SK15032000A3 - Paroxetine maleate - Google Patents

Abstract

Paroxetine maleate and its preparation and use in the treatment and prevention of inter alia depression.

Description

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. An especially important compound among those disclosed is paroxetine, the (-) - trans isomer, 4 ^{(4-fluorophenyl)} -3- ^{(3, 4,} -metyléndioxyfenoxymetyl) 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.

Example 2 of US patent 4007196 describes the production of paroxetine by demethylation of a N-methyl derivative. The paroxetine free base is isolated as an oil by evaporation of the benzene solution. The free base is dissolved in ether and treated with a solution of maleic acid in ethyl ether to give a crystalline product which is recrystallized from 99% ethanol-ether to give the maleic salt, m.p. 136-138 ° C. Except for the melting point, there are no characteristic data which allow the structure to be clearly identified.

In addition, neither benzene nor ether are desirable as solvents in commercial production because of flammability, possible explosive residues and toxic residues, which would require costly control measures. Also, the process described in Example 2 of US patent 4007196 is unsuitable for commercial use as the product is in the form of a very sticky resin.

Surprisingly, new maleate salts of paroxetine have now emerged, which may alternatively be used in place of the hydrochloride currently on the market, or as an intermediate in the production of hydrochloride, and new production methods that are suitable for commercial use.

In one embodiment of the present invention, a paroxetine maleate is provided wherein the ratio of paroxetine to maleic acid (in molar expression) is 1: 1. In another embodiment of the present invention there is provided paroxetine maleate, wherein the ratio of paroxetine to maleic acid (in molar terms) is 2: 1.

In the case of a 1: 1 salt, the maleate anion may be coupled to a proton (hydrogen atom) in bond to paroxetine, or may be coupled to another cation, e.g. alkali metal or ammonium cation. In the first example, the salt may be described as paroxetine hydrogen maleate, while in the second, the salt may be described as a mixed salt.

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.

It has now been found that crystalline paroxetine maleate, in which the ratio of paroxetine to maleic acid (in molar terms) is 1: 1, exists in at least two polymorphic forms.

Accordingly, in another aspect, the invention provides paroxetine maleate (1: 1) of Form A with a melting point of 139-141 ° C and an IR or XRD spectrum substantially as described in Example 1 below; and paroxetine maleate (1: 1) of Form B with a melting point of 136-138 ° C and an IR or XRD spectrum substantially as described in Example 2 below.

The aforementioned paroxetine maleate may be prepared by reacting appropriate stoichiometric amounts of the acid and paroxetine free base. It is preferred that the base be in solution, more preferably both components are in solution. The mixed salts may be prepared by forming the salt precursor in a ratio of 1: 1 in situ or using it in a pre-form; or by reacting it in solution with a solution containing a metal or ammonium ion.

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. Maleic acid may be added as a solid, but is preferably added as a solution in an organic solvent such as ethanol or ethyl acetate, or water, methanol, propan-2-ol or acetone. Maleic acid can also be added in the form of a soluble salt, e.g. ammonium maleate or an amine salt of maleic acid, e.g. with ethylamine or diethylamine.

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%. The concentration of maleic acid, when used in solution, is preferably in the range of 0.1 to 5, preferably 0.5 to 2 molar. Elevated temperatures may be used to increase solubility.

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.

Crystalline salts may be prepared directly by crystallization from a solvent in which the product has limited solubility, or by triruration or other crystallization of the non-crystalline salt. E.g. paroxetine maleate can be recrystallized from a variety of organic solvents, such as e.g. acetonitrile, butanone, sec-butanol, dichloromethane, ethanol, 3-pentanone, propan-2-ol and toluene. 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. The individual polymorphs preferably crystallize directly from the salt solution, although recrystallization of a solution of one polymorph can also be accomplished by seeding another polymorph.

Thus, paroxetine maleate (1: 1) can be produced by crystallization from a solution of paroxetine maleate, which can be produced e.g. mixing the free base solution and the maleic acid solution. Preferably an excess of maleic acid, e.g. a molar ratio between 1: 1 and 1: 1.5, preferably between 1.1 and 1.3. suitable

-4-solvents include ethyl acetate, methanol, ethanol, propan-2-ol, propan-1-ol, secbutanol, butan-1-ol, methyl isobutyl ketone, acetone and acetonitrile, or a mixture of solvents, including mixtures with toluene.

Form B maleate can be produced by recrystallization of Form A (or vice versa). More preferably and preferably, Form B is produced directly by crystallization, similar to Form A, i.e. directly from a solution of paroxetine maleate, which can be produced by mixing the free base solution, commonly as the final phase of the production process and the maleic acid solution. A wide variety of solvents can be used, especially when seeding is also used to ensure the formation of the desired polymorph, but preferred solvents are toluene, butanone, acetone, and dichloromethane. Propan-2-ol may also be used.

