This application claims priority to Indian patent application no 2697/CHE/2010 filed on Sep 15,2010 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to crystalline salts of Esmirtazapine designated as hydrochloride, fumarate, oxalate, maleate and salicylate.

The present invention also relates to process for the preparation of hydrochloride, fumarate, oxalate, maleate and salicylate salts of Esmirtazapine.

BACK GROUND OF THE INVENTION:

Mirtazapine (1, 2, 3, 4, 10, 14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3c][2]benzazep- ine) is a tetracyclic compound of Formula I used for the treatment of depression.

Mirtazapine is sold under the trademark REMERON® and is available in two dosage forms: tablets and orally disintegrating tablets. Both dosage forms of REMERON® are indicated for the treatment of major depressive disorder.

Recently, Esmirtazapine (S-enantiomer of Mirtazapine) of Formula-II is being developed as a therapeutic agent for insomnia and the like.


US Pat. No. 4062848 (US '848) discloses a process for preparing Mirtazapine, wherein 2-chloronicotinonitrile is reacted with l-methyl-3-phenyl-piperazine in the presence dry potassium fluoride and dry DMF to give 2-(4-Methyl-2-phenylpiperazin-l-yl) nicotinonitrile, which is hydrolysed in the presence of potassium hydroxide and ethanol to give (2-(4-Methyl-2-phenylpiperazin-l-yl) nicotinic acid, which is further reduced to 2-(4-Methyl-2-phenylpiperazin-l-yl)pyridin-3-yl)methanol in the presence of dry THF/lithium aluminum hydride and finally 2-(4-Methyl-2-phenylpiperazin-l-yl)pyridin-3-yl)methanol is cyclized to Mirtazapine in the presence of concentrated sulfuric acid.

The optical resolution of racemic Mirtazapine has also been disclosed in US '848 by resoluting of racemic mirtazapine with enantiomerically pure dibenzoyl tartaric acid in ethanol.

The schematic description is as shown below:


Though US '848 discloses the acid addition salts of Mirtazapine obtained by reaction of the free base with a suitable inorganic or organic acid, such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid and ascorbic acid, there is no mention of polymorphic data of the acid addition salts for Esmirtazapine.

The present invention provides crystalline salts of Esmirtazapine. Also provides process for the preparation of the same which is efficient, cost effective and can be reproducible in large scale preparation.

SUMMARY OF THE INVENTION

One aspect of the present invention provides crystalline Esmirtazapine hydrochloride. Another aspect of the present invention is to provide crystalline Esmirtazapine hydrochloride characterized by X-ray powder diffraction.

Yet another aspect of the present invention provides a process for the preparation of crystalline Esmirtazapine hydrochloride comprising the steps of: a) dissolving Esmirtazapine in solvent, b) adding hydrochloric acid, and c) isolating Esmirtazapine hydrochloride salt.

Yet another aspect of the present invention provides crystalline Esmirtazapine fumarate.
Another aspect of the present invention is to provide crystalline Esmirtazapine fumarate characterized by X-ray powder diffraction.

Yet another aspect of the present invention provides a process for the preparation of crystalline Esmirtazapine fumarate which comprises the steps of: a) dissolving Esmirtazapine in solvent, b) adding fumaric acid, and c) isolating Esmirtazapine fumarate salt.

Yet another aspect of the present invention provides crystalline Esmirtazapine oxalate.
Yet another aspect of the present invention provides a process for the preparation of crystalline Esmirtazapine oxalate which comprises the steps of: a) dissolving Esmirtazapine in solvent, b) adding oxalic acid, and c) isolating Esmirtazapine oxalate salt.

Yet another aspect of the present invention provides crystalline Esmirtazapine maleate.

Yet another aspect of the present invention provides a process for the preparation of crystalline Esmirtazapine maleate which comprises the steps of: a) dissolving Esmirtazapine in solvent, b) adding maleic acid, and c) isolating Esmirtazapine maleate
salt.

Yet another aspect of the present invention provides crystalline Esmirtazapine
salicylate.

Yet another aspect of the present invention provides a process for the preparation of
crystalline Esmirtazapine salicylate which comprises the steps of: a) dissolving
Esmirtazapine in solvent, b) adding salicylic acid, and c) isolating Esmirtazapine
salicylate salt.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig.1 depicts an X-ray powder diffraction pattern of Esmirtazapine hydrochloride. Fig.2 depicts an X-ray powder diffraction pattern of Esmirtazapine Fumarate. Fig. 3 depicts an X-ray powder diffraction pattern of Esmirtazapine Oxalate. Fig.4 depicts an X-ray powder diffraction pattern of Esmirtazapine Maleate. Fig.5 depicts an X-ray powder diffraction pattern of Esmirtazapine Salicylate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides crystalline salts of Esmirtazapine such as hydrochloride, fumarate, oxalate, maleate and salicylate. The present invention also provides process for the preparation of hydrochloride, fumarate, oxalate, maleate and salicylate salts of Esmirtazapine.

One embodiment of the present invention provides crystalline Esmirtazapine hydrochloride.

