WO2001077106A1

WO2001077106A1 - A new paroxetine salt and a novel pharmaceutical product containing it

Info

Publication number: WO2001077106A1
Application number: PCT/HU2001/000041
Authority: WO
Inventors: László Czibula; András NEMES; János Kreidl; László Dobay; Ida DEUTSCHNÉ JUHÁSZ; Judit NAGYNÉ BAGDY; Éva WERKNÉ PAPP; Sándorné BÁLINT; István HEGEDŰS; László TERDY; Ferenc SEBŐK
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 2000-04-07
Filing date: 2001-04-06
Publication date: 2001-10-18
Anticipated expiration: 2002-10-07
Also published as: HUP0001414A2; HU0001414D0; HUP0001414A3; HU226912B1; AU2001248658A1

Abstract

The invention relates to a new paroxetine salt, that is the (-)-paroxetine-(+)-L-monotartarate hemihydrate, which is a new antidepressant compound. The invention is related furthermore to a novel pharmaceutical product containing the new compound, the synthesis and use of the new compound, respectively.

Description

A NEW PAROXETINE SALT AND A NOVEL PHARMACEUTICAL

PRODUCT CONTAINING IT

The object of the present invention is the new paroxetine salt, that is the (-)- paroxetine-(+)-L-monotartarate hemihydrate, which is a new antidepressant compound. The invention is related furthermore to a novel pharmaceutical product containing the new compound, the synthesis and use of the new compound, respectively.

The different salts of paroxetine [its chemical name: (-)-trø«s-4-(4-fluorophenyl- 3-(3,4-methylenedioxy-phenoxy-methyl)-piperidine] are the active substance of the known antidepressant drugs (Paxil, Seroxat). The paroxetine base and some acid-additionated salt (in the form of hydrochloride and maleate) were published at first in 1977 in the specification of US Pat. No. 4,007,196.

It became also known later, that the paroxetine-hydrochloride has uncrystallized (amorphous) structure, therefore it is hard to handle in solid state. On the basis of this reason the EP Pat. No. 223,403 specification disclosed a procedure where a well-formulable paroxetine-hydrochloride hemihydrate could be synthesized. Finally, this salt became the active ingredient of the most drugs containing paroxetine substance.

Several synthetic routes are in the literature for the synthesis of the paroxetine- hydrochloride hemihydrate. In addition to the introduced procedures of the already cited US Pat. No. 4,007,196 specification, we published a novel and efficient synthesis - as the result of our own research - in PCT Appl. No. WO 98/01424. The anhydrate form of paroxetine-tartarate was mentioned in this procedure, which - as a new compound - was introduced as one of the intermediate of our synthetic route for processing of the paroxetine- hydrochloride hemihydrate.

Finally we have to refer to PCT Appl. No. WO 99/40084, which also introduced different tartarate-salts beside other paroxetine salts but the specification disclosed only the unstable paroxetine-tartarate anhydrate, which can be synthesized under non-aqueous conditions.

The aim of our invention is the search of a suitable synthesis for a stable paroxetine salt which can be perfectly applied in drugs.

In the course of our experiments we studied the anhydrate form of paroxetine- (+)-L-monotartarate at first. In our investigations we realized that the anhydrate, which was disclosed in PCT Appl. No. WO 98/01424, does not possess chemical and physical properties, suitable to employ it in medicaments.

Surprisingly we found and this is the discovery of our invention; that a new form, the hemihydrate of the paroxetine-(+)-L-tartarate exists, and this is a more advantageous and more stable allotrope than the anhydrate form.

Therefore, the object of our invention is the new paroxetine salt, namely the (-)- paroxetine-(+)-L-monotartarate hemihydrate, furthermore the synthetic procedure of this salt by such a way, as the (-)-paroxetine-(+)-L-monotartarate anhydrate is treated with water.

According to the invention we can also proceed in the way, that we form the salt in accordance with the invention from paroxetine base with 1-1.3 mol equivalent of (+)-L-tartaric acid in the presence of water. The compound according to the invention is suitable to employ it first as active ingredient in antidepressant drugs.

