SK11812000A3 - Salts of paroxetine - Google Patents

Abstract

A salt of paroxetine with an acid selected from the group consisting of sulphuric, tartaric, oxalic, fumaric, propionic, formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, 4-methylbenzenesulphonic, hypophosphorous, lactic, and mandelic acids and glycine, is useful in the treatment and prophylaxis of certain CNS disorders.

Description

Paroxetine salts, process for their preparation, pharmaceutical composition containing them and their use

Technical field

The present invention relates to novel compounds, processes for their preparation and their use in the treatment of disease states.

BACKGROUND OF THE INVENTION

Pharmaceutical products having anti-depressant and anti-Parkinson's properties are described in US-A-3912743 and US-A-4007196. A particularly important compound among the disclosed compounds is paroxetine, the (-) trans isomer of 4 (4'-fluorophenyl) -3- (3 ', 4'-methylenedioxy-phenoxymethyl) piperidine. This compound is used in hydrochloride salt therapy for the treatment and prophylaxis of, inter alia, depression, obsessive-compulsive disorder (OCD) and panic conditions.

Surprisingly, novel paroxetine salts have now been found which can alternatively be used in place of the hydrochloride currently on the market or as an intermediate in the production of hydrochloride.

SUMMARY OF THE INVENTION

The present invention provides salts of paroxetine with an acid selected from the group consisting of sulfuric, tartaric, oxalic, fumaric, propionic, formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, 4-methylbenzenesulfonic, phosphoric, lactic and lactic acid.

Tartaric, glutamic and almondic acids exist in enantiomeric forms and the present invention includes salts with both D- and L-acids and their racemic mixtures, as well as symmetric meso-tartaric acid.

Sulfuric, tartaric, oxalic, fumaric, glutamic and succinic acids are dibasic acids, and therefore the invention includes both salts where the ratio of paroxetine to acid (in molar terms) is 1: 1 and salts where the ratio of paroxetine to

-2 acid (mole) is 2: 1 as well as mixed salts, e.g. with an alkali metal cation or with an ammonium cation.

Citric and phosphoric acids are tribasic acids and therefore the invention includes salts wherein the ratio of paroxetine to acid (in molar terms) is 1: 1, 2: 1 or 3: 1, as well as mixed salts, e.g. with an alkali metal cation or with an ammonium cation.

In one embodiment of the invention, the novel salts are provided in a non-crystalline form, which may be in the form of a solid or an oil. The oil is preferably absorbed onto a solid carrier, in particular a carrier which can be used as a component of a pharmaceutical composition.

In another embodiment, the novel salts of the invention are provided in crystalline form. When the crystalline form exists in multiple polymorphs, all polymorphic forms constitute a further embodiment of the invention.

Paroxetine salts can be prepared by reacting stoichiometric amounts of acid (enantiomer or racemic mixture) and paroxetine free base. It is preferred that the base and / or acid be in solution, more preferably both are in solution. Mixed salts can be made by forming a precursor in a 1: 1 ratio or a hydrogenated salt (paroxetine with an acid, or a metal or ammonium ion with an acid) in situ or using it in solution.

The most commonly used solvents are suitable for mobilizing paroxetine free base, e.g. toluene, alcohols such as methanol, ethanol, propan-2-ol, esters such as ethyl acetate, ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane and ethers such as tetrahydrofuran and diethyl ether. The concentration of the paroxetine base is preferably in the range from 5 to 50% w / v, more preferably in the range from 10 to 30%.

Suitable solvents for the acids used in accordance with the present invention include water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as toluene and benzene, esters such as ethyl acetate, ketones such as acetone and isobutylmethylketone; halogenated hydrocarbons such as chloroform. The concentration of the acid (other than glutamic acid) is preferably in the range of 0.1 to 6.0 molar, e.g. 0.5 to 4.0 molar, especially 1.0 to 3.0 molar. Elevated temperatures may be used to increase solubility. concentration

The glutamic acid is preferably in the range of 0.01 to 1.0 molar, in particular 0.1 to 0.5 molar. The acids may also be used in the form of a soluble salt, such as e.g. an ammonium salt or an amine salt, e.g. ethylamine or diethylamine.

The paroxetine salts can be isolated in solid form by conventional methods from its solutions obtained as above. For example, non-crystalline salts may be prepared by precipitation, spray-drying and freeze-drying of solutions, or by vacuum drying of oils, or by solidification of melts obtained from the reaction of the free base and the acid.

Crystalline salts can be made directly by crystallization from a solvent in which the product has limited solubility, or by trituration or other crystallization of the non-crystalline salt. An increased salt yield is obtained by evaporating some or all of the solvents or crystallizing at an elevated temperature followed by controlled cooling, preferably gradually. Careful control of precipitation and seeding can be used to increase the reproductive capacity of the process and the particle size distribution and product formation.

An alternative method of making paroxetine salts is by reacting the paroxetine salt with an organic acid such as e.g. acetic acid or malic acid. The use of a paroxetine salt other than the starting material is suitable for the production of a crystalline salt or, if a volatile acid such as e.g. acetic acid, to produce non-crystalline salts by methods that include evaporation (e.g., freeze-drying and spray-drying).

Prior to isolation of the paroxetine salt, the water can be removed by azeotropic distillation to avoid formation of hydrates or to obtain the product in anhydrous form. In this case, suitable solvents for the salt solution are those which form an azeotropic mixture with water, such as toluene, pyridine, isopropanol, isobutylmethylketone and xylene. It is also appreciated that such solvent mixtures can also be used for the purpose of assisting azeotropic removal of water.

Conveniently, crystallization can be carried out from any solvent that allows the desired crystalline structure to be formed, by seeding the desired structure if desired or appropriate. In the case of polymorphs, the polymorphs are preferably crystallized directly from the salt solution, although possible

Also, recrystallize a solution of one polymorph by seeding another polymorph.

Suitable solvent systems for crystallizing / recrystallizing the salts of the present invention are listed below:

sulfate: water, butan-1-ol, butan-2-ol. tartrate: ethanol, methanol, isopropanol, toluene. oxalate: ethanol, methanol, acetone, tetrahydrofuran. fumarate: methanol, butanol, tetrahydrofuran. propionate: hexane, cyclohexane, chloroform. formate: diethyl ether, water, alcohols, toluene, ethyl acetate. glutamates: water, methanol, toluene / hexane. succinate: toluene, acetone, or lower alcohols followed by precipitation with ethyl acetate, ether or hexane. Paroxetine succinate may be recrystallized by cooling and optionally by seeding hot solutions in suitable solvents such as e.g. butan-1-ol or acetonitrile. benzoate: as used in salt formation. citrate: toluene, toluene / cyclohexane, isopropanol. phosphate: toluene, ethanol, tetrahydrofuran, isopropanol.

4-Methylbenzenesulfonate: toluene or lower alcohols followed by precipitation

hypophosphite: ether or hexane. toluene or lower alcohols followed by precipitation with ether or hexane. lactate: as used in salt formation. mandelate: isopropanol, toluene. glycinate: as used in salt formation.

The salt can be obtained as a solvate or hydrate when it is contacted with a solvent in which it is soluble during isolation from the solution. Any such solvate or hydrate forms a further aspect of the invention. Solvates can be converted to unsolvates by heating, e.g. oven drying or treatment with a displacement solvent that does not form a solvate.