Another embodiment of the present invention provides crystalline Esmirtazapine hydrochloride characterized by X-ray powder diffraction pattern as shown in Figure 1 with peaks at 12.65, 12.83, 15.21, 17.02, 19.43, 20.38, 21.10, 22.19, 25.47, 25.83, 26.86, 27.95, 28.17 and 29.27 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Esmirtazapine hydrochloride comprising the steps of:

a) dissolving Esmirtazapine in solvent,

b) adding hydrochloric acid, and

c) isolating Esmirtazapine hydrochloride salt.

According to the present invention Esmirtazapine is dissolved in a solvent and hydrochloric acid solution is added to form a white solid. The reaction mass is cooled to 0-10°C and stirred for about 1-3 hrs. The obtained solid is filtered and washed with the same solvent to get Esmirtazapine hydrochloride.

According to the present invention the solvent used for the dissolution of Esmirtazapine is selected from methanol, ethanol, isopropanol, butanol, ethylacetate, methylacetate, toluene, tetrahydrofuran, acetonitrile, acetone, diisopropyl ether, or mixture thereof and the hydrochloric acid solution is aqueous hydrochloric acid, alcoholic hydrochloric acid such as methanolic, ethanolic or isopropanolic hydrochloric acid. Concentration of hydrochloric acid may vary from 1 to 36%, preferably 10-20%, more preferable 15-20%.

Yet another embodiment of the present invention provides crystalline Esmirtazapine fumarate.

Yet another embodiment of the present invention provides crystalline Esmirtazapine fumarate characterized by X-ray powder diffraction pattern as shown in Figure 2 with peaks at 10.65, 12.64, 13.90, 15.41, 18.62, 20.69, 21.42 and 22.10 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Esmirtazapine fumarate comprising the steps of:

a) dissolving Esmirtazapine in solvent,

b) adding fumaric acid, and

c) isolating Esmirtazapine fumarate salt.

According to the present invention Esmirtazapine is dissolved in solvent and fumaric acid is added to form a solid. The reaction mass is cooled to 0-10°C and stirred for about 1-3 hrs. The obtained solid is filtered and washed with the same solvent to get Esmirtazapine fumarate.

According to the present invention the solvent used for dissolution of Esmirtazapine is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol or mixture thereof.

Yet another embodiment of the present invention provides crystalline Esmirtazapine oxalate.

Yet another embodiment of the present invention provides crystalline Esmirtazapine oxalate characterized by X-ray powder diffraction pattern as shown in Figure 3 with peaks at 8.39, 12.45, 14.95, 15.96, 19.50, 20.80, 21.45, 22.31, 22.59, 23.80, 25.02, 25.28 and 27.19 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation Esmirtazapine oxalate comprising the steps of:

a) dissolving Esmirtazapine in solvent,

b) adding oxalic acid, and

c) isolating Esmirtazapine oxalate salt.

According to the present invention Esmirtazapine is dissolved in solvent and oxalic acid
is added to form a solid. The reaction mass is cooled to 0-10°C and stirred for about 1-3
hrs. The obtained solid is filtered and washed with same solvent to get Esmirtazapine
oxalate.

According to the present invention the solvent used is selected from alcohols such as
methanol, ethanol, propanol, isopropanol, butanol or mixture thereof.

Yet another aspect of the present invention provides crystalline Esmirtazapine maleate.

Yet another embodiment of the present invention provides crystalline Esmirtazapine maleate characterized by X-ray powder diffraction pattern as shown in Figure 4 with peaks at 10.29, 17.89, 18.75, 19.02, 19.50, 19.72, 20.81, 21.24, 21.53, 21.80, 22.51, 23.91, 24.24, 24.82, 26.06, 26.89, 28.52, 29.01 and 29.84 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation Esmirtazapine maleate comprising the steps of:

a) dissolving Esmirtazapine in solvent,

b) adding maleic acid, and

c) isolating Esmirtazapine maleate salt.

According to the present invention Esmirtazapine is dissolved in solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol or mixture thereof and maleic acid is added to form a white solid. The reaction mass is cooled to 0-10°C and stirred for about 1-3 hrs. The obtained solid is filtered and washed to get Esmirtazapine maleate.

Yet another embodiment of the present invention provides crystalline Esmirtazapine salicylate.

Yet another embodiment of the present invention provides crystalline Esmirtazapine salicylate characterized by X-ray powder diffraction pattern as shown in Figure 5 with peaks at 7.52, 8.87, 11.67, 12.70, 17.83, 18.58, 20.22, 22.66, 24.61, 24.99 and 25.28 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation Esmirtazapine salicylate comprising the steps of:

a) dissolving Esmirtazapine in solvent,

b) adding salicylic acid, and

c) isolating Esmirtazapine salicylate salt.

According to the present invention Esmirtazapine is dissolved in solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol or mixture thereof and salicylic acid is added to form a white solid. The reaction mass is cooled to 0-10°C and stirred for about 1-3 hrs. The obtained solid is filtered and washed to get Esmirtazapine salicylate.