During our experimental work we studied the change in weight of (-)- paroxetine-(+)-L-monotartarate anhydrate under different relative humidity. It was found that the anhydrate was transformed into hemihydrate in considerable amount even at 63 % relative humidity after 10 days storage at room temperature, but at higher humidity the transformation was complete. The transformation was proved by roentgen diffraction spectra. There is also significant difference between the anhydrate and hemihydrate of paroxetine- tartarate in their thermic behavior (TG, DSC) and IR spectra.

According to the process of our invention we can prepare the paroxetine-(+)-L- tartarate hemihydrate if the anhydrate, to be formed under non-aqueous condition, is treated with water or if the salt, formed from paroxetine base with 1-1.3 mol equivalent amount of (+)-L-tartaric acid, is crystallized in the presence of water. In this latter case the paroxetine base is dissolved preferably in any solvent mixable with water- such as methanol, ethanol, i-propanol, acetone, acetonitril - or is suspended in water and the aqueous solution of 1-1.3 mol equivalent amount of (+)-L-tartaric acid is added either to the solution or the aqueous suspension of the paroxetine base.

In one of the advantageous version of the invention, the ethanol turned out to be the most advantageous solvent to dissolve the paroxetine base for the preparation of the hemihydrate salt. It is favorable to dissolve the (+)-L-tartaric acid in water. In the process according to the invention the temperature of the salt formation is preferably 50-60 °C because of the favorable crystal structure to be formed then the crystallization became complete if it is cooled slowly to 5-10 °C.

In the procedure - according to our invention - the starting material, the paroxetine-(+)-L-monotartarate anhydrate can be synthesized on the basis of Example 24 of PCT Appl. No. WO 98/01424 (see: Specification p. 24 lines 6- 27). However, we can proceed to dissolve the paroxetine base in dry solvent at first. The preferably employed dry solvents should be the 1-4 C atom containing alcohols, methyl-ethyl keton, acetonitril, ethyl acetate, and their mixture of aryl hydrocarbons - such as benzene, toluene, xylene - or chlorinated aliphatic and aryl hydrocarbons - such as dichloromethane, chloroform, chlorobenzene. The solution of 1-1.3 mol equivalent amount of (-t-)-L-tartaric acid dissolved in dry solvent - preferable in methanol or ethanol - was added to the prepared solution of the paroxetine base and the precipitated crystals are separated by usual method, for example by filtration.

One of the earlier starting material, the paroxetine base, according to the invention can be preferable prepared by catalytic hydrogenation of the (-)-trans- N-benzyl-paroxetine. During the procedure the (-)-N-benzyl-paroxetine base is dissolved in solvent which is suitable for hydrogenation and the base itself or any kind of its salt or salt mixture is debenzylated with elemental hydrogen in the presence of palladium on carbon. In the latter case the paroxetine base can be prepared from the salt or salt mixture by acidification.

The well-defined advantage of the detailed procedures of our invention is that a very pure product can be prepared with high yield without additional inserted purification step. This is partly due to the processing of the /rαrøvN-benzyl- paroxetine providing a very pure starting material, which was disclosed in PCT Appl. No. WO 98/01424. On the other hand, the catalytic debenzylation is quantitative and the so obtained pure paroxetine base does not demand extra purification and isolation steps and so either the anhydrate or hemihydrate forms of (-)-paroxetine-(+)-L-monotartarate can be prepared from it in 94-96 % yield, applying the favorably selected solvent respectively the solvent mixtures.

We can apply the paroxetine-tartarate hemihydrate according to the invention for the treatment of the following diseases: depression, alcoholism, panic disease, obesity, bulimia, migraine, anorexia, premenstrual syndrome, social phobia and others.

The novel pharmaceutical product containing the paroxetine-tartarate hemihydrate according to the invention is suitable to treat the above mentioned diseases respectively symptoms or to prevent them. The pharmaceutical product in accordance with the invention thus contains the paroxetine-tartarate hemihydrate and any kind of the therapeutically accepted ingredients and carriers.

The pharmaceutical product according to the invention is most practical to administrate orally but other pharmaceutical forms like solution, suspension and others can be employed.

The active ingredient of the drug can vary between 1-250 mg. It turned out to be the most favorable products, which contained 5-100 mg of the active ingredient.

Within these value the 20, 25, or 40 mg doses seem to be the most efficient. The patient needs to take the drugs 1-6 times, practically 2-3 times a day. We can employ tablets, capsules or other known drug formulas by itself for the treatment.

