FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF TOLVAPTAN"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
\. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF
TOLVAPTAN
FIELD OF THE INVENTION:
The present invention relates to a novel process for the preparation of amorphous form of tolvaptan active pharmaceutical ingredient. The process comprises, providing a solution of tolvaptan active pharmaceutical ingredient in an organic solvent, removing solvent from the solution of tolvaptan active pharmaceutical ingredient by agitated thin film drying and isolating amorphous form of tolvaptan active pharmaceutical ingredient.
BACKGROUND OF THE INVENTION:
Tolvaptan is chemically (±)-4'-[(7-chloro-2, 3, 4, 5-tetrahydro-5-hydroxy-l#-l-benzazepin-1-yl) carbonyl]-o-tolu-m-toluidide and is known from U.S. Patent No. 5,258,510 and is represented by compound of structural formula I.

Tolvaptan is a selective vasopressin V2-receptor antagonist, marketed in USA under the proprietary name SAMSCA and is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia [serum sodium < 125 m Eq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction], including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
U.S. Patent No. 5,258,510 describes a process of preparing amorphous form of tolvaptan active pharmaceutical ingredient by precipitating it in methanol solvent. However, this

process of preparing amorphous form of tolvaptan active pharmaceutical ingredient is not effective on the large scale as it gives mixture of crystalline and amorphous form of tolvaptan active pharmaceutical ingredient and thus is not commercially suitable.
U.S. patent publication no. 2007/0185323 describes a process of preparing amorphous form of tolvaptan active pharmaceutical ingredient by precipitating it in methanol / ether solvents. However, this process of preparing amorphous form of tolvaptan active pharmaceutical ingredient is not effective on the large scale as it gives mixture of crystalline and amorphous form of tolvaptan active pharmaceutical ingredient and thus is not commercially suitable.
U.S. patent publication no. 2009/0306369 describes crystallization of tolvaptan active pharmaceutical ingredient in mixture of methanol / water solvents and the resulting crystalline form is characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 4.7, J 5.4, 18.7, 21.7, 23.5 degrees 2-theta.
PCT publication no. 2010/0026971 described a process of preparing amorphous form of tolvaptan active pharmaceutical ingredient by using spray drying technique.
Indian patent application no. 1577/CHE/2011 describes novel hydrated and anhydrous crystalline form of tolvaptan active pharmaceutical ingredient and processes of preparing the same.
Our own Indian patent application no. 1320/MUM/2011 describes crystalline form II and form III of tolvaptan active pharmaceutical ingredient and processes of preparing the same.
The agitated thin film drying (ATFD) technique is known in prior art such as those described in US patent publication no. 2008/0214823, PCT publication no. 2008/0104956 and 2009/0019661 etc.

The agitated thin film drying (ATFD) technique uses high vacuum along with elevated temperatures which allows operation at lower temperatures. This allows for a short residence time for the product in the drier. The required evaporation can be achieved in a single pass, avoiding product recirculation and possible degradation. The operating pressures are from atmospheric down to 1 mbar. The equipment can be operated at a wide range of temperatures, such as 25 to 350° C or more. The concentrations, solvent type, temperature, vacuum, and feeding rate is set to combinations where the tolvaptan active pharmaceutical ingredient coming from the inlet precipitates essentially instantly.
There is need in the art to provide a process for the preparation of amorphous form of tolvaptan active pharmaceutical ingredient which is effective on large scale and commercially suitable.
SUMMARY OF THE INVENTION:
The present inventors have developed a novel process for preparing amorphous form of tolvaptan active pharmaceutical ingredient. The present process does not require lyophilization or repeated crystallizations. The present process is simple and provides amorphous form of tolvaptan active pharmaceutical ingredient in a single step by agitated thin film drying.
In one aspect of the present invention is provided a novel process for the preparation of amorphous form of tolvaptan active pharmaceutical ingredient.
In another aspect of the present invention is provided a process for the preparation of amorphous form of tolvaptan active pharmaceutical ingredient, wherein the process comprises,
a) providing a solution of tolvaptan active pharmaceutical ingredient in an organic solvent,
b) removing the solvent from the solution obtained in step a) by agitated thin film drying, and

c) isolating amorphous form of tolvaptan active pharmaceutical ingredient from the agitated thin film dryer.
DETAIL DESCRIPTION OF THE INVENTION:
Tolvaptan used for the present invention may be formed by methods disclosed in the art such as those described in U.S. Patent nos. 5,258,510; U.S. patent publication no. 2007/0185323, 2009/0306369 which are incorporated herein by reference only.
A solution of tolvaptan active pharmaceutical ingredient in an organic solvent may be formed by dissolving tolvaptan active pharmaceutical ingredient in an organic solvent at a temperature in the range of 25°C to 50°C to get a solution of tolvaptan active pharmaceutical ingredient in an organic solvent.
Examples of organic solvent may include alcohol solvents, ketone solvents, ester solvents, nitrile solvents, halogenated aliphatic hydrocarbon solvents, ether solvents or mixtures thereof.
The alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ketone solvents may be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
The ester solvents may be selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.
The nitrile solvents may be selected from the group comprising of acetonitrile, propionitrile or mixture(s) thereof.

