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
"THE NOVEL POLYMORPH OF BREXPIPRAZOLE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

THE NOVEL POLYMORPH OF BREXPIPRAZOLE FIELD OF THE INVENTION:
The present invention relates to a novel crystalline Form C of Brexpiprazole. The present invention further relates to process of preparing novel crystalline Form C.
BACKGROUND OF THE INVENTION:
Brexpiprazole is chemically known as 7-{4-[4-(l-Benzothiophen-4-yl)piperazin-l-yl]butoxy}quinolin-2(lH)-one and was first disclosed in U.S patent no. 7,888,362. It is a heterocyclic compound represented by structural formula I

Brexpiprazole (Rexulti, previously known as OPC-34712) is a novel atypical antipsychotic drug. It is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM). The drug received US FDA approval on July 13, 2015 for the treatment of schizophrenia, and as an adjunctive treatment for depression. Although it failed Phase II clinical trials for ADHD, it has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).
US 7,888,362 discloses process for the preparation of 7-{4-[4-(l-Benzothiophen-4-yl)piperazin-l-yl]butoxy}quinolin-2(lH)-one wherein solvent used for reaction is dimethylformamide and crude Brexpiprazole obtained is recrystallized from ethanol. The melting point of Brexpiprazole obtained is 183.5-184.5°C.
US2015/0087655A1 discloses a process for the preparation of 7-{4-[4-(l-benzothiophen-4-yl)piperazin-l-yl]butoxy}quinolin-2(lH)-one anhydride in comparative example 1 using ethanol and acetic acid. In the X-ray powder diffraction spectrum, diffraction peaks were observed at

2θ= 14.4°, 19.1°, 20.2°, 21.3°, and 23.2°. The anhydride obtained was said to contain water in the amount of 0.04% by weight.
US2015/0087655A1, further discloses dihydrate of 7-{4-[4-(l-Benzothiophen-4-yl)piperazin-l-yl]butoxy}quinolin-2(lH)-one or of a salt thereof and the processes for the producing the same. The dihydrate of 7-{4-[4-(l-Benzothiophen-4-yl)piperazh-l-yl]butoxy}quinolin-2(lH)-one having characteristic peaks at diffraction angle 2θ= 8.1°, 8.9°, 15.1°, 15.6°, and 24.4° in an X-Ray powder diffraction pattern measured by copper radiation of λ= 1.5418 A through a monochromator. The dihydrate contains water in the amount of 6.5 to 8.8 wt. %.
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, thermo gravimetric 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 insoluble 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.
Accordingly, the present invention provides a novel crystalline form of Brexpiprazole.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel crystalline form of Brexpiprazole herein after referred to as Form C, characterized by its Powder X-ray diffraction pattern having peaks at 4.25, 8.49, 14.72, 16.18, 17.01, 18.34, 19.92, 21.04, 21.442, 22.68, 24.61, 25.31, and 30.83± 0.2 degrees 26.
A second aspect of the present invention is to provide a process for the preparation of crystalline Form C of Brexpiprazole comprising the steps of:
a. providing a solution of Brexpiprazole in an organic solvent selected from the group
comprising of alcohol, alkyl acetate, aromatic hydrocarbon, alkyl nitrile, halogenated
solvent or mixture thereof;
b. heating the reaction mixture; and
c. isolate Form C of Brexpiprazole by crystallization.
Another aspect of the present invention is to provide a pharmaceutical composition comprising crystalline Form C of Brexpiprazole and one or more pharmaceutically acceptable carriers, diluents, or excipients.
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline Form C of Brexpiprazole may be characterized by Powder X-ray diffraction pattern as depicted in Figure 1.

As set forth herein, aspects of the present invention provide a crystalline Form C of Brexpiprazole and processes for preparation thereof.
Individual embodiments of the present invention are detailed herein below separately.
In one embodiment of the present application, it provides a crystalline Form C of Brexpiprazole characterized by its Powder X-ray diffraction pattern having peaks at 4.25, 8.49, 14.72, 16.18, 17.01, 18.34, 19.92, 21.04, 21.442, 22.68, 24.61, 25.31, and 30.83± 0.2 degrees 29.
In another embodiment of the present invention, it provides a process for the preparation of crystalline Form C of Brexpiprazole comprising the steps of:
a. providing a solution of Brexpiprazole in an organic solvent selected from the group
comprising of alcohol, alkyl acetate, aromatic hydrocarbon, alkyl nitrile, halogenated solvent or mixture thereof;
b. heating the reaction mixture; and
c. isolate Form C of Brexpiprazole by crystallization.
The solution of Brexpiprazole in an organic solvent selected from the group comprising of alcohol, alkyl acetate, alkyl nitrile, aromatic hydrocarbon, halogenated solvent or mixture thereof, is prepared by dissolving Brexpiprazole in a solvent at a temperature in the range of 30°C to 80°C. Alternatively, such a solution is obtained directly from a reaction in which Brexpiprazole is formed. The alcohol solvents used in step (a)may include but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanoly t-butanol, pentanol or and mixture(s) thereof.
The alkyl acetate solvents used in step (a) may include but not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.