The paroxetine free base may be prepared according to the procedures generally disclosed in U.S. Pat. No. 4,007,196 and EP-B-0223403. Acids are commercially available.

The compounds of the present invention can be used to treat and prevent the following disorders: alcoholism depression panic disorder obesity migraine anorexia pre-menstrual syndrome (PMS) trichotillomania fear obsessive-compulsive disorders chronic pain old age dementia bulimia social phobia depression depression in adolescence depression

The disorders specified herein are hereinafter referred to as "disorders".

The present invention further provides a pharmaceutical composition for use in the treatment and / or prevention of disorders comprising a mixture of a salt of the invention with a pharmaceutically acceptable carrier.

The present invention also provides the use of a salt of the invention for the treatment and / or prevention of disorders.

The present invention also provides the use of a salt of the invention for the manufacture of a medicament for the treatment and / or prevention of disorders.

Most preferably, the present invention is applicable to the treatment of depression, OCD and panic.

The formulations of this invention are usually adapted for oral administration, but the present invention also encompasses formulations intended for dissolution when administered parenterally.

The composition is usually presented in unit dosage form containing from 1 to 200 mg of active ingredient calculated as the free base, more typically from 5 to 100 mg, e.g. 10 to 50 mg, such as e.g. 10, 12.5, 15, 20, 30 or 40 mg in humans. Most preferably, a single dose is 20 mg of active ingredient calculated as the free base. Such a formulation is normally taken 1 to 6 times a day, e.g. 2, 3 or 4 times, so that the total amount of active ingredient administered ranges from 5 to 400 mg of active ingredient calculated as the free base. Most preferably, a single dose is administered once daily.

Preferred dosage forms are tablets or capsules.

The formulations of the invention may be made by conventional mixing methods such as mixing, filling and compression.

Suitable carriers for use in the present invention include a diluent, a binder, a disintegrant, a colorant, a flavoring, and / or a preservative. These agents can be used in conventional manner, e.g. similar to those used for antidepressants on the market.

Specific examples of pharmaceutical formulations include those described in EP-B-0223403 and US 4,007,196, where the products of the invention can be used as active ingredients.

The following examples serve to illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 - Manufacture of tablets

ingredients 20 mg tablet 30 mg tablet Paroxetine salt Calcium phosphate (DCP) Microcrystalline cellulose Sodium starch glycolate Magnesium stearate 20.00 mg (calculated as free base) 83.34 mg 50.67 mg 8.34 mg 1.67 mg 30,00 mg (calculated as free base) 125.0 mg 76.0 mg 12.5 mg 2.5 mg

Commercial origin of ingredients

Calcium phosphate - Emcompress or Ditab * Microcrystalline cellulose - Avicel PH 102 *

Sodium starch glycolate - Explotab. * ‘Trade names

-7 Procedure

1. Sieve the DCP through a sieve and weigh into a planetary mixer.

2. Add paroxetine 30 mesh salt to the container.

3. Add Avicel 20 mesh and Explotab and mix all powders for 10 min.

4. Add magnesium stearate and mix for 5 min.

Use the following punches when tabletting pentagonal tablets:

mg tablet 9.5 mm with circular circumference mg tablet 8.25 mm with circular circumference

Tablets can be satisfactorily manufactured on a single punch or rotary press.

Example 2 - Manufacture of tablets

ingredients 10 mg tablet 20 mg tablet 30 mg tablet Paroxetine salt Sodium starch glycolate Granular calcium phosphate (DITAB) or Dicafos Magnesium Stearate 10 mg (calculated as free base) 2.98 158.88 mg 1.75 mg 20 mg (calculated as free base) 5.95 317.75 mg 3,50 mg 30 mg (calculated as free base) 8.93 476.63 mg 5,25 mg

Approach

1. The paroxetine salt, sodium starch glycolate and calcium phosphate dihydrate are sieved and mixed together in a suitable mixer. (Planetary, cuble or high-performance with knives).

2. Magnesium stearate is added and the mixture is compressed into a tablet using a simple punch or rotary tablet.

Example 3 - Paroxetine sulfate as a 1: 1 salt

Aqueous sulfuric acid solution (1.5 mL, 2 molar) was added to a solution of paroxetine free base (1.0 g) in propan-2-ol (10 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was removed by evaporation and the residue was stirred in a mixture of hexane (10 mL) and butan-1-ol (10 mL) until the product crystallized. Finally, the crystals were filtered off, washed with hexane and dried in vacuo.

1.1. Mp 128-130 ° C

IR nujol suspension:

Belts at 1632, 1500, 1324, 1114, 1065, 1005, 925, 884, 844, 761, 672, 614, 578

X-ray powder (Cu K _2a )

Angle [° 26] Rel. Int. 9.3 10.1 14.3 26.4 14.8 13.5 15.3 19.0 16.9 33.3 17.7 22.6 18.7 44.4 19.2 100.0 20.3 65.4 20.9 27.3 21.5 11.5 22.3 15.6 23,415 10.8 23,720 16.9 24,325 25.9 24,475 26.8 25,640 62.5 26,950 40.2

28,340 36.5 30,335 20.4

Example 4 - Paroxetine sulfate as a 2: 1 salt

Aqueous solution of sulfuric acid (1.5 mL, 2 molar) was added to a solution of paroxetine free base (2.1 g) in toluene (20 mL) with vigorous stirring. Almost immediately the solid began to separate. The mixture was diluted with hexane (40 mL) and butanol (20 mL) and stirred rapidly to form a crystalline solid. After stirring for 1 h, the crystals were filtered off, washed with hexane and dried in vacuo.

1.1. Mp 247-250 ° C

IR nujol suspension:

Strips at 1627, 1511, 1230, 1161, 1040, 958, 825, 779, 613, 593 cm ^-1 . X-ray powder (Cu K _2a )

Angle [° 26] Rel. Int. 5,300 25.3 13,215 9.6 15,185 27.3 17,595 46.7 18,290 100.0 18,980 35.0 19,465 44.3 20,755 39.2 21,420 53.0 21,635 64.3 23,305 21.8 24,875 54.7 26,075 28.2 26,615 59.1 30,355 26.5 31,710 16.3

Example 5 - Paroxetine sulfate as a 2: 1 salt

Paroxetine base (54.9 g) was dissolved in a mixture of propan-2-ol (500 mL) and water (20 mL). To the stirred clear solution was slowly added a mixture of sulfuric acid (8.3 g, 98%), water (20 mL) and propan-2-ol (200 mL); during the addition process, paroxetine sulfate crystals (2: 1) were seeded to induce crystallization. After stirring for 2 h, the mixture was stored at 4 ° C overnight, then filtered, washed with propan-2-ol (100 mL) and dried with hot air. Yield: 54.8 g.

Example 6 - Production of non-crystalline paroxetine sulfate (2: 1)

Concentrated sulfuric acid (1.6 g) was diluted to 10 ml with water and the solution was slowly added to a stirred mixture of paroxetine base (11.0 g) and water (20 ml). The clear solution was evaporated under reduced pressure to give a white, brittle glassy material.