According to the invention in the pharmaceutical product we can use as ingredient carrier, dilutor, moisturizer, dying and other ingredients to be known by them. The mixing of the above listed ingredients and the active ingredient (paroxetine-tartarate hemihydrate) is carried out by known drug preparation procedure.

The following examples describes the invention in details:

AJ Synthesis of the starting materials

Example 1 Synthesis of (-)-Paroxetine base ( according to the Example 22 of the PCT Pat. No. WO 98/01424 ; see from p. 22 line 16 to p. 23 line 6).

8.4 g (0.02 mol) of (-)-4-(4-fluorophenyl)-3-(4,3-methylenedioxy- phenoxymethyl)-piperidine (so called: (-)-^rørø-N-benzylparoxetine) was dissolved in 120 ml of ethanol and it was hydrogenated with 0.6 g of 10% palladium on carbon catalyst for 2-3 hours at 30-40 °C in autoclave at a pressure of 2 x 10⁵ Pa. The catalyst was filtered under nitrogen after the debenzylation was completed. The filtrate was evaporated to dryness, leaving the (-)- paroxetine base, uncoloured oil, weight: 6.5 g. Example 2

Synthesis of (-)-Paroxetine base

8.4 g (0.02 mol) of (-)-trørø-N-benzyl-paroxetine was suspended in the mixture of 60 ml of ethanol and 60 ml of ion exchanged water in autoclave, its solution was prepared by adding 1.5 ml of acetic acid and 1.5 ml of sulfuric acid to it, and it was hydrogenated with 0.6 g of 10% palladium on carbon catalyst for 2.5-

3 hours at 40-50 °C at the pressure of 1.5-2 x 10⁵ Pa. After completion of the debenzylation the catalyst was filtered off under nitrogen. The pH of the filtrate was adjusted to 4-5 with cc. aqueous ammonium solution and the alcohol was evaporated in vacuum. The residue was diluted with 40 ml of water, 100 ml of dichloromethane was added and the pH of the solution was adjusted to 9.0 with cc aqueous ammonium solution during stirring. After phase separation, the aqueous phase was extracted with 30 ml of dichloromethane. The combined dichloromethane phases were dried with magnesium sulfate, the drying agent was filtered off and the filtrate was evaporated to dryness in vacuum. The residual uncolored oil is the paroxetine base, weight: 6.55 g.

Example 3 Synthesis of the (-)-Paroxetine base

Following the procedure as it was described in Example 2, but instead of 1.6 ml of cc. sulfuric acid the 3.5 ml of cc. hydrochloride acid was employed. The weight of the prepared paroxetine base was: 6.6 g. Example 4

Synthesis of (-)-Paroxetine-(+)-L-monotartarate anhydrate

4.95 g of paroxetine base was dissolved in dry ethanol, the solution was heated to 50-55 °C and the 50-55 °C solution of the 2.6 g of (+)-L-tartaric acid prepared in 25 ml of dry ethanol was added. The solution was cooled slowly to 5-10 °C in one hour then the crystal suspension was filtered. The precipitated product was washed altogether with 10 ml of dry ethanol in two parts, then dried in vacuum at 60-70 °C, to give paroxetine-tartarate anhydrate: 6.83 g.

Water content: 0.1% [α]_D ²⁰: - 51° (c = 1, DMF)

Melting point: 177-179 °C.

Morphologic characterization of paroxetine-tartarate anhydrate

Roentgen Diffraction

Philips PW 1840 Instrument under the following conditions generated the data:

CuK-_α radiation, 40 kV, 55 mA

Gonionmeter speed: 0.05 °2θ/s

Sensitivity: 2 x 10 cps

Time constant: 5 sec

Gap length: 0.05 mm

sh.: shoulder

Example 5 Synthesis of (-)-Paroxetine-(+)-L-monotartarate anhydrate

4.95 g of paroxetine base was dissolved in 60 ml of toluene, the solution was heated to 55-60 °C and the solution of 55-60 °C temperature of 2.48 g of (+)-L- tartaric acid prepared in 20 ml of dry methanol was added. This mixture was cooled to 5-10 °C and the crystal suspension was filtered, washed in two parts covered with 20 ml of acetone, then dried at 60-70 °C in vacuum, to give (-)- paroxetine-(+)-L-monotartarate anhydrate: 6.58 g (yield: 91.5%). Water content: 0.07% [α]²⁰ _D: - 51.3 ° (c = 1, DMF) Melting point: 177-179 °C

