KR20010041947A - Crystalline Form of Paroxetine - Google Patents

Abstract

The present invention relates to pure and solvent free, for example crystalline paroxetine free base and its use in the treatment of depression.

Description

Crystalline Form of Paroxetine

The present invention relates to novel pharmaceutically active compounds, in particular paroxetine in new crystalline form.

Pharmaceutical products with anti-depressive and anti-Parkinson's disease characteristics are disclosed in US Pat. No. 3,393,433 and US Pat. No. 4007196. Of particular importance among the disclosed compounds are paroxetine, the (-) trans isomer of 4- (4'-fluorophenyl) -3- (3 ', 4'-methylenedioxy-phenoxymethyl) -piperidine .

In this document, the compounds are generally isolated in the form of acid salts, in particular hydrochloride. Paroxetine in the hydrochloride form is acceptable for human use and is particularly recommended for the treatment and prevention of depression, obsessive compulsive disease (OCD) and panic disorder.

Paroxetine hydrochloride is described in the literature in crystalline hemihydrate form (see European Patent Publication No. 0223403 by Beecham Group) and in various crystalline anhydride forms (International Patent Publication No. 96/24595 by SmithKline Beecham). ) Is disclosed.

Previous literature discloses paroxetine free base only in oil form, which is not considered therapeutic and prefers crystalline forms that can be more easily purified and processed into dosage forms.

The present invention provides the use of crystalline paroxetine free base in crystalline form, and as a therapeutic agent.

The crystalline paroxetine free base is characterized by a distinct band at about 3330 cm ⁻¹ in the infrared spectrum (nujol mull), which does not appear in the infrared spectrum of the liquid form paroxetine. Applicants produced samples having melting points in the range of 45-47 ° C.

Paroxetine free base can be prepared from an organic solvent such as propan-2-ol solution by crystallization. Crystallization is an effective way to remove impurities and / or solvents.

Thus, another aspect of the present invention provides paroxetine free base that is substantially pure, for example, at least 98% pure, preferably at least 99% pure, more preferably at least 99.5% pure.

Another aspect of the invention is a paroxetine free base that is substantially free of solvents, for example, containing less than 2%, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1% solvent. to provide.

Suitable paroxetine free base solutions can be prepared by adding a base, for example triethylamine, to the crystalline paroxetine salt, in particular paroxetine hydrochloride. Alternatively, the solution may be prepared by basifying amorphous paroxetine hydrochloride, or paroxetine hydrochloride in crystalline anhydride form or hydrated form.

The preparation of paroxetine free base and paroxetine maleate salt is disclosed in Example 2 of US Pat. No. 4007196. Paroxetine acetate can also be used. Processes for preparing suitable salts are disclosed in European Patent Publication No. 0223403.

Paroxetine free bases can also be prepared in solution by adding a base, such as potassium hydroxide, to a solution of an N-protected paroxetine compound, for example N-phenoxycarbonyl paroxetine.

Crystallization of paroxetine free base from solution is carried out in conventional manner, for example by addition of a nonsolvent, evaporation of solvent, cooling of saturated solution, addition of seed or crystal seed or supersaturated solution of free base or free base in oil form. You can start by scraping the sides of the container.

Crystallization is preferably carried out using crystalline seed of crystalline paroxetine free base. This crystalline seed can be prepared from the solution by conventional methods as described above.

The product of the present invention may be formulated for treatment by paroxetine hydrochloride by the method disclosed in European Patent Publication No. 0223403 or International Patent Publication No. 96/00477.

The amount of paroxetine used is adjusted so that a single dose is a therapeutically effective amount. The single dose is preferably 10 to 100 mg (measured with respect to the free base) of paroxetine. More preferably, the single dose of paroxetine is 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. Most preferably, the single dose of paroxetine is 20 mg.

Therapeutic uses of the paroxetine product of the present invention include alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome, referred to below as "disease". (PMS), treatment of adolescent depression, pneumomania, mood modulation and substance abuse.

Accordingly, the present invention provides a pharmaceutical composition for the treatment and prophylaxis of said disease comprising the product of the invention and a pharmaceutically acceptable carrier, the use of the product of the invention for the manufacture of a medicament for the treatment or prophylaxis of said disease and Provided is a method of treating a disease comprising administering an effective amount or prophylactic amount of a product of the invention to a patient suffering from said disease.