Example 7 - Production of Paroxetine Sulfate (2: 1)

Concentrated sulfuric acid (16 g) was diluted to 100 ml with water and the solution was slowly added to a stirred mixture of paroxetine base (109.8 g) and water (200 ml). The clear solution was allowed to cool overnight, then mixed and seeded until crystallization was complete. The product was collected by filtration, washed with propan-2-ol and dried under vacuum.

Yield: 96.7 g.

Example 8 - Crystallization of Non-crystalline Paroxetine Sulfate (2: 1)

The non-crystalline paroxetine sulfate produced in Example 6 was suspended in propan-2-ol (200 mL), stirred vigorously, and gradually heated to reflux. After 2 hours, it was observed that the paroxetine sulfate form changed so that the mixture was cooled, filtered, washed with cold propan-2-ol and dried in vacuo to give crystalline paroxetine sulfate (2: 1). Yield: 8.5 g.

Example 9 - L (+) - Paroxetine tartrate 1: 1

L (+) - tartaric acid (1.25 g) was dissolved in propan-2-ol (10 ml) with heating and mixed with a stirred solution of paroxetine base (2 g) in toluene (20 ml). The formed crystalline suspension was stirred for an additional hour at room temperature. Finally, the product was filtered off, washed with acetone and dried under reduced pressure.

Yield 2.65 g.

Example 10 - L (+) - Paroxetine tartrate 1: 1

A solution of L (+) - tartaric acid (1.0 g) in methanol was mixed with a solution of paroxetine base (1.75 g) in methanol (15 ml) and stirred at room temperature. The crystals were collected within a few minutes and the suspension was stirred for an additional hour at room temperature. Finally, the crystals were filtered off, washed with acetone and dried under reduced pressure.

Yield 2.01 g.

Example 11 - Larger scale production of L (+) - tartrate of paroxetine 1: 1

L (+) - tartaric acid (25 g) was dissolved in propan-2-ol (200 ml) with heating and mixed with a solution of paroxetine base (42 g) in toluene (400 ml). The resulting crystalline precipitate was stirred at room temperature for 1 hour, then at 0 ° C for an additional hour. Finally, the crystals were filtered off, washed with acetone and dried under reduced pressure.

Yield 59.88 g.

1.1. M.p. 176-178 ° C

IR nujol suspension:

Strips at 1718, 1062, 1504, 1490, 1465, 1242, 1190, 1106, 833, 780, 650 cm ^-1 .

-12 X-ray powder (Cu K _2a )

Angle [° 20] Rel. Int. 6.1 12.8 14.2 44.7 16.2 25.7 17.3 42.6 17.9 100.00 20.1 24.0 20.4 30.6 21.9 34.5 22.3 48.6 22.6 48.6 23.0 33.0 24.0 42.2 25.1 36.9 25.7 52.5 26.1 59.5 27.3 27.8 28.6 21.3 34.3 24.2

Example 12 - D (-) - Paroxetine tartrate 1: 1

D (-) - tartaric acid (1.25 g) was dissolved in propan-2-ol (10 ml) with heating and mixed with a stirred solution of paroxetine base (2.1 g) in toluene (20 ml). The rapidly formed crystalline suspension was stirred for an additional hour at room temperature. Finally, the product was filtered off, washed with acetone and dried under reduced pressure.

Yield 2.70 g.

Example 13 - Larger scale production of paroxetine D (-) - tartrate 1: 1

D (-) tartaric acid (25 g) was dissolved in propan-2-ol (200 ml) with heating and quickly added to a solution of paroxetine base (42 g) in toluene (400 ml). A crystalline precipitate rapidly formed and was stirred at room temperature for 1 hour, then at 0 ° C for an additional hour. Finally, the crystals were filtered off, washed with toluene and dried under reduced pressure.

Yield 57.59 g.

1.1. Mp 174-176 ° C

IR nujol suspension:

Strips at 3489, 3354, 1726, 1616, 1462, 1184, 1097, 936, 831, 794, 694 cm ^-1 . Main peaks of powder X-ray (Cu K _2a )

Angle [° 20] Rel. Int. (%) 4.4 100.00 16.5 11.6 16.8 27.7 17.3 70.9 17.6 52.9 20.5 15.1 24.3 13.3 25.2 10.6 25.9 10.4 26,3 18.5 26.4 15.4 28.5 12.7 28.8 15.9

Example 14 - Preparation of a 2: 1 non-crystalline salt with L (+) - tartaric acid

L (+) - tartaric acid (1.0 g) was heated in propan-2-ol (10 ml) to form a solution and this was mixed with a solution of paroxetine base (5.0 g) in toluene (20 ml).

The resulting solution was stirred at room temperature, and then hexane (50 mL) was added and a white solid precipitated. The suspension was stirred for an additional 1 h, then the solid was filtered off, washed with hexane and dried under reduced pressure. The X-ray showed that the solid is non-crystalline in nature.

Yield: 4.32 g.

Example 15 - Production of a 2: 1 crystalline salt with D (-) - tartaric acid

D (-) - tartaric acid (1.0 g) was heated in propan-2-ol to form a solution. The solution was mixed with a stirred solution of paroxetine base (5.0 g) in toluene (20 mL). Crystallization was started over two minutes and the suspension was stirred at room temperature for a further 1 hour. Finally, the product was filtered off, washed with toluene and dried under reduced pressure.

Yield: 5.69 g.

Example 16 - Large scale production of crystalline salt 2: 1 with D (-) - tartaric acid

D (-) - tartaric acid (10 g) was dissolved in propan-2-ol (100 ml) with heating and then mixed with a stirred solution of paroxetine base (50.4 g) in toluene (200 ml). Crystals precipitated over 5 min and the suspension was stirred at room temperature for 1 h and then for an additional 1 h in an ice / water bath. Finally, the crystals were filtered off, washed with toluene and dried under reduced pressure.

Yield: 57.12 g.

IR nujol suspension:

Strips at 3436, 1650, 1556, 1491, 12121, 1120, 1035, 931, 832, 783, 631, 538 cm ^-1 .

Main peaks of powder X-ray (Cu K2a)

Angle [° 2Θ] Rel. Int. (%) 3.6 35.1 5.5 33.8 15.6 20.6 16.5 24.4

16.9 53.0 17.1 51.5 17.6 67.7 18.0 57.6 18.7 100.0 19.2 65.2 19.5 74.4 20.1 55.5 21.1 76.1 21.6 38.8 22.9 70.5 23.2 59.7 23.5 53.3 24.3 40.1 27.2 35.3 27.8 27.6 28.7 38.0 28.9 33.6 31.8 27.6

Example 17 - Production of a 2: 1 crystalline salt with L (+) - tartaric acid

Acid L (+) - potassium tartrate (1.0 g) was heated in a mixture of ethanol (120 ml) and water (40 ml) to form a solution. Paroxetine base (4.2 g) in toluene was added and the mixture was stirred at room temperature for several hours to keep it clear. Then the solvent was removed by evaporation and the residue was redissolved in toluene. The evaporation process was repeated and the residue was stirred with fresh toluene for 30 min to give a crystalline product which was filtered off, washed with toluene and dried under reduced pressure. Yield: 2.18 g.