Inoculation with the desired polymorph can be incorporated into the process to ensure reliability of polymorph formation and control of crystal size distribution.

Toluene or toluene-containing mixtures have been found to be among the most suitable solvents for the production of paroxetine maleate Form B.

The manufacturing properties of Form B are better than Forms A since this polymer is more granular and easier to filter, wash and dry. Accordingly, the present invention provides a particularly acceptable process for producing paroxetine maleate (1: 1), which avoids the use of unsuitable solvents, and the solution of paroxetine free base is produced in toluene and is directly converted to the maleate salt. Known processes for the production of paroxetine use toluene as the solvent of choice. Prior to the discovery of the production of paroxetine maleate Form B in the present invention, no process was known which could simply use toluene solutions of the free base as a starting material, since treatment of such solutions resulted in the formation of paroxetine maleate as an oil or resin.

An alternative process for producing paroxetine maleate begins by reacting the paroxetine salt with an organic acid, such as e.g. acetic acid, which is more preferred than the use of paroxetine free base. 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 acetic acid is used, of non-crystalline salts by methods which include evaporation (e.g. freeze-drying and spray-drying).

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

Before the isolation of paroxetine maleate, the water may be removed from the salt-containing solution by azeotropic distillation to avoid 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.

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 premenstrual syndrome (PMS) trichotillomania fear obsessive-compulsive disorders chronic pain senile 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 may be adapted for administration by any route and examples are oral, sublingual, rectal, topical, parenteral, intravenous or intramuscular administration. If desired, the formulations may be formulated so that the paroxetine salt is released slowly.

The drugs may be e.g. in the form of tablets, capsules, lozenges, ampoules, granules, lozenges, soluble powders or liquid preparations, e.g. solutions or suspensions or suppositories.

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.

Examples of Embodiments of the Invention

Example 1

Preparation of Paroxetine Maleate (1: 1) in Form A

Maleic acid (14.8 g, 0.128 mol) was stirred in ethyl acetate (100 mL) and the solution was warmed carefully. Then, the paroxetine free base (42.7 g) in ethyl acetate was added rapidly with stirring, and the suspension clarified rapidly and then solidified immediately. Heating was continued while the solution was at reflux and the mixture became miscible. The reaction mixture was allowed to cool with stirring and the cold solution was filtered and washed with ethyl acetate (25 mL) and dried in a vacuum oven at 40 ° C for 3 hours to give paroxetine maleate Form A. NMR showed a 1: 1 ratio for paroxetine: maleic acid.

Mp 139-141 ° C.

IR 1674, 1360, 1306, 1269, 1248, 1190, 1137, 1101, 1026, 863, 834, 783, 706, 597;

angle [° 2?] d-value and [Á] figures peaks of intensity 5.10 17,30 8649 8.04 10.99 106 8.78 10.10 64 10.26 8.62 692 11.98 7.38 77 13.91 6.36 829 15.43 5.74 15500 15.88 5.58 5242 16.13 5.49 586 17.71 5.00 745 18.67 4.75 635 19.37 4.59 475 20.29 4.37 1544

20.52 4.32 1945 20.90 4.25 493 21.32 4.16 384 23.18 3.83 376 24.30 3.66 2263 25.00 3.56 912 25.80 3.45 566 26.52 3.36 1640 27.96 3.19 1616 28.76 3.10 671 30.00 2.98 1030 30.34 2.94 552 31,10 2.87 1980 32.10 2.79 1005 32.77 2.74 342 33.36 2.69 529

Example 2

Preparation of paroxetine maleate (1: 1) in form B by recrystallization of form A from butanone

A suspension of paroxetine maleate Form A (0.5 g) in butanone (4 mL) was stirred vigorously and heated to reflux. The solution was allowed to cool slowly to room temperature to give paroxetine maleate Form B as a granulated white crystalline solid which was collected by filtration and dried under vacuum over phosphorus pentoxide. NMR showed a ratio of paroxetine to maleic acid of 1: 1, butanone content of about 0.1% by weight.

MP: 136až138 C.

