Field of the Invention:

The present invention provides a process for the preparation of amorphous form of (±)-4'-
[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-lH-l-benzazepin-l-yl)carbonyl]-o-tolu-iso-toluidide represented by the following structural formula-1:

Formula-1 "(±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-lH-l-benzazepin-l-yl)carbonyl]-o-tolu-m-toluidide" is commonly known as Tolvaptan. Tolvaptan is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis and the syndrome of inappropriate antidiuretic harmone (SIADH). Tolvaptan was approved by USFDA on May 19, 2009, and is sold by Otsuka pharmaceutical company under the trade name Samsca and in India under the trade name Tolvat, Tolsama and Natrise. Tolvaptan is also known as "OPC-41061".

Background of the Invention:

Benzazepine compounds such as Tolvaptan and process for their preparation was first disclosed in US 5258510.

The main concern for the formulation development of Tolvaptan was the low bio-availability of Tolvaptan.

The low bio-availability of Tolvaptan was due to its insoluble nature in water, and it is pH independent solubility. In order to improve the dissolution and thereby enhance the bio-availability, amorphous powder is used in the tablet formulation. The amorphous form of Tolvaptan was first reported in US5258510.

JP4210355B disclosed the preparation of amorphous Tolvaptan composite by adding Tolvaptan with hydroxypropylcellulose in pharmaceutical preparation.

WO 2008156217 disclosed a novel pharmaceutical solid preparation that has superior disintegration properties and excellent solubility leading to sufficient absorbability of active ingredients through gastrointestinal tract. The pharmaceutical solid (i.e. amorphous composite of Tolvaptan) was prepared by mixing Tolvaptan, hydroxypropyl cellulose containing a hydroxypropyl group and at least one member selected from carmellose, sodium carboxy methyl starch, crospovidone and low substituted hydroxy propylcellulose.

All the prior art processes involves the preparation of Tolvaptan amorphous composite, which is obtained by mixing excipients to Tolvaptan. Till date, there is no alternative process available for the preparation of amorphous form of Tolvaptan.

The above problem is solved by the present invention and provides a simple process for the preparation of amorphous form of Tolvaptan, which has high bio availability and useful in the synthesis of pharmaceutical composition to treat hypervolemic and euvolemic hyponatremia associated with congestive heart failure, cirrhosis and the syndrome of inappropriate antidiuretic harmone (SIADH).

Brief description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan, comprising of:

a) Dissolving the crystalline form of Tolvaptan in a suitable solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan,
d) optionally slurrying the amorphous Tolvaptan obtained in step-(c) in a suitable hydrocarbon solvent to provide amorphous Tolvaptan.

The second aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan, comprising of:

a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable solvent,
b) quenching the reaction mixture with an aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer to dryness to provide amorphous

Tolvaptan.
The third aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a suitable chloro solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding a suitable hydrocarbon solvent to the compound obtained in step-(c) at 25-35°C and then distilling off the solvent from the reaction mixture to provide amorphous Tolvaptan.
The fourth aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable chloro solvent,
b) quenching the reaction mixture with an aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,
e) adding a suitable hydrocarbon solvent to the compound obtained in step-(d) at 25-35°C and then distilling off the solvent from the reaction mixture to provide amorphous Tolvaptan.
The fifth aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan having less than 10% crystallinity, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a suitable solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding a suitable hydrocarbon solvent to the compound obtained in step-(c) at 25-35°C and then distilling off the solvent from the reaction mixture to provide amorphous

Tolvaptan having less than 10% crystallinity.
The sixth aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan having less than 10% crystallinity, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable solvent,
b) quenching the reaction mixture with aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,
e) adding a suitable hydrocarbon solvent to the compound obtained in step-(d) at 25-35°C and then distilling off the solvent from the reaction mixture to provide amorphous Tolvaptan having less than 10% crystallinity.
Brief description of the drawings:
Figure-1: Illustrates the powder X-Ray diffraction pattern of amorphous Tolvaptan
Detailed description of the Invention:
As used herein the present invention the term "suitable solvent" refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet.ether, benzene, toluene, xylene and the like; "chloro solvents" such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform, chloro benzene and the like; "ester solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dioxane and the like; "alcoholic solvents" such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol and isopentanol and the like; "nitrile solvents" such as acetonitrile, propionitrile, and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone and the like; and "polar solvents" such as water and acetic acid; and/or mixtures thereof.