IR nujol suspension:

Strips at 1572, 1463, 1226, 1187, 1098, 1035, 943, 835, 781,721, 598, 542 cm ^-1 .

-16Main peaks of powder X-ray (Cu K _2a )

Angle [° 20] Rel. Int. (%) 6.0 41.9 13.0 29.7 15.6 75.8 15.9 40.5 16.7 49.9 17.8 69.3 18.0 61.3 19.1 37.6 20.7 63.4 21.2 57.5 21.9 53.2 22.4 80.1 23.1 39.0 24.7 55.5 24.9 59.2 25.5 49.4 26.0 32.7 26.6 57.2 27.6 38.1 28.0 30.9 28.9 25.3 33.1 23.6

Example 18 - Production of paroxetine meso-tartrate 1: 1

A solution of meso-tartaric acid (2.14 g) in water (19 mL) was made by heating to reflux temperature. Propan-2-ol (20 mL) and paroxetine base (4.2 g) in toluene (20 mL) were added and the mixture was stirred, then the solvents were removed by distillation under reduced pressure. Toluene (20 mL) was added and the distillation repeated to give the tartrate 1: 1

-17 as a non-crystalline solid. Trituration with heptane caused crystallization of the solid and the white powder product was filtered, washed with heptane and dried under reduced pressure.

Yield: 3.52 g.

Mp: 168-171 ° C

IR nujol suspension:

Strips at 1725, 1622, 1463, 1378, 1267, 1104, 944, 824, 779, 677 cm ^-1 .

Main peaks of powder X-ray (Cu K _2a )

Angle [° 20] Rel. Int. (%) 4.7 71.2 9.4 20.6 11.1 2.1 12.8 2.6 14.6 25.9 15.2 16.9 15.7 15.1 16.6 44.5 17.4 70.0 17.9 44.0 16.7 55.8 19.1 100.0 19.7 49.4 20.7 34.7 21.0 47.3 21.6 3.1 22.4 37.6 23.0 45.3 23.4 56.1 23.7 52.5 24.8 45.3 25.3 50.7

25.8 36.7 26.1 16.3 27.0 5.1 27.5 14.5 28.1 30.1 29.4 7.2 29.9 29.5 30.2 21.1 31.0 7.9 31.5 15.2 31.9 13.8 32.4 13.1 33.2 4.0 33.6 10.9

Example 19 - Production of paroxetine oxalate (1: 1)

Oxalic acid (1.15 g) was dissolved in methanol (50 mL) with heating. A solution of paroxetine base in toluene (4.2 g in 20 mL) was added and the reaction mixture was stirred at room temperature. The solvents were removed in vacuo to give a white glassy solid form of non-crystalline paroxetine oxalate. Trituration with heptane caused crystallization to a white powdery solid, which was filtered, washed with heptane and dried under reduced pressure.

Yield: 2.93 g.

T. t. Mp 122-134 ° C

IR nujol suspension:

Strips at 1732, 1634, 1505, 1376, 1038, 930, 835, 720, 538 cm ^-1 . X-ray powder (Cu K _2a )

Angle [° 2Θ] Rel. Int. (%) 8.1 3.1 10.6 2.7

T

12.9 9.2 13.8 18.8 15.7 30.1 16.3 34.4 19.1 100.0 19.7 77.1 20.1 63.1 21.4 65.2 22.6 54.9 23.1 44.1 24.8 38.4 26.1 44.3 26.7 47.0 27.3 38.9 28.9 31.3 30.5 24.8 32.1 27.3 33.0 27.7 34.6 54.6

Example 20 - Production of Paroxetine Oxalate (2: 1)

Oxalic acid (1.15 g) was added to methanol (40 mL) and the mixture was warmed to dissolve the acid completely. Paroxetine base in toluene α (8.4 g in 40 mL) was added and the solution was stirred at room temperature. White crystals separated rapidly. The product was filtered off, washed with heptane and dried under reduced pressure. Yield: 7.34 g.

t. Mp 207-211 ° C

IR nujol suspension:

Strips at 1585, 1509, 1377, 1286, 1081, 926, 831, 761,604, 574 cm ^-1 .

X-ray powder (Cu K _2a )

Angle [° 2θ] Rel. Int. (%) 5.4 3.9 6.3 2.8 8.4 7.3 11.1 8.1 12.6 11.3 13.4 7.1 14.2 27.8 14.9 23.3 16.0 54.4 16.4 59.6 16.7 86.3 17.2 38.8 18.4 81.8 18.6 77.4 19.4 51.2 19.9 53.0 20.5 63.1 21.6 100.0 22.2 40.6 22.7 40.3 23.1 37.5 23.4 29.3 25.4 95.6 26.9 55.2 27.8 41.2 30.1 34.6 31.8 27.3 32.6 25.5 34.0 23.1

Example 21 - Salt Production 1: 1

Fumaric acid (0.3 g) was heated in a mixture of toluene (5 mL) and propan-2-ol (5 mL) to form a solution. This solution was mixed with a solution of paroxetine free base (1 g) in toluene with stirring. The crystals were separated over 2 min and the suspension was stirred at room temperature for a further 1 h. Finally, the product was filtered off, washed with toluene and dried under reduced pressure.

The molar ratio of paroxetine to fumaric acid = 1: 1.

Example 22 - Production of salt 1: 1 on a larger scale

Fumaric acid (30 g) was heated in propan-2-ol until the solid dissolved and the warm solution was mixed with a solution of paroxetine free base (84 g) in toluene (500 mL) with stirring. The crystals separated rapidly and the suspension was stirred for 1 h at room temperature, then 1 h at 0 ° C (ice / water bath). Finally, the crystals were filtered off, washed with toluene and dried under reduced pressure.

Yield: 102.31 g.

The molar ratio of paroxetine to fumaric acid = 1: 1. Characteristic data for 1: 1 paroxetine fumarate salt:

T. t. Mp 180-182 ° C

IR nujol suspension:

Strips at 1706, 1659, 1504, 1487, 1466, 1295, 1184, 1032, 833, 792, 636 cm ^-1 . Main peaks of powder X-ray (Cu K _2a )

Angle [° 26] Rel. Int. (%) 4.8 11.8 14.4 58.0 16.4 53.7 16.9 16.7 17.9 100.0 19.0 20.1 19.2 24.9

20.0 55.8 20.2 25.2 21.6 27.1 24.0 626 24.3 60.4 26.6 46.5 28.3 58.2 29.0 40.5 32.9 19.4

Example 23 - Salt Production 2: 1

Fumaric acid (0.3 g) was heated in propan-2-ol (10 ml) until the solid dissolved and this solution was mixed with paroxetine free base (2.1 g) in toluene (20 ml). The mixture was stirred for 1 h at room temperature and gel started to separate. Diethyl ether (20 mL) was added and the product crystallized. The suspension was stirred for an additional 1 h. Finally, the crystals were filtered off, washed with diethyl ether and dried under reduced pressure.

Yield: 1.79 g Molar ratio of paroxetine to fumaric acid = 2: 1.

Example 24 - Large scale salt production 2: 1

Fumaric acid (9 g) was heated in propan-2-ol (200 mL) until the solid dissolved and the warm solution was added to a solution of paroxetine free base (63 g) in toluene (600 mL). The mixture was stirred at room temperature and the product crystallized. After 1 h more toluene was added to collect the crystals by filtration. The product was washed with toluene and dried under reduced pressure.

