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
"NOVEL POLYMORPHIC FORMS OF TOLVAPTAN."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17,thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL POLYMORPHIC FORMS OF TOLVAPTAN
FIELD OF THE INVENTION:
The present invention relates to novel crystalline polymorphs of tolvaptan hereinafter referred as crystalline form II and crystalline form III. The present invention further relates to a process of preparing crystalline form II and crystalline form III of tolvaptan and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Tolvaptan is chemically (±)-4'-[(7-chloro-2, 3, 4. 5-tetrahydro-5-hydroxy-1H-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.

Formula I
Tolvaptan has been approved in USA and sold in market under the proprietary name SAMSCA. It is a selective vasopressin V2-receptor antagonist 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 tolvaptan by the crystallization in methanol solvent.

U.S. patent publication no. 2007/0185323 describes crystallization of tolvaptan in methanol / ether solvents. The resulting product is amorphous in nature.
U.S. patent publication no. 2009/0306369 describes crystallization of tolvaptan 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, 15.4, 18.7, 21.7, 23.5 degrees 2-theta. which is hereinafter referred as crystalline form I.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC) as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment.

Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Therefore, there is a need in the art for developing additional solid state forms of tolvaptan.
The present applicant of the patent has surprisingly found new crystalline polymorphic forms of tolvaptan, which is designated as form II and form III.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide novel polymorphs of tolvaptan hereinafter referred as crystalline form II and crystalline form III of tolvaptan.
A second aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form II or crystalline form III of tolvaptan.
Another aspect of the present invention is to provide a process of preparing crystalline form II comprising crystallization of tolvaptan crystalline form I in a mixture of alcohol and water solvents.
Another aspect of the present invention is to provide a process of preparing crystalline form III comprising crystallization of tolvaptan crystalline form I or tolvaptan crystalline form II in an alcohol solvent in the presence of aqueous solution of alkali metal hydroxide.

DETAIL DESCRIPTION OF THE INVENTION:
A crystalline form II of tolvaptan may be characterized by X-ray diffraction pattern having peaks at 11.6, 12.2, 13.3, 13.8, 16.2, 19.7, 21.3, 22.3, 23.2, 25.6± 0.2 degrees two theta.
A crystalline form 11 of tolvaptan may be characterized by X-ray diffraction pattern as depicted in Figure 1.
A crystalline form III of tolvaptan may be characterized by X-ray diffraction pattern having peaks at 7.5, 9.2, 11.0, 13.5, 14.3, 17.8, 19.2,20.3,24.3,26.9,28.1 ± 0.2 degrees two theta.
A crystalline form III of tolvaptan may be characterized by X-ray diffraction pattern as depicted in Figure 2.
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.
The crystalline form II of tolvaptan may be formed by dissolving tolvaptan crystalline form I in mixture of alcohol and water solvents at 55-75°C and then resulting solution may be cooled gradually up to 25°C and then resulting solids may be filtered, washed with water and dried at a temperature in the range of 40-60°C for a period of 1 hour to 8 hours under reduced pressure.
The examples of alcohol solvents may include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof.
The crystalline form III of tolvaptan may be formed by treating a solution of tolvaptan crystalline form 1 or form II in an above mentioned alcohol solvent with aqueous alkali

metal hydroxide at a temperature in the range of 25°C to 30°C for a period of 30 minutes to 4 hours and then resulting solids may be filtered, washed with water and dried at a temperature in the range of 35°C to 70°C for a period of 30 minutes to 4 hours under reduced pressure.
The examples of an alkali metal hydroxide may be selected from the group comprising of sodium hydroxide, potassium hydroxide or lithium hydroxide.
A pharmaceutical composition of tolvaptan comprising crystalline form II of tolvaptan and pharmaceutically acceptable excipients
A pharmaceutical composition of tolvaptan comprising crystalline form III of tolvaptan and pharmaceutically acceptable excipients
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 depicts X-ray diffraction pattern of crystalline form II of tolvaptan. Figure 2 depicts X-ray diffraction pattern of crystalline form III of tolvaptan.
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker
D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis
conditions were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: Continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha[A]: 1.54060

Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
The advantages of Tolvaptan crystalline form II and III are as follows:
1. Free-flowing nature
2. Non hygroscopic nature
3. Free from residual solvents like alcohols.
4. Easy to formulate into oral tablet dosage form.
5. Low static charge
EXAMLES:
In the following examples, 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 crystalline form II of tolvaptan
Tolvaptan crystalline form I (10gm) was dissolved in mixture of methanol (90ml) and
water (10ml) at 55-75°C and resulting transparent solution was stirred 10 minutes at 55-
75°C and then it was cooled to 25°C. The resulting solids were filtered, washed with
water (10ml) and dried at 50°C for 1 hour under reduced pressure to get title compound.
Yield: 9.8gm
Purity: 99.86% (By HPLC)
XRD: As depicted in Figure 1

Example 2: Preparation of crystalline form III of tolvaptan
A solution of tolvaptan crystalline form I (10gm) in ethanol (150ml) was added aqueous
sodium hydroxide solution (5%, 150ml) and the resulting solution was stirred for 2 hours
at 25oC and then resulting solids were filtered, washed with water (10ml) and dried at 50-
55°C for a period of 2 hours under reduced pressure to get title compound.
Yield: 9.7gm
Purity: 99.93% (By HPLC)
XRD: As depicted in Figure 2
Example 3: Preparation of crystalline form III of tolvaptan
A solution of tolvaptan crystalline form II (5gm) in n-butanol (75ml) was added aqueous
potassium hydroxide solution (2.5%, 75ml) and the resulting solution was stirred for 3
hours at 25°C and then resulting solids were filtered, washed with water (5ml) and dried
at 55°C for a period of 2 hours under reduced pressure to get title compound.
Yield: 4.8gm
Purity: 99.95% (By HPLC)
XRD: As depicted in Figure 2

WE CLAIM:
1. A compound which is a crystalline form II of tolvaptan having substantially the same X-ray diffraction pattern as depicted in Figure 1 -
2. The compound of claim no. 1, is further characterized by X-ray diffraction pattern having peaks at 11.6, 12.2, 13.3, 13.8, 16.2, 19.7, 21.3, 22.3, 23.2, 25.6 ± 0.2 degrees two theta.
3. A process of preparing crystalline form II comprising crystallization of tolvaptan crystalline form I in a mixture of alcohol and water solvents.
4. Tne process according to claim no. 3, wherein crystalline form II of tolvaptan is formed by dissolving tolvaptan crystalline form I in mixture of alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof and water solvents at 55-75°C and then resulting solution may be cooled gradually up to 25°C and then resulting solids may be filtered, washed with water and dried at a temperature in the range of 40-60°C for a period of 1 hour to 8 hours under reduced pressure.
5. A compound which is a crystalline form III of tolvaptan having substantially the same X-ray diffraction pattern as depicted in Figure 2.

6. The compound of claim no. 6, is further characterized by X-ray diffraction pattern having peaks at 7.5, 9.2, 11.0, 13.5, 14.3, 17.8, 19.2, 20.3, 24.3, 26.9, 28.1 ± 0.2 degrees two theta.
7. A process of preparing crystalline form III comprising crystallization of tolvaptan crystalline form I or tolvaptan crystalline form II in an alcohol solvent in the presence of aqueous solution of alkali metal hydroxide.

8. The process according to claim no. 8, wherein crystalline form III of tolvaptan is formed by treating a solution of tolvaptan crystalline form I or form II in an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or mixture(s) thereof with aqueous alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide at a temperature in the range of 25°C to 30°C for a period of 30 minutes to 4 hours and then resulting solids may be filtered, washed with water and dried at a temperature in the range of 35°C to 70°C for a period of 30 minutes to 4 hours under reduced pressure.
9. A pharmaceutical composition of tolvaptan comprising crystalline form II of tolvaptan and pharmaceutically acceptable excipients.
10. A pharmaceutical composition of tolvaptan comprising crystalline form III of tolvaptan and pharmaceutically acceptable excipients.