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 CRYSTALLINE FORM OF METOPIMAZINE"
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.

FIELD OF THE INVENTION:
The present invention relates to novel crystalline form of Metopimazine. The present invention further relate to a processes of preparing novel crystalline form of Metopimazine and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Chemically Metopimazine is 1 -[3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl] propyl]-4-piperidine carboxamide and is known from German patent no. DE1092476 and is represented by compound of structural formula I.

Metopimazine is a dopamine D2 receptor antagonist and is indicated for the prevention and treatment of nausea and vomiting.
Indian Patent Application no. IN360/CHE/2010 describe crystalline form of Metopimazine compound of structural formula I (herein after referred as Form A), which is characterized by its Powder X-ray diffraction pattern having peaks at 4.37, 8.75, 9.76, 13.16, 17.59, 19.10, 19.62, 19.92, 21.73, 22.05, 26.05 and 31.6 ± 0.2 degrees 20 and by its differential scanning calorimetry showing endothermic peak at 173.65°C.

Indian Patent Application no. IN360/CHE/2010 describe crystallization process of Metopimazine comprises heating a solution of Metopimazine in a mixture of solvents selected from alcohols, esters, hydrocarbons, chloro, polar aprotic nitrile and ketone to reflux, followed by cooling and filtering the reaction mixture to isolate crystalline form of Metopimazine.
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 pharmaceutical^ 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 there is provided a novel crystalline form of Metopimazine.
SUMMARY OF THE INVENTION;
A first aspect of the present invention is to provide a novel crystalline form of Metopimazine herein after referred as Form B.
A second aspect of the present invention is to provide a process for the preparation of crystalline form B of Metopimazine comprising the steps of:
a. providing a solution of Metopimazine in an organic solvent selected from the group
comprising of alcohol, alkyl acetate or alkyl nitrile solvent;
b. heating the reaction mixture and
c. isolating crystalline form B of Metopimazine.
Another aspect of the present invention is to provide a process for the preparation of crystalline form B of Metopimazine comprising the steps of:
a. providing a solution of Metopimazine in a solvent selected from the group comprising of
water, alcohol alkyl acetate or alkyl nitrile solvent;
b. heating the reaction mixture and
c. isolating crystalline form B of Metopimazine.
Another aspect of the present invention is to provide a process for the preparation of crystalline form B of Metopimazine comprising the steps of:
a. providing a solution of Metopimazine in a solvent selected from the group comprising of
water, alcohol, alkyl acetate or alkyl nitrile solvent;
b. acidifying the reaction mixture;
c. heating the resulted solution;

d. basifying the resulted solution and
e. isolating crystalline form B of Metopimazine.
Another aspect of the present invention is to provide a process for the preparation of crystalline form B of Metopimazine comprising the steps of:
a. providing a solution of Metopimazine in a solvent selected from the group comprising of
water, alcohol, alkyl acetate or alkyl nitrile solvent and
b. isolating crystalline form B of Metopimazine.
Another aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form B of Metopimazine and a pharmaceuticall acceptable carrier.
Another aspect of the present invention is to provide method of treating nausea and vomiting comprising administering in human being a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of crystalline form B of Metopimazine and a pharmaceutically acceptable carrier.
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline form B of Metopimazine may be characterized by Powder X-ray diffraction pattern as depicted in Figure 1.
A crystalline form B of Metopimazine may be characterized by DSC thermogram as depicted in Figure 2.
A crystalline form B of Metopimazine may be characterized by its Powder X-ray diffraction pattern having peaks at 8.41, 10.43, 12.19, 13.84, 16.25, 16.82,18.45, 18.97,20.37,21.33,22.57, 23.94, 24.55, 25.81 and 28.44 ± 0.2 degrees 20
A crystalline form B of Metopimazine may be characterized by its differential scanning calorimetry showing endothermic peak at 188.76°C.

A solution of Metopimazine in an solvent selected from the group comprising of water, alcohol, alkyl acetate or alkyl nitrile may be prepared by dissolving Metopimazine in a solvent at a temperature in the range of 30°C to 80°C. Alternatively, such a solution may be obtained directly from a reaction in which Metopimazine is formed.
The examples of alcohol solvents may include but not limited to methanol, ethanol, propanol, isopropanol, butanol. isobutanol, t-butanol orpentanol.
The examples of alkyl acetate solvents may include but not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate or pentyl acetate.
The examples of nitrile solvents may include but not limited to acetonitrile or propionitrile.
A solution of Metopimazine in an organic solvent may be acidified with a weak acid such as acetic acid, citric acid, tartaric acid or fumaric acid.
The solution of Metopimazine may be refluxed for a period of 30 minutes to 3 hours and excess organic solvent may be distilled out from the reaction mixture.
The solution of Metopimazine may be basified with an aqueous solution of ammonia and resulting solution may be cooled to a temperature in the range of 0°C to -5°C.
The crystalline form B of Metopimazine may be isolated by the steps of cooling and filtering of reaction mixture.
The crystalline form B of Metopimazine may be washed with chilled organic solvent selected from the group of alcohols, alkyl acetates or alkyl nitrile solvent.
The crystalline form B of Metopimazine may be dried under reduced pressure at a temperature in the range of 40°C to 60°C.
BRIEF DESCRIPTION OF THE DRAWING:

Figure 1 depicts Powder X-ray diffraction pattern of crystalline form B of Metopimazine. Figure 2 depicts DSC thermogram of crystalline form B of Metopimazine
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples 1 to 4 were obtained on
PANalytical, X'Pert PRO, Netherland, diffractometer equipped with X-celerator detector using
Copper Kαl (λ= 1.5406 A) radiation with scanning range between 4.00-40° 20 at scanning speed
ofl.267min.
Differential Scanning Calorimetry (DSC) thermogram of the product of Examples 1 to 4 were
obtained on Mettler Toledo, DSC 823e Switzerland calorimeter equipped with STARe software
using endothermic measurement range from 40° to 250° at raise 10°C/min.
EXAMPLES:
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:
A solution of Metopimazine (l0gm) in methanol (550ml) was heated at 60-64°C for 30 minutes. The methanol solvent (400 ml) was distilled out from the reaction mixture and resulting solution was cooled to 0-5°C and stirred for an hour. The resulting solids were filtered, washed with chilled methanol (10ml) and dried at 55°C under reduced pressure. Yield= 9.4 gm
XRD: As depicted in Figure 1 DSC: As depicted in Figure 2
Example: 2:

A solution of Metopimazine (l0gm) in acetonitrile (550ml) was heated at 75-80°C for 30 minutes. The acetonitrile solvent (400 ml) was distilled out from the reaction mixture and resulting solution was cooled to 0-5°C and stirred for an hour. The resulting solids were filtered, washed with chilled acetonitrile (12ml) and dried at 60°C under reduced pressure. Yield= 9.2 gm
XRD: As depicted in Figure 1 DSC: As depicted in Figure 2
Example: 3:
A solution of Metopimazine (5gm) in ethyl acetate (1800ml) was heated at 72-75°C for 30 minutes. The ethyl acetate solvent (400 ml) was distilled out from the reaction mixture and resulting solution was cooled to 0-5°C and stirred for an hour. The resulting solids were filtered, washed with chilled ethyl acetate (6ml) and dried at 60°C under reduced pressure. Yield= 4.4 gm
XRD: As depicted in Figure 1; DSC: As depicted in Figure 2
Example: 4:
A solution of Metopimazine (lOgm) in methanol (100ml) and acetic acid (4.0 ml) was heated at 50-64°C for 30 minutes. The reaction mixture was basified with an aqueous ammonia solution (6.2 ml) and resulting solution was cooled to 0-5°C and stirred for an hour. The resulting solids were filtered, washed with chilled methanol (10ml) and dried at 55°C under reduced pressure. Yield- 9.2 gm
XRD: As depicted in Figure 1 DSC: As depicted in Figure 2

WE CLAIM:
1. A crystalline form B of Metopimazine characterized by its Powder X-ray diffraction pattern as depicted in figure no.l.
2. A crystalline form B of Metopimazine characterized by its differential scanning calorimetry showing endothermic peak at about 188°C.
3. A crystalline form B of Metopimazine characterized by its Powder X-ray diffraction pattern having peaks at 8.41, 10.43, 12.19, 13.84, 16.25, 16.82, 18.45, 18.97, 20.37, 21.33,22.57,23.94, 24.55, 25.81 and 28.44 ± 0.2 degrees 20.
4. A process for the preparation of crystalline form B of Metopimazine comprising the steps of:
a. providing a solution of Metopimazine in an organic solvent selected from the group
comprising of alcohol, alkyl acetate or alkyl nitrile solvent;
b. heating the reaction mixture and
c. isolating crystalline form B of Metopimazine.
5. A process for the preparation of crystalline form B of Metopimazine comprising the steps
of:
a. providing a solution of Metopimazine in a solvent selected from the group comprising
of water, alcohol, alkyl acetate or alkyl nitrile solvent;
b. heating the reaction mixture and
c. isolating crystalline form B of Metopimazine.
6. A process for the preparation of crystalline form B of Metopimazine comprising the steps
of:
a. providing a solution of Metopimazine in a solvent selected from the group comprising
of water, alcohol, alkyl acetate or alkyl nitrile solvent and
b. isolating crystalline form B of Metopimazine.

7. A process for the preparation of crystalline form B of Metopimazine comprising the steps
of:
a. providing a solution of Metopimazine in a solvent selected from the group comprising
of water, alcohol, alkyl acetate or alkyl nitrile solvent;
b. acidifying the reaction mixture;
c. heating the resulted solution;
d. basifying the resulted solution and
e. isolating crystalline form B of Metopimazine.
8. The process according to claim nos. 4, 5, 6.and 7 wherein alcohol solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol or pentanol; alkyl acetate solvent is selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate or pentyl acetate and alkyl nitrile solvent is selected from the group comprising of acetonitrile or propionitrile.
9. A pharmaceutical composition comprising crystalline form B of Metopimazine and a pharmaceutically acceptable carrier.
10. A method of treating nausea and vomiting comprising administering in human being a
pharmaceutical composition comprising a therapeutically or prophylactically effective
amount of crystalline form B of Metopimazine and a pharmaceutically acceptable carrier.