to 10% by volume. A suitable amount of the amine salt crystal habit modifier is 5 to 25 mol%, preferably 10 to 20 mol%.
Mol% range.

[0013] Crystallization is initiated by conventional methods such as cooling the hot solution or removing the solvent by evaporation or heating. Method of the invention or WO96 / 24595
It is advantageous to add seed crystals of the crystalline paroxetine hydrochloride propan-2-ol solvate produced by the process of

The crystalline paroxetine hydrochloride propan-2-ol solvate having a modified crystal habit obtainable by the process of the invention is in a different crystalline form than the previously known products . This new product forms another aspect of the present invention.

One feature of the new shape that differs from previously known shapes is in particle size distribution and average particle volume. Conventionally produced paroxetine hydrochloride-propan-2-ol solvate crystals are large and long, typically most of the materials have a length greater than 300μ and a length-width ratio of 40: 1, greater for example, volume measured by laser light scattering in a crystalline form is 10,000Myu ³ or more. In contrast, in the novel form of paroxetine hydrochloride propan-2-ol solvate, most of the substance is less than 100μ in length, preferably less than 75μ, more preferably less than 50μ, The length to width ratio is 20: 1 or less, preferably 1
5: 1 or less, more preferably 10: 1 or less, the capacity is 5,000Myu ³ or less, preferably, 2,500Myu ³ or less, more preferably in a crystalline 1,000 microns ³ below. The products of the present invention have one, two or all three of these desirable characteristics.

[0016] During our course of research, we believe that one particular crystallographic axis is important for the rapid desolvation of paroxetine hydrochloride propan-2-ol solvate. I got the knowledge. Thus, in another embodiment of the present invention, the average distance between crystal facets characterized by Miller indices (0,1,0) and (0, ￣1,0) in the monoclinic P2 ₁ space group is Paroxetine hydrochloride propan-2-ol solvate is provided that has a modified crystal habit that is minimized, preferably less than or equal to 100 μ.

Paroxetine hydrochloride-propan-2-ol solvate having these characteristics is more easily processed and deoxidized than conventionally produced paroxetine hydrochloride-propan-2-ol solvate. It has been found that it can be solvated.

The crystallization step optionally includes isolating the crystals and may include washing and drying to remove surface solvents. However, advantageously, the crystalline solvate is used as a feed for desolvation and paroxetine hydrochloride.
Anhydrides, in particular Form A anhydrides, are obtained.

Thus, in a further aspect, the present invention relates to a method for heating a crystalline propan-2-ol solvate obtainable by a method according to the invention, wherein said propane-2ol is bound.
A method for producing a crystalline anhydride of paroxetine hydrochloride by removing all.

The desolvation is conveniently carried out in an oven, preferably under vacuum, suitably at about 6
It is carried out by heating at a temperature of 0 ° C.

The resulting anhydride desirably contains less than 3%, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1% of propan-2-ol. I do. Advantageously, the crystalline anhydride is paroxetine hydrochloride Form A anhydride.

The crystalline paroxetine / hydrochloride / anhydride obtained by the present invention is EP-A
-0223403 or the formulations disclosed in WO 96/00477.

The therapeutic uses of paroxetine / hydrochloride / anhydride of the present invention include alcoholism, anxiety, depression, obsessive-compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, disease Hunger, anorexia, social phobia, premenstrual syndrome (PMS),
Treatment of adolescent depression, trichothromoney, dysthymia, and substance abuse (hereinafter "disorder").

Most suitably, the anhydride obtainable according to the invention is applied for the treatment of depression, OCD and panic.

Although the compositions prepared according to the present invention are generally suitable for oral administration, dissolving formulations for parenteral administration are also within the scope of the present invention.

The composition is usually used by human patients to convert active ingredient 1 based on free base.
It is provided as a unit dose composition containing from 200 to 200 mg, more usually from 5 to 100 mg, for example from 10 to 50 mg, for example 10, 12.5, 15, 20, 25, 30 or 40 mg. Most preferably, unit doses contain 20 mg of active ingredient, calculated on free base. Such compositions are typically 1 to 6 per day.
Dosing, for example, 2, 3 or 4 times a day, such that the total dose of the active agent is in the range from 5 to 400 mg of active ingredient, calculated on the free base. Most preferably, the unit dose is administered once a day.

