SK15902000A3 - Paroxetine 10-camphorsulfonate for treatment of cns disorders - Google Patents

Abstract

Paroxetine 10-camphorsulfonates are useful in the treatment of certain CNS disorders.

Description

Technical field

The present invention relates to paroxetine 10-camphorsulphonate, to methods for its preparation and to its 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. 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 hydrochloride salt therapy for the treatment and prophylaxis of, inter alia, conditions, depression, obsessive-compulsive disorder (OCD), and panic conditions.

Surprisingly, a new salt of paroxetine has now been found, which may alternatively be used in place of the hydrochloride currently on the market or as an intermediate in the production of the hydrochloride.

SUMMARY OF THE INVENTION

The present invention provides paroxetine 10-camphorsulfonate. 10-Camphorsulfonic acid exists in enantiomeric forms and the present invention includes salts with both D - (+) - 10-camphorsulfonic acid and (1 R) - 10-camphorsulfonic acid and racemic mixtures of both salts.

In one embodiment of the invention, the new salt is 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 salt of the invention is provided in crystalline form. When the crystalline form exists in more than one polymorph, all polymorphic forms constitute a further embodiment of the invention.

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Paroxetine 10-camphorsulfonates can be prepared by reacting stoichiometric amounts of acid and paroxetine free base. It is preferred that the base be in solution, more preferably both components are in solution. Elevated temperature may be used to adjust the acid to solution, but good yields may be obtained by evaporation of one of the solvents or by controlled cooling, preferably gradually. 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, but solvents in which the camphor is present -10-sulfonic acids too insoluble, should be avoided. Suitable solvents for camphor-10-sulfonic acids are water, alcohols, ethyl acetate and acetic acid.

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

The crystalline salt can be produced by crystallization or recrystallization from suitable solvents.

When the salt is obtained as a solvate, upon contact with a solvent in which it is soluble, such solvated forms constitute a further aspect of the invention. The solvates can be converted to the unsolvate salt by heating, e.g. oven drying or treatment with a displacement solvent that does not form a solvate.

Before the isolation of the paroxetine salt, the water can be removed by azeotropic distillation to prevent the formation of hydrates or to obtain the product in anhydrous form.

In such a case, suitable solvents for the salt solution are those which form an azeotropic mixture with water, e.g. toluene and propan-2-ol. It would also be useful to use solvent mixtures to aid in the azeotropic removal of water.

More generally, if desired or appropriate, crystallization can be performed from any solvent that allows the desired crystalline structure to be formed using seed crystals of the desired structure.

If polymorphs are present, the individual polymorphs preferably crystallize directly

-3 ······································· From a salt solution, although recrystallization of one of the polymorphs may also be accomplished by seeding with seed crystals of another polymorph.

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 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 aging dementia bulimia social phobia depression in adolescence dysthymia

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

The present invention further provides a method of treating and / or preventing any of said disorders by administering an effective and / or prophylactic amount of a salt of the invention to a patient indicative of such treatment.

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.

Compositions comprising a salt of the invention are usually adapted for oral administration, but compositions intended for dissolution for parenteral administration are also within the scope of the invention.

The preparation is usually presented in unit dosage form containing from 1 to 200 mg of the active ingredient calculated on the free base, more usually from 5 to 100 mg,

-4 · t t t t t napr napr. Napr.... Napr napr napr napr....... 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 anidepressants 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

Production of crystalline paroxetine D - (+) - 10-camphorsulfonate

A solution of paroxetine base in toluene (5 mL, 6.38 mmol) was added to a solution of D (+) - 10-camphorsulfonic acid (1.48 g, 6.38 mmol) in methanol (20 mL). The mixture was allowed to stand at room temperature for 20 min and the solvent was removed in vacuo.

The residual residue was dissolved in toluene (20 mL) and the solvent was removed in vacuo. Trituration with diethyl ether (approximately 50 mL) and filtration under nitrogen gave a white solid, which was washed with diethyl ether (2 x 20 mL) and dried in a vacuum drier.

Yield 3.50 g.

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Example 2

Larger scale production of crystalline salt

A solution of paroxetine base in toluene (75 mL, 95.7 mmol) was added to a solution of D (+) - 10-camphorsulfonic acid (22.2 g, 95.7 mmol) in methanol (300 mL). The solvent was removed in vacuo, the residue was dissolved in toluene (100 mL) and the solvent was removed in vacuo. Trituration with diethyl ether (approximately 350 mL) gave a white solid, which was filtered, washed with diethyl ether (2 x 100 mL) and dried in vacuo.

Yield 54.46 g.

¹ H NMR (CDCl 3) showed a 1: 1 ratio of D (+) - 10-camphorsulfonic acid and paroxetine.

T. t. = 109 ° C (phase change)

IR nujol suspension:

Strips at 1740, 1501, 1464, 1376, 1183, 1034, 828, 768, 601, 515 cm ^-1 .