Yield: 58.86 g.

The molar ratio of paroxetine to fumaric acid = 2: 1.

Example 25 - Production of non-crystalline salt

Paroxetine fumarate (2 g) (produced as in Example 22) was heated in methanol (50 mL) to form a solution. The solvent was removed by evaporation in a water bath at a temperature between 70 and 80 ° C. The product was a glassy solid whose X-ray showed it to be a non-crystalline substance.

Characteristic data for 1: 1 paroxetine fumarate salt:

T. t. Mp 164-165 ° C

IR nujol suspension:

Strips at 1644, 1508, 1464, 1246, 1205, 1138, 1044, 934, 836, 835, 722, 674 cm ^-1 .

Main peaks of powder X-ray (Cu K _2a )

Angle [° 20] Rel. Int. (%) 11.4 3.8 12.4 9.4 12.9 3.9 15.3 5.4 15.8 6.9 16.5 11.8 18.2 25.8 19.4 100.0 19.8 41.9 32.6 22.6 31.4 23.0 39.2 27.8 38.2 28.4 14.3 33.4 12.1

-24Example 26

Propionic acid (0.5 mL) was added to a solution of paroxetine free base (2 g) in toluene (20 mL). No crystals separated until the solution was diluted with hexane (40 mL) to give an oil which crystallized over 1 h. The suspension was stirred for an additional 1 h at room temperature. Finally, the crystals were filtered off, washed with hexane and dried under reduced pressure.

Yield: 0.60 g.

Example 27

Propionic acid (15 mL) was added to a solution of paroxetine free base (63 g) in toluene (150 mL). The mixture was diluted with hexane (1500 mL) to give an oil which started to crystallize over a few minutes. The suspension was stirred for 1 h at room temperature, then for 1 h at 0 ° C (ice / water bath). The product was filtered off, washed with hexane and dried under reduced pressure. Since some of the oil did not crystallize, more hexane was added and the mixture was stirred overnight at room temperature. Finally, the product was filtered off, washed with hexane and dried under reduced pressure.

Yield: 60.0 g.

Characteristics of paroxetine propionate:

T. t. Mp 89-81 ° C

IR nujol suspension:

Strips at 1634, 1604, 1461, 1289, 1249, 1223, 1193, 1036, 979, 870, 808, 721, 671

Main peaks of powder X-ray (Cu K2 ₀ )

Angle [° 20] Rel. Int. (%) 5.7 37.8 8.1 29.2 16.2 40.6 16.6 69.8 17.1 100.0

18.9 83.0 19.2 24.1 19.7 23.6 21.7 98.5 22.2 20.7 22.5 42.3 22.6 38.4 22.9 21.6 23.3 45.3 23.7 70.0 25.2 54.2 27.3 20.6 27.8 46.2 28.1 44.4 29.5 29.0 32.0 21.1

Example 28 - Production of crystalline paroxetine formate

A solution of paroxetine base in toluene (2 mL, 2.55 mmol) was added to a solution of formic acid (0.12 g, 2.50 mmol) in toluene (10 mL). The solvent was removed under reduced pressure to give a white solid. Trituration with diethyl ether (c. 10 mL) and filtration under nitrogen gave a white solid, which was washed with diethyl ether (2 x 10 mL) and dried.

Yield: 0.84 g.

Example 29 - Large scale production of crystalline salt

A solution of paroxetine base in toluene (120 mL, 153.0 mmol) was added to a solution of formic acid (7.2 g, 156.0 mmol) in toluene (300 mL). The solvent was removed under reduced pressure to give a white solid. Trituration with diethyl ether (c. 400 ml)

Filtration gave a white solid, which was washed with diethyl ether (2 x 100 mL) and dried under reduced pressure.

Yield: 56.10 g.

¹ H NMR (CDCl 3) showed a 1: 1 ratio between formic acid and paroxetine.

IR nujol suspension:

Strips at 1638, 1574, 1508, 1490, 1462, 1377, 1342, 1279, 1246, 1204, 1136, 1090, 1044, 934, 913, 836, 804, 786, 762, 722, 674, 603, 577, 542cm ' ¹ .

Main peaks of powder X-ray (Cu K _2a )

Angle [° 26] Rel. Int. (%) 12.6 16.3 16.3 11.4 16.8 29.8 16.9 29.8 18.6 10.1 19.5 100.0 20.2 20.9 20.4 16.9 21.0 13.5 21.5 11.8 22.1 32.8 22.7 30.4 23.1 42.3 25.8 13.6 27.8 41.6 28.7 11.3 29.0 14.2 29.7 10.6 32.6 11.4 34.0 12.1

Example 30 - Production of non-crystalline paroxetine L-glutamate

A solution of paroxetine base in toluene (5 mL, 6.38 mmol) was added to a suspension of L-glutamic acid (0.94 g, 6.38 mmol) in hot methanol (45 mL). The mixture was heated to reflux for 1 h, allowed to cool, filtered and the solvent was removed under reduced pressure. The residual oil was diluted with toluene (15 mL) and the solvent was removed under reduced pressure. Trituration with diethyl ether (c. 20 mL) and filtration under nitrogen gave a white powder, which was washed with diethyl ether (2 x 10 mL) and dried. (Yield: 2.64 g, 87%).

¹ H NMR (DMSO) shows a 1: 1 ratio between glutamic acid and paroxetine. IR nujol suspension:

Strips at 1465, 1377, 1223, 1186, 1037, 931, 831, 721, 541 cm ^-1 .

Example 31 - Production of non-crystalline paroxetine D-glutamate

A solution of paroxetine base in toluene (5 mL, 6.38 mmol) was added to a suspension of D-glutamic acid (0.94 g, 6.38 mmol) in hot methanol (45 mL). The mixture was heated to reflux for 1 h, allowed to cool, filtered and the solvent was removed under reduced pressure. The residual oil was diluted with toluene (30 mL) and the solvent was removed under reduced pressure. Trituration with diethyl ether (c. 20 mL) and filtration under nitrogen gave a pale brown solid, which was washed with diethyl ether (2 x 10 mL) and dried in vacuo.

Yield: 2.65 g.

¹ H NMR (DMSO) showed a 1: 1 ratio between D-glutamic acid and paroxetine. IR nujol suspension:

Strips at 1558, 1465, 1377, 1224, 1117, 10738, 931, 832, 722, 541 cm ^-1 .

Example 32 - Production of 1: 1 crystalline salt with L-glutamic acid

Paroxetine free base (2.1 g) in toluene was added to a suspension of Lglutamic acid (0.8 g) in propan-2-ol (90 ml) and water (15 ml), stirred and diluted with additional toluene (100 ml). . The mixture was carefully warmed to dissolve the acid

The mixture was evaporated. The evaporation residue was stirred at room temperature with a mixture of toluene (50 mL) and n-hexane (50 mL) until it was apparent that the product crystallized and then an additional hour. Finally, the crystals were collected by filtration, washed with hexane, and dried under reduced pressure.

