This application claims priority to Indian patent application numbered 1577/CHE/2011 filed on May 06, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to novel hydrated crystalline form of Tolvaptan and process for the preparation thereof.

The present invention further relates to anhydrous crystalline form of Tolvaptan and process for the preparation thereof.

BACKGROUND OF THE INVENTION:

Tolvaptan, chemically known as (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o tolu-m-toluidide (OPC-41061), is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH), the trade name is Samsca, Tolvaptan is structurally as shown below.

U.S patent 5258510 discloses a process for the benzazepines and its derivatives thereof. The diffculties arise in the preparation especially when a C5-substituent is required or if electron with -drawing groups are present in the aromatic ring. The preparation of Tolvaptan required 11 liner steps, involves very critical conditions that limit the generality of this approach in Scheme -1;

Scheme -1

U.S application No US20090306369 disclosed a process for the preparation of crystalline Tolvaptan by using methanol and water.

WO 2010026971 application disclosed an industrial method for the preparation of amorphous Tolvaptan by using spray drying technique. In this process, Tolvaptan and hydroxypropylcellulose were dissolved in dichloromethane and ethanol. The resulting mixture was treated by a spray dryer and immediately dried by a vacuum dryer, thus obtaining amorphous Tolvaptan.

Still, there is a need to develop a novel polymorph and process for preparation of crystalline Tolvaptan with out contamination of other polymorphic form. The inventors of the present invention found a novel crystalline polymorphic form and an efficient process for the preparation of crystalline Tolvaptan which is safe, cost effective and eco-friendly process.

SUMMARY OF THE INVENTION:

The main object of the present invention relates to novel hydrated crystalline form of Tolvaptan and process for the preparation thereof.

In another aspect, the present invention relates to crystalline Tolvaptan monohydrate having water of hydration around 4%.

Yet another object of the present invention relates to anhydrous crystalline form of Tolvaptan and process for the preparation thereof.

Yet another object of the present invention relates to purification of crystalline anhydrous Tolvaptan.

Another aspect of the present invention provides a process for the preparation of crystalline Tolvaptan monohydrate comprising the steps of:

a) dissolving Tolvaptan in isopropyl alcohol,

b) adding water,

c) cooling the reaction mass, and

d) isolating crystalline Tolvaptan monohydrate.

Yet another aspect of the present invention provides an anhydrous crystalline Tolvaptan.

Yet another aspect of the present invention provides a process for the preparation of crystalline anhydrous Tolvaptan comprising the steps of

a) dissolving Tolvaptan in an organic solvent or mixture of solvents,

b) optionally adding a second solvent,

c) removing the solvent, and

d) isolating anhydrous crystalline Tolvaptan

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig.1 depicts X-ray powder diffraction (XRD) pattern of hydrated crystalline form of Tolvaptan.

Fig.2 depicts the Differential Scanning Calorimetry (DSC) thermogram of hydrated crystalline form of Tolvaptan.

Fig.3 depicts the TGA/DTA thermogram of hydrated crystalline form of Tolvaptan.

Fig 4 depicts X-ray powder diffraction (XRD) pattern of crystalline anhydrous form of Tolvaptan.

Fig.5 depicts the Differential Scanning Calorimetry (DSC) thermogram of crystalline anhydrous form of Tolvaptan.

Fig.6 depicts the TGA/DTA thermogram of crystalline anhydrous form of Tolvaptan.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to crystalline Tolvaptan monohydrate and process for the preparation thereof.

In one embodiment, the present invention relates to crystalline Tolvaptan monohydrate characterized by PXRD pattern as shown in Figure 1.

In another embodiment, the present invention relates to crystalline Tolvaptan monohydrate characterized by PXRD diffraction having reflections at about 12.2 ± 0.2, 17.9 ± 0.2, 21.9 ± 0.2, 23.1 ±0.2 2theta.

Yet another embodiment, the present invention relates to crystalline Tolvaptan monohydrate characterized by DSC thermogram as shown in Figure 2.

Yet another embodiment, the present invention relates to crystalline Tolvaptan monohydrate characterized by TGA thermogram as shown in Figure 3.

Yet another embodiment, the present invention relates to process for the preparation of crystalline Tolvaptan monohydrate comprising the steps of

a) dissolving Tolvaptan in isopropyl alcohol,

b) adding water,

c) cooling the reaction mass, and

c) isolating crystalline Tolvaptan monohydrate

According to the present invention, Tolvaptan is added with isopropanol and heated to reflux temperature. To the resultant solution is added water slowly and maintained at room temperature for over night. Cooled the reaction mixture and filtered to obtain crystalline Tolvaptan monohydrate.