The main object of the present invention is to provide a process for the preparation of amorphous form of Tolvaptan, which has high bio-availability.
The amorphous Tolvaptan of the present invention contain preferably less than about 10% crystallinity, and more preferably is essentially free of crystalline Tolvaptan and is non-hygroscopic.
The term "essentially free of crystalline Tolvaptan" means that no crystalline Tolvaptan can be detected in the PXRD of amorphous Tolvaptan.
The term "non-hygroscopic" regarding the amorphous Tolvaptan of the present invention is means that a tendency of amorphous Tolvaptan to absorb water is very negligible or it does not absorb water.
The amorphous Tolvaptan which is essentially free of crystalline form is obtained by the present invention, by distilling off the solvent from the reaction mixture completely to dryness. This can be carried out under reduced pressure in round bottomed flask, or by using buchi rotavapour, or roto cone vacuum dryer.
The first aspect of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a suitable solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan,
d) optionally slurrying the amorphous Tolvaptan obtained in step-(c) in a suitable hydrocarbon solvent to provide amorphous Tolvaptan.
Wherein,
In step-a) the "suitable solvent" is selected from chloro solvents, ether solvents, ester solvents, ketone solvents and nitrile solvents (or) its mixture with an alcoholic solvent; and
In step-d) the "suitable hydrocarbon solvent" is selected from n-hexane, n-heptane, n-pentane, cyclohexane, pet. ether, benzene, toluene and xylene.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:

a) Dissolving the crystalline form of Tolvaptan in a mixture of dichloromethane and methanol,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan,
d) slurrying the amorphous Tolvaptan obtained in step-(c) in cyclohexane to provide amorphous Tolvaptan.
The other preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a mixture of dichloromethane and methanol,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan,
d) slurrying the amorphous Tolvaptan obtained in step-(c) in n-pentane to provide amorphous Tolvaptan.
The other preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in tetrahydrofuran,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan.
The other preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in acetone,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan.
The second aspect of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-

3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable solvent,
b) quenching the reaction mixture with an aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer to dryness to provide amorphous Tolvaptan.
Wherein:
In step-(a) the "suitable solvent" is selected from chloro solvents, ether solvents and nitrile solvents (or) its mixture with an alcoholic solvent; and the "suitable reducing agent" is selected from lithium aluminium hydride, sodium borohydride, diisobutyl aluminium hydride, L-selectride, diborane, aluminium hydride, sodium cyano borohydride, 9-BBN-pyridine and tributyltin hydride; and
In step-b) the "inorganic acid" is selected from hydrochloric acid, hydrobromic acid and sulfuric acid.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with sodium borohydride in a mixture of dichloromethane and methanol,
b) quenching the reaction mixture with an aqueous hydrochloric acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer to dryness to provide amorphous Tolvaptan.
The "distillation to dryness" in the first and second aspects of the present invention means that total solvent from the reaction vessel is removed. This can be carried out under reduced pressure in a round bottomed flask (RBF) or by using buchi rotavapor, roto conce vacuum dryer etc.
The amorphous Tolvaptan obtained in the first and second aspects of the present invention can be taken out directly from the reaction vessel or by making slurry in a suitable