BJ Synthesis of the compound according to the invention

Example 6

Synthesis of (-)-Paroxetine-(+)-L-monotartarate hemihydrate

5 g of (-)-paroxetine-(+)-L-monotartarate anhydrate was stirred in 25 ml of ion exchanged water for one hour at 30-35 °C then it was cooled to 5-10 °C then the crystal suspension was filtered. The prepared crystals were dried to constancy of weight at max. 50 °C, to give the title compound; 4.95 g Water content: 11.84 %, [αj²⁰ _D: - 51 ° (c = 1 , DMF), Melting point: 177-179 °C.

Physico-chemical characterization of the paroxetine-tartarate hemihydrate

I., Roentgen Diffraction

Philips PW 1840 Instrument under the following conditions generated the data:

CuK_α radiation, 40 kV, 55 mA

Gonionmeter speed: 0.05 °2θ/s

Sensitivity: 2 x 10³ cps Time constans: 5 sec

Gap length: 0.05 mm

Sh.: shoulder

II., Infrared Spectroscopy

The IR spectra was obtained using potassium bromide pellet applying 4 cm^"1 resolution on a PER-KIN-ELMER 1000 spectrometer. The most significant IR bands of the compound are listed below (cm^"1): O-H 3437,3371 c =o 1719, 1674

Ar-O-C 1246, 1188

Ar-F 1223

Ar 1605,831,815

Further characteristic absorption wavelengths: 2895,01512, 1492, 1395, 1334, 1031, 780, 638

Example 7

Preparation of (-)-Paroxetine-(+)-L-monotartarate hemihydrate

4.95 g of paroxetine base was dissolved in 10 ml of ethanol, the solution was heated to 50-60 °C then the solution of 50-60 °C temperature of 2.6 g (+)-L- tartaric acid dissolved in 50 ml of distilled water was added. The solution was cooled slowly to 5-10 °C, the crystal suspension was filtered. The crystals were washed in two parts, altogether with 20 ml of distilled water and were dried at max. 50 °C, to give 6.8 g of the title compound, water content: 1.86 %, [α]²⁰ _D: - 51 ° (c = 1, DMF), melting point: 177-179 °C.

Example 8

Preparation of (-)-Paroxetine-(+)-L-monotartarate hemihydrate

4.95 g of paroxetine base was suspended in 20 ml of distilled water, the solution of 2.6 g of (+)-L-tartaric acid prepared in 60 ml of distilled water was added and the mixture was stirred for two hours at 50-60 °C under nitrogen. Then the solution was cooled to 5-10 °C, the crystal suspension was filtered, the crystals were washed with altogether 20 ml of distilled water in two parts and were dried at max. 50 °C, to give 7.0 g of the titled compound (yield: 95.6%), water content: 1.85%, [α]²⁰ _D: - 50.9 ° (c = 1, DMF), melting point: 176-179 °C.

Example 9

The procedure of the pharmaceutical product

The corpus of one 20 mg (count on the paroxetine base) filmtablet contains the following substances:

The above ingredients were prepared and they were manufactured by pharmaceutical moisture(wet) granulation. Tablets were pressed from the granulates then they were covered by film layer.

Claims

What we claim is:

1. (-)-Paroxetine-(+)-L-monotartarate hemihydrate.

2. A process for the preparation of the compound in Claim 1, characterized by treating the (-)-paroxetine-(+)-L-monotartarate anhydrate with water.

3. A process for the preparation of the compound in claim 1, characterized by reacting the paroxetine base with 1-1.3 mole equivalent amount of (+)-L-tartaric acid in the presence of water.

4. A pharmaceutical product, characterized by containing the (-)-paroxetine-(+)- L-monotartarate hemihydrate , as the active ingredient.

5. A pharmaceutical product in claim 4, for use in the treatment or prevention of depression, alcoholism, panic disease, obesity, bulimia, migraine, anorexia, premenstrual syndrome, social phobia ad other diseases.