The invention is illustrated by the following examples.

Example 1 Preparation of Crystalline Paroxetine Free Base

Triethylamine (67.6 g) was added to dissolve paroxetine hydrochloride (50 g) in dichloromethane (250 ml) and stirred at 20 ° C. for 12 h. Solid triethylamine hydrochloride was removed by filtration and the filtrate was washed twice with water (2 × 200 ml), dried over anhydrous magnesium sulfate and evaporated to give a viscous oil and removed to a large extent to be a solvent. Propan-2-ol (165 ml) was added and the mixture was warmed and stirred until a homogeneous solution was formed. The solution was cooled to −10 ° C. and the side of the container was scraped off to initiate sowing. After 12 hours the product was filtered off, washed with propan-2-ol (50 ml at -10 ° C) and dried under reduced pressure.

<Example 2>

The paroxetine free base solution (formed from 80 g of paroxetine hydrochloride hemihydrate) in propan-2-ol was dried under reduced pressure to remove the solvent. About 13 g of residual oil was seeded with crystals of paroxetine free base and left for 18 hours to form a white crystalline solid.

HPLC purity 98.04%

Residual Propan-2-ol less than 0.1% (wt / wt)

Melting point 45-47 캜

<Example 3>

Paroxetine mesylate (10.0 g) was added to water (100 ml) and the mixture was stirred until a homogeneous solution was observed. Ethyl acetate (100 ml) was added, followed by aqueous sodium hydroxide solution (10 wt%, 20 ml) and the biphasic mixture was vigorously stirred for 5 minutes. After the layer was formed, the organic layer was separated and washed with water (100 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure in a water bath heated to 40 ° C. until no more solvent was removed to give a pale orange-brown viscous oil.

Analysis with ¹ H nmr (CDCl ₃ ) revealed that the product was a paroxetine free base containing 5.6% (wt / wt) ethyl acetate.

The crystalline paroxetine free base was seeded in a viscous oil and left at 21 ° C. for 24 hours to obtain a crystalline solid paroxetine free base. The product was dried at 21 ° C. for 6 hours under reduced pressure.

Product weight: 7.5 g. Ethyl acetate content: 0.8% (wt / wt).

The product was dried under reduced pressure for another 3 hours at 21 ° C. to give a paroxetine free base containing 0.2% (wt / wt) of ethyl acetate (result by ¹ H nmr).

HPLC purity: 98.7%

<Example 4>

Aqueous sodium hydroxide solution (20 wt%, 20 ml) is added to a stirred suspension of paroxetine hydrochloride propan-2-ol solvate (10.0 g) in a mixture of ethyl acetate (100 ml) and water (100 ml) and the mixture is 5 minutes. Stirring vigorously. After the layer was formed, the organic layer was separated and washed with water (100 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure in a water bath heated to 40 ° C. for 30 minutes and a light brown viscous oil was obtained when the solvent appeared to be completely removed.

Analysis by ¹ H NMR (CDCl ₃ ) showed the product to be a paroxetine free base containing 5.5% (wt / wt) ethyl acetate.

The product was seeded with crystalline paroxetine free base and left at 21 ° C. for 24 hours to give a light brown crystalline solid. The product was dried at 21 ° C. for 6 hours under reduced pressure.

Product weight: 8.1 g, ethyl acetate, 0.8% (wt / wt) (result by ¹ H nmr)

The product was dried under reduced pressure for another 3 hours at 21 ° C. to give a paroxetine free base containing 0.2% (wt / wt) of ethyl acetate (result by ¹ H nmr).

<Example 5>

Paroxetine acetate (10.0 g) was added to water (100 ml) and the mixture was stirred until a homogeneous solution was observed. Ethyl acetate (100 ml) was added, followed by aqueous sodium hydroxide solution (10 wt%, 20 ml) and the biphasic mixture was vigorously stirred for 5 minutes. After the layer was formed, the organic layer was separated and washed with water (100 ml). The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure in a water bath heated to 40 ° C. until a solvent was completely removed to give a colorless viscous oil.

Analysis by ¹ H NMR (CDCl ₃ ) showed the product to be a paroxetine free base containing 5.9% (wt / wt) ethyl acetate.

Crystalline paroxetine free base was seeded in viscous oil and left at 21 ° C. for 24 hours. The crystalline product was dried at 21 ° C. for 6 hours under reduced pressure.