POWDER X-RAY DIFFRACTION (PXRD)

The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 9/0 configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 26 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Example-1: Preparation of Esmirtazapine hydrochloride salt.

Esmirtazapine (5 g) was dissolved in ethyl acetate (25 ml) and 20% IPA-HC1 (5 ml) was added. The white solid thus formed was stirred for about 1-2 hours. The obtained solid was filtered, washed with ethyl acetate (10 ml) and then dried the solid to get Esmirtazapine hydrochloride salt (4.8g). Melting Point: 286-289°C; HC1 content: 13.49%.

ExampIe-2: Preparation of Esmirtazapine fumarate salt.

Esmirtazapine (5 g) was dissolved in ethanol (25 ml) and fumaric acid (2.2 g) was added. The white solid thus formed was cooled to 0-5°C and stirred for about 1-2 hours. The obtained solid was filtered, washed with chilled ethanol (10 ml) and then dried the solid to get Esmirtazapine fumarate salt (4.5g). Melting Point: 148-151°C; Fumaric acid content: 23.38 %.

Example-3: Preparation of Esmirtazapine oxalate salt.

Esmirtazapine (5 g) was dissolved in ethanol (25 ml) and Oxalic acid (1.8 g) was added. The white solid thus formed was cooled to 0-5°C and stirred for about 1-2 hours. The obtained solid was filtered, washed with chilled ethanol (10 ml) and then dried the solid to get Esmirtazapine oxalate salt (4.0g). Melting Point: 101-104°C; Oxalic acid content: 35.77%.

Example-4: Preparation of Esmirtazapine maleate salt.

Esmirtazapine (5 g) was dissolved in ethanol (25 ml) and maleic acid (2.3 g) was added. The white solid thus formed was cooled to 0-5°C and stirred for about 1-2 hours. The obtained solid was filtered, washed with chilled ethanol (10 ml) and then dried the solid to get Esmirtazapine maleate salt (6.9g). Melting Point: 210-213°C; Maleic acid content: 30.9%.

Example-5: Preparation of Esmirtazapine salicylate salt.

Esmirtazapine (5 g) was dissolved in ethanol (25 ml) and fumaric acid (2.75 g) was added. The white solid thus formed was cooled to 0-5°C and stirred for about 1-2 hours. The obtained solid was filtered, washed with chilled ethanol (10 ml) and then dried the solid to get Esmirtazapine salicylate salt (5.5g) Melting Point: 134-136.5°C; Salicylic acid content 34.32%.

We Claim:

1. A crystalline Esmirtazapine salt of formula-Ill

wherein HX is an acid selected from hydrochloric acid, fumaric acid, oxalic acid, maleic acid and salicylic acid.

2. The Esmirtazapine salt according to the claim 1, wherein crystalline
esmirtazapine hydrochloride salt of formula IIIa

and has powder X-ray diffraction peaks at 12.83, 19.43, 20.38, 21.10, 25.83 ± 0.2 two- theta values; wherein crystalline esmirtazapine fumarate salt of formula IIIb

and has powder X-ray diffraction peaks at 10.65, 18.62, 21.42 ± 0.2 two-theta values; wherein crystalline esmirtazapine oxalate salt of formula IIIc


and has powder X-ray diffraction peaks at 8.39, 15.96, 19.50,20.50 ± 0.2 two-theta values; wherein crystalline esmirtazapine maleate salt of formula IIId

and has powder X-ray diffraction peaks at 17.85, 20.81, 22.51 ± 0.2 two-theta values; wherein crystalline esmirtazapine salicylate salt of formula Hie

and has powder X-ray diffraction peaks at 7.52, 17.83, 22.61, 24.61, ± 0.2 two-theta values.

3. A compound according to claim 2, process of the preparation of crystalline esmirtazapine hydrochloride comprising the steps of:

a) dissolving Esmirtazapine in ethyl acetate

b) adding hydrochloric acid, and

c) isolating Esmirtazapine hydrochloride salt.

4. A compound according to claim 2, process of the preparation of crystalline
esmirtazapine fumarate comprising the steps of:

a) dissolving Esmirtazapine in ethanol

b) adding fumaric acid, and

c) isolating Esmirtazapine fumarate salt.

5. A compound according to claim 2, process of the preparation of crystalline
esmirtazapine oxalate comprising the steps of:

a) dissolving Esmirtazapine in ethanol

b) adding oxalic acid, and

c) isolating Esmirtazapine oxalate salt.

6. A compound according to claim 2, process of the preparation of crystalline
esmirtazapine maleate comprising the steps of:

a) dissolving Esmirtazapine in ethanol

b) adding maleic acid, and

c) isolating Esmirtazapine maleate salt.

7. A compound according to claim 2, process of the preparation of crystalline
esmirtazapine salicylate comprising the steps of :

a) dissolving Esmirtazapine in ethanol

b) adding salicylic acid, and

c) isolating Esmirtazapine salicylate salt.

8. The process according to claims 3-7, wherein esmirtazapine salt is isolated by
filtration.