hydrocarbon solvent, followed by filtration and then drying.
The third aspect of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a suitable chloro solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding a suitable hydrocarbon solvent to the compound obtained step-(c) at 25-35°C and then distilling off the solvent from the reaction mixture to provide amorphous Tolvaptan.
Wherein;
In step-a) the "suitable chloro solvent" is selected from dichloromethane, dichloroethane, carbon tetrachloride, chlorobenzene and chloroform; and
In step-d) the "suitable hydrocarbon solvent" is selected from n-hexane, n-heptane, n-pentane, cyclohexane, pet.ether, benzene, toluene and xylene.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in dichloromethane,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding n-pentane to the compound obtained in step-(c) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan.
The fourth aspect of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable chloro solvent,
b) quenching the reaction mixture with an aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,

e) adding a suitable hydrocarbon solvent to the compound obtained in step-(d) at 25-3 5°C
and then distilling off the solvent completely from the reaction mixture to provide
amorphous Tolvaptan. Wherein:
The "suitable chloro solvent" in step-(a) and "suitable hydrocarbon solvent" in step-(e) are same as defined in step-(a) and step-(d) of third aspect of the present invention respectively;
The "suitable reducing agent" in step-(a) and the "inorganic acid" in step-(b) are same as defined in step-(a) and step-(b) of the second aspect of the present invention respectively.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with sodium borohydride in dichloromethane,
b) quenching the reaction mixture with an aqueous hydrochloric acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,
e) adding cyclohexane to the compound obtained in step-(d) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan.
The fifth aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan having less than 10% crystallinity, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a suitable solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding a suitable hydrocarbon solvent to the compound obtained in step-(c) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan having less than 10% crystallinity.
Wherein:
The "suitable solvent" is selected from ketone solvents, ether solvents, ester solvents and nitrile solvents (or) its mixture with an alcoholic solvent (or) a mixture of chloro solvent and an

alcoholic solvent; and the "suitable hydrocarbon solvent" is selected from n-hexane, n-heptane, n-pentane, cyclohexane, pet.ether, benzene, toluene and xylene.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan having less than 10% crystallinity, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a mixture of dichloromethane and methanol,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding n-pentane to the compound obtained in step-(c) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan having less than 10% crystallinity.
The sixth aspect of the present invention is to provide a process for the preparation of amorphous Tolvaptan having less than 10% crystallinity, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable solvent,
b) quenching the reaction mixture with aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,
e) adding a suitable hydrocarbon solvent the compound obtained in step-(d) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan having less than 10% crystallinity.
Wherein:
The "suitable solvent" in step-(a) and "suitable hydrocarbon solvent" in step-(e) are same as defined in step-(a) and step-(d) of fifth aspect of the present invention respectively;
The "suitable reducing agent" in step-(a) and the "inorganic acid" in step-(b) are same as defined in step-(a) and step-(b) of the second aspect of the present invention respectively.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Tolvaptan having less than 10% crystallinity, comprising of:

a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with sodium borohydride in a mixture if dichloromethane and methanol,
b) quenching the reaction mixture with aqueous hydrochloric acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,
e) adding n-pentane to the compound obtained in step-(d) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan having less than 10% crystallinity.
The N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methyl phenyl)-2-methylbenzamide compound of formula-2 is reduced using a suitable reducing agent selected from lithium aluminium hydride, sodium borohydride, diisobutyl aluminium hydride, L-selectride, diborane, aluminium hydride, sodium cyano borohydride, 9-BBN-pyridine and tributyltin hydride in a suitable solvent selected from chloro solvents, alcoholic solvent, hydrocarbon solvents, ether solvents, nitrile solvents, polar solvents and/or mixtures thereof, followed by distillation of the solvent from the reaction mixture provides Tolvaptan. Converting the obtained compound into amorphous form of Tolvaptan by the process disclosed in the first and third of the present invention.
Optionally, if the conversion of obtained Tolvaptan is carried out by the process disclosed in fifth aspect of the present invention provides amorphous Tolvaptan having less than 10% crystallinity.
The crystalline form of Tolvaptan used in the present invention and its process for preparation is disclosed in US8273735 B2.
The amorphous tolvaptan of the present invention is non-hygroscopic and free-flowing powder. The study of hygroscopic nature of amorphous Tolvaptan of the present invention was carried out by exposing the amorphous Tolvaptan to ammonium chloride solution for about 24 hours.
Water content of the amorphous Tolvaptan of the present invention before and after exposure to ammonium chloride was measured by using a Karl Fisher Titrator and the results are