Preferred unit dosage forms include tablets or capsules, and include formulations suitable for controlled or delayed release.

The compositions of the present invention can be formulated by conventional methods of mixing, filling and compressing, such as blends. Carriers suitable for use in the present invention include diluents, binders, disintegrants, colorants, flavoring agents and / or preservatives. These agents can be used by conventional means, for example, by means similar to those already used for commercially available antidepressants.

Specific examples of pharmaceutical compositions in which the anhydrous products of the present invention can be used as the active ingredient include those disclosed in EP-B-0223403 and US Pat. No. 4,007,196.

Accordingly, the present invention also relates to a pharmaceutical composition for the treatment or prevention of a “disorder”, comprising paroxetine / hydrochloride / anhydride obtainable according to the invention and a pharmaceutically acceptable carrier; Use of paroxetine / hydrochloride / anhydride obtainable according to the present invention for the manufacture of a medicament for the treatment or prevention of "", and an effective or prophylactic amount in a human suffering from one or more "disorders". Administering paroxetine / hydrochloride / anhydride obtainable according to the present invention,
Provide treatment for “disorders”.

The present invention is illustrated by the following examples. In the examples, drying was performed under standard conditions for comparative purposes. Conventionally prepared paroxetine hydrochloride propan-2-ol solvate contains about 6% propan-2-ol under these dry conditions. Paroxetine hydrochloride having a still smaller amount of propan-2-ol can be obtained by extending the drying time or increasing the drying temperature.

Comparative Example A solution of paroxetine hydrochloride (10 g) in propan-2-ol (170 ml) was heated at reflux under a nitrogen atmosphere and then cooled 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 reduced the propan-2-ol content to 3.1%. Crystal length by microscope: 300-500μ.

Example 1 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 diethylamine.
Treated with hydrochloride (0.5 g). The reaction mixture was cooled slowly to room temperature with stirring. After 3.5 hours, the resulting white crystalline solid was filtered, washed with propan-2-ol (40 ml), dried at 60 ° C. for 20 hours under vacuum,
Paroxetine hydrochloride containing 2.5% by weight of 2-ol was obtained. Heating under vacuum for a further 72 hours reduced the propan-2-ol content 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 acetic acid (25 ml)
Processed. The reaction mixture was cooled slowly 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 obtain 2.8% by weight of propan-2-ol as needle crystals.
Paroxetine hydrochloride was obtained. Crystal length by microscope: 40-80μ.

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 without stirring under argon. Seed crystals (0.1 g) of paroxetine / hydrochloride / propan-2-ol solvate were added and the reaction mixture was stirred.
Rapid crystallization followed, resulting in a thick suspension. The suspension was left for 15 minutes, filtered, washed with propan-2-ol (10 ml), at 60 ° C. for 20 hours,
Paroxetine containing 2.1% by weight of propan-2-ol
The hydrochloride was obtained.

Example 4 A solution of paroxetine hydrochloride (5.16 g) in propan-2-ol (70 ml) was heated at reflux and then cooled to 60 ° C. Ammonium acetate (
(0.1 g) was added and the mixture was further cooled and stirred vigorously at 35-40 ° C for 2 hours. The resulting solid was filtered, washed with propan-2-ol (15 ml),
Vacuum dried at 60 ° C. for 20 hours to obtain paroxetine / hydrochloride / anhydride Form A containing 1.6% of propan-2-ol. Microscopic crystal length: 30-60μ; length-width ratio: about 7: 1.