Product weight: 8.2 g, ethyl acetate content: 0.8% (wt / wt) (result by ¹ H nmr).

The product was dried under reduced pressure for another 3 hours at 21 ° C. to give a paroxetine free base containing 0.2% (wt / wt) of ethyl acetate (result by ¹ H nmr).

HPLC purity: 99.2%

<Example 6>

A mixture of paroxetine free base (2.0 g) and heptane (50 ml) was stirred and warmed to 55 ° C. under a nitrogen atmosphere. The resulting clear solution was decanted from a small amount of insoluble residue and cooled to 21 ° C. with stirring for 30 minutes under a nitrogen atmosphere. The mixture was cooled to 0 ° C. with continued stirring for 10 minutes, and the resulting white crystalline solid was collected by filtration and washed with cold heptane (5 ml at 0 ° C.). The product was dried at 21 ° C. for 4 hours under reduced pressure to afford the following white crystalline solid, paroxetine free base.

Product weight: 1.0 g. Heptane content 0.1% (wt / wt) (result by ¹ H nmr).

HPLC purity: 99.6%

<Example 7>

A mixture of paroxetine free base (1.1 g) and heptane (25 ml) was stirred and warmed to 55 ° C. under a nitrogen atmosphere. The resulting clear solution was decanted from a small amount of insoluble residue and then cooled to -5 ° C with stirring under a nitrogen atmosphere. After stirring at −5 ° C. for 10 minutes, the crystalline product was collected by filtration, washed with cold hexane (5 ml at 5 ° C.) and dried under reduced pressure at 21 ° C. for 4 hours to give the following free-flowing white crystalline solid Paroxetine free base was obtained.

Product weight: 0.52 g. Hexane content less than 0.1% (result by ¹ H nmr)

HPLC purity: 98.2%

<Example 8>

Paroxetine mesylate (3.0 g) was added to water (35 ml) and the mixture was stirred until a homogeneous solution was observed. Ethyl acetate (35 ml) was added, followed by aqueous sodium hydroxide solution (10 wt%, 7.5 ml) and the biphasic mixture was vigorously stirred for 5 minutes. After the layer was formed, the organic layer was separated and washed with water (35 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure for 30 minutes in a water bath heated to 40 ° C. to give a pale orange-brown viscous oil. Heptane (55 ml) was added to the residue and the mixture was stirred and then warmed to 55 ° C. under nitrogen atmosphere. The resulting clear solution was decanted from a small amount of insoluble residue and then cooled to -5 ° C with stirring under a nitrogen atmosphere. After stirring at −5 ° C. for 10 minutes, the crystalline product was collected by filtration, washed with cooled heptane (10 ml at −5 ° C.) and dried under reduced pressure at 21 ° C. for 4 hours to yield a free-flowing white crystalline solid. Phosphorous paroxetine base was obtained.

Product weight: 1.1 g. Heptane content below 0.1% (wt / wt) (result by ¹ H nmr). Ethyl acetate was not observed by ¹ H nmr.

HPLC purity: 99.2%

<Example 9>

In a conical flask equipped with a magnetic bar, paroxetine acetate (40.4 g), water (400 ml) and ethyl acetate (300 ml) were added. The mixture was stirred until all paroxetine acetate was dissolved, and then 60 g of 10% by weight aqueous sodium hydroxide solution was added. The suspension was stirred for an additional 30 minutes. The resulting layer was separated and the aqueous layer was extracted with ethyl acetate (1 × 100 ml). The combined organic layers were washed with water (2 x 200 ml), dried over sodium sulfate, evaporated under reduced pressure to give an oil, and left to crystallize slowly to give crystalline paroxetine base.

Yield = 32.9 g

Claims (8)

Paroxetine free base in crystalline form. Crystalline paroxetine free base, characterized by a pronounced band at about 3330 cm ⁻¹ in the infrared spectrum (nusol method). Paroxetine free base in virtually pure form. Paroxetine free base virtually solvent free. A pharmaceutical composition comprising the product of claim 1 and a pharmaceutically acceptable carrier. Use of the product of any one of claims 1 to 4 in the manufacture of a antidepressant drug. A method of treating depression comprising administering to a patient suffering from depression an effective amount of a product of any one of claims 1-4. The process for preparing the product of any one of claims 1 to 4 comprising crystallizing the paroxetine free base from an oil or a solution.