1.1. Mp 92-98 ° C.

IR nujol suspension:

Strips at 1650, 1598, 1573, 1507, 1207, 1043, 933, 826, 804, 648, 540 cm ^-1 . X-ray powder (Cu K _2a )

Angle [° 2Θ] Rel. Int. (%) 13.4 11.9 15.7 18.4 17.4 38.9 17.5 33.1 19.1 100.0 19.7 55.0 20.2 31.6 20.8 32.9 21.5 44.1 22.5 66.5 22.7 60.0 24.0 38.0 24.4 24.1 27.3 35.9 29.2 20.6 30.5 14.6 32.2 15.2 33.2 15.7 34.0 23.5

Example 33 - Production of crystalline paroxetine D-glutamate 1: 1

A solution of paroxetine base (4.2 g) in toluene (10 mL) was added to a suspension of D-glutamic acid (1.88 g, 12.76 mmol) in water (35 mL) and toluene (40 mL). The reaction mixture was stirred and brought to reflux temperature and all water was removed using a Dean and Stark apparatus. Almost immediately the solid separated. The mixture was cooled to 0 ° C and the reaction mixture was diluted with propan-2-ol (80 mL) with stirring to give paroxetine D-glutamate as a 1: 1 salt as a white crystalline solid. The product was filtered off under nitrogen and dried under reduced pressure. = 195 ° C.

Molar ratio by ¹ H NMR of paroxetine to D-glutamic acid = 1: 1 IR nujol suspension:

Strips at 2741, 1642, 1584, 1510, 1315, 1150, 1078, 947, 867, 675, 538 cm ^-1 . X-ray powder (Cu K _2a )

Angle [° 20] Rel. Int. (%) 3.8 44.3 6.2 3.1 6.9 2.8 9.7 10.9 11.5 35.7 11.9 17.8 12.5 5.5 13.2 11.1 14.2 22.8 14.7 3.7 15.3 12.8 16.0 28.9 16.3 12.4 16.8 9.2 17.6 9.0 18.3 78.5

18.6 37.8 19.3 74.8 19.9 51.8 20.3 36.2 20.8 27.3 22.3 27.9 22.7 100.0 23.5 66.6 23.9 41.2 24.4 33.9 25.0 19.4 26.1 13.9 26.6 10.8 27.1 19.6 27.9 48.2 28.7 30.4 31.0 14.4 31.6 15.7 32.2 16.3 33.3 24.1 34.4 22.6

Example 34 - Production of crystalline paroxetine succinate 1: 1

Succinic acid (0.35 g) was dissolved in propan-2-ol (5 ml) with heating and mixed with a solution of paroxetine base (1 g) in toluene (10 ml). The solution was diluted with ethyl acetate (15 mL) and hexane (20 mL). Initially, an oil formed, but then crystallized within 15 min under scoring and ultrasound. The suspension was stirred at about 20 ° C for an additional hour, then the crystals were filtered off, washed with ethyl acetate and dried under reduced pressure.

Yield: 0.92 g.

Example 35 - Larger scale production of crystalline paroxetine succinate 1: 1

Succinic acid (20 g) was dissolved in propan-2-ol (300 ml) with heating and mixed with a solution of paroxetine base (60 g) in toluene 500 ml. The warm solution was diluted with ethyl acetate (500 mL) and hexane (800 mL) and stirred vigorously. Within minutes, crystals began to separate and stirring was continued at 20 ° C for 1 hour and then at 0 ° C for a further 1 hour. Finally, the crystals were filtered off, washed with ethyl acetate and dried under reduced pressure.

Yield: 66.24 g.

T. t. Mp 116-117 ° C.

IR nujol suspension:

Strips at 1713, 1573, 1488, 1464, 1272, 1185, 1032, 833, 793, 721,627 cm ^{@ 1} .

Main peaks of powder X-ray (Cu K _2a )

Angle [° 20] Rel. Int. (%) 4.8 6.0 11.3 15.8 14.4 33.7 16.3 60.1 17.8 99.3 19.2 25.1 19.9 61.4 21.6 20.5 21.8 26.8 23.9 72.8 24.1 100.0 24.5 25.9 25.5 34.6 26.4 72.6 27.1 28.4 27.3 26.7 28.2 32.4

28.6 21.9 29.0 27.4 29.4 35.8 32.8 17.5

Example 36 - Alternative production of crystalline paroxetine succinate 1: 1

Succinic acid (0.7 g) was heated in propan-2-ol (10 ml) to give a solution which was then added to a solution of paroxetine free base (4.2 g) in toluene (10 ml). The mixture was diluted with diethyl ether (30 mL) and hexane (30 mL) and the formed oil crystallized under scoring and sonication. The suspension was stirred for about an additional hour, then filtered, washed with diethyl ether and dried under reduced pressure.

Yield: 0.99 g.

Example 37 - Production of crystalline paroxetine succinate 1: 1

A solution of succinic acid (0.35 g) in hot propan-2-ol was mixed with a solution of paroxetine base (1 g) in toluene (10 mL). The mixture was stirred at about 20 ° C and then diluted with hexane (15 mL) to form an oil which crystallized on standing. The solid was filtered off, washed with hexane and dried under reduced pressure.

Yield: 0.6 g.

Example 38 - Production of crystalline paroxetine succinate 2: 1

A solution of succinic acid (0.35 g) in methanol (10 mL) was added to a solution of paroxetine free base (2.1 g) in toluene (10 mL). The solvent was removed by evaporation under reduced pressure to give a white brittle foam. Diethyl ether (25 mL) and hexane (25 mL) were added and the solid was triturated to give a solid, readily miscible material. After stirring for 30 min, the product was filtered off, washed with diethyl ether and dried under reduced pressure.

Example 39 - Production of paroxetine benzoate

Paroxetine base (2.1 g) in toluene (5 mL) was added to a suspension of benzoic acid (0.78 g, 6.38 mmol) in toluene (15 mL) and stirred vigorously. The solvent was removed from the resulting clear solution by evaporation under high vacuum to give paroxetine benzoate.

Yield: 2.9 g.

The molar ratio of paroxetine to benzoic acid = 1: 1

IR nujol suspension:

Strips at 2879, 1627, 1509, 1376, 1037, 932, 830, 799, 695 cm · ¹ .

Example 40 - Production of Paroxetine Citrate (1: 1)

A solution of paroxetine base (4.2 g) in toluene (25 ml) was added to a suspension of citric acid (2.45 g) in water (4 ml) and the mixture was heated to reflux to give a clear solution. Water was removed by heating to reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent was decanted. Fresh toluene (20 mL) was added to the solid residue and the mixture was again heated to reflux in a Dean and Stark apparatus. Finally, toluene was removed under reduced pressure and the residue was stirred with heptane overnight and dried to give paroxetine citrate 1: 1 as a yellowish powder.

Example 41 - Production of Paroxetine Citrate (2: 1)

A solution of paroxetine base (4.2 g) in toluene (30 ml) was added to a suspension of citric acid (1.23 g) in water (2 ml) and the mixture was heated to reflux to give a clear solution. Water was removed by heating to reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent was decanted. To the solid residue was added propan-2-ol (30 mL) and the mixture was heated to reflux temperature for 30 min, then cooled to room temperature (about 22 ° C) to form a yellowish precipitate. The product, paroxetine citrate 2: 1 was collected by filtration under a nitrogen atmosphere and dried under vacuum.