Based on the above data, the amorphous Tolvaptan is non-hygroscopic in nature.
PXRD analysis of Tolvaptan of the present invention was carried out using BRUKER/AXS X-ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° at a continuous scan speed of 0.03°/min.
The particle size distribution of Tolvaptan of the present invention is measured using Malvern Mastersizer 2000 instrument.
The amorphous Tolvaptan of the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The reduction of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 is represented schematically as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of amorphous Tolvaptan using a mixture of dichloromethane and methanol as a solvent medium
Tolvaptan (25 gms), followed by dichloromethane (225 ml) and methanol (25 ml) were charged into a clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure until complete dryness to get amorphous solid. The obtained solid was slurried in cyclohexane (125 ml). Filtered the solid, washed with cyclohexane and then dried to get amorphous Tolvaptan.
Further the obtained compound was micronized and then dried at 75-85°C for about 24 hours. The obtained compound was cooled to 20-30°C provide amorphous Tolvaptan. Yield: 23.2 gms; PXRD of the obtained compound was shown in figure-1. Particle size distribution (Before micronization): D(0.1) is 6.42 um; D(0.5) 19.98 um; D(0.9) is 51.20 um; D(4,3) is 25.22 um; Specific surface area: 0.457 m2/g.
Particle size distribution (After micronization): D(0.1) is 0.15 um; D(0.5) is 5.27 um; D(0.9) is 19.77 um; D(4,3) is 9.32 um; Specific surface area: 10.2 m7g.
Example-2: Preparation of amorphous Tolvaptan using a mixture of dichloromethane and methanol as a solvent medium
Tolvaptan (25 gms), followed by dichloromethane (225 ml) and methanol (25 ml) were charged into a clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure until complete dryness to get a amorphous solid. The obtained solid was slurried in n-pentane (125 ml). Filtered the solid, washed with n-pentane and then dried to get amorphous Tolvaptan; Yield: 22.8 gms; Water content: 0.74 % w/w; PXRD of the obtained compound was shown in figure-1.
Example-3: Preparation of amorphous Tolvaptan using a mixture of dichloromethane and methanol as a solvent medium

Tolvaptan (25 gms), followed by dichloromethane (225 ml) and methanol (25 ml) were charged into a clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture; filtrate was transferred into buchi rotavapour and then distilled off the solvent under reduced pressure until complete dryness to get amorphous solid. The obtained solid was slurried in cyclohexane. Filtered the solid, washed with cyclohexane and then dried to get amorphous Tolvaptan. Yield: 23.0 gms; PXRD of the obtained compound was shown in figure-1.
Example-4: Preparation of amorphous Tolvaptan using a mixture of dichloromethane and methanol as a solvent medium
Tolvaptan (25 gms), followed by dichloromethane (225 ml) and methanol (25 ml) were charged into a clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture; filtrate was transferred into buchi rotavapour and then distilled off the solvent under reduced pressure to get amorphous solid. The amorphous solid was slurried in n-pentane. Filtered the solid, washed with n-pentane and then dried to get amorphous Tolvaptan.
Yield: 22.6 gms; PXRD of the obtained compound was shown in figure-1. Particle size distribution : D(0.1) is 29.85 urn; D(0.5) 130.08 μm; D(0.9) is 394.74μm; D(4,3) is 176.66 μm;; Specific surface area: 0.099 m2/g.
Example-5: Preparation of amorphous Tolvaptan using tetrahydrofuran as a solvent medium
Tolvaptan (50 gms) and tetrahydrofuran (250 ml) were charged into a clean & dry RBF. The reaction mixture was heated to 40°C and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure until complete dryness to get amorphous Tolvaptan. Yield: 45 gms; PXRD of the obtained compound was shown in figure-1.
Example-6: Preparation of amorphous Tolvaptan using acetone as a solvent medium
Tolvaptan (25 gms) and acetone (625 ml) were added to clean & dry RBF. The reaction
mixture was heated 50-60°C and stirred until the compound was dissolved. Filtered the reaction
mixture, distilled off the solvent from the filtrate under reduced pressure until complete dryness I