According to the present invention, hydrated crystalline form of Tolvaptan is a monohydrate having water content of about 4%.

According to the present invention, hydrated crystalline form of Tolvaptan is a dihydrate having water content of about 8%.

According to the present invention, hydrated crystalline form of Tolvaptan is a sesqui having water content of about 6%.

Another embodiment of the present invention relates to crystalline anhydrous Tolvaptan and process for the preparation thereof.

Yet another embodiment, the present invention relates to crystalline anhydrous Tolvaptan characterized by PXRD pattern as shown in Figure 4.

Another embodiment, the present invention relates to crystalline anhydrous Tolvaptan characterized by PXRD diffraction having reflections at about 4.6 ± 0.2, 11.7 ± 0.2, 13.5 ± 0.2, 13.9 ± 0.2, 15.3 ± 0.2, 16.4 ± 0.2,18.6± 0.2, 23.3± 0.2 2 theta.

Yet another embodiment, the present invention relates to crystalline anhydrous Tolvaptan characterized by DSC thermogram as shown in Figure 5.

In yet another embodiment, the present invention relates to crystalline anhydrous Tolvaptan characterized by TGA thermogram as shown in Figure 6.

Another embodiment of the present invention relates to process for the preparation of crystalline anhydrous Tolvaptan comprising the steps of

a) dissolving Tolvaptan in an organic solvent or mixture of solvents,

b) optionally adding a second solvent,

c) removing the solvent, and

d) isolating crystalline anhydrous Tolvaptan

According to the present invention, Tolvaptan is dissolved in an organic solvent selected form ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or their mixtures thereof. The resultant mixture is optionally added a second solvent selected from water or alcohols such as methanol, ethanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol and optionally given carbon treatment,. Removing the solvent using conventional techniques such as filtration, distillation, vacuum-distillation affords crystalline anhydrous Tolvaptan.

According to the present invention, the crystalline anhydrous Tolvaptan have a water content of less than about 2%.

Yet another aspect of the present invention is to provide purification of crystalline anhydrous Tolvaptan comprising the steps of

a) dissolving Tolvaptan in an organic solvent or mixture of solvents,

b) removing the solvent, and

c) isolating crystalline anhydrous Tolvaptan

According to the present invention, Tolvaptan is dissolved in an organic solvent selected form alcohols such as methanol, ethanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile or their mixtures thereof. Optionally giving carbon treatment and removing the solvent by using conventional techniques such as as filtration, distillation, vacuum-distillation to obtain crystalline anhydrous Tolvaptan.

The examples given below illustrate few aspects of the invention and should not be construed to limit the scope of the present invention.

EXAMPLES

Example 1: Process for the preparation of Crystalline Tolvaptan hydrate Crude Tolvaptan (10 g) was dissolved in Isopropyl alcohol (300 ml) at reflux temperature. A clear solution was formed. To the reaction mass was added 200 ml of water for one to two hours. The resulted solids were cooled to room temperature and stirred for overnight. The solids were separated by filtration and dried to give pure tolvaptan monohydrtare (8g) (HPLC purity 99.7 %).

M.C - 3.9%

Example 2: Process for the preparation of crystalline anhydrous Tolvaptan Crude Tolvaptan (5 g) was dissolved in Methylisobutylketone 150 ml with stirring at 120-130° C over a period of 60 minutes. A clear solution was formed. Stirred the reaction mass at reflux temperature for one to two hours. Cooled the reaction mass to room temperature and stirred for overnight. The obtained solids were separated by filtration and dried to give pure anhydrous tolvaptan (7g) (HPLC purity 99.5 %). M.C = 0.7

Example 3: Process for the preparation of crystalline anhydrous Tolvaptan Tolvaptan (100 g) was dissolved in methanol (2000 ml) and 5 g of activated carbon was added and stirred for 30 minutes. Removed the carbon by filtration through celite bed. Methanol was removed by atmospheric distillation up to 5 volumes, cooled the reaction mass to 0-5 °C. The Resulted solid was filtered and washed with water (500 ml). The wet solid was dried at 50 ° C under vacuum to give pure anhydrous Tolvaptan. (HPLC purity 99.7 %).