The aromatic hydrocarbon solvent is selected from the group comprising of toluene, xylene, Ethyl benzene or mixture(s) thereof.
The alkyl nitrile solvents used in step (a) may include but not limited to acetonitrile, propionitrile or mixture(s) thereof.
The halogenated solvents used in step (a) may include but not limited to dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, benzyl chloride, m-chlorotoluene or mixture(s) thereof.
The crystalline Form C of may be isolated by the steps of cooling, filtering of reaction mixture, washing, drying and the combination thereof.
The crystalline Form C of Brexpiprazole is optionally, treated with water.
The crystalline Form C of Brexpiprazole may be further, washed with chilled organic solvent selected from the group of alcohols, alky acetates alkyl nitrile, halogenated solvents or mixture(s) thereof.
r
The crystalline Form C of Brexpiprazole may be dried under reduced pressure at a temperature in the range of 40°C to 80°C.
DRIEF DESCRIPTION OF THE DRAWING:
Figure-1 depicts Powder X-ray diffraction pattern of crystalline Form C of Brexpiprazole.
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples was obtained on PANalytical, XPert PRO, diffractometer equipped with X-celerator detector using Copper Ka (λ- 1.5406 A) radiation with scanning range between 3.00-40° 2θ at scanning speed of 101°/Sec.

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
l-Benzo[b]thiophen-4-ylpiperazine hydrochloride (10gm) and Potassium carbonate (10.8 gm) were suspended in isopropanol (80 ml). The reaction mixture was heated to 40-45°C, and 7-(4-Bromobutoxy)-quinoline-2(lH)-one (11gm) and Potassium iodide (6.5 gm) were added at above temperature. The reaction mixture was then refluxed for 8-10 hours. After completion of reaction, the mixture was cooled to 25-30°C and filtered. The isolated solid was suspended in water, stirred and filtered to obtain solid. The solid obtained was dried at 60-70°C for 6 hours
r
under vacuum.
Yield- 12.0gm
XRD: As depicted in Figure 1
Example: 2 7-{4-[4-(l-Benzothiophen-4-yl)piperazin-l-yl]butoxy}quinolin-2(lH)-one crude (10gm) was dissolved in mixture of Methanol (100ml) and Dichloromethane (100ml) at temperature 40-45°C. Clear solution was filtered at 40-45°C. Filtrate was cooled to 0-5°C and maintained for 1 hour at 0-5°C. Solid was filtered and washed with chilled methanol. The solid obtained was dried at 60-70°C for 6 hours under vacuum.
Yield= 7.0gm (HPLC Purity: 99.5% ) XRD: As depicted in Figure 1
Example: 3
l-Benzo[b]thiophen-4-ylpiperazine hydrochloride (lOgm) and Potassium carbonate (10.8 gm) were suspended in methanol (80 ml). The reaction mixture was heated to 40-45°C, and 7-(4-Bromobutoxy)-quinoline-2(lH)-one (11gm) and Potassium iodide (6.5 gm) were added at above temperature. The reaction mixture was then refluxed for 8-10 hours. After completion of

reaction, the mixture was cooled to 25-30°C and filtered. The isolated solid was suspended in water, stirred and filtered to obtain solid. The solid obtained was dried at 60-70°C for 6 hours under vacuum. Yield= 10.0gm
XRD: As depicted in Figure 1
Example: 4
l-Benzo[b]thiophen-4-ylpiperazine hydrochloride (10gm) and Potassium carbonate (10.8 gm) were suspended in methanol (80 ml) and dichloromethane (80 ml). The reaction mixture was heated to 40-45°C, and 7-(4-Bromobutoxy)-quinoline-2(lH)-one (11gm) and Potassium iodide (6.5 gm) were added at above temperature. The reaction mixture was refluxed for 8-10 hours. After completion of reaction, the mixture was cooled to 25-30°C and filtered. The isolated solid was suspended in water, stirred and filtered to obtain solid. The solid obtained was dried at 60-70°C for 6 hours under vacuum. Yield= 8.5gm
XRD: As depicted in Figure 1

WE CLAIM:
1. A crystalline Form C of Brexpiprazole, characterized by Powder X-ray diffraction pattern having characteristic peaks at values of 4.25, 8.49, 17.01, 18.34, 19.92, 21.04, 21.442, 22.68, and 30.83± 0.2 degrees (20).
2. A process for the preparation of crystalline Form C of Brexpiprazole comprising the steps of:
a. providing a solution of Brexpiprazole in an organic solvent selected from the group
comprising of alcohol, alkyl acetate, aromatic hydrocarbon, alkyl nitrile, halogenated
solvent or mixture thereof;
b. heating the reaction mixture(s) and,
c. isolate Form C of Brexpiprazole by crystallization.
3. The process according to claim 2, wherein the alcoholic solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
4. The process according to claim 2, wherein the alkyl acetate solvent is selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.
5. The process according to claim 2, wherein the aromatic hydrocarbon solvent is selected from the group comprising of toluene, xylene, Ethyl benzene or mixture(s) thereof.
6. The process according td claim 2, wherein alkyl nitrile solvent is selected from the group comprising of acetonitrile, propionitrile or mixture(s) thereof.
7. The process according to claim 2, where in the halogenated solvents is selected from the group comprising dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, benzyl chloride, m-chlorotoluene or mixture(s) thereof.
8. The process according to claim 2, wherein the crystalline Form C is isolated by the steps of cooling, filtering of reaction mixture, washing, drying and the combination thereof.
9. The process according to claim 2 or 7, the crystalline Form C of Brexpiprazole is dried under reduced pressure at a temperature in the range of 40°C to 80°C.

10. A pharmaceutical composition comprising crystalline Form C of Brexpiprazole a pharmaceutically acceptable carrier.