to get amorphous Tolvaptan.
Yield: 22 gms; PXRD of the obtained compound was shown in figure-1.
Example-7: Preparation of amorphous Tolvaptan using ethyl acetate as a solvent medium
Tolvaptan (25 gms) and ethyl acetate (2000 ml) were added to clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure until complete dryness to get amorphous Tolvaptan. Yield: 20 gms; PXRD of the obtained compound was shown in figure-1.
Example-8: Preparation of amorphous Tolvaptan using dichloromethane as a solvent medium
Tolvaptan (25 gms) and dichloromethane (625 ml) were added to clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate until complete dryness to get amorphous Tolvaptan. Yield: 23.0 gms; PXRD of the obtained compound was shown in figure-1.
Example-9: Preparation of amorphous Tolvaptan using dichloromethane as a solvent medium
Tolvaptan (20 gms) and dichloromethane (1000 ml) were charged into a clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure and added n-pentane (50 ml) at 25-35°C. Co-distillation of the solvent from the reaction mixture to get amorphous Tolvaptan. Yield: 11 gms; PXRD of the obtained compound was shown in figure-1.
Example-10: Preparation of amorphous Tolvaptan using tetrahydrofuran as a solvent medium
Tolvaptan (20 gms) and tetrahydrofuran (180 ml) were added to clean & dry RBF. The reaction mixture was heated to 40°C and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure and added n-pentane (100 ml) at 25-35°C. Co-distillation of the solvent from the reaction mixture to get

amorphous Tolvaptan. !
Yield: 15 gms; The obtained compound is having less than 10% crystallinity.
Example-11: preparation of amorphous Tolvaptan using acetone as a solvent medium
Tolvaptan (20 gms) and acetone (180 ml) were added to clean & dry RBF. The reaction mixture was heated to 50-60°C and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure and added n-pentane (100 ml) at 25-35°C. Co-distillation of the solvent from the reaction mixture to get amorphous Tolvaptan. Yield: 15 gms; The obtained compound is having less than 10% crystallinity.
Example-12: preparation of amorphous Tolvaptan using dichloromethane and methanol as a solvent medium
Tolvaptan (20 gms), followed by dichloromethane (180 ml) and methanol (20 ml) were added to clean & dry RBF. The reaction mixture was heated to reflux temperature and stirred until the compound was dissolved. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure and added n-pentane (100 ml) at 25-35°C. Co-distillation of the solvent from the reaction mixture to get amorphous Tolvaptan. Yield: 16.5 gms; The obtained compound is having less than 10% crystallinity.
Example-13: Preparation of amorphous Tolvaptan using a mixture of dichloromethane and methanol as a solvent medium
A mixture of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 (25 gms) and dichloromethane (75 ml) was stirred for 15 minutes at 25-35°C. The reaction mixture was cooled to -10 to -4°C, sodium borohydride (1.04 gms) was added to it lot wise at -10 to -4°C and then stirred for 20 minutes. Methanol (25 ml) was added slowly to the reaction mixture at -10 to -4°C and stirred until the reaction was completed. After completion of the reaction, pH of the reaction mixture was neutralized with aqueous hydrochloric acid. The temperature of the reaction mixture was raised to 10-20°C. Both the organic and aqueous layers were separated; distilled off the solvent from the organic layer under reduced pressure until complete dryness to get amorphous Tolvaptan. Yield: 20 gms; PXRD of the obtained compound was shown in figure-1.