Main peaks of powder X-ray (CuK2 ₀ ):

Angle (degrees 2Θ) Relative intensity (%) 5,965 39.9 6,400 56.5 6,665 36.8 11,880 44.0 13,765 31.5 15,055 29.1 16,200 38.4 16,945 68.0 17,970 39.2 19,360 28.5 20,825 32.8 21,630 43.0 22,270 36.8

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23,365 21.2 24,255 100.0 25,190 75.4 27,105 35.1 29,720 15.5 30,360 18.6 32,360 15.7 32,800 14.9

Example 3

Production of crystalline paroxetine (1R) - (-) - 10-camphorsulfonate

A solution of paroxetine base in toluene (5 mL, 6.38 mmol) was added to a solution of (1R) - (-) - 10-camphorsulfonic acid (1.48 g, 6.38 mmol) in methanol (20 mL). The mixture was allowed to stand at room temperature for 20 min and the solvent was removed in vacuo.

The residue was dissolved in toluene (20 mL) and the solvent was removed in vacuo. Trituration with diethyl ether (about 50 mL) and filtration under nitrogen gave a white solid, which was washed with diethyl ether (2 x 20 mL) and dried under reduced pressure.

Yield 3.18 g.

Example 4

Large scale production of crystalline salt

A solution of paroxetine base in toluene (66 mL, 84.16 mmol) was added to a solution of (1R) - (-) - 10-camphorsulfonic acid (19.5 g, 93.94 mmol) in methanol (200 mL). The mixture was allowed to stand at room temperature for 40 min and the solvent was removed by evaporation. The residual residue was triturated with diethyl ether (approximately 350 mL), stirred at room temperature for 16 h and filtered to give a white solid, which was washed with diethyl ether (2 x 100 mL) and dried under reduced pressure.

Yield 43.77 g.

-7 ····································· ¹ H NMR (CDCl 3) showed a ratio of (1R) - (-) - 10-camphorsulfonic acid to paroxetine of 1: 1.

MP: Mp = 136-139 ° C.

IR nujol suspension:

Strips at 1736, 1604, 1503, 1462, 1376, 1278, 1194, 1037, 827, 670, 602, 538 cm ^-1 . Main peaks of powder X-ray (CuK _2a ):

Angle (degrees 2Θ) Relative intensity (%) 6,105 19.0 6,645 14.2 13,615 10,0 15,715 17.0 16,785 100.0 17,175 53.2 17,735 16.7 19,205 10.5 19,550 18.9 20,050 13.6 20,430 13.0 21,200 25.5 21,760 14.3 22,270 16.4 23,350 13.2 24,345 42.7 24,905 19.8 25,160 26.1 25,925 19.4 29,015 10.8 30,860 10.6

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Example 5 Production of tablets

ingredients 20 mg tablet 30 mg tablet • 10-camphorsulfonate 20,00 mg 30,00 mg paroxetine (converted to free (converted to free • base) base) Calcium phosphate (DCP) 83.34 mg 125.0 mg Microcrystalline cellulose 50.67 mg 76.0 mg Sodium starch glycolate 8.34 mg 12.5 mg Magnesium stearate 1,67 mg 2.5 mg

Commercial origin of ingredients:

Calcium phosphate - Emcompress or Ditab *

Microcrystalline cellulose - Avicel PH 102 *

Sodium starch glycolate - Explotab. * * Trade names

Approach

1. Sieve DCP through sieve and weigh into 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.

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Example 6 Production of tablets

ingredients 10 mg tablet 20 mg tablet 30 mg tablet Paroxetine 10-camphorsulfonate 10 mg 20 mg 30 mg (converted to (converted to (converted to free base) free base) free base) Sodium starch glycolate 2.98 5.95 8.93 Granular phosphate 158.88 mg 317.75 mg 476.63 mg calcium (DITAB) or Dicafos Magnesium stearate 1.75 mg 3,50 mg 5,25 mg

Approach

1. Paroxetine 10-camphorsulfonate, sodium starch glycolate and calcium phosphate dihydrate are sieved and mixed together in a suitable mixer. (Planetary, cuble or high-performance with knives).

2. Add magnesium stearate and compress the mixture into a tablet using a single punch or rotary tablet.

Claims (11)

PATENT CLAIMS Paroxetine camphorsulfonate. 2. Paroxetine (D) - (+) - 10-camphorsulfonate. 3. Paroxetine (1 R) - (-) - 10-camphorsulfonate. Paroxetine 10-camphorsulfonate according to claim 1, 2 or 3, which is in non-crystalline form. Paroxetine 10-camphorsulfonate according to claim 1, 2 or 3, which is in crystalline form. A process for the preparation of paroxetine 10-camphorsulfonate according to claim 1, 2, 3 or 4, comprising precipitation, spray drying or freeze-drying of a paroxetine 10-camphorsulfonate solution or vacuum drying of oily forms of 10-camphorsulfonate or solidification of melts 10. the camphorsulfonate to a solid form. A process for the preparation of paroxetine 10-camphorsulfonate according to claim 1, 2, 3 or 5, characterized in that it comprises crystallization or recrystallization from a solution of 10-camphorsulfonate. Process according to claim 6 or 7, characterized in that the solution, oil or melt of paroxetine 10-camphorsulfonate is produced from paroxetine free base by treatment with 10-camphorsulfonic acid. 9th Paroxetine 10-camphorsulfonate for use in the treatment and / or prevention of one or more of the disorders selected from the group consisting of alcoholism, fear, depression, obsessive-compulsive disorder, panic disorder, chronic disorder. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -11 pain, obesity, aging dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, trichotillomania and dysthyemia.