Example 5 A solution of paroxetine hydrochloride (4.54 g) in propan-2-ol (70 ml) was heated at reflux and then cooled to 60 ° C. Ammonium chloride(
0.1 g) is added and the reaction mixture is stirred vigorously and slowly stirred for 4 hours over 4 hours.
Cool to 5-50 ° C. The resulting slurry was cooled to room temperature, filtered, and propane-
After washing with 2-ol (10 ml) and vacuum drying at 60 ° C. for 20 hours, paroxetine / hydrochloride / anhydride Form A containing 1.1% of propan-2-ol was obtained. Crystal length by microscopy: 30-60μ; length-width ratio: about 6: 1.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72 Inventor David Alan Jones United Kingdom, Thienne 11.9 A.N., Kent, Tonbridge, Near Lee, Old Powder Mills, Smithkline Beechham Pharmaceuticals F-term (reference) 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA01 AA04 BA13 BC50 GA06 GA15 MA01 MA04 ZA11 ZA12 ZA15

Claims (15)

[Claims] 1. A solution of paroxetine hydrochloride in propan-2-ol is prepared, and a crystal habit modifier compound is added to the solution.
A method for producing crystalline paroxetine / hydrochloride / propan-2-ol solvate, comprising crystallizing a hydrochloride / propan-2-ol solvate. 2. The method according to claim 1, wherein the crystal habit modifier is an ionic compound or a compound that can be easily ionized. 3. The method according to claim 1, wherein the crystal habit modifier is a carboxylic acid or an amine salt. 4. A portion exceeding 50% by weight of the product, Miller indices (0,1,0) and in P2 ₁ space group monoclinic (0, 1,0) between the facets having Paroxetine / hydrochloride / propane-2 consisting of crystals having a distance of less than 100 μm
4. The process according to claim 1, for the preparation of all solvates. 5. A crystalline paroxetine / hydrochloride / propan-2-ol solvate having a modified crystal habit obtainable by the method according to claim 1 or 2. 6. A crystalline paroxetine hydrochloride having a modified crystal habit, wherein more than 50% by weight of the substance are crystals having a length of less than 100μ, preferably less than 75μ, more preferably less than 50μ. -Propan-2-ol solvate. 7. A modified crystal wherein more than 50% by weight of the substance is a crystal having a length-to-width ratio of not more than 20: 1, preferably not more than 15: 1, more preferably not more than 10: 1. Crystalline paroxetine / hydrochloride / propan-2-ol solvate having a habit. 8. A portion exceeding 50 wt% of the material 5,000Myu ³ or less, preferably, 2,500Myu ³ or less, more preferably, a crystal having a 1,000 microns ³ below capacity, denatured habit Crystalline paroxetine / hydrochloride / propane having
2-ol solvate. 9. Miller index (0,1,0) in a monoclinic P2 ₁ space group
And the distance between the crystal facets characterized by (0, ￣1,0) is 5
A crystalline paroxetine / hydrochloride / propan-2-ol solvate having a modified crystal habit of not more than 100 μm for a portion exceeding 0% by weight. 10. Paroxetine / hydrochloric acid by heating a crystalline propan-2-ol solvate obtainable by the method of claim 1, 2 or 3 to remove bound propan-2-ol. A method for producing a crystalline anhydride of a salt. 11. A pharmaceutical composition for treating or preventing "disorders", comprising paroxetine / hydrochloride / anhydride obtainable by the method according to claim 1, 2 or 3, and a pharmaceutically acceptable carrier. 12. Use of paroxetine / hydrochloride / anhydride obtained by the method according to claim 1, 2 or 3 for the manufacture of a medicament for treating or preventing a "disorder". 13. An effective or prophylactic amount of paroxetine / hydrochloride / anhydride obtainable by a method according to claim 1, 2 or 3 in a human suffering from one or more "disorders". A method for treating a "disorder", comprising administering. 14. Propane in this standard compared to dry paroxetine hydrochloride propan-2-ol solvate, which is more easily desolvated and conventionally crystallized under standard drying conditions. Less than 75% of the 2-ol, preferably
Paroxetine that retains less than 50%, more preferably less than 25%
Hydrochloride / propan-2-ol solvate. 15. A paroxetine hydrochloride / propan-2-ol solvate according to any one of claims 1 to 14, or paroxetine hydrochloride produced by the method according to any one of claims 1 to 14. -A method for drying propan-2-ol solvate.