Yield: 3.1 g.

-34IR spectrum (nujol suspension):

Strips at 2970, 2360, 1738, 1622, 1487, 1134, 929, 830, 668 cm ^-1 .

Example 42 - Production of Paroxetine Citrate (2: 1)

A solution of paroxetine base (6.3 g) in toluene (25 mL) was added to a suspension of citric acid (1.23 g) in water (2.5 mL) and the mixture was heated to reflux to give a clear solution. Water was removed by heating to reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent was decanted. Residual toluene was removed under reduced pressure and the solid product was stirred with heptane overnight, filtered and dried under reduced pressure to give paroxetine citrate 3: 1 as a yellowish powder. Yield: 5.1 g.

IR spectrum (nujol suspension):

Strips at 2970, 2359, 1738, 1558, 1487, 1366, 1035, 929, 830, 720 cm ^-1 .

Example 43 - Production of Paroxetine Nitrate

Concentrated nitric acid (1.7 g, 1.2 mL, 19.14 mmol) was diluted with water (28 mL) and the solution was mixed with a solution of paroxetine base (6.3 g) in toluene (15 mL). The mixture was heated to reflux in a Deana and Stark apparatus under nitrogen until all water was removed and the resulting solution was cooled to room temperature and evaporated to an oil. Upon dilution of the oil with toluene (10 mL), the product crystallized; heptane (100 mL) was added to the crystals, and the suspension was stirred at room temperature. Finally, the crystals were collected by filtration, washed with heptane and dried in vacuo. Yield: 5.1 g.

T. t. Mp 95-99 ° C

IR nujol suspension:

Strips at 1630, 1504, 1458, 1321, 1037, 930, 834, 719, 574 cm ^-1 .

X-ray powder (Cu K _2a )

Angle [° 2Θ] Rel. Int. (%) 6.5 1.3 8.1 0.3 9.7 1.3 11.5 1.0 13.0 19.5 13.7 12.9 14.0 7.8 14.5 4.6 15.8 11.8 16.7 17.1 18.0 52.4 19.1 76.9 19.4 100.0 21.0 17.2 23.1 39.3 23.9 27.4 24.2 32.3 24.7 17.5 25.9 14.7 26.9 40.3 27.2 38.4 28.1 23.1 28.8 26.6 29.7 15.7 31.0 11.8 32.0 17.5 33.5 10.4

Example 44 - Paroxetine phosphate 1: 1 salt

A solution of paroxetine base (2.1 g) in toluene (20 mL) was diluted with acetone (20 mL). Orthophosphoric acid in propan-2-ol (1.5 mL, 3.675 molar) was added and the mixture was diluted with additional propan-2-ol (20 mL) and stirred for 1 h at room temperature. The product crystallized and was filtered off, washed with propan-2-ol and dried under vacuum.

Yield: 1.92 g.

Example 45 - Production of paroxetine phosphate in the form of a 1: 1 salt on a larger scale

Orthophosphoric acid in propan-2-ol (45 mL, 3.675 molar) was added to a solution of paroxetine base (63 g) in toluene (600 mL). The mixture was stirred for 1 h and then diluted with acetone (600 mL). Crystallization was started over a few minutes and the suspension was stirred for 1 h at room temperature and for an additional 1 h in an ice / water bath. The crystalline product was filtered off, washed with propan-2-ol and dried under vacuum. Yield: 74.53 g.

T. t. Mp 207-210 ° C

IR nujol suspension:

Strips at 1606, 1512, 1466, 1225, 1190, 1079, 1040, 953, 831, 722, 608, 577 cm ^-1 .

Main peaks of powder X-ray (Cu K _2a )

Angle [° 2Θ] Rel. Int. (%) 14.0 48.6 17.4 80.1 19.8 71.4 21.4 96.3 23.6 65.3 24.8 100.0 26.2 48.6

Example 46 - Production of paroxetine phosphate in the form of a 2: 1 salt

A solution of paroxetine base (4.2 g) in toluene (20 mL) was treated with a solution of orthophosphoric acid in propan-2-ol (1.5 mL, 3.675 molar). Propan-2ol (20 mL) 1 was added and a white solid precipitated. The suspension was stirred for 1 h at room temperature and then the product was filtered off, washed with propan-2-ol and dried under vacuum.

Yield: 3.40 g.

IR nujol suspension:

Strips at 1573, 1466, 1225, 1189, 1039, 876, 834, 782, 720, 547 cm · ¹ .

Example 47 - Production of 2: 1 non-crystalline paroxetine phosphate

Paroxetine base (4.2 g) in toluene (10 mL) was added to a suspension of an aqueous solution of orthophosphoric acid (0.37 mL, 14.6 molar, 85%) in methanol (50 mL) with stirring to form a clear solution. The solvents were removed by distillation in vacuo to give an oil which was dissolved in toluene (30 mL) and the solvent was removed again. The resulting glassy solid was triturated with heptane (50 mL) to give a white powdery non-crystalline solid, which was filtered off, washed with heptane and dried under vacuum.

Yield: 2.51 g.

Example 48 - Crystallization of 2: 1 paroxetine phosphate

The non-crystalline paroxetine phosphate produced in Example 47 (1 g) was suspended in a mixture of ethanol (18 ml) and propan-2-ol (20 ml) and was heated to reflux temperature with stirring. After 30 min. The mixture was allowed to cool, then collected by filtration and dried under vacuum. The product was found to be crystalline paroxetine phosphate 2: 1. Yield. 0.89 g.

The molar ratio of paroxetine to phosphoric acid = 2: 1.

IR nujol suspension:

Strips at 1606, 1468, 1377, 1225, 1040, 952, 783, 609, 578 cm ^-1 .

-38 X-ray powder (Cu K _2a )

Angle [° 20] Rel. Int. (%) 4.6 70.2 8.3 2.3 11.3 8.9 12.5 10.7 14.0 100.0 14.5 16.5 15.3 39.9 15.6 29.8 16.0 25.5 17.4 90.7 17.7 74.6 18.2 49.2 19.2 52.4 20.4 60.0 20.6 50.6 21.5 77.3 21.8 83.6 22.7 40.7 23.5 60.0 24.3 41.5 24.8 78.4 26.2 39.9 28.3 11.3 30.7 8.5 31.5 6.9 33.6 1.5

Example 49 - Production of crystalline paroxetine 4-methylbenzenesulfonate

A solution of paroxetine base in toluene (2.1 g in 5 mL) was mixed with a solution of 4-methylbenzenesulfonic acid monohydrate (1.21 g) in methanol (15 mL). The solvent was removed in vacuo, replaced with fresh toluene (10 mL) and evaporated again. The residue was triturated with diethyl ether (15 mL) to give a white crystalline solid which was filtered, washed with diethyl ether (2 x 10 mL) and dried in a vacuum desiccator.

Yield: 3.09 g.