Example-14: Preparation of amorphous Tolvaptan using tetrahydrofuran as a solvent
medium
A mixture of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-berizo[b]azepine-l-carbonyl)-
3-methyl phenyl)-2-methylbenzamide compound of formula-2 (25 gins) and tetrahydrofuran (75 ml) was stirred for 15 minutes at 25-35°C. The reaction mixture was cooled to -10 to -4°C, sodium borohydride (1.04 gms) was added to it lot wise at -10 to -4°C and then stirred until the reaction was completed. After completion of the reaction, pH of the reaction mixture was neutralized with aqueous hydrochloric acid. The temperature of the reaction mixture was raised to 10-20°C. Both the organic and aqueous layers were separated; distilled off the solvent from the organic layer under reduced pressure until complete dryness to get amorphous Tolvaptan. Yield: 18.0 gms; PXRD of the obtained compound was shown in figure-1.
Example-15: Preparation of amorphous Tolvaptan using dichloromethane as a solvent medium
A mixture of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methyl phenyl)-2-methylbenzamide compound of formula-2 (25 gms) and dichloromethane (75 ml) was stirred for 15 minutes at 25-35°C. The reaction mixture was cooled to -10 to -4°C, sodium borohydride (1.04 gms) was added to it lot wise at -10 to -4°C and then stirred until the reaction was completed. After completion of the reaction, pH of the reaction mixture was neutralized with aqueous hydrochloric acid. The temperature of the reaction mixture was raised to 10-20°C. Both the organic and aqueous layers were separated; distilled off the solvent from the organic layer under reduced pressure until complete dryness to get amorphous Tolvaptan. Yield: 16.0 gms; PXRD of the obtained compound was shown in figure-1.
Example-16: Preparation of amorphous Tolvaptan using dichloromethane as a solvent medium
A mixture of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methyl phenyl)-2-methylbenzamide compound of formula-2 (25 gms) and dichloromethane (75 ml) was stirred for 15 minutes at 25-35°C. The reaction mixture was cooled to -10 to -4°C, sodium borohydride (1.04 gms) was added to it lot wise at -10 to -4°C and then stirred until the reaction was completed. After completion of the reaction, pH of the reaction mixture was neutralized with aqueous hydrochloric acid. The temperature of the reaction mixture was raised

to 10-20°C. Both the organic and aqueous layers were separated; distilled off the solvent from the organic layer under reduced pressure and added cyclohexane (125 ml) at 25-35°C. Co-distillation of the solvent from the reaction mixture to get amorphous Tolvaptan. Yield: 16.2 gms; PXRD of the obtained compound was shown in figure-1.

Example-17: Preparation of amorphous Tolvaptan using a mixture of dichloromethane and methanol as a solvent medium

A mixture of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-
3-methylphenyl)-2-methylbenzamide compound of formula-2 (25 gms) and dichloromethane (75 ml) was stirred for 15 minutes at 25-35°C. The reaction mixture was cooled to -10 to -4°C, sodium borohydride (1.04 gms) was added to it lot wise at -10 to -4°C and then stirred for 20 minutes. Methanol (25 ml) was added slowly to the reaction mixture at -10 to -4°C and stirred until the reaction was completed. After completion of the reaction, pH of the reaction mixture was neutralized with aqueous hydrochloric acid. The temperature of the reaction mixture was raised to 10-20°C. Both the organic and aqueous layers were separated; distilled off the solvent from the organic layer under reduced pressure and added n-pentane (125 ml) at 25-35°C. Co-distillation of the solvent from the reaction mixture to get amorphous Tolvaptan. Yield: 20 gms; The obtained compound is having less than 10% crystallinity.