IR (nujol suspension) 1709, 1385, 1280, 1247, 1195, 1134, 1045, 931, 904, 876, 862, 838, 816, 805, 779, 714, 595, 543;

-9XRD

angle [° 2?] d-value and [A] figures peaks of intensity 5.11 17.28 79 8.35 10.58 19 10.47 8.44 292 12.90 6.86 420 13.64 6.49 339 13.97 6.34 196 14.41 6.14 428 15.51 5.71 724 16.32 5.43 1624 16.60 5.34 973 17.78 4.98 1332 19.75 4.49 3102 20.21 4.39 5868 20.68 4.29 729 21.25 4.18 420 21.95 4.04 1197 22.13 4.01 876 22.80 3.89 581 23.65 3.76 576 24.46 3.64 1747 24.97 3.56 5227 25.88 3.44 955 27.69 3.22 454 28.23 3.16 566 29.26 3.05 2470 29.94 2.98 1866 30.76 2.90 552

31.26 2.86 697 32.02 2.79 605 32.44 2.75 557 33.01 2.71 571 33.88 2.64 458

Example 3

Preparation of paroxetine maleate (1: 1) in form A by recrystallization from propan-2-ol

A suspension of paroxetine maleate Form A (0.5 g) in propan-2-ol (4 mL) was stirred vigorously and heated to reflux. The solution was allowed to cool to room temperature to give paroxetine maleate Form A as white plate-like crystals which were collected by filtration and dried under vacuum over phosphorus pentoxide. The infrared spectrum was the same as that of the product of Example 1.

Example 4

Preparation of paroxetine maleate (1: 1) in form A by recrystallization from acetonitrile

A suspension of paroxetine maleate Form A (0.5 g) in acetonitrile (4 mL) was stirred vigorously and heated to reflux to dissolve. The solution was allowed to cool to room temperature to give paroxetine maleate Form A as large white plate-like crystals which were collected by filtration and dried under vacuum over phosphorus pentoxide. The infrared spectrum was the same as that of the product of Example 1.

Example 5

Preparation of paroxetine maleate (1: 1) in Form B by recrystallization of Form A from toluene

A suspension of paroxetine maleate Form A (0.5 g) in toluene (8 mL) was vigorously stirred and heated and about half of the solvent was distilled off. An additional 3 mL of toluene was added and the reaction mixture was allowed to cool to room temperature. After 2 hours, a white solid formed which was collected by filtration and dried in vacuo

-11 vacuum to form paroxetine maleate Form B as a granular solid. The infrared spectrum was the same as that of the product of Example 2.

Example 6

Preparation of paroxetine maleate (1: 1) in form A by recrystallization from sec-butanol

A suspension of paroxetine maleate Form A (0.5 g) in secondary butanol (4 mL) was stirred vigorously and heated to reflux. The solution was allowed to cool to room temperature to give paroxetine maleate Form A as a white crystalline solid which was collected by filtration and dried in vacuo over phosphorus pentoxide. The infrared spectrum was the same as that of the product of Example 1.

Example 7

Preparation of paroxetine maleate Form B by recrystallization of Form A from dichloromethane

A suspension of paroxetine maleate Form A (0.5 g) in dichloromethane (3 mL) was stirred vigorously and heated to reflux. The solution was allowed to cool to room temperature for 5 hours to give paroxetine maleate Form B as a white granular solid, which was collected by filtration and dried under vacuum over phosphorus pentoxide. The infrared spectrum was the same as that of the product of Example 2.

Example 8

Preparation of paroxetine maleate (1: 1) in form A by recrystallization from ethanol

A suspension of paroxetine maleate Form A (0.5 g) in ethanol (3 mL) was vigorously stirred and heated to reflux. The solution was allowed to cool to room temperature to give paroxetine maleate Form A as a white crystalline solid which was collected by filtration and dried under vacuum over phosphorus pentoxide. The infrared spectrum was the same as that of the product of Example 1.

Example 9

Preparation of paroxetine maleate Form B by recrystallization of Form A from 3-pentanone

A suspension of paroxetine maleate Form A (0.5 g) in 3-pentanone (4 mL) was stirred vigorously and heated to reflux. The solution was allowed to cool to room temperature to give paroxetine maleate Form B as a white crystalline solid. The product was collected by filtration and dried under vacuum over phosphorus pentoxide. The infrared spectrum was the same as that of the product of Example 2.

Example 10

Preparation of Paroxetine Maleate (1: 1) in Form A

To a solution of paroxetine free base (15.16 g) in toluene (75 mL) was added a solution of maleic acid (5.34 g) in ethyl acetate (37.5 mL) with vigorous stirring. The solid crystallized rapidly and after 20 min was collected by filtration and dried under vacuum at 40 ° C. The infrared spectrum was the same as that of the product of Example 1.