The halogenated aliphatic hydrocarbon solvents may be selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The ether solvents may be selected from the group comprising of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
The solution of tolvaptan active pharmaceutical ingredient may be optionally treated with activated charcoal and the resulting solution is filtered through hyflo bed to get filtrate.
The resulting filtrate is fed into an agitated thin film dryer (ATFD). The solvent is subsequently removed from the solution by agitated thin film drying.
The drying process may be accompanied by heating at a temperature in the range of 30°C to 60°C and at a vacuum of 600-720 mm Hg.
The feeding rate of the solution may be controlled in such a way to facilitate the thin film formation and the evaporation rate. The rotor and vapor duct can have a sealing system so that the drying can preferably be carried under vacuum. Vacuum operation also facilitates amorphous form of tolvaptan active pharmaceutical ingredient to be obtained without degradation.
The term "isolating amorphous form of tolvaptan active pharmaceutical ingredient" according to the present invention includes unloading, amassing, gathering, scaling and/or piling amorphous form of tolvaptan active pharmaceutical ingredient.
The amorphous form of tolvaptan active pharmaceutical ingredient may be optionally further dried under vacuum at a temperature in the range of 55°C to 75oC for a period of 1

hour to 8 hours to obtain amorphous form of tolvaptan active pharmaceutical ingredient with desired residual solvent content.
EXAMPLES:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of amorphous form of tolvaptan active pharmaceutical ingredient.
A solution of tolvaptan active pharmaceutical ingredient (lOOgm) in methanol (1200ml) was fed into ATFD at a vacuum of 600-720 mm Hg and ajacket temperature of 45-54°C. The obtained solid was dried in a vacuum tray drier at a vacuum of 670 mm Hg and a temperature of 70°C for 5 hours to get title compound. Yield: 82gm
Example 2: Preparation of amorphous form of tolvaptan active pharmaceutical ingredient.
A solution of tolvaptan active pharmaceutical ingredient (lOOgm) in methanol (1200ml) was treated with activated charcoal (l0 gm) and the resulting solution was filtered through hyflo bed to get filtrate. The resulting filtrate was fed into ATFD at a vacuum of 600-720 mm Hg and a jacket temperature of 45-54°C. The obtained solid was dried in a vacuum tray drier at a vacuum of 670 mm Hg and a temperature of 70°C for 6 hours to get title compound. Yield: 80gm

WE CLAIM:
1. A novel process for the preparation of amorphous form of tolvaptan active
pharmaceutical ingredient, wherein the process comprises,
a) providing a solution of tolvaptan active pharmaceutical ingredient in an organic solvent,
b) removing the solvent from the solution obtained in step a) by agitated thin film drying, and
c) isolating amorphous form of tolvaptan active pharmaceutical ingredient from the agitated thin film dryer.

2. The process according to claim no. 1, wherein the solution of tolvaptan active pharmaceutical ingredient in an organic solvent is formed by dissolving tolvaptan active pharmaceutical ingredient in an organic solvent at a temperature in the range of 25°C to 50°C.
3. The process according to claim nos. 1 and 2, wherein an organic solvent is selected from the group comprising of alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof, ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof, ester solvent such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof, nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof, halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof, ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.

4. The process according to claim no. 1, wherein the solution of tolvaptan active pharmaceutical ingredient is optionally treated with activated charcoal and the resulting solution is filtered through hyflo bed to get filtrate, followed by resulting filtrate is fed into an agitated thin film dryer (ATFD) and then the solvent; is subsequently removed from the solution by agitated thin film drying.
5. The process according to claim nos. 1 and 4, wherein the drying process is accompanied by heating at a temperature in the range of 30°C to 60°C and at a vacuum of 600-720 mm Hg.
6. The process according to claim no. 1, wherein an amorphous form of tolvaptan active pharmaceutical ingredient isolated from the agitated thin film dryer by steps of unloading, amassing, gathering, scaling and/or piling.
7. The process according to claim no. 7, wherein the isolated amorphous form of tolvaptan active pharmaceutical ingredient is optionally further dried under vacuum at a temperature in the range of 55°C to 75°C for a period of 1 hour to 8 hours to obtain amorphous form of tolvaptan active pharmaceutical ingredient with desired residual solvent content.