Example-18: Preparation of amorphous Tolvaptan using tetrahydrofuran as a solvent medium
A mixture of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methyl phenyl)-2-methylbenzamide compound of formula-2 (25 gms) and tetrahydrofuran (75 ml) was stirred for 15 minutes at 25-35°C. The reaction mixture was cooled to -10 to -4°C, sodium borohydride (1.04 gms) was added to it lot wise at -10 to -4°C and then stirred until the reaction was completed. After completion of the reaction, pH of the reaction mixture was neutralized with aqueous hydrochloric acid. The temperature of the reaction mixture was raised to 10-20°C. Both the organic and aqueous layers were separated; distilled off the solvent from the organic layer under reduced pressure and added cyclohexane (125 ml) at 25-3 5°C. Co-distillation of the solvent from the reaction mixture to get amorphous Tolvaptan.
Yield: 20 gms; The obtained compound is having less than 10% crystallinity.

We Claim:

1. A non-hygroscopic amorphous free-flowing powder form of Tolvaptan.

2. The amorphous tolvaptan of claim 1, wherein upon exposure to an atmosphere of about 30% humidity for a period of about 24 hours, a weight gain thereof is less than 0.5 weight percents of its total weight.

3. A process for the preparation of amorphous Tolvaptan, comprising of:

a) Dissolving the crystalline form of Tolvaptan in a suitable solvent selected from chloro solvents, ester solvents, ether solvents, nitrile solvents, ketone solvents or its mixture with an alcoholic solvent,

b) filtering the reaction mixture,

c) distilling off the solvent from the filtrate to dryness to provide amorphous Tolvaptan,

d) optionally slurrying the amorphous Tolvaptan obtained in step-(c) in a suitable hydrocarbon solvent to provide amorphous Tolvaptan.

4. A process for the preparation of amorphous Tolvaptan, comprising of:

a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable solvent selected from chloro solvents, ether solvents, nitrile solvents or its mixture with an alcoholic solvent,

b) quenching the reaction mixture with aqueous inorganic acid,

c) separating both the organic and aqueous layers,

d) distilling off the solvent from the organic layer to dryness to provide amorphous Tolvaptan.

5. A process for the preparation of amorphous Tolvaptan, comprising of:
a) Dissolving the crystalline form of Tolvaptan in a suitable chloro solvent,
b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding a suitable hydrocarbon solvent to the compound obtained in step-(c) at 25-35°C and then distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan.

6. A process for preparation of amorphous Tolvaptan, comprising of:
a) Reducing the N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide compound of formula-2 with a suitable reducing agent in a suitable chloro solvent,
b) quenching the reaction mixture with aqueous inorganic acid,
c) separating both the organic and aqueous layers,
d) distilling off the solvent from the organic layer,
e) adding a suitable hydrocarbon solvent to the compound obtained in step-(d) at 25-35°C and distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan.

7. A process for preparation of amorphous Tolvaptan having less than 10% crystallinity,
comprising of:

a) Dissolving the crystalline form of Tolvaptan in a suitable solvent selected from ester solvents, ether solvents, nitrile solvents, ketone solvents or its mixture with an alcoholic solvent, or a mixture of chloro solvent and an alcoholic solvent,

b) filtering the reaction mixture,
c) distilling off the solvent from the filtrate,
d) adding a suitable hydrocarbon solvent to the compound obtained in step-(c) at 25-35°C and distilling off the solvent completely from the reaction mixture to provide amorphous Tolvaptan having less than 10% crystallinity.

8. A process according to claim 4 and 6, wherein:
The suitable reducing agent is selected from lithium aluminium hydride, sodium borohydride, diisobutyl aluminium hydride, L-selectride, diborane, aluminium hydride,
sodium cyano borohydride, 9-BBN-pyridine and tributyltin hydride; and the suitable inorganic acid is selected from hydrochloric acid, hydrobromic acid and sulfuric acid.

9. Amorphous Tolvaptan having particle size distribution of D(0.9) less than 100 μm, preferably less than 50 μm, and more preferably less than 20 μm.

10. An amorphous Tolvaptan having water content less than 1.5 % (w/w), preferably less than 1%, more preferably less than 0.8%.