Example 4: Process for the preparation of crystalline anhydrous Tolvaptan Crude Tolvaptan (5 g) was dissolved in ethanol (150ml) with stirring at 80-90° C over a period of 60 minutes. A clear solution was formed. The reaction mass was maintained under stirring at reflux temperature for one to two hours. The resulted solution was cooled to room temperature and stirred for overnight. The obtained solids were separated by filtration and dried to give pure anhydrous tolvaptan (8.5g) (HPLC purity 99.6 %). (All individual impurities less than 0.1 %) M.C = 0.3%

Example 5: Process for the preparation of crystalline anhydrous Tolvaptan Crude Tolvaptan (5 g) was added ethyl acetate (250 ml) under stirring at 80-90° C over a period of 60 minutes. A clear solution was formed. The reaction mass was maintained at reflux temperature for one to two hours. The resulted solution was distilled off atmospherically and then cooled to room temperature and stirred for overnight. The obtained solids were separated by filtration and dried to give pure tolvaptan (6.5g) (HPLC purity 99.9 %). M.C=0.41%

Example 6: Process for the preparation of crystalline anhydrous Tolvaptan Crude Tolvaptan (5 g) was added ethyl acetate (50 ml) and methanol (20 ml). The reaction mixture was maintained at 70-90° C for a period of 60 minutes. A clear solution was formed. The reaction mass was stirred at reflux temperature for one to two hours. Added 0.5 g of activated carbon and continued the maintenance under reflux for 30 minutes. Carbon was removed by filtration through celite bed. The resulted solution was distilled off atmospherically and cooled to room temperature and stirred for overnight. Thus obtained solids were separated by filtration and dried to give pure anhydrous tolvaptan
(8g) with all impurities less than 0.10% M.C = 0.13%

Example 7: Process for the preparation of crystalline anhydrous Tolvaptan Crude Tolvaptan (10 g) was added in methanol (200 ml) and raised the temperature to reflux temperature. A clear solution was formed. The reaction mass was added 200 ml of water for one to two hours at reflux temperature. The resulted solids were cooled to room temperature and stirred for overnight. Thd obtained solids were separated by filtration and dried to give pure anhydrous tolvaptan (7.5g) (HPLC purity 99.89 %). M.C = 0.41%

Example 8: Process for the preparation of crystalline anhydrous Tolvaptan Crude Tolvaptan (10 g) is added ethanol (200 ml) and raised the temperature to reflux temperature. A clear solution was formed. The reaction mass was maintained under stirring at reflux temperature and added 200 ml of water for one to two hours. The resulted solids were cooled to room temperature and stirred for overnight. The obtained solids were separated by filtration and dried to give pure anhydrous tolvaptan (8.6g) (HPLC purity 99.6 %). M.C = 0.2%

We Claim:

1. Tolvaptan monohydrate.

2. Crystalline Tolvaptan monohydrate characterized by PXRD diffraction having reflections at least selected from one at about 12.2 ± 0.2, 17.9 ± 0.2, 21.9 ± 0.2, 23.1 ± 0.2 26.

3. A process for the preparation of crystalline Tolvaptan monohydrate comprising the steps of;

a) dissolving Tolvaptan in isopropyl alcohol,

b) adding water,

c) cooling the reaction mass, and

d) isolating crystalline Tolvaptan monohydrate.

4. The process according to claim 3, wherein the water in step b is added at reflux temperature and the crystalline Tolvaptan monohydrate is isolated by filtration.

5. Anhydrous crystalline Tolvaptan.

6. Anhydrous crystalline Tolvaptan characterized by PXRD diffraction having reflections at least selected from one at about 4.6 ± 0.2, 11.7 ± 0.2, 13.5 ± 0.2, 13.9 ± 0.2, 15.3 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 23.3 ± 0.2 20.

7. A process for the preparation of anhydrous crystalline Tolvaptan comprising the steps of;

a) dissolving Tolvaptan in an organic solvent or mixture of solvents,

b) optionally adding a second solvent,

c) removing the solvent, and

d) isolating anhydrous crystalline Tolvaptan.

8. The process according to claim 7, wherein the organic solvent is selected form alcohols such as methanol, ethanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitrites such as acetonitrile, propionitrile or mixtures thereof and the second solvent is water.

9. A pharmaceutical composition comprising tolvaptan monohydrate or anhydrous tolvaptan and a pharmaceutical^ acceptable carrier.

10. Tolvaptan having purity more than 99.8% by HPLC