Yield: [18.60 g, 41 mmol, 90.7%]

Example 11

Preparation of paroxetine maleate (1: 1) in Form B

N-phenyloxycarbonylparoxetine (5.00 kg), potassium hydroxide flakes (4.50 kg), and toluene (75.0 L) were heated to reflux under a nitrogen atmosphere with good stirring for more than 40 min. After stirring at reflux for 4 h 45 min, the contents of the reactor were allowed to cool to room temperature. Water (50 L) was added and the mixture was stirred for 30 min and then allowed to settle for 30 min. The lower aqueous layer was discharged from the reactor and the remaining toluene solution was heated to reflux. Water was removed by heating to reflux with a Dean and Stark apparatus. Toluene (11.5 L) was added and a similar amount of the reaction solvent was removed by distillation. The remaining mixture was cooled to approximately 100 ° C, stirred vigorously, and a mixture of maleic acid (1.04 kg) and seed crystals of paroxetine maleate Form B (40 g) was added in four portions via a solids hopper. Gradually, the temperature was lowered and crystallization started between 60 ° C and 50 ° C. The temperature was maintained at 40 ° C for two hours to effect most of the crystallization. Finally, the temperature was lowered to about 15 ° C and the product of paroxetine maleate Form B was

-13 was collected in a centrifuge, washed with toluene and dried in a vacuum oven at 50 ° C. Yield 3.1 kg.

Example 12

Preparation of paroxetine maleate (2: 1)

A solution of maleic acid (0.74 g) in ethanol (100 mL) was added to a solution of paroxetine in toluene (10 mL of a 0.42 g / mL solution) and the solution was stirred at room temperature for 30 min. The solvent was removed by evaporation in vacuo to give a viscous oil which was redissolved in chloroform. The chloroform solution was evaporated to dryness to give a white solid.

NMR showed a 2: 1 ratio of paroxetine to maleic acid.

Example 13

ingredients 20 mg tablet 30 mg tablet Paroxetine salt 20,00 mg (recalculated to free base) 30,00 mg (recalculated to free 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 dihydrate - Emcompress or Ditab * Microcrystalline cellulose - Avicel PH 102 *

Sodium starch glycolate - Explotab. * * Trade names

-14Postup

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:

9.5 mg circular tablet 20 mg 8.25 mm circular tablet

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

ingredients 10 mg tablet 20 mg tablet 30 mg tablet Paroxetine maleate 10 mg 20 mg 30 mg (1: 1 or 2: 1) (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. 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. Add magnesium stearate and compress the mixture into a tablet using a single punch or rotary tablet.

Claims (15)

PATENT CLAIMS 1. Paroxetine maleate, wherein the ratio of paroxetine to maleic acid in a molar ratio of 1: 1. 2. Paroxetine maleate, wherein the ratio of paroxetine to maleic acid is 2: 1 molar. Paroxetine maleate according to claim 1 or 2 in non-crystalline form. Paroxetine maleate according to claim 1 or 2 in crystalline form. 5. Paroxetine maleate (1: 1) in form A having a melting point of 139-141 ° C and its IR or XRD spectrum is essentially as described in Example 1. 6. Paroxetine maleate (1: 1) in Form A having a melting point of 136-138 ° C and its IR or XRD spectrum is essentially as described in Example 2. 7. A process for the production of paroxetine maleate according to claim 1, 2 or 3, comprising precipitation from a paroxetine maleate solution, spray drying or freeze drying of the paroxetine maleate solution, evaporation of the paroxetine maleate solution to a glassy material or vacuum drying of oily forms of paroxetine maleate. , or solidification of paroxetine maleate melts. A process for producing paroxetine maleate according to claims 1, 2, 4, 5 or 6, characterized in that it comprises crystallization or recrystallization from a solution of paroxetine maleate. A process for the preparation of paroxetine maleate (1: 1) in Form A, comprising crystallizing from a solution of paroxetine maleate in ethyl acetate, methanol, ethanol, propan-2-ol, propan-1-ol, sec-butanol , butan-1-ol, methyl iso-16-butyl ketone, acetone or acetonitrile, or a mixture of solvents, including mixtures with toluene. 10. A process for the preparation of paroxetine maleate (1: 1) in Form B, comprising crystallizing from a solution of paroxetine maleate in toluene or butanone, acetone, dichloromethane or propan-2-ol or in a mixture of said solvents with toluene. Method according to claim 9 or 10, characterized in that the solution is seeded with seed crystals of the desired polymorph. A process according to claim 7, 8, 9, 10 or 11, characterized in that the oil or melt of paroxetine maleate is prepared by treating the free base of paroxetine or an organic salt thereof with maleic acid or an ammonium or amine salt thereof. 13. A process for the preparation of paroxetine maleate (1: 1) in form B, characterized in that the paroxetine free base solution, which is the final stage in the manufacture of paroxetine, is treated with maleic acid, and form B crystallizes from said solution. The process of claim 13, wherein the paroxetine free base or the resulting maleate is in solution in toluene or in a solvent mixture containing toluene. Use of paroxetine maleate in the manufacture of a pharmaceutical composition for the treatment and / or prevention of one or more disorders.