Example 50 - Production of crystalline paroxetine 4-methylbenzenesulfonate

A solution of paroxetine base in toluene (42 g in 100 mL) was added to the acid solution

Of 4-methylbenzenesulfonic acid (24.2 g) in methanol (300 mL). The solvent was removed in vacuo, the residue was diluted with toluene (200 mL) and the solvent was removed again in vacuo. Trituration with diethyl ether (c. 300 mL) gave a white crystalline solid which was filtered, washed with diethyl ether (2 x 50 mL) and dried in a vacuum desiccator.

Yield: 61.13 g.

T. t. 105-109 ° C

IR nujol suspension:

Strips at 1603, 1504, 1465, 1377, 1224, 1188, 1159, 1119, 1030, 999, 930, 830, 779, 722, 684, 564 cm ^-1 .

Main peaks X-ray powder (Cu K _2a )

Angle [° 2Θ] Rel. Int. (%) 4.9 32.8 7.3 21.6 9.9 14.6 12.9 22.3 14.9 22.8 15.9 18.2

16.3 28.0 17.0 17.2 17.3 23.3 17.8 21.1 18.5 34.7 19.0 19.0 19.4 31.2 19.8 45.0 20.5 28.6 20.8 15.7 22.1 100.0 28.0 15.1

Example 51 - Production of Paroxetine Hypophosphite

Paroxetine base (4.2 g) in toluene (10 mL) was added to a 50% aqueous phosphoric acid solution (1.32 mL, 9.7 molar) and the mixture was stirred at approximately 20 ° C. Thereafter, the solvents were removed by distillation under reduced pressure to give non-crystalline paroxetine hypophosphite as a brittle glassy solid. The solid was triturated with heptane to give a crystalline salt as a white solid, which was filtered under nitrogen and dried under vacuum.

Yield 5.1 g.

The molar ratio of paroxetine to phosphoric acid = 1: 1.

IR nujol suspension:

Strips at 2352, 1602, 1466, 1377, 1151, 1975, 836, 722, 539 cm ^-1 .

X-ray powder (Cu K _2a )

Angle [° 2Θ] Rel. Int. (%) 8.2 6.2 9.9 1.1 12.9 1.7 15.6 30.3

16.4 46.1 17.5 17.8 18.6 22.9 19.2 67.1 19.5 36.4 21.2 100.0 21.8 41.0 22.5 24.2 22.6 21.3 23.5 11.6 24.2 73.6 24.9 70.3 25.5 17.7 26.1 9.0 27.6 35.7 28.8 40.0 29.3 11.7 29.9 15.4 31.5 13.5 32.7 14.2 33.1 19.0 34.3 8.6

Example 52 - Production of L (+) - Paroxetine Lactate

Paroxetine base (2.1 g) in toluene (5 mL) was added to a suspension of L - (+) lactic acid (0.63 g, 6.38 mmol) in methanol (10 mL) and stirred at approximately 20 ° C until a clear solution was obtained. Then the solvents were removed in vacuo to give a white glassy non-crystalline salt of paroxetine with L - (+) lactic acid. The solid was triturated with heptane and the white powdered solid form of crystalline paroxetine L - (+) lactate was filtered, washed with heptane and dried under vacuum.

1.1. Mp = 98-103 ° C

IR nujol suspension:

Strips at 1647, 1588, 1464, 1377, 1195, 1038, 930, 785, 721 cm ^-1 .

X-ray powder (Cu K _2a )

Angle [° 20] Rel. Int. (%) 5.4 6.2 7.8 50.7 8.4 1.2 9.4 0.1 10.4 3.6 11.9 1.3 15.6 39.6 16.3 100.0 16.5 95.2 17.4 61.8 17.7 58.3 18.7 37.4 18.9 14.3 19.6 19.0 20.0 4.5 20.9 8.4 21.4 38.8 21.9 93.4 22.1 61.5 22.9 48.2 23.6 45.7 24.0 28.2 24.8 9.1 25.1 11.8 25.6 7.9

26.2 9.4 26.8 18.2 27.8 40.5 28.4 40.7 29.3 11.0 29.6 15.1 30.1 13.2 31.2 8.0 31.6 10.6 32.2 30.2 32.6 15.7 33.0 10.1 33.7 12.1 34.4 12.1

Example 53 - Production of R (-) mandelate of paroxetine

Paroxetine base (4.2 g) in toluene (10 mL) was added to a suspension of R - (-) mandelic acid (1.94 g, 12.76 mmol) in methanol (20 mL) and stirred at approximately 20 ° C until a clear solution was obtained. The solvents were removed by evaporation under reduced pressure to give an off-white glassy form of non-crystalline paroxetine mandelate. This solid was triturated with heptane (50 mL) and the white powdered solid was filtered, washed with heptane and dried under vacuum.

Yield: 3.9 g.

1.1. Mp = 78-83 ° C

IR nujol suspension:

Belts at 1617, 1463, 1267, 1183, 1015, 984, 870, 735, 539, 516 cm ¹ . Main peaks of powder X-ray (Cu K _2a )

Angle [° 20] Rel. Int. (%) 3.6 8.7 9.1 8.2

T

9.5 29.1 10.5 2.7 13.5 7.9 15.5 10.6 18.2 27.3 18.4 28.9 19.1 100.0 19.5 40.5 20.4 66.4 21.6 30.5 23.0 24.9 23.6 24.7 25.3 18.5 27.2 32.1 27.7 24.9 28.0 20.7 28.8 22.0 29.3 19.9 31.9 15.9 34.1 11.3

Claims (9)

PATENTOVÉ NÄgpKY ♦ A salt of paroxetine with an acid selected from the group consisting of sulfuric, tartaric, oxalic, fumaric, propionic, formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, 4-methylbenzenesulfonic, phosphoric, lactic and mandelic. 2. A salt of paroxetine with sulfuric, tartaric, mesotartan, oxalic, fumaric, glutamic, succinic, citric, or phosphoric acid, wherein the ratio of paroxetine to acid (in moles) is 1: 1, 2: 1 or 3: 1, and if the ratio is less than the theoretical maximum, the salt is a hydrogenated salt or a mixed salt with a cation other than hydrogen. 3. A salt of paroxetine with tartaric, glutamic, lactic or mandelic acid, wherein the acid is in the D or L form or as a racemic mixture thereof. A paroxetine salt according to any preceding claim, which is in a non-crystalline form. The paroxetine salt of claim 1, 2 or 3, which is in crystalline form. A process for producing a paroxetine salt according to any one of the preceding claims, characterized in that it comprises precipitation, spray-drying or freeze-drying of the paroxetine salt solution, or vacuum drying of paroxetine salt oils, or solidification of the molten paroxetine salt. A process for producing a paroxetine salt according to any one of claims 1 to 5, characterized in that it comprises crystallization or recrystallization from a solution of the paroxetine salt. Process according to claim 6 or 7, characterized in that the solution, oil or molten paroxetine salt is produced by treating paroxetine free base or its organic acid salt with an acid or a salt thereof (including a hydrogenated salt), or by reacting the hydrogenated paroxetine salt with a cation. other than hydrogen. Pharmaceutical composition for the treatment and / or prevention of disorders, characterized in that it comprises a paroxetine salt according to any one of claims 1 to 5 or a product produced according to any one of claims 6 to 8, together with a pharmaceutically acceptable carrier. Use of a paroxetine salt for the manufacture of a medicament for the treatment and / or prevention of one or more disorders in a mammal.